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Skills SparkFun Ambient Light Sensor Breakout - TEMT6000 Description: Basic breakout board for the TEMT6000 Ambient Light Sensor. Only what you need, nothing you don’t. Sensor acts like a transistor - the greater the incoming light, the higher the analog voltage on the signal pin. Customer Comments I had a question about the output this sensor gives off… I’m using it with a basic stamp 2pe microcontroller and haven’t been sure how to convert the analog output into lux. Is there a specific equation I have to use for this or are there several (like ones that include temperature, etc)? Although the datasheet does not provide this information, an email to Vishay got some dynamic response data. The upshot is that for the fastest response to changing light conditions one must have a high current flowing through the device. Icmax is defined at 20ma. With the 10K resistor (assuming no current out the signal line), and a 5 volt supply, than the maximum collector current is 5/10K or a tiny 500 micro amps. At this condition, rise and fall times are around 15 micro seconds. Increase Ic (by lowering the value of the resistor) and you can drop the times to bellow 10 usec. SFE, how about a breakout board with this sensor and a logarithmic amplifier? I don’t care for the difference between 100 lux and 105 lux, which you won’t notice anyway, but I do care about the difference between 10 lux, 100 lux and 1000 lux. Log amp, please! With a photoresistor you build a voltage divider which is anything but linear, this one is linear. Also, a phototransistor has a much wider range and is faster. Phototransistors are being used to trigger slave strobe light in photostudios, a photoresistor is orders of magnitude too slow for this. Would this be a good device for measuring and data logging sunlight in a garden? Also, is there a waterproof version, or a good way to waterproof this without diffusing the light from hitting the sensor? Thanks! Amazingly simple to use. I’m using it as a trigger in a spectrometer, gives the go signal when the emission starts. highly stable and incredibly easy to work with. Only problem is, my fingers are too big Remarkable. I swapped this in place of a potentiometer in my Arduino project and it worked exactly as expected without any changes. It’s great to have this as a breakout. Now I have to modify the software to provide some dampening. I would like to use this in an application where I need much higher resolution, but it won’t need to measure more than 2 lux or so. If I just put a big resistor on the ground pin, will that effectively multiply the voltage on the signal pin? Also, while this won’t need to actively measure more than 2 lux, it will still regularly be exposed to 100+ lux while it’s on. If putting the resistor on there will fry a 5V picaxe I/O pin, it won’t work. If this doesn’t work, I’d appreciate any ideas for something that would. I would just use a CdS photoresistor, but linearity is very helpful. SparkFun is an online retail store that sells the bits and pieces to make your electronics projects possible. Whether it's a robot that can cook your breakfast or a GPS cat tracking device, our products and resources are designed to make the world of electronics more accessible. In addition to products, SparkFun also offers classes and online tutorials to help educate individuals in the wonderful world of embedded electronics.

High-contrast waveguides in sputtered pure TeO2 glass thin films. We present a technological approach to the realization of channeled optical waveguides, starting from reactively sputtered tellurite glass thin films, grown on silica-coated 4" Si wafers. In particular, optical lithographic process and etching recipes have been developed to overcome the solubility of TeO(2) films in aqueous solutions, and to process them into high-index contrast structures with minimized post-etch roughness. Optical tests on preliminary rib waveguide geometries feature 6.3 dB/cm propagation loss for fundamental TE mode at lambda = 1.5 microm.

Q: Access: generating a .DOC file cannot be opened on an iDevice I am generating a .DOC file in an old access-VBA application using the typical GetObject("", Word.Document) strategy. I can open this .doc just fine in windows, however I cannot open it on an iPad\iPhone. The strange thing is, if I open this .doc in MS word, save it again as a .doc, I can then open it on an iPad. What do I have to do to ensure that this .doc gets saved as something that isn't "an invalid format" on an idevice? Any ideas? EDIT 1: I Found some code that looks like: DoCmd.OutputTo ...,..., "Rich Text Format",... and am wondering if this is correct? EDIT 2: What I am seeing is DoCmd.OutputTo as a RTF is what the iDevices do not seem to like. Any other way to go about doing this? A: This is because you are actually saving the file in RTF (Rich Text Format), but giving it a .DOC extension. MS Word can figure out the difference, but the iPad cannot. To get the file to open on both devices, give the document a .RTF extension instead of .DOC.

News: 1930-1959 This guide recommends resources for finding information in the news - past and present. The UW Libraries has many newspapers on microfilm in addition to those listed here. For help finding more, email [email protected] Newspapers as Primary Sources Newspapers were the primary means of communcating news during this time period; however, the Depression impacted the industry. Patricia Dooley explains that in "early 1931, the owners of the New york World were forced by hard times to sell the paper for a mere $5 million to the Scripps-Howard chain." In response to the economic conditions, a group of reporters and editors established the American Newspaper Guild in 1933. Dooley writes that the Guild was "the first successful attempt to organize the nontechnical side of newspaper production." The Guild was controversial at first, but it still exists today as The Newspaper Guild. Indexes the Sydney Morning Herald, other capital city dailies, and national weeklies for articles in the social sciences and humanities through 1994. Beginning in 1995, only The Australian, the newspaper of record, is scanned for articles within the scope of PAIS. Microfilm of Australian newspapers may be available through Interlibrary Loan.

Seeding Change in Weather Modification Globally Seeding Change in Weather Modification Globally Operational programmes to modify the weather – including to disperse fog, enhance rain and snowfall, and suppress hail – are taking place in more than 50 countries worldwide. Since the discovery in the late 1940s that crystals of silver iodide can form ice crystals in some water vapor, scientists have been working to understand how to alter the way water forms and moves within a cloud. Despite decades of research, deep skepticism still surrounds cloud seeding due, in part, to the challenge of verifying the efficacy of the technique – establishing cause and effect – given the complexity and variability of weather systems. Warm or cold, polluted or clean, over a mountain or a field, a cloud’s characteristics are key to the success or failure of cloud seeding efforts. New tools are enabling meteorologists to study and understand clouds and their modification with greater precision than ever, while new technologies such as nanotechnology are expanding the possibilities for the field. Bolstered by an international drive for research and funding to secure water resources, scientists are cautiously working to modernize rainmaking for the 21st century. “Water is the basic sustenance of life on Earth, with water and the air we breathe as the two primary issues in this century,” says Dr. Roelof Bruintjes of the U.S. National Center for Atmospheric Research (NCAR) and chair of the WMO Expert Team on Weather Modification. “Improving our understanding of cloud and precipitation processes are the number one priority and the better we understand them, the better we can potentially impact cloud processes with cloud seeding.” The fundamental challenge of weather modification is identifying and locating the best clouds for the job. Without clouds, these technologies are powerless. While “cloud seeding could be a tool to enhance water resources, it is not a ‘drought busting’ because we need clouds,” says Bruintjes, whose early training in weather modification was in South Africa. “Nobody can make a cloud or chase away a cloud.” “The basic concept of weather modification, especially precipitation enhancement, is to find a rate-limiting process related to the conversion of cloud water to precipitation in natural clouds, and to bypass it with a minimum level of artificial stimulation,” says Dr. Masataka Murakami of the Institute for Space-Earth Environmental Research at Nagoya University in Japan. “Therefore, it is important to find the clouds that have the potential to precipitate but cannot exert that ability.” Indeed, says Dr. Abdullah Al Mandoos, director of the National Centre for Meteorology and Seismology in the United Arab Emirates (UAE): “Any country that has a plan to implement cloud seeding projects needs to investigate the physical and chemical properties of the frequent and available clouds in their territory.” Part of finding the “right” clouds depends of the temperature. Increasing precipitation requires one of two approaches to help water particles collide, merge, and grow: glaciogenic seeding and hygroscopic seeding. Glaciogenic seeding uses agents, such as silver iodide, that initiate ice formation in “cold clouds,” those colder than 0 °C and that have supercooled water. Because silver iodide has a crystalline shape similar to natural ice, it can create ice earlier in the lifetime of a cloud, giving it more time to grow precipitation-sized particles.In “warm clouds,” convective clouds with large parts warmer than -10 °C, scientists can use hygroscopic seeding, generally with a simple salt. The salt helps water droplets to collide and produce rain. For either glaciogenic or hygroscopic seeding, it is essential to determine if clouds in a region are already efficient or if cloud seeding can potentially make a difference. “The main cloud seeding methods provide centers for drops and ice crystals to form on,” Bruintjes says. “If these particles already exist in optimal size and concentration in some regions of the world, cloud seeding would not have an impact.” The location of the clouds is also highly significant. Clouds in the tropics differ from clouds in the mid-latitudes because temperature influences how cloud processes operate. “In addition, clouds in different regions with different levels of pollution can also develop precipitation differently – and even in one region depending on the pollution on a specific day,” Bruintjes says. Anything that alters clouds can affect seeding. Some of the most successful cases of cloud seeding in the world have happened in mountainous regions, with glaciogenic seeding of “orographic” clouds. In these regions, clouds form from air flowing over mountains. They are an especially attractive target for cloud seeding because high-elevation snowpacks can store water for a region year-round. In Japan, for example, where water shortage is a transient, not chronic, problem, Murakami says that glaciogenic seeding of orographic snow clouds can be a preventive measure in late spring and early summer. Such operational programmes can be conducted “once the long-term prediction of precipitation becomes more accurate and reliable and when we can predict water shortage with a lead time of a few months,” he says. Bruintjes and Murakami point to examples of snowpack enhancement projects in Wyoming, USA, and the Snowy Mountains in Australia. In the Snowy Mountains, scientists have been using glaciogenic seeding on cold fronts to the west of the mountains. In the colder months, ground-based generators spray a mixture of silver iodide that the winds carry east to clouds over the mountains. In an analysis of results from the initial 2005-2009 experiment, researchers found a positive, but not statistically significant, impact of seeding on snowfall; however, they found the targeting of the seeding efforts “unequivocally successful”, with levels of silver iodide higher in seeded areas compared to unseeded ones. A secondary analysis showed enhanced levels of seeding materials that suggested additional ice particles and thus an impact on cloud precipitation processes. The project continues to this date, well beyond the initial trials. Some reports suggest that snowfall has increased by up to 14%. Measuring the impact of cloud seeding initiatives is challenging. “Usually we revert to a randomized experiment similar to what is used in the medical community when they test a new drug,” Bruintjes says. Like in a medical experiment, where no two people are alike, “no cloud is the same as another, and there are many factors that can play a role in the development of precipitation in a cloud.” Over the last 10 years, cloud seeding experiments have benefited from advances in numerical models that can simulate seeding more accurately, as well as improved observational tools to understand the physical processes in clouds due to seeding. These tools include more precise satellite capability and ground-based and airborne dual-polarization radars that can better measure precipitation size. “Although not perfect, it has been a great step forward,” Bruintjes says. “As we get better at weather prediction, we can better predict a change.” Another member of the WMO Expert Team on Weather Modification, Andrea Flossmann of Observatoire de Physique du Globe de Clermont Ferrand in France, says that researchers have been working to improve the statistical approaches necessary to validate the randomized approach. “Still, reliable campaigns remain costly, requiring numerous test clouds, both seeded and not,” she says. One such group is Murakami’s research team, which received a 2015 grant award from the UAE Research Programme for Rain Enhancement Science. “We are working to better evaluate, and ultimately improve, the effectiveness of precipitation enhancement in arid and semi-arid regions through a sound scientific research consisting of data analysis, laboratory experiments, field observation and numerical modelling,” he says. A major aim of the work is to clarify the microphysical structures of clouds suitable for seeding and their occurrence frequency over the eastern mountain areas of the UAE. UAE Research Programme for Rain Enhancement Science Rain enhancement in the UAE The US$ 5 million UAE Research Programme for Rain Enhancement Science launched in 2015 as an international initiative to advance the research and technology of rain enhancement. According to its director, Alya Al Mazroui, the program has two goals: to boost research in rain enhancement worldwide, and to increase rainfall in the UAE and other arid and semi-arid regions in the world. Water is a critical issue in the UAE with its 10 000 year-old groundwater supplies running low, and demand for water expected to double in the next 15 years by some estimates. Desalinated seawater accounts for 40% of the country’s water supply. With the high cost of desalination, the UAE has been conducting cloud seeding as a possible lower-cost alternative. In 2016, UAE undertook 177 cloud seeding operations, mostly using hygroscopic seeding in the eastern mountain ranges on the border with Oman to raise levels in aquifers and reservoirs. According to a report from 2015, greater-than-normal cloud cover enabled more missions that year. As part of its rain enhancement program, the UAE is working to lead the way for greater investments and technological advancements in weather modification. Al Mandoos says he is proud of the “UAE as a global hub that develops the best technologies that contribute to the water shortage solutions.” In addition to the award to Murakami’s team for improving cloud seeding validation, other recipients of the 2015 award were projects to “use nanotechnology to manufacture more effective seeding materials and land cover modification to enhance the confluence areas and improve the convection initiation,” says Al Mandoos. Using nanotechnology, researchers could potentially create new chemicals for cloud seeding that better mimic the crystalline structure of ice at a nanoscale. The UAE Program team is working with awardees over the next three years to help them implement their research projects. Al Mandoos of the UAE points to the WMO Guiding Principles for the Planning of Weather Modification Activities as an important resource for countries looking to improve water security. “The guidelines state that countries that practice cloud seeding must investigate seeded and unseeded clouds through a statistical randomization method,” he says. “The outcome of this statistical randomization process must then be supported with an analysis that validates the original cloud seeding operations.” Caution advised The 2015 WMO Statement on Weather Modification also discusses weather modification techniques to suppress hail and disperse fog, and it mentions recent interest in climate engineering. “Recently, seeding has been proposed as a climate mitigation strategy, to increase cloud brightness and increase the part of solar radiation reflected into space,” Flossmann says. The WMO report offers caution for such global-scale efforts, pointing out the historical difficulties in proving cause and effect for seeding interventions at the local scale. Global-scale cloud seeding does have a historical precedence but in an unexpected way: through inadvertent weather modification. For example, volcanic eruptions have injected particles into stratosphere that have reduced temperatures globally for 2 to 3 years after the eruptions (e.g. such eruptions are thought to have contributed to the “little ice age” in the 19th century). As another example of inadvertent weather modification, Flossmann says that satellites have observed that particles released by ship chimneys modify cloud properties of the stratocumulus cloud deck above, appearing to brighten the clouds. For all weather modification – intentional or not – it is important to remember that “the atmosphere has no walls,” Flossmann says. “What you add may not have the desired effect in your vicinity, but by being transported along might have undesired effects elsewhere.” But above all, it’s all about the clouds. “There is no one-size-fits-all solution,” she says. “It depends very much on the specific cloud whether adding particles to it will have any effect at all, and if it has an effect that it is in the desired direction.” Award Winners of the UAE Rain Enhancement Programme - The United Arab Emirates announced the winners of the Rain Enhancement Programme on 17 January. The US$5 million funding went to Professor Giles Harrison of the University of Reading, Professor Hannele Korhonen of the Finnish Meteorological Institute and Dr Paul Lawson of SPEC Inc. Author Lisa M.P. Munoz is a science writer and content strategist based in Washington, D.C., USA. She is a former press officer and editor for WMO.

“We are with him in a very precautionary moment because we don’t want to repeat the same injury,” Emery told the press. “At the moment he is starting to train but not with us [for all] and for tomorrow he isn’t in the group.” So, it seems as if Nacho Monreal’s comeback will have to be put back slightly. The Spaniard hasn’t played much football of late and the onus is now on Sead Kolasinac to perform in his absence. To see how the Bosnian gets on, head to our live streaming page for more information on how to watch Arsenal v Sporting CP.

Q: Running the XCode 3.1 application in XCode 4.1? I am new developer on iPhone. My problem is that I have installed the XCode 4.1 after changed the settings in the edit project settings it shows XCode 3.1 is missing so if any one know about it give me solution to solve the problem. A: you should set the base SDK version in project settings and Target settings as well. you should check if you have specified the base SDK at both places. Best of luck.

An inverter is a device for converting a direct current into an alternating current (a sine wave of 220V and 50 Hz in general), which includes an inverter unit, a filtering unit, a control unit, a converging unit, a booster unit, a communication unit, a switch fitting and other components, thereby achieving the objective to convert the direct current into the alternating current in coordination with all components. A common inverter mainly includes a combined inverter and an integrated inverter. With the more and more requirements for a distributed power station, the combined inverter plays a more and more important role in the distributed power station. The combined inverter has advantages such as a wide voltage range from 250V to 800V, flexible component configuration, a small volume, light weight, convenient transportation, easy installation, small floor space, therefore, construction difficult of the combined inverter in various applications is low, and the combined inverter can be installed without a lifting apparatus. However, as the power of the combined inverter is increased, the weight of the combined inverter becomes heavier and heavier, and the advantages of the combined inverter such as the flexible installation and convenient transportation are diminished, which does not facilitate installation and transportation in the construction site, and reduces applicability of the combined inverter having high power. In view of the disadvantages of the combined inverter described above, it is urgent to provide a combined inverter which can achieve flexible installation and transportation.

Timeline of United States inventions (1890–1945) A timeline of United States inventions (1890–1945) encompasses the ingenuity and innovative advancements of the United States within a historical context, dating from the Progressive Era to the end of World War II, which have been achieved by inventors who are either native-born or naturalized citizens of the United States. Copyright protection secures a person's right to his or her first-to-invent claim of the original invention in question, highlighted in Article I, Section 8, Clause 8 of the United States Constitution which gives the following enumerated power to the United States Congress: In 1641, the first patent in North America was issued to Samuel Winslow by the General Court of Massachusetts for a new method of making salt. On April 10, 1790, President George Washington signed the Patent Act of 1790 (1 Stat. 109) into law which proclaimed that patents were to be authorized for "any useful art, manufacture, engine, machine, or device, or any improvement therein not before known or used." On July 31, 1790, Samuel Hopkins of Philadelphia, Pennsylvania, became the first person in the United States to file and to be granted a patent under the new U.S. patent statute. The Patent Act of 1836 (Ch. 357, 5 Stat. 117) further clarified United States patent law to the extent of establishing a patent office where patent applications are filed, processed, and granted, contingent upon the language and scope of the claimant's invention, for a patent term of 14 years with an extension of up to an additional 7 years. From 1836 to 2011, the United States Patent and Trademark Office (USPTO) has granted a total of 7,861,317 patents relating to several well-known inventions appearing throughout the timeline below. Some examples of patented inventions between the years 1890 and 1945 include John Froelich's tractor (1892), Ransom Eli Olds' assembly line (1901), Willis Carrier's air-conditioning (1902), the Wright Brothers' airplane (1903), and Robert H. Goddard's liquid-fuel rocket (1926). Progressive Era (1890–1919) Through most of the 1800s, Americans viewed the nation’s westward expansion as a symbol of its providence as a land of wealth and progress. But Indian tribes resisted the encroachment of settlers in their territories, setting off decades of violence. The federal government gradually pushed the tribes to more isolated areas, offering U.S. citizenship, but few opportunities, to those who agreed to accept allotments of land on reservations. 1890 Stop sign A stop sign is a traffic sign, usually erected at road junctions such as a four-way intersection, that instructs drivers to stop and then to proceed only if the way ahead is clear. The idea of placing stop signs at road junctions was first conceived in 1890 when William Phelps Eno of Saugatuck, Connecticut proposed and devised the first set of traffic laws in an article published in Rider and Driver. However, the first use of stop signs did not appear until 1915 when officials in Detroit, Michigan installed a stop sign with black letters on a white background. Throughout the years and with many alterations made to the stop sign, the current version with white block-lettering on a red background that is used in the United States as well as emulated in many other countries around the world today, did not come into use until the Joint Committee on Uniform Traffic Control Devices adopted the design in 1975. 1890 Tabulating machine The tabulating machine is an electrical device designed to assist in summarizing information and, later, accounting. The results of a tabulation are electrically coupled with a sorter while displayed on clock-like dials. The concept of automated data processing had been born. In 1890, Herman Hollerith invented the mechanical tabulating machine, a design used during the 1890 Census which stored and processed demographic and statistical information on punched cards. 1890 Shredded wheat Shredded wheat is a type of breakfast cereal made from whole wheat. Shredded wheat also comes in a frosted variety, which has one side coated with sugar and usually gelatin. Shredded wheat was invented in 1890 by Henry Perky of Watertown, New York. 1890 Babcock test The Babcock test was the first inexpensive and practical test which were used to determine the fat content of milk. Invented by Stephen Moulton Babcock in 1890, the test was developed to prevent dishonest farmers who could, until the 1890s, water down their milk or remove some cream before selling it to the factories because milk was paid by volume. 1890 Smoke detector A smoke detector is a device that detects smoke and issues a signal. Most smoke detectors work either by optical detection or by physical process, but some of them use both detection methods to increase sensitivity to smoke. Smoke detectors are usually powered by battery while some are connected directly to power mains, often having a battery as a power supply backup in case the mains power fails. The first automatic electric fire alarm was co-invented in 1890 by Francis Robbins Upton and Fernando J. Dibble. Upton and Dibble were issued U.S. patent #436,961. Upton was an associate of Thomas Alva Edison, although there is no evidence that Edison contributed to this invention. 1891 Incandescent Lamp One of the most dramatic improvements occurred in artificial lighting. Thomas Edison’s development of an electric lamp that did not rely on open flames made lighting more practical for factories, offices, and homes, and transformed city life. 1891 Ferris wheel A Ferris wheel is a non-building structure, consisting of an upright wheel with passenger gondolas attached to the rim. Opened on June 21, 1893 at the Chicago World's Fair, the original Ferris Wheel was invented two years earlier by the Pittsburgh, Pennsylvania bridge-builder George Washington Gale Ferris Jr. in 1891. 1891 Dow process The Dow process is the electrolytic method of bromine extraction from brine, and was Herbert Henry Dow's second revolutionary process for generating bromine commercially in 1891. 1891 Tesla coil A Tesla coil is a type of resonant transformer circuit invented by Nikola Tesla around 1891. Nikola Tesla used these coils to conduct innovative experiments in electrical lighting, phosphorescence, x-ray generation, high frequency alternating current phenomena, electrotherapy, and the transmission of electrical energy without wires for point-to-point telecommunications, broadcasting, and the transmission of electrical power. 1891 Rotary dial The rotary dial is a device mounted on or in a telephone or switchboard that is designed to send electrical pulses, known as pulse dialing, corresponding to the number dialed. The early form of the rotary dial used lugs on a finger plate instead of holes. The rotary dial was invented by Almon Brown Strowger in 1891. Strowger filed U.S. patent#486,909 on December 21, 1891 that was later issued on November 29, 1892. 1891 Pastry fork A pastry fork, also known as a "pie fork", is a fork designed for eating pastries and other desserts while holding a plate. The fork has 3 or 4 tines. The 3 tine fork has a larger, flattened and beveled tine on the side while the 4 tine fork has the 1st and 2nd tine connected or bridged together and beveled. On July 7, 1891, Anna M. Mangin of Queens, a borough of New York City, filed the first patent for the pastry fork. U.S. patent #470,005 was later issued on March 1, 1892. 1891 Schrader valve A Schrader valve consists of a hollow cylindrical metal tube, typically brass, with the exterior end threaded. The interior end takes a variety of forms depending on its application. In the center of the exterior end is a metal pin pointing along the axis of the tube; the pin's end is flush with the end of the valve body. Generally, all Schrader valves are used on tires. They have threads and bodies of a single standard size at the exterior end, so caps and tools generally are universal for the valves on all automobile and bicycle pneumatic tires. Also, pressure valves can be used on Schrader valves in place of caps in order to measure the pressure of pneumatic tires. In 1891, George Schrader, the son of German-American immigrant August Schrader, invented the Schrader valve. A patent was issued on April 11, 1893. 1892 Bottle cap Bottle caps, or closures, are used to seal the openings of bottles of many types. They can be small circular pieces of metal, usually steel, with plastic backings, and for plastic bottles a plastic cap is used instead. Caps can also be plastic, sometimes with a pour spout. Flip-Top caps like Flapper closures provide controlled dispensing of dry products. The crown cork, the first form of a bottle cap, possessed flanges bent over a sealed bottle to compress the liquid inside. It was invented and patented in 1892 by William Painter of Baltimore, Maryland. 1892 Dimmer Dimmers are devices used to vary the brightness of a light. By decreasing or increasing the RMS voltage and hence the mean power to the lamp it is possible to vary the intensity of the light output. Although variable-voltage devices are used for various purposes, a dimmer is specifically those devices intended to control lighting. Dimmers are popularly used in venues such as movie theatres, stages, dining rooms, restaurants, and auditoriums where the need or absence of light during activities requires constant change. The dimmer was invented in 1892 by Granville Woods. 1892 Bicycle seat (padded) A bicycle seat, unlike a bicycle saddle, is designed to support the rider's buttocks and back, usually in a semi-reclined position. First known as the "Garford Saddle", the padded bicycle seat was invented in 1892 by Arthur Lovett Garford of Elyria, Ohio. 1892 internal combustion-powered tractor A tractor is a distinctive farm vehicle specifically designed to deliver a high tractive effort at slow speeds, for the purposes of hauling a trailer or machinery used in agriculture or construction. Agricultural implements may be towed behind or mounted on the tractor, and the tractor may also provide a source of power if the implement is mechanized. While steam powered tractors had been built earlier, In 1892, John Froelich invented and built the first gasoline-powered tractor in Clayton County, Iowa. 1893 Zipper The zipper is a popular device for temporarily joining two edges of fabric. Zippers are found on trousers, jeans, jackets, and luggage. Whitcomb L. Judson was an American mechanical engineer from Chicago who was the first to invent, conceive of the idea, and to construct a workable zipper. Using a hook-and-eye device, Judson intended for this earliest form of the zipper to be used on shoes. He also conceived the idea of the slide fastener mechanism in conjunction with the invention of the zipper. Patents were issued to Judson for the zipper in 1891, 1894, and 1905. 1893 Spectroheliograph The spectroheliograph is an instrument used in astronomy that captures a photographic image of the Sun at a single wavelength of light, a monochromatic image. The spectroheliograph was invented in 1893 by George Ellery Hale and independently later by Henri Alexandre Deslandres in 1894. 1893 Pinking shears Pinking shears are a type of scissors that have blades of which are sawtoothed instead of straight. Used to cut woven cloth, pinking shears leave a zigzag pattern instead of a straight edge. The earliest patent for pinking shears was U.S. patent #489,406 which was issued to Louise Austin of Whatcomb, Washington on January 3, 1893. Early 1890s Phantoscope A film projection machine created by Charles Francis Jenkins in the early 1890s. Jenkin's machine was the first projector to allow each still frame of the film to be illuminated long enough before advancing to the next frame sequence. 1894 Stadimeter A stadimeter, a type of optical rangefinder, is an optical device for estimating the range to an object of known height by measuring the angle between the top and bottom of the object as observed at the device. It is similar to a sextant, in that the device is using mirrors to measure an angle between two objects but differs in that one dials in the height of the object. The stadimeter was invented in 1894 by Bradley Allen Fiske, a Rear-Admiral in the United States Navy. The first sea tests, conducted in 1895, showed that it was equally useful for fleet sailing and for navigation. Likewise, the stadimeter proved useful during the Battle of Manila Bay during the Spanish–American War. U.S. patent #523,721 was issued to Fiske on July 31, 1894. 1894 Mousetrap A mousetrap is a specialized type of animal trap designed primarily to catch mice. However, it may also trap other small animals. Mousetraps are usually set in an indoor location where there is a suspected infestation of rodents. The first mouse trap was invented by William C. Hooker of Abingdon, Illinois, exactly three years before James Henry Atkinson developed a prototype called the "Little Nipper". Atkinson probably saw the Hooker trap in shops or in advertisements, and copyied it as the basis for his own model. Hooker received US patent #528671 for his invention, the mousetrap, in 1894. 1894 Medical glove Medical gloves are disposable gloves used during medical examinations and procedures that help prevent contamination between caregivers and patients. Medical gloves are made of different polymers including latex, nitrile rubber, vinyl and neoprene; they come unpowdered, or powdered with cornstarch to lubricate the gloves, making them easier to put on the hands. In 1894, William Stewart Halsted, the Surgeon-in-Chief of Johns Hopkins Hospital, invented the medical glove in an effort to make medical care safer and more sterile for patients and health care workers. 1895 Cyclocomputer A cyclocomputer or cyclometer is a device mounted on a bicycle that calculates and displays trip information, similar to the instruments in the dashboard of a car. The computer with display, or head unit, usually is attached to the handlebar for easy viewing. In 1895, Curtis Hussey Veeder invented the cyclometer. 1895 Clipless pedal Clipless pedals are bicycle pedals that require a special cycling shoe with a cleat fitted to the sole, which locks into a mechanism in the pedal and thus holds the shoe firmly to the pedal. Most clipless pedals lock onto the cleat when stepped on firmly and unlock when the heel is twisted outward, although in some cases the locking mechanism is built into the cleat instead of the pedal. The clipless pedal was invented in 1895 by Charles Hanson of Peace Dale, Rhode Island. 1895 Volleyball Volleyball is an Olympic sport in which two teams of 6 active players are separated by a net. Each team tries to score points against one another by grounding a ball on the other team's court under organized rules. William G. Morgan invented the sport first known as "Mintonnette" in 1895 while studying at a YMCA in Holyoke, Massachusetts. It was later renamed volleyball by Alfred S. Halstead. 1897 Cotton candy Cotton candy is a soft confection made from sugar that is heated and spun into slim threads that look like a mass of cotton. It was co-invented in 1897 by William Morrison and John C. Wharton, candy-makers from Nashville, Tennessee. 1897 Muffler A muffler is a device for reducing the amount of noise emitted by a machine. On internal combustion engines, the engine exhaust blows out through the muffler. The internal combustion engine muffler was invented by Milton O. Reeves who received a patent in 1897. 1897 Tapered roller bearing Tapered roller bearings are bearings that can take large axial forces as well as being able to sustain large radial forces. They were co-invented by German-American Henry Timken and Reginald Heinzelman. On August 27, 1897, Timken and Heizelman filed U.S. patent #606,635 which was issued to them jointly on June 28, 1898. 1897 Ice cream scoop An ice cream scoop is any specialized spoon used to dish and serve ice cream. Most ice cream scoops are hemispherical-shaped and contain a mechanical device to force the ice cream out of the scoop. The ice cream scoop was invented by African-American Alfred L. Cralle who was issued U.S. patent #576,395 on February 2, 1897. 1897 Charcoal briquette A charcoal briquette, or briquet is a block of flammable charcoal matter which is used as fuel to start and maintain a fire, mainly used for food preparation over an open fire or a barbecue. Charcoal briquettes are made by using a process which consists of compressing charcoal, typically made from sawdust and other wood by-products, with a binder and other additives. The binder is usually starch. Some charcoal briquettes may also include brown coal, mineral carbon, borax, sodium nitrate, limestone, raw sawdust, and other additives like paraffin or petroleum solvents to aid in ignition. The design of the charcoal briquette was invented and patented by Ellsworth B. A. Zwoyer in 1897. 1897 Billiards cue chalk Cue chalk is a calcite or carbonate base applied to the tip of the cue stick used in billiards in order for players to reduce friction between the cue and bridge hand during shooting, as well as for a smoother stroke. Cue tip chalk was co-invented in its modern form by straight rail billiard pro William A. Spinks and chemist William Hoskins in 1897. U.S. patent #578,514 for cue chalk was issued to Spinks and Hoskins on March 9, 1897. 1898 Candy corn Candy corn is a confection in the United States and Canada, popular primarily in autumn around Halloween, that mimics the shape and coloration of corn kernels—a broad yellow end, a tapered orange center, and a pointed white tip. Candy corn is made primarily from sugar, corn syrup, artificial coloring and binders. It is generally thought that George Renninger, an employee of the Wunderlee Candy Company, invented candy corn in the 1880s. However, the earliest references credit the Goelitz Confectionery Company, now known as the Jelly Belly Candy Company, for introducing candy corn or "chicken feed" to the American public in 1898. 1898 Remote control A remote control is an electronic device used to operate any machine, such as a television, remotely. Many of these remotes communicate to their respective devices through infrared signals and radio control. In Madison Square Garden, at the Electrical Exhibition, Nikola Tesla gave the first demonstration of a boat propelling in water, controlled by his remote control which he designed using radio signals. Tesla received a patent for his invention in 1898. 1898 Semi-automatic shotgun A semi-automatic, or self-loading shot gun is a firearm that requires only a trigger pull for each round that is fired, unlike a single-action revolver, a pump-action firearm, a bolt-action firearm, or a lever-action firearm, which all require the shooter to chamber each successive round manually. In 1898, John Moses Browning invented the first semi-sutomatic shot gun, later patenting it in 1900. Naming it the Auto-5, Browning's semi-automatic relied on long recoil operation. This design remained the dominant form in semi-automatic shotguns for approximately 50 years, being widely used and the preferred weapon of choice among soldiers fighting in World War I. Production of the Auto-5 ceased in 1999. 1898 Semi-truck A type of truck connected to a detachable semi-trailer that carries freight. Developed by Alexander Winton as a means of transporting cars without wasting their mileage. 1898 Filing cabinet (vertical) A filing cabinet is a piece of office furniture usually used to store paper documents in file folders. In the most simple sense, it is an enclosure for drawers in which items are stored. A vertical file cabinet has drawers that extend from the short side (typically 15 inches) of the cabinet. The vertical filing cabinet was invented by Edwin G. Seibels in 1898, thus revolutionizing efficient record-keeping and archiving by creating space for offices, schools, and businesses. 1898 Installer bit Installer bits are a type of twist drill bit for use with a hand-portable power tool. Installer bits are also known as bell-hanger bits or fishing bits. The key distinguishing feature of an installer bit is a transverse hole drilled through the web of the bit near the tip. Once the bit has penetrated a wall, a wire can be threaded through this transverse hole, and the bit pulled back through the drilled hole. The installer bit was invented and patented by Sinclair Smith of Brooklyn, New York in 1898. 1898 Sousaphone The sousaphone, sometimes referred to as a marching tuba, is a wearable tuba descended from the hélicon. It was designed such that it fits around the body of the wearer and so it can be easily played while being worn. The sousaphone is named after John Philip Sousa but was invented by C.G. Conn in 1898. 1899 Wing warping Wing warping consists of the twisting motion of the wings of an aircraft to produce lateral control. The entire wing structure twists slightly in a helical motion in the desired direction. The concept of wing warping is attributed to Wilbur Wright who in 1899, came up with the idea and with the conclusion that the roll of an aircraft could be controlled by the motion of that aircraft's wings. Exemplified by the twisting of a long, narrow box, the Wright brothers incorporated wing warping on their 1899 glider that used ropes to pull on the wings. Later on, the young French engineer Robert Esnault-Pelterie replaced wing warping in 1904 with the aileron on a copy he made of a 19th-century Wright glider. However, it was Henry Farman, a French aviator, who was the first to use the aileron as an integral part of the wing structure in place of wing warping in 1908. 1899 Flash-lamp The electric flash-lamp is a device that uses an electrical circuit to trigger a fuse to ignite explosive powder such as magnesium, for a brief sudden burst of bright light "flash" from a chemical reaction of flash powder burning. It was principally used for flash photography in the early 20th century, but had other uses as well. The flash-lamp was invented and patented on November 7, 1899 by New York City resident Joshua Lionel Cowen. 1900 Duckpin bowling Duckpin bowling is a variation of bowling that uses balls which are significantly smaller than those used in ten-pin bowling, weighing each, which are devoid of finger holes. The pins are correspondingly shorter and lighter than their ten-pin equivalents. Hence, when the pins are knocked down, they resemble a "flock of flying ducks". While the rules remained almost identical to those of the Ten-pin game, one rule change was made: A bowler is allowed to use three bowls on each turn. Strikes would still be strikes and spares still spares, but when all pins were knocked down on the third ball, it counts as a score of ten. During the summer of 1900, some bowlers at Diamond Alleys in Baltimore, Maryland thought it might be interesting to resize the pins to match the 6-inch ball. Thus, the inventor of duckpin bowling, John Van Sant, used a wood turner to do exactly that. 1900 Nickel-zinc battery A nickel-zinc battery is a type of rechargeable battery that may be used in cordless power tools, cordless telephone, digital cameras, battery operated lawn and garden tools, professional photography, flashlights, electric bike, and light electric vehicle sectors. In 1900, Thomas Alva Edison filed U.S. Patent #684,204 for the nickel-zinc battery. It was issued on October 8, 1901. 1900 Merrill-Crowe process The Merrill-Crowe process is a separation technique for removing gold from a cyanide solution. The basic process was conceptualized and patented by Charles Washington Merrill around 1900, then later refined by Thomas B. Crowe, working for the Merrill Company. 1900 Carbide lamp Carbide lamps, also known as acetylene gas lamps, are simple lamps that produce and burn acetylene which is created by the reaction of calcium carbide with water. The first carbide lamp was invented and patented in New York City on August 28, 1900 by Frederick Baldwin. 1900 Fly swatter A fly swatter is a hand-held device for swatting and killing flies and other insects. The first modern fly-destruction device was invented in 1900 by Robert R. Montgomery, an entrepreneur based in Decatur, Illinois. On January 9, 1900, Montgomery was issued U.S. patent #640,790 for the "Fly-Killer". 1900 Thumbtack A thumbtack is a short nail or pin with a large, slightly rounded head made of metal which is used to fasten documents to a background for public display and which can easily be inserted or removed by hand. The thumbtack was invented by Edwin Moore around 1900, the year in which he founded the Moore Push-Pin Company. 1901 Key punch A keypunch is a device for manually entering data into punched cards by precisely punching holes at locations designated by the keys struck by the operator. Early keypunches were manual devices. Later keypunches were mechanized, often resembling a small desk, with a keyboard similar to a typewriter, and with hoppers for blank cards and stackers for punched cards. In 1901, Herman Hollerith invented and patented the mechanical key punch that was operated by keys, like a typewriter, and that advanced the card automatically to the next column after each punch. Later models would be motor driven with rudimentary programming features. 1901 Mercury-vapor lamp A mercury-vapor lamp is a gas discharge lamp which uses mercury in an excited state to produce light. The arc discharge is generally confined to a small fused quartz arc tube mounted within a larger borosilicate glass bulb. The outer bulb may be clear or coated with a phosphor. In either case, the outer bulb provides thermal insulation, protection from ultraviolet radiation, and a convenient mounting for the fused quartz arc tube. In 1901, Peter Cooper Hewitt invented and patented the mercury-vapor lamp. 1901 Assembly line Used globally around the world, an assembly line is a manufacturing process in which interchangeable parts are added to a product in a sequential manner in order to create a finished product more quickly than with older methods. This type of manufacturing greatly reduces the amount of time taken to assemble a product, thus reducing production, material, and labor costs so that an affordable product cost can be passed onto consumers. According to a book entitled Michigan Yesterday & Today authored by Robert W. Domm, the assembly line and its basic concept is credited to Ransom Olds, who used it to build the first mass-produced automobile, the Oldsmobile Curved Dash. Olds patented the assembly line concept, which he put to work in his Olds Motor Vehicle Company factory in 1901. This development is often overshadowed by Henry Ford, who perfected the assembly line by installing driven conveyor belts that could produce a Model T in ninety-three minutes. 1901 Safety razor (disposable) A safety razor protects the skin from all but the edge of the blade while shaving skin. King Camp Gillette, a traveling hardware salesman of Fond du Lac, Wisconsin invented the double-edged, disposable safety razor attached to a re-usable razor handle. Beforehand, dull razors were taken to barbers for sharpening. With Gillette's double-edged and disposable blades, a uniform shave on a man's face could be achieved with a fresh blade and disposed after it was used. Gillette applied for a patent in 1901. It was granted in 1904. 1901 Windowed envelope A windowed envelope is a conventional envelope with a plastic window to allow the recipient's address to be printed on the paper contained within. Windowed envelopes save the expense of printing or labor of addressing, and in addition save time in preparing the message for dispatch when the customary addresses are already on the letter paper itself. Calling it the "outlook envelope", Americus F. Callahan of Chicago was the first to patent the windowed envelope. U.S. patent #701,839 was filed on December 9, 1901 and issued on June 10, 1902. 1901 Radio direction finder A radio direction finder (RDF) is a device for finding the direction to a radio source. Due to radio's ability to travel very long distances and "over the horizon", it makes a particularly good navigation system for ships, small boats, and aircraft that might be some distance from their destination. The radio direction finder is the earliest form of radio navigation. It was first patented by American physicist John Stone Stone. He filed on January 23, 1901 and was granted the patent (U.S. Patent 716,134) on December 16, 1902. 1902 Hearing aid A hearing aid is an electro-acoustic body-worn apparatus which typically fits in or behind the wearer's ear, and is designed to amplify and modulate sounds for the wearer. Although hearing aids in some form or fashion such as the ear trumpet were developed in previous years, the first electric hearing aid was invented by Miller Reese Hutchison in 1902. 1902 Postage meter A postage meter is a mechanical device used to create and apply physical evidence of postage, or franking, to mailed matter. Postage meters are regulated by a country's postal authority; for example, in the United States, the United States Postal Service specifies the rules for the creation, support, and use of postage meters. A postage meter imprints an amount of postage, functioning as a postage stamp, a cancellation and a dated postmark all in one. The postage meter was invented by Chicago inventor Arthur Pitney, receiving a patent for the invention on October 14, 1902. 1902 Teddy bear A teddy bear is a stuffed toy bear. They are usually stuffed with soft cotton and have smooth and soft fur. It is an enduring form of a stuffed animal that has become a collector's item. The first teddy bear was invented in 1902 by Morris Michtom, owner of a Brooklyn toy store, who was inspired by Clifford Berryman's political cartoon Drawing the Line in Mississippi that depicted President Theodore "Teddy" Roosevelt on a hunting trip in Mississippi who spared the life of a Louisiana black bear cub. Michtom asked for and received President Roosevelt's permission to use his name for the hand-sewn bears called "Teddy bears" that he invented and his wife helped construct. 1902 Periscope (collapsible) A periscope is an instrument for observation from a concealed position, known for use in submarines. In a simple form, it is a tube in each end of which are mirrors set parallel to each other and at an angle of 45 with a line between them. Periscopes allow a submarine, submerged at a shallow depth, to search for targets and threats in the surrounding sea and air. When not in use, the periscope is retracted into the hull. A sub commander in tactical conditions must exercise discretion when using his periscope, since it creates an observable wake and may be detectable to radar, giving away the sub's position. The invention of the collapsible periscope for use in submarine warfare is credited to Simon Lake in 1902, who called his device the omniscope or skalomniscope. Later, it was made to be raised and turned by hand. 1902 Mercury arc valve A mercury arc valve is a type of electrical rectifier which converts alternating current into direct current. Rectifiers of this type were used in electric motor power supplies for industry, in electric railways, streetcars, and diesel-electric locomotives. They also found use in static inverter stations and as rectifiers for high-voltage direct current power transmission. Mercury arc rectifiers were invented by Peter Cooper Hewitt in 1902. 1902 Air conditioning Air conditioning is the cooling and de-humidification of indoor air for thermal comfort. Using a system of coils as a solution to cool and remove moisture from muggy air in a printing plant that was wrinkling magazine pages, Willis Carrier invented and manufactured the world's first mechanical air conditioning unit in 1902. Carrier's invention – encompassing the first system to provide man-made control over temperature, humidity, ventilation and air quality, was first installed as a solution to the quality problems experienced at a Brooklyn printing plant, Sackett-Wilhelms Lithographing and Publishing Company. Air conditioning not only spawned a company and an industry, but also brought about profound economic, social and cultural changes. 1903 Tea bag A tea bag is a small, porous paper, silk or nylon sealed bag containing tea leaves for brewing tea. Tea bags were invented by Thomas Sullivan around 1903. The first tea bags were made from silk. Sullivan was a tea and coffee merchant in New York who began packaging tea samples in tiny silk bags, but many customers brewed the tea in them. 1903 Offset printing press Offset printing is a commonly used printing technique where the inked image is transferred from a plate to a rubber blanket, then to the printing surface. Ira Washington Rubel invented the first offset printing press in 1903. 1903 Airplane A fixed-wing aircraft, or airplane, is a heavier-than-air craft whose lift is generated by air pressure differential between the upper and lower wing surfaces. The Wright brothers, Wilbur and Orville Wright of Dayton, Ohio, made the first powered and sustained airplane flights under control of the pilot in the Wright Flyer I on December 17, 1903 in Kitty Hawk, North Carolina. In the two years afterward, they developed their flying machine into the world's first practical fixed-wing aircraft. By October 1905, the Wright Flyer III was capable and proven to circle in the air 30 times in 39 minutes for a total distance of 24.5 miles. The brothers' fundamental breakthrough was their invention of "three-axis control", which enabled the pilot to steer the aircraft effectively and to maintain its equilibrium. This required method has become standard on all fixed-wing aircraft. From the beginning of their aeronautical work, the Wright brothers focused on unlocking the secrets of control to conquer "the flying problem", rather than on developing more powerful engines as some other experimenters did. Charles Edward Taylor built the first aircraft engine and was a vital contributor of mechanical aspects in the building and maintaining of early Wright engines and airplanes. Although there were many earlier attempts at heavier-than-air powered flight, some of which achieved successful short hops, and disputed earlier claims of sustained flight, the Wright brothers are officially credited by the Fédération Aéronautique Internationale, the international record-setting body for aeronautics and astronautics, as achieving "the first sustained and controlled heavier-than-air powered flight". In addition, U.S. patent number #821393 for the airplane, was filed by Orville Wright on March 23, 1903 and was issued in May 1906. 1903 Windshield wipers The windshield wiper is a bladed device used to wipe rain and dirt from a windshield. In 1903, Mary Anderson is credited with inventing the first operational windshield wiper. In Anderson's patent, she called her invention a window cleaning device for electric cars and other vehicles. Operated via a lever from inside a vehicle, her version of windshield wipers closely resembles the windshield wiper found on many early car models. Anderson had a model of her design manufactured. She then filed a patent (U.S. patent number 743,801) on June 18, 1903 that was issued to her by the U.S. Patent Office on November 10, 1903. 1903 Wood's glass Wood's glass is a light filter used in communications during World War I. An "invisible radiation" technique which worked both in infrared daylight communication and ultraviolet night communications, it does not transmit visible light, leaving the 'invisible radiation' as a signal beam. Wood's glass was invented by Robert Williams Wood in 1903. 1903 Wood's lamp A Wood's lamp is a diagnostic tool used in dermatology which shines ultraviolet light onto the skin of the patient; a technician then observes any subsequent fluorescence. Though the technique for producing a source of ultraviolet light was devised by Robert Williams Wood in 1903 using "Wood's glass", not until 1925 was the technique used in dermatology by Margarot and Deveze for the detection of fungal infection of hair. 1903 Baler (round) A baler is a piece of farm machinery used to compress a cut and raked crop (such as hay, straw, or silage) into compact bales that are easy to handle, transport and store. Several different types of balers are commonly used, each producing a different type of bales – rectangular or cylindrical (round), of various sizes, bound with twine, netting, or wire. The round hay baler was invented by Ummo F. Luebben of Sutton, Nebraska, which he conceived with his brother Melchior in 1903, and then patented in 1910. The invention of the round hay baler revolutionized the laborious task of haying into a one-man, low-cost operation with a machine that automatically gathered the hay, rolled into a round bale, and ejected it.1904 Automatic transmissionAn automatic transmission is an automobile gearbox that changes gear ratios automatically as the vehicle moves, freeing the driver from having to shift gears manually. Modern automatic transmissions trace their origins to an early "horseless carriage" gearbox that was developed in 1904 by the Sturtevant brothers of Boston, Massachusetts.1904 Banana split A banana split is an ice cream-based dessert. In its classic form it is served in a long dish called a boat. A banana is cut in half lengthwise (hence the split) and laid in the dish. There are many variations, but the classic banana split is made with scoops of vanilla, chocolate and strawberry ice cream served in a row between the split banana. Although the banana as an exotic fruit was introduced to the American public in the 1880s, it was later in 1904, that the banana split was invented in the town of Latrobe, Pennsylvania by 23-year-old pharmacy apprentice David Strickler, who was inspired to create a new sundae after seeing a soda jerk during a visit to Atlantic City. According to The Food Chronology, written in 1995 by James Trager, Strickler concocted his sundae to include three scoops of ice cream on a split banana, topped with chocolate syrup, marshmallow, nuts, whipped cream, and a cherry that sold for a dime. Other soda jerks soon imitated Strickler's banana split, albeit in other forms.1904 Pantograph (diamond-shaped) A pantograph is a device that collects electric current from overhead lines for electric trains or trams. The term stems from the resemblance to pantograph devices for copying writing and drawings. In 1904, the diamond-shaped roller pantograph was invented by John Q. Brown of the Key System shops for their commuter trains which ran between San Francisco and the East Bay section of the San Francisco Bay Area in California. A patent was issued on July 5, 1904.1904 Dragline excavator Drag-line excavation systems are heavy equipment used in civil engineering and surface mining. In civil engineering the smaller types are used for road and port construction. The larger types are used in strip-mining operations to move overburden above coal, and for tar-sand mining. A drag line bucket system consists of a large bucket which is suspended from a boom, a large truss-like structure, with wire ropes. The bucket is maneuvered by means of a number of ropes and chains. The hoist rope, powered by large diesel or electric motors, supports the bucket and hoist-coupler assembly from the boom. The drag rope is used to draw the bucket assembly horizontally. By skillful maneuvre of the hoist and the drag ropes the bucket is controlled for various operations. The dragline excavator was invented in 1904 by John W. Page.1905 Batting helmetA batting helmet is the protective headgear worn by batters in the game of baseball or softball. It is meant to protect the batter's head from errant pitches thrown by the pitcher. A batter who is "hit by pitch", due to an inadvertent wild pitch or a pitcher's purposeful attempt to hit him, may be seriously, even fatally, injured. In 1905, a New York Giants (the team now known as the San Francisco Giants) baseball player named Roger Bresnahan, after missing thirty days of the baseball season and lying in a hospital bed due to a head injury (or beaning), created, with assistance from the A.J. Reach Company, a crude, leather, vertically sliced football helmet over his cap that is considered to be the first batting helmet. The headgear was unpopular, even with Bresnahan at the time, and it wasn't until the mid-1950s that his idea was accepted.1905 Liquid ring pumpA liquid ring pump is a rotating positive displacement pump that is powered by an induction motor and is typically used as a vacuum pump or as a gas compressor. The liquid ring pump was invented in 1905 by Lewis H. Nash. Production soon began thereafter at the Nash Engineering Company. Nash filed U.S. patent #1,091,529 on February 24, 1910 and was issued to him on March 31, 1914.1905 Ice pop An ice pop is a frozen water-based dessert on a stick. It is made by freezing a colored, flavored liquid around a stick. Once the liquid freezes solid, the stick can be used as a handle to hold the ice pop. The ice pop was invented by 11-year-old Frank Epperson in 1905. Living in San Francisco, California, Epperson had left a fruit drink out overnight, with a stirrer in it, thus making it freeze. In 1923, Epperson got a patent on his "frozen ice on a stick". Epperson also invented the twin ice pop, with two sticks so it could be shared by two children. The most famous brand name associated with the ice pop is Popsicle.1906 Typesetting Typesetting is the retrieval of the stored letters and the ordering of them according to a language's orthography for visual display. Typesetting was invented by John Raphael Rogers of Brooklyn, New York who filed U.S. patent #837127 on October 8, 1906 and issued to him on November 27, 1906.1906 Flushometer A flushometer, or royal flushometer is a water pressure system that uses an inline handle to flush toilets and urinals. By using pressurized water directly from the supply line, there is a faster recycle time between flushes. The flushometer is still in use today in homes and public restrooms around the world. The flushometer was invented in 1906 by American businessman and inventor William Elvis Sloan.1906 Audion tube The Audion is an electronic amplifier device and was the forerunner of the triode, in which the current from the filament to the plate was controlled by a third element, the grid. A small amount of power applied to the grid could control a larger current from the filament to the plate, allowing the Audion both to detect radio signals and to provide amplification. The Audion tube was invented by Lee De Forest in 1906.1907 Curtain rod A curtain rod or traverse rod is a device used to suspend curtains, usually above windows or along the edges of showers, though also wherever curtains might be used. The flat, telescoping curtain rod was invented by Charles W. Kirsch of Sturgis, Michigan, in 1907. However, they were not in use until the 1920s. Kirsch also invented the traverse curtain rod in 1928.1907 Electrostatic precipitator An electrostatic precipitator (ESP), or electrostatic air cleaner is a particulate collection device that removes particles from a flowing gas (such as air) using the force of an induced electrostatic charge. Electrostatic precipitators are highly efficient filtration devices that minimally impede the flow of gases through the device, and can easily remove fine particulate matter such as dust and smoke from the air stream. In 1907, the California physicist Frederick G. Cottrell invented and received a patent for the electrostatic precipitator.1907 Paper towel A paper towel has the same purposes as conventional towels such as drying hands, wiping windows, dusting, cleaning up spills. However, paper towels can only be used once after they blot wet surfaces. A school teacher in Ashland, Ohio, named Kurt Klier, gave students individual paper squares, so that the single towel in the bathroom would not be infected with germs. When Arthur Scott, head of the Scott Paper Company heard about it, he decided to try to sell a load of paper that had been made too thick to use as toilet paper.1908 Candy appleCandy apples, also known as toffee apples outside of North America, are whole apples covered in a hard sugar candy coating. While the topping varies from place to place, they are almost always served with a wooden stick of sorts in the middle making them easier to eat. Toffee apples are a common treat at autumn festivals in Western culture in the Northern Hemisphere, such as Halloween and Guy Fawkes Night because these festivals fall in the wake of the annual apple harvest. Dipping fruits into a sugar syrup is an ancient tradition. However, the origin of the red candy apple is attributed to Newark, New Jersey candymaker who conceived the idea of dipping apples into a red cinnamon candy mixture he had on hand. In addition, dipping apples in hot caramel a 1950s American invention attributed to Kraft salesman Dan Walker.1909 Skee ballSkee ball is a common game found in arcades and one of the first redemption games. Skee ball is similar to bowling except it is played on an inclined lane and the player aims to get the ball to fall into a hole rather than knock down pins. The object of the game is to collect as many points as possible by rolling balls up an incline and into the designated point value holes. Skee ball was invented and patented in 1909 by J.D. Estes of Philadelphia.1909 Paper shredderPaper shredders are used to cut paper into chad, typically either strips or fine particles. Government organizations, businesses, and private individuals use shredders to destroy private, confidential, or otherwise sensitive documents. The first paper shredder is credited to prolific inventor Abbot Augustus Low of Horseshoe, New York. His patent for a "waste paper receptacle" to offer an improved method of disposing of waste paper received a U.S. patent on August 31, 1909.1909 Suppressor A suppressor or silencer is a device either attached to or part of the barrel of a firearm to reduce the amount of noise and flash generated by firing the weapon. It generally takes the form of a cylindrically shaped metal tube with various internal mechanisms to reduce the sound of firing by slowing the escaping propellant gas, and sometimes by reducing the velocity of the bullet. Hiram Percy Maxim, the son of famous machine gun inventor Hiram Stevens Maxim, is credited with inventing the suppressor in 1909.1909 Gin rummy Gin rummy, or Gin for short, is a simple and popular two-player card game with a standard 52-card pack. The objective of Gin Rummy is to score more points than your opponent improving one's hand by forming melds and eliminating deadwood. Gin rummy was invented by Elwood T. Baker and his son, C. Graham Baker in 1909.1910 Headset A headset is a headphone combined with a microphone. Headsets provide the equivalent functionality of a telephone handset with hands-free operation. They are used in call centers and by people in telephone-intensive jobs. The first-ever headset was invented in 1910, by a Stanford University student named Nathaniel Baldwin.1911 Fifth wheel coupling The fifth wheel coupling provides a pivoting link between a semi-trailer and the towing truck, tractor unit, leading trailer or dolly. Some recreational vehicles have a fifth wheel configuration, requiring the coupling to be installed in the bed of a pickup truck as a towing vehicle. The coupling consists of a coupling pin (or kingpin) on the front of the semi-trailer, and a horseshoe-shaped coupling device called a fifth wheel on the rear of the towing vehicle. In 1911, Charles Martin invented the fifth wheel coupler consisting of a round plate with a hole in it, attached to a frame mounted on his tractor.1911 Erector Set An Erector Set is a toy construction set that consists of collections of small metal beams with regular holes for nuts, bolts, screws, and mechanical parts such as pulleys, gears, and small electric motors. Popular in the United States, the brand name is currently used for Meccano sets (themselves patented in 1901). The erector set was invented in 1911 by Alfred Carlton Gilbert and was manufactured by the A. C. Gilbert Company at the Erector Square factory in New Haven, Connecticut. The first sets were called by A.C. Gilbert "The Erector / Structural Steel & Electro-Mechanical Builder". Accessory sets were also available to allow children to upgrade basic sets.1911 Binder clipA binder clip, or a banker's clip or foldback clip, is a simple device for binding sheets of paper together. It leaves the paper intact and can be removed quickly and easily unlike the staple. The binder clip was invented in 1911 by Washington, D.C. resident Louis E. Baltzley who was motivated by a desire to help his father, Edwin, a prolific writer and inventor, keep manuscripts in order. The original design was modified five times, but the essential mechanism has never changed.1911 Automobile self starterAn automobile self-starter is an electric motor that initiates rotational motion in an internal combustion engine before it can power itself, therefore eliminating the hand crank used to start engines. In 1911, Charles F. Kettering invented the automobile self-starter while working at National Cash Register and then sold them for installation on cars at the Cadillac company. There had been many attempts at producing an electric starter before, but none of them were successful. Most designs at that time called for the use of an electric motor attached to the engine's flywheel. However, in order to fit in the car's engine compartment, the device would have to be small, and therefore it would be unable to produce a sufficient enough amount of torque.1911 Road surface markingA road surface marking is any kind of device or material that is used on a road surface in order to convey official information for drivers and pedestrians. Edward N. Hines originated the concept of painting a line down the center of a road to separate traffic in opposing directions. They were first used in Wayne County, Michigan in 1911.1912 AutopilotAn autopilot is a mechanical, electrical, or hydraulic system used to guide a vehicle without assistance from a human being. Most people understand an autopilot to refer specifically to aircraft, but self-steering gear for ships, boats, space craft, and missiles is sometimes also called autopilot. The first aircraft autopilot was invented by Lawrence Sperry in 1912. Sperry demonstrated it in 1914, and proved the credibility of the invention by flying the aircraft with his hands away from the controls and visible to onlookers.1912 Electric blanketAn electric blanket is a blanket with an integrated electrical heating device usually placed above the top bed sheet. The first electric blanket was invented in 1912 by American physician Sidney I. Russell. This earliest form of an electric blanket was an 'underblanket' under the bed that covered and heated from below. In 1937, Electric 'overblankets which lie on top of the sleeping person were introduced in the United States.1912 Traffic light (electric)The traffic light, also known as traffic signal, is a signaling device positioned at a road intersection, pedestrian crossing, or other location. Its purpose is to indicate, using a series of colors, the correct moment to stop, drive, ride or walk, using a universal color code. The color of the traffic lights representing stop and go are likely derived from those used to identify port (red) and starboard (green) in maritime rules governing right of way, where the vessel on the left must stop for the one crossing on the right. In Salt Lake City, Utah, policeman Lester Wire invented the first red-green electric traffic lights.1913 Formica (plastic)Formica is a hard durable plastic laminate used for countertops, cupboard doors, and other surfaces which are heat-resistant and easy to clean. Formica was invented in 1913 by Herbert A Faber and Daniel J. O'Connor of Westinghouse Electric.1914 Regenerative circuitThe regenerative circuit allows an electronic signal to be amplified many times by the same vacuum tube or other active component such as a field effect transistor. A regenerative circuit is often an AM detector, converting the RF signal on the antenna to an audio waveform. Their use of positive feedback greatly increases both the selectivity and sensitivity of a simple receiver. Positive feedback builds up the input signal to very high levels. Edwin Armstrong, invented and patented the regenerative circuit while he was a junior in college, in 1914.1914 Traffic cone Traffic cones, also called toddlers, road cones, safety cones, construction cones, pylons, or Witches' Hats, are usually cone-shaped markers that are placed on roads or sidewalks to temporarily redirect traffic in a safe manner. Traffic cones were invented in 1914 by Charles P. Rudabaker.1914 Fortune cookie A fortune cookie is a crisp cookie usually made from flour, sugar, vanilla, and oil with a "fortune" wrapped inside. A "fortune" is a piece of paper with words of faux wisdom or a vague prophecy. In the United States, it is usually served with Chinese food in Chinese restaurants as a dessert. The message inside may also include a list of lucky numbers and a Chinese phrase with translation. Contrary to belief, the fortune cookie associated as a Chinese invention is a fallacy. In 1914, the Japanese-American named Makoto Hagiwara of the Japanese Tea Garden in San Francisco, California, introduced the fortune cookie and is thus recognized as its inventor.1915 Skeet shooting Skeet shooting is an Olympic sport where participants attempt to break clay disks flung into the air at high speed from a variety of angles. The firearm of choice for this task is usually a high quality, double-barreled over and under shotgun with 28/30 inch barrels and open chokes. The event is in part meant to simulate the action of bird hunting. The shooter shoots from eight positions on a semicircle with a radius of , and an 8th position halfway between stations 1 and 7. There are two houses that hold devices known as "traps" that launch the targets, one at each corner of the semicircle. Skeet shooting began in Andover, Massachusetts in 1915, when grouse hunter Charles Davis invented a game he called "shooting around the clock" to improve his wingshooting.1915 Single-sideband modulation Single-sideband modulation (SSB) is a refinement of amplitude modulation that more efficiently uses electrical power and bandwidth. Single-sideband modulation produces a modulated output signal that has a bandwidth identical to that of the original baseband signal, unlike amplitude modulation which has double the bandwidth. Although John Renshaw Carson invented SBB in 1915, his patent was not granted until March 27, 1923.1916 Hamburger bun A hamburger bun is a bread roll sliced horizontally containing a hamburger, usually a patty consisting of ground meat that also typically contains lettuce, bacon, tomato, onion, pickles, cheese and condiments such as mustard, mayonnaise, ketchup and relish. The hamburger bun was invented in 1916 by a fry cook named Walter Anderson, who co-founded White Castle in 1921.1916 Lincoln Logs Lincoln Logs is the name of a children's toy consisting of notched miniature wooden logs, used to build miniature forts, cabins, and buildings. Lincoln Logs were invented in 1916 by John L. Wright, son of famous American architect Frank Lloyd Wright. 1916 Supermarket A supermarket is a self-service store offering a wide variety of food and household merchandise, organized into departments. It is larger in size and has a wider selection than a traditional grocery store. The concept of a "self-service" grocery store was invented by American entrepreneur Clarence Saunders and his Piggly Wiggly stores. Beforehand, customers would shop at a general store where a clerk behind a counter would fetch inventory in limited quantity for customers to purchase. With Saunders' new innovation of self-service, customers would be able to choose a wider selection of goods at competitive prices. Saunders' first store opened in Memphis, Tennessee, in 1916. 1916 Cloverleaf interchange A cloverleaf interchange is a two-level interchange in which left turns, in countries that drive on the right, are handled by loop roads. To go left, in right-hand traffic, vehicles first pass either over or under the other road, then turn right onto a one-way three-fourths loop ramp (270°) and merge onto the intersecting road. The cloverleaf was first patented in the United States by Arthur Hale, a civil engineer in Maryland, on February 29, 1916. 1916 Tow truck A tow truck is a vehicle used to transport motor vehicles to another location, generally a repair garage, or to recover vehicles which are no longer on a drivable surface. Vehicles are often towed in the case of breakdowns or collisions, or may be impounded for legal reasons. The tow truck was invented in 1916 by Ernest Holmes, Sr., of Chattanooga, Tennessee. He was a garage worker who was inspired to create the invention after he was forced to pull a car out of a creek using blocks, ropes, and six men. An improved design led him to manufacture wreckers. 1916 Condenser microphone A condenser microphone, also called a capacitor microphone or electrostatic microphone, is a microphone containing a capacitor that has two plates with a voltage between them. In the condenser microphone, one of these plates is made of very light material and acts as the diaphragm. The diaphragm vibrates when struck by sound waves, changing the distance between the two plates and therefore changing the capacitance. Specifically, when the plates are closer together, capacitance increases and a charge current occurs. When the plates are further apart, capacitance decreases and a discharge current occurs. A voltage is required across the capacitor for this to work. This voltage is supplied either by a battery in the mic or by external phantom power. The condenser microphone was invented in 1916 at Bell Laboratories by Edward Christopher 'E.C.' Wente, which became possible with the advent of the vacuum tube (valve) to act as an amplifier of the low signal output. 1916 Light switch (toggle) A toggle light switch is a switch, most commonly used to operate electric lights, permanently connected equipment, or electrical outlets whereby the switch handle does not control the contacts directly, but through an intermediate arrangement of internal springs and levers. The toggle light switch is safe, reliable, and durable, but produces a loud "snap" or "click" noise when a person's finger manually flips the toggle light switch into the on/off position. The design for the toggle light switch was patented in 1916 by William J. Newton and Morris Goldberg of Lynbrook, New York. 1917 Stream cipher In cryptography, a stream cipher is a symmetric key cipher where plaintext bits are combined with a pseudorandom cipher bit stream, typically by an exclusive-or (xor) operation. In a stream cipher the plaintext digits are encrypted one at a time, and the transformation of successive digits varies during the encryption. Also known as a state cipher, the stream cipher was invented in 1917 by Gilbert Sandford Vernam at Bell Labs. 1917 Marshmallow creme Marshmallow creme, better known as marshmallow "fluff" in the United States, is a food item that is a sweet, spreadable, marshmallow-like confection. It is typically used with peanut butter on the fluffernutter sandwich. In addition, marshmallow creme and Nutella can be spread on graham crackers to emulate s'mores. Marshmallow creme is a New England creation invented in 1917 by Archibald Query of Somerville, Massachusetts. 1918 Superheterodyne receiver In electronics, a superheterodyne receiver uses frequency mixing or heterodyning to convert a received signal to a fixed intermediate frequency, which can be more conveniently processed than the original radio carrier frequency. Virtually all modern radio and television receivers use the superheterodyne principle. The superheterodyne receiver was invented in 1918 by Edwin Armstrong. It was introduced to the market place in the late 1920s. 1918 French dip sandwich A French dip sandwich, also known as a beef dip, is a hot sandwich consisting of thinly sliced roast beef (or, sometimes, other meats) on a "French roll" or baguette. It is usually served au jus ("with juice"), that is, with beef juice from the cooking process. Beef broth or beef consommé is sometimes substituted. Despite the sandwich's name, the French dip sandwich was not invented in France, but in the United States. Both Philippe the Original's and Cole's Pacific Electric Buffet, two restaurants in Los Angeles, claim to have invented the French dip sandwich. Philippe Mathieu may have possibly invented the sandwich by accident around the year 1918, who according to one story, accidentally dropped a sandwich in a pan of au jus. Another story is that a fireman to Philippe's restaurant found his roast beef sandwich roll to be too hard. Thus, Philippe had it dipped in juice. Whatever the origin, Cole's Pacific Electric Buffet also claims to have invented the French dip sandwich as well.1918 Torque wrench A torque wrench is a tool used to precisely apply a specific torque to a fastener such as a nut or bolt. It is usually in the form of a socket wrench with special internal mechanisms. It was invented by Conrad Charles Bahr in 1918. However, it wasn't until much later on March 16, 1937, that Bahr received U.S. patent #2,074,079 for the invention of the torque wrench.1918 Crystal oscillator A crystal oscillator is an electronic circuit that uses the mechanical resonance of a vibrating crystal of piezoelectric material to create an electrical signal with a very precise frequency. This frequency is commonly used to keep track of time as used in quartz wristwatches, to provide a stable clock signal for digital integrated circuits, and to stabilize frequencies for radio transmitters and receivers. The first crystal-controlled oscillator, using a crystal of Rochelle Salt, was invented by Alexander M. Nicholson. However, it is generally accepted that Dr. Walter Guyton Cady was the first to use a quartz to control the frequency of an oscillator circuit. Nevertheless, Nicholson is still regarded as the inventor of the crystal oscillator.1918 Grocery bag Shopping bags are medium-sized bags, typically around 10–20 litres (2.5 to 5 gallons) in volume, that are often used by grocery shoppers to carry home their purchases. They can be single-use (disposable), used for other purposes or designed as reusable shopping bags. The grocery bag with handles was invented in 1918 by Walter Deubener of St. Paul Minnesota. U.S. patent #1,305,198 was issued to Deubener on May 27, 1919.1918 Hydraulic brake The hydraulic brake is an arrangement of braking mechanism which uses brake fluid, typically containing ethylene glycol, to transfer pressure from the controlling unit, which is usually near the operator of the vehicle, to the actual brake mechanism, which is usually at or near the wheel of the vehicle. In 1918, the hydraulic brake was invented by Malcolm Loughead, which replaced the mechanical brake which was used previously on automobiles.1919 Blender A blender is an upright, stationary kitchen appliance used to mix alcoholic beverages and puree food. Blenders are also used to prepare emulsions, such as mayonnaise, and cream soups. In 1919, Polish-American Stephen J. Poplawski of Racine, Wisconsin invented, designed, and manufactured beverage mixers used in preparation for malted milk served at soda fountains. It consisted of a spinning blade on a long rod extending down into a cup. Poplawski patented his invention of the blender in 1922.1919 Silica gel Silica gel is a granular, porous form of silica made from sodium silicate. Silica gel is a solid. The synthetic route for silica gel was invented and patented by chemistry professor Walter A. Patrick at Johns Hopkins University, Baltimore, Maryland in 1919.1919 Toaster (pop-up) The toaster is typically a small electric kitchen appliance designed to toast multiple types of bread products such as sliced bread, bagels, and English muffins. Although not the first to invent the toaster, the pop-up toaster was invented by Charles Strite in 1919, consisting of a variable timer and springs in order to prevent burnt toast. Strite received a patent for his invention on May 29, 1919. Roaring Twenties and the Jazz Age (1920–1928)1920 Eskimo Pie An Eskimo Pie is a vanilla ice cream bar between two wafers of chocolate and wrapped in aluminum foil. The confection was invented in Iowa in the year 1920 by Danish-American Christian Nelson. First known as the I-Scream Bar, the name was changed the following year to Eskimo Pie at the suggestion of American chocolatier Russell Stover.1920 Jungle gym The jungle gym, also known as monkey bars or climbing frame, is a piece of playground equipment made of many pieces of thin material, such as metal pipe or, in more current playgrounds, rope, on which children can climb, hang, or sit. The monkey bar designation was for the resemblance that playing children had to the rambunctious, climbing play of monkeys, though the term nowadays often refers specifically to a single row of overhead bars designed to be swung across. The jungle gym was invented and patented by Sebastian Hinton of Chicago in 1920.1921 PolygraphNot to be confused with an earlier and different invention with the same name, a polygraph, popularly referred to as a lie detector, is an instrument that measures and records several physiological indices such as blood pressure, pulse, respiration, and skin conductivity while the subject is asked and answers a series of questions, in the belief that deceptive answers will produce physiological responses that can be differentiated from those associated with non-deceptive answers. The polygraph was invented in 1921 by John Augustus Larson, a medical student at the University of California at Berkeley and a police officer of the Berkeley Police Department in Berkeley, California. According to Encyclopædia Britannica, the polygraph was on its 2003 list of the 325 greatest inventions.1921 FlowchartA flowchart is common type of chart, representing an algorithm or process, showing the steps as boxes of various kinds, and their order by connecting these with arrows. Flowcharts are used in analyzing, designing, documenting or managing a process or program in various fields. The second structured method for documenting process flow, the "flow process chart", was invented by Frank Gilbreth to members of ASME in 1921 as the presentation "Process Charts—First Steps in Finding the One Best Way".1921 Adhesive bandagePopularly known by the brand name Band-Aid, an adhesive bandage is a self-sticking taped and small dressing used for injuries not serious enough to require a full-size bandage. This easy-to-use dressing with adhesive tape was invented by Earle Dickson in 1921.1921 HeadrestIn an automobile, the headrest or head restraint is a device attached to the top of the seat behind the occupant's head. Most headrests are cushioned for comfort, are height adjustable and most commonly finished in the same material as the rest of the seat. The automobile headrest was invented by Benjamin Katz, a resident of Oakland, California, in 1921. U.S. patent #1,471,168 for the headrest was issued to Katz on October 16, 1923.1921 Garage doorA garage door is a large door on a garage that can either be opened manually or by a garage door opener. Garage doors are necessarily large to allow passage of automobiles and/or trucks. In 1921, C. G. Johnson of Detroit, Michigan invented the "Overhead Door", the first upward-lifting garage door. To market the garage door, Johnson mounted a small prototype of his door on the back of his Model T Ford and drove around the United States signing up distributors.1922 Blowout preventer (ram)A ram blowout preventer is a large valve that can seal off a wellhead by using ram-types employing steel cut off rams to seal the borehole. During drilling or well interventions, the valve may be closed if overpressure from an underground zone causes formation fluids such as oil or natural gas to enter the wellbore and threaten the rig. In 1922, James Smither Abercrombie collaborated with Harry S. Cameron with the idea of creating a mechanically operated ram-type blowout preventer. A patent was issued in January 1926.1922 Convertible A convertible is a type of automobile in which the roof can retract and fold away having windows which wind-down inside the doors, converting it from an enclosed to an open-air vehicle. Many different automobile body styles are manufactured and marketed in convertible form. Ben P. Ellerbeck conceived the first practical retractable hardtop system in 1922—a manually operated system on a Hudson coupe that allowed unimpeded use of the rumble seat even with the top down.1922 Water skiingWater skiing is a sport where one or more persons is pulled behind a motor boat or a cable ski installation on a body of water wearing one or more skis. Water skiing began in 1922 when Ralph Samuelson used two boards as skis and a clothesline as a tow rope on Lake Pepin in Lake City, Minnesota. The sport remained a little-known activity for several years. Samuelson took stunts on the road, performing shows from Michigan to Florida. In 1966 the American Water Ski Association formally acknowledged Samuelson as the first on record. Samuelson was also the first ski racer, first to go over a jump ramp, first to slalom ski, and the first to put on a water ski show.1922 Radial arm sawA radial arm saw has a circular saw mounted on a sliding horizontal arm. In addition to making length cuts a radial arm saw may be configured with a dado blade to create cuts for dado, rabbet or half lap joints. Some radial arm saws allow the blade to be turned parallel to the back fence allowing a rip cut to be performed. In 1922, Raymond De Walt of Bridgeton, New Jersey invented the radial arm saw. A patent was applied for in 1923 and awarded to De Walt in 1925.1922 Audiometer An audiometer is a machine used for evaluating hearing loss. Audiometers are standard equipment at ENT clinics and in audiology centers. They usually consist of an embedded hardware unit connected to a pair of headphones and a feedback button, sometimes controlled by a standard PC. The invention of this machine is generally credited to Dr. Harvey Fletcher of Brigham Young University who invented the first audiometer in 1922.1922 Neutrodyne The neutrodyne is a particular type of Tuned Radio Frequency (TRF) radio receiver, in which the instability-causing inter-electrode capacitance of the triode RF tubes is cancelled out or "neutralized". Louis Alan Hazeltine invented and patented the neutrodyne circuit in 1922 while under contract to the U.S. Naval Yard outside Washington, D.C. Hazeltine's invention effectively neutralized the high-pitched squeals that plagued early radio sets.1923 BulldozerA bulldozer is a crawler or a continuous tracked tractor, equipped with a substantial metal plate or blade, used to push large quantities of soil, sand, or rubble during construction work. In 1923, a farmer named James Cummings and a draftsman named J. Earl McLeod co-invented and created the first designs. A replica is on display at the city park in Morrowville, Kansas where the two built the first bulldozer.1923 Cotton swabCotton swabs consist of a small wad of cotton wrapped around either one or both ends of a small rod. They are commonly used in a variety of applications including first aid, cosmetics application, for cleaning, and arts & crafts. The cotton swab was invented by Leo Gerstenzang in 1923, who invented the product after attaching wads of cotton to a toothpick. His product, which he named "Baby Gays", went on to become the most widely sold brand name, "Q-tip".1923 Instant cameraAn instant camera is a type of camera with self-developing film. The earliest instant camera, which consisted of a camera and portable darkroom in a single compartment, was invented in 1923 by Samuel Shlafrock. In 1947, Edwin H. Land invented a new camera that produced photographic images in 60 seconds. A colored photograph model would follow in the 1960s and eventually receive more than 500 patents for Land's innovations in light and plastic technologies.1924 Locking pliers Locking pliers, Mole grips or Vise-Grips are pliers that can be locked into position, using an over-center action. One side of the handle includes a bolt that is used to adjust the spacing of the jaws, the other side of the handle, especially in larger models, often includes a lever to push the two sides of the handles apart to unlock the pliers. William Petersen of DeWitt, Nebraska, invented and patented a primitive version of a wrench in 1921. However, it wasn't until 1924 that the first locking pliers with a locking handle that Petersen called the Vise-Grip was patented.1924 CheeseburgerA cheeseburger is a hamburger with cheese added to it. Traditionally the cheese is placed on top of the patty, but the burger can include many variations in structure, ingredients, and composition. The term itself is a portmanteau of the words "cheese" and "hamburger." The cheese is usually sliced, and then added to the cooking hamburger patty shortly before the patty finishes cooking which allows the cheese to melt. Lionel C. Sternberger is believed to have invented the "cheese hamburger" in the 1920s in the Northeast portion of Los Angeles County. The earliest year attributed to the invention of the cheeseburger by Sternberger is in 1924, while others claimed that he invented it as late as 1926. According to American Heritage, "a local restaurateur was identified as the inventor of the cheeseburger at his death in 1964. Cooking at his father's short-order joint in Pasadena in the early 1920s, the lad experimentally tossed a slice (variety unknown) on a hamburger 'and lo! the cheeseburger sizzled to life."1924 Earth inductor compassThe Earth inductor compass is a device for determining aircraft direction using the magnetic field of the Earth. The operation of the compass is based on the principle of electromagnetic induction with the Earth's magnetic field acting as the induction field for an electric generator. A variation generated voltage, thus allows the Earth inductor compass to determine direction. The earth inductor compass is an American invention. It was designed in 1924 by Morris Titterington at the Pioneer Instrument Company. Designed to compensate for the weaknesses of the magnetic compass, the Earth inductor compass provided pilots with a more stable and reliable reference instrument.1924 Gas chamber execution A gas chamber is an apparatus for killing, consisting of a sealed chamber into which a toxic gas is introduced. The most commonly used poisonous agent is hydrogen cyanide; carbon dioxide and carbon monoxide have also been used. In an effort to make capital punishment more humane, the State of Nevada introduced death by gas chamber. Convicted murderer John Gee took 6 minutes to die.1924 Moviola A Moviola is a device that allows a film editor to view film while editing. It was the first machine for motion picture editing in order to study individual shots in their cutting rooms that determine where the best cut-point might be. The vertically oriented Moviolas were the standard for film editing in the United States until the 1970s when horizontal flatbed editor systems became more common. In 1924, the Moviola was invented in the United States by Dutch-American Iwan Serrurier.1924 Radio altimeter A radio altimeter measures altitude above the terrain presently beneath an aircraft or spacecraft. This type of altimeter provides the distance between the plane and the ground directly below it, as opposed to a barometric altimeter which provides the distance above a pre-determined datum, usually sea level. In 1924, American engineer Lloyd Espenschied invented the radio altimeter. However, it took 14 years before Bell Labs was able to put Espenschied's device in a form that was adaptable for aircraft use.1925 Automatic volume control Automatic volume control or automatic gain control (AGC) is an adaptive system found in many electronic devices. The average output signal level is fed back to adjust the gain to an appropriate level for a range of input signal levels. In 1925, Harold Alden Wheeler invented the automatic volume control which remains today, a standard feature of AM radio.1925 Masking tape Masking tape is a pressure-sensitive tape made with an easy-to-tear thin paper, and fly back and a removable pressure-sensitive adhesive. In 1925, Richard G. Drew, an employee of the Minnesota Mining and Manufacturing Company (3M), invented the first masking tape, a two-inch-wide tan paper strip backed with a light, pressure-sensitive adhesive. Drew filed U.S. patent #1,760,820 on May 28, 1928 and was issued to him on May 27, 1930.1925 Reuben sandwich A Reuben sandwich is a hot sandwich of layered meat, sauerkraut and Swiss cheese, with a dressing, usually Russian or Thousand Island dressing, that is grilled between slices of rye bread. The origins of the Reuben sandwich is disputed. The earliest claim of inventing the Reuben sandwich comes from Omaha, Nebraska, in 1925 when Ukrainian-American grocer Reuben Kulakofsky fed players in a late-night poker game at the Blackstone Hotel in downtown Omaha. The owner of the hotel was so taken with Reuben's sandwich that he put it on the hotel restaurant menu, designated by its inventor's name. It wasn't until 1956 when a waitress at the Blackstone named Fern Snider entered Reuben's sandwich in a national sandwich competition, one of the earliest documentations given to the name of the sandwich. Another story is that the Reuben sandwich hails from New York City. Arnold Reuben, who opened his deli counter in Manhattan in 1928, has been claimed to have invented the Reuben "eleven years earlier as a sandwich stand in Atlantic City."1926 Tilt-A-Whirl Tilt-A-Whirl is an amusement ride that consists of seven freely spinning cars, each holding three or four passengers, attached at fixed pivot points on a rotating platform. Designed for commercial use at amusement parks, fairs and carnivals in which it is commonly found, the Tilt-A-Whirl is commonly known for making riders experience nausea. The Tilt-A-Whirl was invented in 1926 by Herbert Sellner, who first operated it at an amusement park in White Bear Lake, Minnesota. More than likely, Sellner discovered its unpredictable dynamics not through mathematical analysis but by building one and trying it out.1926 Garage door openerA garage door opener is a motorized device that opens and closes a garage door. Most are controlled by switches on the garage wall, as well as by a remote control carried in the garage owner's vehicle. In 1926, the electric garage door opener was invented by C.G. Johnson, the inventor of the garage door and founder of the Overhead Door Corporation.1926 Power steeringPower steering is a system for reducing the steering effort on vehicles by using an external power source to assist in turning the roadwheels. In 1926, Francis W. Davis of Waltham, Massachusetts invented power steering.1926 Drive throughA drive-through, or drive-thru, allows customers to purchase products without leaving their cars. In 1926, City Center Bank, which became UMB Financial Corporation under R. Crosby Kemper opened what is considered the first drive-up window. In-n-Out Burger claims to have built the first drive-through restaurant in 1948. Harry and Esther Snyder, the chain's founders, built their first restaurant in Baldwin Park, California, with a two-way speaker to enable patrons to order directly from their cars without the intermediation of a carhop.1926 Liquid-fuel rocketThe liquid-fuel rocket is a rocket with an engine that uses propellants in liquid form. On March 16, 1926 in Auburn, Massachusetts, Dr. Robert H. Goddard, the "father of modern rocketry", launched the first liquid-fueled rocket in history, which used liquid oxygen and gasoline as propellants.1927 Bread slicerSliced bread is a loaf of bread which has been pre-sliced and packaged for commercial convenience. The automatic commercial bread slicer was invented in 1927 by Otto Frederick Rohwedder. His machine both sliced and wrapped a loaf of bread. In 1928, the bread slicer was improved by Gustav Papendick, a baker from St. Louis, Missouri.1927 JukeboxA jukebox is a partially automated music-playing device, usually a coin-operated machine, that can play specially selected songs from self-contained media. The traditional jukebox is rather large with a rounded top and has colored lighting on the front of the machine on its vertical sides. The classic jukebox has buttons with letters and numbers on them that, when combined, are used to indicate a specific song from a particular record. The Automatic Music Instrument Company built and introduced the first electric automated musical instrument which later became known as the jukebox during the 1930s.1927 Garbage disposalA garbage disposal is a device, usually electrically powered, installed under a kitchen sink between the sink's drain and the trap which shreds food waste into pieces small enough to pass through plumbing. The garbage disposal was invented in 1927 by John W. Hammes. After eleven years of development, his InSinkErator company put his disposer on the market in 1968.1927 Pressure washerA pressure washer is a high pressure mechanical sprayer that can be used to remove loose paint, mold, grime, dust, mud, and dirt from surfaces and objects such as buildings, vehicles, and concrete road surfaces. Frank Ofeldt in the United States invented the steam pressure washer or "high-pressure Jenny" in 1927.1927 Resonator guitarA resonator guitar or resophonic guitar is an acoustic guitar whose sound is produced by one or more spun metal cones resonators instead of the wooden sound board (guitar top/face). The resonator guitar was invented in 1927 by John Dopyera.1927 Kool-AidKool-Aid is a powdered drink mix that comes in an assortment of different flavors. "Kool-Ade" was invented in 1927 by Edwin Perkins in Hastings, Nebraska. Perkins devised a method of removing the liquid from a drink called "Fruit Smack" so the remaining powder could be re-packaged in envelopes, which Perkins designed and printed, all under a new name to be called "Kool-Ade". The name of the powdered drink was later to be changed at a later time to Kool-Aid.1927 Corn dogThe corn dog, pogo, dagwood dog, pluto pup or corny dog is a hot dog coated in cornbread batter and deep fried in hot oil, although some are baked. Almost all corn dogs are served on wooden sticks, though some early versions were stickless. Although a contending topic as numerous claims of the origins of the corn dog have surfaced, the earliest reference to what resembles a corn dog appeared in U.S. patent 1,706,491 filed in 1927 by Stanley S. Jenkins and issued in 1929. A competing claim to the invention of the corn dog is by George Boyington, the creator of Pronto Pups (made of pancake batter) who in 1938 or 1939, created a "batter-dipped, deep fried hot dog" after a rain storm in Rockaway Beach, Oregon ruined and made his hot dogs mushy. Another story is that Neil Fletcher supposedly invented corn dogs, first selling them at the Texas State Fair in 1942.1927 Negative feedback amplifierA negative feedback amplifier, or more commonly simply a feedback amplifier, is an amplifier which uses negative feedback to improve performance and reduce sensitivity to parameter variations due to manufacturing or environmental uncertainties. It was invented by Harold Stephen Black in 1927.1927 Quartz clockThe quartz clock is a clock that keeps time by using an electronic oscillator regulated by a quartz crystal. This allows for significantly better accuracy than mechanical clocks. The first quartz clock was built in 1927 by Warren Marrison and J.W. Horton at Bell Telephone Laboratories.1928 Recliner A recliner is a reclining armchair. It has a backrest that can be tilted back, causing a footrest to extend from the front. Edward Knabusch and Edwin Shoemaker invented the first recliner in Monroe, Michigan in 1928 when they modified a wooden porch chair so that the seat moved forward as the back reclined. A padded model was later developed.1928 Ice cube tray An ice cube tray is a tray divided into compartments. It is designed to be filled with water, then placed in a freezer until the water freezes to ice, producing ice cubes. The first flexible ice cube tray was invented by Lloyd Groff Copeman in 1928.1928 Bubble gum Bubblegum is a type of chewing gum especially designed for blowing bubbles. Bubblegum was invented by Frank Henry Fleer in 1906, but was not successful; the formulation of Fleer's "Blibber-Blubber", was too sticky. In 1928, Walter E. Diemer invented a superior formulation for bubble gum, which he called " Double Bubble."1928 Clip-on tie The clip-on tie is a bow tie or four-in-hand tie which is permanently tied, with a dimple just below the knot, and which is fixed to the front of the shirt collar by a metal clip. Alternately, the tie may have a band around the neck fastened with a hook and eye. The clip-on tie was reportedly invented on December 13, 1928 in Clinton, Iowa, USA. The name of the inventor remains unknown.1928 Electric razor The electric razor has a rotating, vibrating or oscillating blade to remove unwanted hair. The electric razor does not require the use of shaving cream, soap, or water. The razor is powered by a small DC motor, and usually has rechargeable batteries, though early ones were powered directly by house current. The electric razor was invented in 1928 by Col. Jacob Schick.1928 Iron lung An iron lung is a large machine that enables a person to breathe when normal muscle control has been lost or the work of breathing exceeds the person's ability. It is a form of a medical ventilator. Philip Drinker invented the iron lung while working at Harvard University in 1928. Great Depression and World War II (1929–1945)1929 Freon Freon is an odorless, colorless, nonflammable, and noncorrosive chlorofluorocarbon and hydrochlorofluorocarbon refrigerant, which is used in air conditioning, refrigeration and some automatic fire-fighting systems. Refrigerators from the late 19th century until 1929 used toxic gases, ammonia, methyl chloride, and sulfur dioxide as refrigerants. This new "miracle compound" was co-invented in 1929 by Charles Midgley Jr. and Charles Kettering.1929 Tampon (applicator) A tampon is a mass of absorbent material into a body cavity or wound to absorb bodily fluid. The most common type in daily use is disposable and designed to be inserted into the vagina during menstruation to absorb the flow of blood. The ancient Egyptians first invented disposable tampons made of softened papyrus around 2500 B.C. The ancient Greeks followed this with tampons made from lint wrapped around a small piece of wood. But it was not until 1929 that Earle Haas of Denver, Colorado first invented the modern tampon with an applicator. Dr. Haas submitted the design for patent in 1931, and in 1936, the tampon was first sold in the United States. He later gave his invention the brandname Tampax, which is still one of the main tampon brands today.1929 Eyelash curler An eyelash curler is a hand-operated mechanical device for curling eyelashes for cosmetic purposes. The earliest patent for an eyelash curler was filed on August 15, 1929 and issued to William E. McDonell and Charles W. Stickel of Rochester, New York on April 7, 1931.1929 SunglassesSunglasses or sun glasses are a visual aid which feature lenses that are coloured or darkened to prevent strong light from reaching the eyes. For centuries, Chinese judges had routinely worn smoke-colored quartz lenses to conceal their eye expressions in court. However, these were not intended for blocking sunlight from eyes. It wasn't until the 20th century that what is now considered to be sunglasses were invented. In 1929, Sam Foster invented and mass-produced the first tinted eyewear pieces solely intended to block out sunlight.1929 Frozen foodFrozen food is food preserved by the process of freezing. Freezing food is a common method of food preservation which slows both food decay and, by turning water to ice, makes it unavailable for most bacterial growth and slows down most chemical reactions. Clarence Birdseye offered his quick-frozen foods to the public. Birdseye got the idea during fur-trapping expeditions to Labrador in 1912 and 1916, where he saw the natives use freezing to preserve foods.1929 Cyclotron A cyclotron is a type of particle accelerator that accelerate charged particles using a high-frequency, alternating voltage. The cyclotron was invented in 1929 by Ernest O. Lawrence at the University of California at Berkeley.1930 TiltrotorA tiltrotor is an aircraft which uses a pair or more of powered rotors (sometimes called proprotors) mounted on rotating shafts or nacelles at the end of a fixed wing for lift and propulsion, and combines the vertical lift capability of a helicopter with the speed and range of a conventional fixed-wing aircraft. In September 1930, George Lehberger devised the basic concept of tilt rotor aircraft, that is, a relatively low disc loading thruster (propeller) that can tilt its axis from the vertical (for vertical lift) to the horizontal (for propulsive thrust). On September 16, 1930, Lehberger was issued U.S. patent #1,775,861.1930 Car audioCar audio/video (car AV) is a sound or video system fitted in an automobile. In 1930, the Galvin Corporation introduced the first commercial car radio, the Motorola model 5T71, which sold for between $110 and $130 and could be installed in most popular automobiles. Inventors Paul Galvin and Joe Galvin came up with the name Motorola when their company started manufacturing car radios.1930 CheesesteakA cheesesteak, or a Philly cheesesteak, is a long, crusty roll filled with thinly sliced sautéed ribeye beef and melted cheese. Generally, the cheese of choice is Cheez Whiz, but American and provolone are common substitutions. The art of cheesesteak preparation lies in the balance of flavors, textures and what is often referred to as the "drip" factor. Other toppings may include fried onions, sautéed mushrooms, ketchup and hot or sweet peppers. The cheesesteak was invented in 1930 by Philadelphian hot dog vendor Pat Olivieri who one day decided to substitute beef instead of a hot dog in a hoagie bun. A taxicab driver noticed the alluring aroma and asked for his own sandwich. Through word of mouth, Olivieri's sandwiches the following day were highly sought after by taxi cab drivers around Philadelphia. Due to booming business, Olivieri soon opened up his own shop, Pat's King of Steaks on 9th Street and Passyunk Avenue. Eventually, according to legend, he added cheese to the steak. The cheesesteak is considered to be a cultural icon of the city of Philadelphia.1930 Bathysphere A bathysphere is a pressurized metal sphere that allows people to go deep in the ocean, to depths at which diving unaided is impossible. This hollow cast iron sphere with very thick walls is lowered and raised from a ship using a steel cable. The bathysphere was invented by William Beebe and Otis Barton in 1930. William Beebe, an American naturalist and undersea explorer, tested the bathysphere in 1930, going down to in a diameter bathysphere. Beebe and Otis Barton descended about in a larger bathysphere in 1934. They descended off the coast of Nonsuch Island, Bermuda in the Atlantic Ocean. During the dive, they communicated with the surface via telephone.1930 Chocolate chip cookie A chocolate chip cookie is a drop cookie which features chocolate chips as its distinguishing ingredient. The traditional recipe combines a dough composed of butter and both brown and white sugar with semi-sweet chocolate chips. Ruth Wakefield of Whitman, Massachusetts invented chocolate chips and chocolate chip cookies in 1930. Her new cookie invention was called the "Toll House Cookie" which used broken-up bars of semi-sweet chocolate.1930 Thermistor A thermistor is a type of resistor with electrical resistance inversely proportional to its temperature. The word is a portmanteau of thermal and resistor. The thermosistor was invented by Samuel Ruben in 1930.1931 Electric guitarAn electric guitar is a guitar using pickups to convert its metal string vibration into electricity. This is amplified with an instrument amplifier. The output is altered with guitar effects such as reverb or distortion. The earliest electric guitar, known as a "frying pan", was a hollow bodied acoustic instrument with tungsten steel pickups invented by George Beauchamp and Adolph Rickenbacker in 1931. The electric guitar was a key instrument in the development of musical styles that emerged since the late 1940s, such as Chicago blues, early rock and roll, rockabilly, and 1960s blues rock. Electric guitars are used in almost every popular music genre. U.S. patent #2,089,171 was filed by Beauchamp on June 2, 1934 and issued on August 10 1937.1931 Strobe lightThe strobe light, commonly called a strobe, is a device used to produce regular flashes of light. Modern uses of strobe lights serve a purpose for safety warning, and motion detection. Strobes can be found atop most police cars, ambulances, and fire trucks. The origin of strobe lighting dates to 1931, when Harold Eugene Edgerton invented a flashing lamp to make an improved stroboscope for the study of moving objects, eventually resulting in dramatic photographs of objects such as bullets in flight.1931 AerogelAerogel is a low-density solid-state material derived from gel in which the liquid component of the gel has been replaced with gas. The result is an extremely low-density solid with several remarkable properties, most notably its effectiveness as a thermal insulator. It was first invented by Samuel Stephens Kistler in 1931, as a result of a bet with Charles Learned over who could replace the liquid inside of a Fruit preserves jar with gas without causing shrinkage.1931 Bug zapper A bug zapper is a device that attracts and kills insects that are attracted by light. A light source attracts insects to an electrical grid, where they are electrocuted by touching two wires with a high voltage between them. The earliest bug zappers appear as early as 1911. However, the first bug zapper patented was by Harrison L. Chapin and William F. Folmer who filed on September 23, 1931 and received U.S. patent #1,962,439 on June 12, 1934.1932 Miniature snap-action switch A miniature snap-action switch, also trademarked and frequently known as a micro switch, is an electric switch that is actuated by very little physical force, through the use of a tipping-point mechanism, sometimes called an "over-center" mechanism. Common applications of micro switches include the door interlock on a microwave oven, levelling and safety switches in elevators, vending machines, and to detect paper jams or other faults in photocopiers. The miniature snap-action switch was invented in 1932 by Peter McGall, who was an employee of the Burgess Battery Company in Freeport, Illinois.1932 Toilet brush A toilet brush is a domestic implement designed for the cleaning of the lavatory pan. The modern plastic version was invented by William C. Schopp of Huntington Park, California, USA. U.S. patent #1,927,350 was submitted on March 24, 1932 and issued on September 19, 1933.1932 Golf cart A golf cart or golf buggy is a small vehicle designed originally to carry two golfers and their golf clubs around a golf course. The earliest known golf cart was an electric one, built in California around the year 1932 by an unnamed golfer who was physically unable to walk to all 18 holes on a golf course. However, it was Merle Williams of Long Beach, California who in 1951, introduced golf carts to the public.1932 Staple remover A staple remover allows for the quick removal of a staple from a material without causing damage. The form of destapler described was invented by William G. Pankonin of Chicago, Illinois. A patent application for the same was filed on December 12, 1932, granted on March 3, 1936, and published on April 3, 1936 as a patent.1932 Radio telescopeA radio telescope is a form of directional radio antenna used in radio astronomy. They differ from optical telescopes in that they operate in the radio frequency portion of the electromagnetic spectrum where they can detect and collect data on radio sources. Radio telescopes are typically large parabolic or dish antenna used singularly or in an array. Karl Guthe Jansky started the field of radio astronomy serendipitous in 1932 when his directional antenna found radio static that he later identified as coming from the Milky Way.1932 Tape dispenserA tape dispenser holds a roll of tape and has a mechanism on one end to easily shear the tape. Dispensers vary widely based on the tape they dispense. Clear tape dispensers are commonly made of plastic, and may be disposable. Other dispensers are stationary and may have sophisticated features to control tape usage and improve ergonomics. The first tape dispenser with a built-in cutting edge was invented in 1932 by John A. Borden, another 3M employee.1933 Landing Vehicle TrackedA Landing Vehicle Tracked (LVT), also known as amtracks, alligators, or in their fire support variants as buffaloes, were amphibious tracked vehicles capable of crawling out of the water and onto the beach and beyond. Used primarily by the United States Armed Forces in the Pacific War against the Empire of Japan during World War II, later versions were thinly armored, and some were equipped with a light tank turret to provide fire support, making them equivalent to light amphibious tanks. Highly versatile in their use, LVT's landed supplies ashore at Guadalcanal and soldiers ashore at Tarawa, other variations of the LVT were equipped with flamethrowers during the Peleliu Campaign. The LVT was derived from the Alligator, an amphibious vehicle invented by Donald Roebling in 1933 as a rescue vehicle for downed aviators in the Florida Everglades.1933 Multiplane cameraThe multiplane camera is a special motion picture camera used in the traditional animation process that moves a number of pieces of artwork past the camera at various speeds and at various distances from one another, creating a three-dimensional effect, although not stereoscopic. Various parts of the artwork layers are left transparent, to allow other layers to be seen behind them. The movements are calculated and photographed frame-by-frame, with the result being an illusion of depth by having several layers of artwork moving at different speeds. The further away from the camera, the slower the speed. The multiplane effect is sometimes referred to as a parallax process. As a former director and animator of Walt Disney Studios, Ub Iwerks in 1933 invented the multiplane camera using four layers of flat artwork before a horizontal camera.1933 Frequency modulation In telecommunications, frequency modulation (FM) conveys information over a carrier wave by varying its frequency. While working in the basement laboratory of Columbia's Philosophy Hall, Edwin Armstrong invented wide-band frequency modulation radio in 1933. Rather than varying the amplitude of a radio wave to create sound, Armstrong's method varied the frequency of the wave instead. FM radio broadcasts delivered a much clearer sound, free of static, than the AM radio dominant at the time. Armstrong received a patent on wideband FM on December 26, 1933.1933 Impact sprinklerAn impact sprinkler is a type of irrigation sprinkler that pivots on a bearing on top of its threaded attachment nut, and is driven in a circular motion by a spring-loaded arm that is pushed back by the water stream, then returning to "impact" the stream. This produces an intermittent diffusion of the stream that provides a uniform waterfall closer to the sprinkler. In 1933, the impact sprinkler was invented and patented by lemon tree grower and farmer Orton Englehardt of Glendora, California.1934 Trampoline (modern)A trampoline is a gymnastic and recreational device consisting of a piece of taut, strong fabric stretched over a steel frame using many coiled springs to provide a rebounding force which propels the jumper high into the air. In a trampoline, the fabric is not elastic itself; the elasticity is provided by the springs which connect it to the frame. While the trampoline is an old invention which relied on crude and flawed designs, the modern trampoline was invented by George Nissen and Larry Griswold around 1934.1934 Acrostic (puzzle)An acrostic is a type of word puzzle, related somewhat to crossword puzzles, that uses an acrostic form with lettered clues and numbered blanks. The acrostic puzzle was invented in 1934 by Elizabeth Kingsley, first appearing in the March 31 edition of the Saturday Evening Post.1935 Richter magnitude scale The Richter magnitude scale, or local magnitude scale, assigns a number to quantify the amount of seismic energy released by an earthquake. It is a base-10 logarithmic scale obtained by calculating the logarithm of the combined horizontal amplitude of the largest displacement from zero on a Wood–Anderson torsion seismometer output. Co-invented in 1935 by Charles Richter along with Beno Gutenberg of the California Institute of Technology, the Richter magnitude scale was firstly intended to be used only in a particular study area in California, and on seismograms recorded on a particular instrument, the Wood-Anderson torsion seismometer.1935 Black light A Black light or UV Light is a lamp emitting electromagnetic radiation that is almost exclusively in the soft ultraviolet range, and emits little visible light. The black light was invented by William H. Byler, in 1935.1935 Parking meter A parking meter is a device used to collect money in exchange for the right to park a vehicle in a particular place for a limited amount of time. The parking meter was invented by Carl C. Magee of Oklahoma City, Oklahoma in 1935. Magee also holds the patent for a "coin controlled parking meter", filed on May 13, 1935 and issued on May 24, 1938.1935 Surfboard fin The surfboard fin, or keel, is the part of the back of a surfboard that enters the water. Similar to a rudder on a boat the surfboard fin works to steer the board and provide stability. The surfboard fin prevents a surfer from uncontrollably spinning in circles while trying to ride a wave. The surfboard fin was invented by Tom Blake in 1935.1935 pH meter A pH meter is an electronic instrument used to measure the pH (acidity or alkalinity) of a liquid. In 1935, Arnold Orville Beckman invented the pH meter.1935 Gomco clamp A Gomco clamp, otherwise known as a Yellen clamp, is a specialized clamp for performing circumcisions on a human male's penis. y using a Gomco clampe, the time required is less than that by any other method, sutures are never used, no bleeding is encountered, and it leaves a clean-cut incision which heals perfectly in 36 hours with practically no chance of infection because the mucous membrane and skin are securely clamped together. The Gomco clamp was inented in 1935 by Hiram S. Yellen and Aaron Goldstein. The Gomco clamp was then market by Goldstein through his private company, the Goldstein Manufacturing Company and later patented in 1940.1936 Reed switchA reed switch is an electrical switch consisting of two ferromagnetic and specially shaped contact blades (reeds) positioned in a hermetically sealed glass tube with a gap between them and in a protective atmosphere. Operated by an applied magnetic field, reed switches are used as reed relays, automotive sensors, robotics sensors, security sensors and are found in many toys and games. The reed switch was invented in 1936 by W. B. Elwood at Bell Telephone Laboratories.1936 Phillips-head screwThe Phillips-head screw is a crosshead screw design lying in its self-centering property, useful on automated production lines that use power screwdrivers. The Phillips-head screw was invented and patented by Henry F. Phillips in 1936.1936 Stock car racingStock car racing is a form of automobile racing. Shorter ovals are called short tracks, unpaved short tracks are called dirt tracks, and longer ovals are known as superspeedways. On March 8, 1936, the first stock car race was held on the Daytona Beach Road Course, promoted by local racer Sig Haugdahl. The race was 78 laps (250 miles) long for street-legal family sedans sanctioned by the American Automobile Association (AAA) for cars built in 1935 and 1936. The city posted a $5000 purse with $1700 for the winner. In 1948, stock car racing became a regulated sport when Bill France, Sr. created NASCAR.1936 Programming languagesA programming language is a machine-readable artificial language. Programming languages can be used to create programs that specify the behavior of a machine, to express algorithms precisely, or as a mode of human communication. The first programming languages predate the modern computer. In mathematical logic and computer science, lambda calculus, also written as λ-calculus, is a formal system designed to investigate function definition, function application and recursion. It was invented by Alonzo Church and Stephen Cole Kleene in the 1930s as part of an investigation into the foundations of mathematics, but has now emerged as a useful tool in the investigation of problems in computability, recursion theory, and as a fundamental basis and a modern paradigm to computer programming and software languages.1936 Compact fluorescent lampA compact fluorescent lamp is a fluorescent lamp designed to replace an incandescent lightbulb. Some CFL's fit into light fixtures formerly used for incandescent lamps and they are designed to produce the same amount of visible light found in incandescent light. CFLs generally use 70% less energy and have a longer rated life. In 1941, George Inman devised the first practical fluorescent lamp while working for General Electric. The key patent for this light source, U.S. patent #2,259,040 was filed by Inman on April 22, 1936 and issued to him on October 14, 1941. In 1976, Edward E. Hammer invented the first helical or spiraled compact fluorescent lamp, but due to the difficulty of the manufacturing process for coating the interior of the spiral glass tube, General Electric did not manufacture or sell the device. Other companies began manufacturing and selling the device in 1995.1936 Chair liftA chair lift is a type of aerial lift, which consists of a continuously circulating steel cable loop strung between two end terminals and usually over intermediate towers, carrying a series of chairs. They are the primary onhill transport at most ski areas, but are also found at amusement parks, various tourist attractions, and increasingly, in urban transport. James Curran, an engineer from the Union Pacific Railroad, invented and built the first chair lift in the world. Known as the Proctor Mountain Ski Lift, it was located in Sun Valley, Idaho.1936 Strain gaugeA strain gauge is a device used to measure the strain of an object. As the object is deformed, the foil is deformed, causing its electrical resistance to change. The strain gauge was invented in 1936 by Edward E. Simmons, a professor at the California Institute of Technology, and re-invented in 1938 by Arthur C. Ruge, an earthquake specialist at the Massachusetts Institute of Technology.1936 Bass guitarThe bass guitar is a stringed instrument played primarily with the fingers or thumb (either by plucking, slapping, popping, tapping, or thumping), or by using a plectrum. The bass guitar is similar in appearance and construction to an electric guitar, but with a longer neck and scale length, and four, five, or six strings. In 1936, the Audiovox bass, the earliest electric solid-body bass guitar made out of walnut and neck-through construction, was invented by Paul Tutmarc of Seattle, Washington. Later in 1951, the bass guitar was perfected when Leo Fender introduced the precision bass, a fretted, solid-body instrument.1937 O-ring An O-ring, also known as a toric joint, is a mechanical gasket in the shape of a torus containing a loop of elastomer with a disc-shaped cross-section. It is designed to be seated in a groove and compressed during assembly between two or more parts, creating a seal at the interface. The O-ring was invented in 1937 by Danish-American machinist Niels Christensen.1937 Photosensitive glass Photosensitive glass is a clear glass in which microscopic metallic particles can be formed into a picture or image by exposure to short wave radiations such as ultraviolet light. Photosensitive glass was invented in November 1937 by S. Donald Stookey of Corning Glass Works.1937 Digital computer A digital computer is a device capable of solving problems by processing information on discrete form. It operates on data, including magnitudes, letters, and symbols that are expressed in binary form. While working at Bell Labs in November 1937, George Stibitz, who is internationally recognized as the father of the modern digital computer, built the world's first relay-based computer which calculated binary addition.1937 Shopping cartA shopping cart is a metal or plastic basket on wheels supplied by a shop, especially a supermarket, for use by customers inside the shop for transport of merchandise to the check-out counter during shopping. Often, customers are allowed to leave the carts in the parking lot, and store personnel return the carts to the shop. The first shopping cart was invented by Sylvan Goldman in 1937, owner of the Humpty Dumpty supermarket chain in Oklahoma City.1937 Sunglasses (polarized)Polarized sunglasses are protective eyewear which incorporate oscillated lenses shifting the sun's rays in the opposite direction. Polarized sunglasses were invented in 1937 by Edwin Land.1937 KlystronA klystron is a specialized linear-beam vacuum tube. Klystrons are used as amplifiers at microwave and radio frequencies to produce both low-power reference signals for superheterodyne radar receivers and to produce high-power carrier waves for communications and the driving force for modern particle accelerator. Russell and Sigurd Varian of Stanford University are generally considered to be the inventors. Their prototype was completed in August 1937.1937 Cyclamate Cyclamate is an artificial sweetener 30–50 times sweeter than sugar, making it the least potent of the commercially used artificial sweeteners. It was invented in 1937 by graduate student Michael Sveda at the University of Illinois.1938 Beach ballA beach ball is an inflatable ball for beach and water games. Their large size and light weight take little effort to propel; they travel very slowly and generally must be caught with two hands, making them ideal for lazy games and for children. Their lightness and size make them difficult to use in even moderate wind. The beach ball was invented in California by Jonathon DeLonge in 1938.1938 FiberglassThe technique of heating and drawing glass into fine fibers has been used for millennia. The use of these fibers for textile applications is more recent. The first commercial production of fiberglass was in 1936. In 1938, fiberglass was invented by Russell Games Slayter of Owens-Corning.1938 XerographyXerography, which means "dry writing" in Greek, is a process of making copies. Xerography makes copies without using ink. In this process, static electricity charges a lighted plate; a plastic powder is applied to the areas of the page to remain white. The photocopier was invented in 1938 by Chester Floyd Carlson who marketed his revolutionary device to about 20 companies before he could interest any. The Haloid Company, later called the Xerox Corporation, marketed it, and xerography eventually became common and inexpensive.1938 Nylon In 1938, a team of researchers working under Wallace H. Carothers at E. I. du Pont de Nemours and Company invented a plastic that can be drawn into strong, silk-like fibers. Nylon soon became popular as a fabric for hosiery as well as industrial applications such as cordage.1938 Operant conditioning chamber Also known as a Skinner box, an operant conditioning chamber is a laboratory apparatus used in the experimental analysis of behavior to study animal behavior. The operant conditioning chamber was invented in 1938 by B. F. Skinner.1938 Soft serve ice creamNot to be confused with regular ice cream of the slow, churned type which was invented in China over two millennia ago, soft serve is a distinctive type of frozen dessert that is similar to, but much softer than, ice cream. In 1938, J.F. "Grandpa" McCullough and his son Alex co-invented soft serve ice cream, devising a new way to serve ice cream in its soft, creamy form that it takes before going into the deep freeze to make it scoopable. After Alex McCullough commissioned Harry Oltz in 1939 to design the first soft serve ice cream machine, similar to ones used for making frozen custard, the Dairy Queen franchise was founded when Sherb Noble opened the first store in 1940.1938 TeflonIn chemistry, polytetrafluoroethylene is a synthetic fluoropolymer which finds numerous applications. PTFE is best known by the DuPont brand name Teflon. PTFE was accidentally invented by Roy Plunkett of Kinetic Chemicals in 1938.1939 Yield signIn road transport, a yield sign or give way sign indicates that a vehicle driver must prepare to stop if necessary to let a driver on another approach proceed. However, there is no need to stop if his way is clear. A driver who stops has yielded his right of way to another. The yield sign, but not the yield traffic rule itself, was invented in 1939 by Tulsa police officer Clinton Riggs.1939 VU meterA VU meter is often included in analog circuit, audio equipment to display a signal level in Volume Units. It is intentionally a "slow" measurement, averaging out peaks and troughs of short duration to reflect the perceived loudness of the material. It was originally invented in 1939 by the combined effort of Bell Labs and broadcasters CBS and NBC for measuring and standardizing the levels of telephone lines. The instrument used to measure VU is called the volume indicator (VI) instrument. Most users ignore this and call it a VU meter.1939 Starting gate A starting gate, also known as starting stalls, is a machine used in the sports of thoroughbred horse and dog racing to ensure a fair start in a race. The starting gate was invented by Clay Puett of Chillicothe, Texas when it was used at Lansdowne Park in Vancouver, British Columbia, Canada for the first time on July 1, 1939. U.S. patent #2,232,675 was filed by Puett on August 7, 1939 and issued to him on February 18, 1941.1939 Twist tie A twist tie is a metal wire that is encased in a thin strip of paper or plastic and is used to tie the openings of bags, such as garbage bags or bread bags. A twist tie is used by wrapping it around the item to be fastened, then twisting the ends together. The original twist tie was invented by the California-based packaging company T and T Industries, Inc. It was patented in 1939 and marketed as the Twist-Ems.1939 Automated teller machineAn automated teller machine (ATM) is a computerized telecommunications device that provides the clients of a financial institution with access to financial transactions in a public space without the need for a cashier, human clerk or bank teller. ATMs are known by various other names including automatic banking machine, cash machine, and various regional variants derived from trademarks on ATM systems held by particular banks. Financial transcationssuch as deposits, withdrawals, and transfers of accounts may be conducted at ATM's by inserting an ATM card. In 1939, Armenian-American inventor Luther George Simjian initially came up with the idea of creating a hole-in-the-wall machine that would allow customers to make financial transactions. The idea was met with a great deal of skepticism after Citicorp tested it. In later years and after Simjian filed 20 patents related to the device, the idea and the gradual usage of ATM's became more widespread around the world.1939 VocoderA vocoder, a portmanteau of the words voice and encoder, is an analysis and synthesis system, mostly used for speech. In the encoder, the input is passed through a multiband filter, each band is passed through an envelope follower, and the control signals from the envelope followers are communicated to the decoder. The decoder applies these control signals to corresponding filters in the (re)synthesizer. Research physicist Homer Dudley invented the Vocoder at Bell Labs in 1939 which served the purpose of improving the voice-carrying capabilities of his employer's telephone lines.1940 Fluxgate magnetometer A fluxgate magnetometer measures the direction and magnitude of magnetic fields. Fluxgate magnetometer sensors are manufactured in several geometries and recently have made significant improvements in noise performance, crossfield tolerance and power utilization. The fluxgate magnetometer was invented by Victor Vacquier in 1940 while working for Gulf Research in Pittsburgh.1941 Aerosol Bomb An Aerosol bomb is a hand-held container or dispenser from which an aerosol is released. Developed in 1941 by Lyle D. Goodhue and William N. Sullivan and patented in 1943. 1941 Deodorant Deodorants are substances applied to the body to reduce body odor caused by the bacterial breakdown of perspiration. Jules Montenier holds a number of patents. Arguably, his January 28, 1941 patent for Astringent Preparation is his most famous which dealt with solving the problem of the excessive acidity of aluminum chloride, then and now the best working antiperspirant, by adding a soluble nitrile or a similar compound. This innovation found its way into "Stopette" deodorant spray, which Time Magazine called "the best-selling deodorant of the early 1950s".1941 Acrylic fiber Acrylic fibers are synthetic fibers made from a polymer Polyacrylonitrile with an average molecular weight of ~100,000, about 1900 monomer units. To be called acrylic in the United States, the polymer must contain at least 85% acrylonitrile monomer. Typical comonomers are vinyl acetate or methyl acrylate. The Dupont Corporation invented the first acrylic fibers in 1941 and trademarked them under the name "Orlon".1941 Electric guitar (solid body) A solid body electric guitar, made up of hardwood with a lacquer coating, is an electric guitar that has no hollow internal cavity to accommodate vibration. There are no sound holes such as those used to amplify string vibrations in acoustic guitars. The sound that is audible in music featuring electric guitars is produced by pickups on the guitar that convert the string vibrations into an electrical signal, usually fed into an amplifier or a speaker. The solid body guitar was invented in 1941 by American recording artist Les Paul.1942 BazookaA bazooka is a shoulder-fired, man-portable recoilless rocket anti-tank weapon that features a solid rocket motor for propulsion, allowing for high explosive (HE) and high-explosive anti-tank (HEAT) warheads to be delivered against armored vehicles, machine gun nests, and fortified bunkers at ranges beyond that of a standard thrown grenade or mine. The bazooka was co-invented in February 1942 by Edward Uhl, then a lieutenant in the United States Army, and Colonel Leslie Skinner.1943 Magnetic proximity fuzeA magnetic proximity fuze is a type of proximity fuze that initiates a detonator in a piece of ordnance such as a land mine, naval mine, depth charge, or shell when the fuse's magnetic equilibrium is upset by a magnetic object such as a tank or a submarine. In 1943, Panayottis John Eliomarkakis of Philiadelphia filed U.S. patent #2,434,551 which was issued on January 13, 1948.1943 Modern Coal Burning Steam LocomotiveThis invention was only primarily used with steam locomotives that had booster valves or superchargers to heat the fire even hotter to produce extra power. The coal used was semi-bituminous and bituminous coal only inside the steam locomotives. Sadly, this invention lasted until 1960 when Diesel's fully replaced American railroads.1943 SlinkyA Slinky or "Lazy Spring" is a toy consisting of a helical spring that stretches and can bounce up and down. It can perform a number of tricks, including traveling down a flight of steps end-over-end as it stretches and re-forms itself with the aid of gravity and its own momentum. The Slinky was invented in 1943 by American engineer Richard T. James while working in his home laboratory to invent a set of springs that could be used to support sensitive instruments on board ships and stabilize them even in rough seas. When he once accidentally knocked one of his springs off a shelf, James saw that, rather than flopping in a heap onto the floor, the spring "stepped" in a series of arcs from the shelf, to a stack of books, to a tabletop, to the floor, where it re-coiled itself and stood upright. In 1945, the James first exhibited his new toy at the Gimbels, a department store located in Philadelphia. He sold 400 Slinkys in 90 minutes which was the start of a sensation that continues to this day. 1945 Microwave ovenA microwave oven cooks or heats food by dielectric heating. Cooking food with microwaves was discovered by Percy Spencer on October 8, 1945, while building magnetrons for radar sets at Raytheon. Spencer was working on an active radar set when he noticed a strange sensation, and saw that a peanut candy bar he had in his pocket started to melt. Although he was not the first to notice this phenomenon, as the holder of 120 patents, Spencer was no stranger to discovery and experiment, and realized what was happening. The radar had melted his candy bar with microwaves. The first food to be deliberately cooked with microwaves was popcorn, and the second was an egg. In 1947, Raytheon under Percy Spencer demonstrated the world's first microwave oven built at the company which was called the "Radarange".1945 Cruise controlCruise control automatically controls the rate of motion of a motor vehicle. The driver sets the speed and the system will take over the throttle of the car to maintain the same speed. Cruise control was invented in 1945 by a blind inventor and mechanical engineer named Ralph Teetor. His idea was born out of the frustration of riding in a car driven by his lawyer, who kept speeding up and slowing down as he talked. The first car with Teetor's system was the Chrysler Imperial in 1958. This system calculated ground speed based on driveshaft rotations and used a solenoid to vary throttle position as needed.1945 Block heater A block heater warms the engine of an automobile in order to ease and speed starting and vehicle warm-up in cold weather. The most common type is an electric heating element connected through a power cord often routed through the vehicle's grille. The block heater may replace one of the engine's core plugs, or may be installed in line with one of the radiator or heater hoses. The block heater, first known as a head bolt heater, was invented in 1945 by Andrew Freeman in Grand Forks, North Dakota. Freeman used some scrap hoses and copper tubing onto the heating element of an old flat-iron and produced the first headbolt heater, which warmed the engine's water jacket and the oil film between cylinder heads and pistons. U.S. patent #2,487,326 was filed on November 4, 1946 and issued to Freeman on November 8, 1949. See alsoTimelines of United States inventionsTimeline of United States inventions (before 1890) Timeline of United States inventions (1946–1991) Timeline of United States inventions (after 1991)Related topics' History of United States patent law Lemelson Foundation Lemelson–MIT Prize List of African-American inventors and scientists List of inventors List of inventors killed by their own inventions List of military inventions List of prolific inventors List of Puerto Ricans List of Puerto Ricans in the United States Space Program NASA spinoff technologies National Inventors Hall of Fame Native American contributions Science and technology in the United States Technological and industrial history of the United States Timeline of United States discoveries United States Patent and Trademark Office United States patent law Yankee ingenuity Footnotes Further reading Deitch, Joanne Weisman, "A Nation of Inventors", Carlisle, Massachusetts : Discovery Enterprises Limited, 2001 Haven, Kendall, "100 Greatest Science Inventions of All Time", Westport, Connecticut : Libraries Unlimited, 2006 Hopping-Egan, Lorraine, "Inventors and Inventions", New York City, New York : Scholastic, Incorporated, 1997 Ngeow, Evelyn, "Inventors and Inventions", New York City, New York : Marshall Cavendish Corporation, 2008 Philbin, Tom, "The 100 Greatest Inventions of All Time", New York City, New York : Kensington Publishing Corporation, 2003 External links American Inventors Google: U.S. Patents Search PBS: They Made America MIT: Invention Dimension NASA: Scientific and Technical Information: NASA Spinoff National Inventors Hall of Fame Foundation The Great Idea Finder United States Patent and Trademark Office * *List of United States inventions and discoveries United States United States inventions Inventions 1890 1945

Dejalhttp://dejal.org enDejalNews #75: Time Out tips & supporter pollhttp://dejal.org/blog/2019/02/dejalnews-75-time-out-tips-supporter-poll <p><img src="/files/dejalnews/header.png" alt="DejalNews header" width="100%" border="0" /> </p> <p><b>DejalNews 2019-02</b>, <i>issue #75</i></p> <h4>Welcome</h4> <p>This is <i>DejalNews</i>, an occasional newsletter from <a href="/">Dejal</a>.</p> <p><i><b>If you want to receive these newsletters in your email inbox, head over to the <a href="/subscribe/">DejalNews subscribe page</a> to sign up.</b></i></p> <h4>Time Out tips</h4> <p>So far I've been sticking to my goal of a <a href="/blog/">Dejal blog post</a> each week. No idea if I can keep it up, but I want to try.</p> <p>Following the <a href="/blog/2019/01/dejalnews-74-its-back">previous <i>DejalNews</i> newsletter</a>, a couple of weeks ago I <a href="/blog/2019/02/time-out-tip-dry-eye-blink-reminders">posted a Time Out tip to help with dry eyes</a>, and last week I <a href="/blog/2019/02/time-out-tip-lifetime-supporter">posted about making your own lifetime supporter option</a>. Check out those posts if you missed them.</p> <h4>Auto-renewing Time Out supporter option?</h4> <p>Speaking of the Time Out supporter options, there's something I've been considering for a while. As you may know, currently the 3-, 6-, and 12-month supporter options are one-time payments; they don't automatically renew. Which is fine for many people, who either only want to buy once, or want to choose when to renew. But lots of customers do renew their support when it expires, which I greatly appreciate.</p> <p>So I was wondering if people would like and use an option to automatically renew their supporter status. To be clear, this would be completely optional, in addition to the current non-renewing choices.</p> <p>I've created <a href="/poll/2019/02/timeout-auto-renew">a poll to ask about this option</a>.</p> <p>I know this newsletter doesn't have a huge readership (since I removed the old subscribers rather than risk anyone thinking it spam), but I would really appreciate it if everyone who reads this would vote on this poll. Thank you.</p> <p><i>- David</i></p> DejalNewsWed, 20 Feb 2019 04:36:50 +0000David Sinclair11517 at http://dejal.orgWould you like an option to automatically renew the Time Out supporter status?http://dejal.org/poll/2019/02/timeout-auto-renew <form action="/rss.xml" accept-charset="UTF-8" method="post" id="poll-view-voting"> <div><div class="poll"> <div class="vote-form"> <div class="choices"> <div class="form-radios"><div class="form-item" id="edit-choice-0-wrapper"> <label class="option" for="edit-choice-0"><input type="radio" id="edit-choice-0" name="choice" value="0" class="form-radio" /> I don&#039;t use Time Out</label> </div> <div class="form-item" id="edit-choice-1-wrapper"> <label class="option" for="edit-choice-1"><input type="radio" id="edit-choice-1" name="choice" value="1" class="form-radio" /> I only use Time Out for free</label> </div> <div class="form-item" id="edit-choice-2-wrapper"> <label class="option" for="edit-choice-2"><input type="radio" id="edit-choice-2" name="choice" value="2" class="form-radio" /> No, I only want to pay once</label> </div> <div class="form-item" id="edit-choice-3-wrapper"> <label class="option" for="edit-choice-3"><input type="radio" id="edit-choice-3" name="choice" value="3" class="form-radio" /> No, I prefer to choose when to renew</label> </div> <div class="form-item" id="edit-choice-4-wrapper"> <label class="option" for="edit-choice-4"><input type="radio" id="edit-choice-4" name="choice" value="4" class="form-radio" /> Yes, I&#039;d like to have that option, but may not use it</label> </div> <div class="form-item" id="edit-choice-5-wrapper"> <label class="option" for="edit-choice-5"><input type="radio" id="edit-choice-5" name="choice" value="5" class="form-radio" /> Yes, I&#039;d definitely use that option</label> </div> </div> </div> <input type="submit" name="op" id="edit-vote" value="Vote" class="form-submit" /> </div> <input type="hidden" name="form_build_id" id="form-17b1dc74f02b11cb77e2113bc45a8a13" value="form-17b1dc74f02b11cb77e2113bc45a8a13" /> <input type="hidden" name="form_id" id="edit-poll-view-voting" value="poll_view_voting" /> </div> </div></form> http://dejal.org/poll/2019/02/timeout-auto-renew#commentsWed, 20 Feb 2019 04:29:13 +0000David Sinclair11516 at http://dejal.orgTime Out tip: lifetime supporter?http://dejal.org/blog/2019/02/time-out-tip-lifetime-supporter <p><a href="/timeout/"><img src="/timeout/images/icon.png" align="right" /></a>In ye olde days, software was sold once, for what would be considered nowadays to be a high price, and every year or so the developer would release a major paid upgrade, typically charging about half of the original price.</p> <p>I still do this for <a href="/simon/">Simon</a>, my pro tool to monitor websites and servers for changes or failures, since that model is still common for pro apps. Though it is also available on <a href="https://go.setapp.com/stp124?refAppID=201&amp;stc=site&amp;utm_medium=available_on_setapp_button&amp;utm_source=201&amp;utm_campaign=blog">Setapp</a>, as part of a subscription along with hundreds of other apps.</p> <p>But for <a href="/timeout/">Time Out</a>, my popular break reminder app, I wanted to try something different. I introduced a "supporter" model, where people can get the main features completely free, but be rewarded for supporting ongoing development with extra features. </p> <p>Unlike old-school purchases, the supporter purchases are much cheaper, only a few bucks, and for a specific period of time, 3, 6, or 12 months. The extra features can be tried for an hour at a time, or are unlocked permanently with any supporter level. The "catch", such as it is, is that when I update the app, I may add new features that are only available to current supporters, so if your support has expired, you won't get those features unless you renew your support. Of course, you can try them, to help decide if you want to renew.</p> <p>That seems really fair to me; you can have breaks for free, or get extra features cheaply, and if you like my improvements, you can help pay for their development. Or continue using the older features forever without paying more.</p> <p>Win/win &mdash; you get a useful app that is regularly improved, and I get to eat. I also don't have to hold back major features for a big paid upgrade; I can add things whenever desired.</p> <p>Even so, I occasionally get people asking about a lifetime purchase option. I don't currently offer that, since I feel it would be detrimental to the long-term survival of the app. However, you can effectively make your own lifetime option, by purchasing multiple 12-month supporter statuses. Each one you purchase will extend your supporter status by a year. So if you envision using Time Out for the next 5 years, purchasing 5 times will extend your support that long. Or whatever duration you want to use.</p> <p>Of course, it’s worth reiterating that you don't have to pay more than once if you don't want to. You can become a supporter at whatever level you feel comfortable with, and not pay again unless you want to show your appreciation (kinda like a tip jar). After your supporter status expires, all of the advanced features that you had when you were a supporter will remain available permanently. You’d only need to renew if I add new features in the future that you want to use.</p> timeouttipsMon, 11 Feb 2019 22:56:00 +0000David Sinclair11514 at http://dejal.orgTime Out tip: dry eye blink remindershttp://dejal.org/blog/2019/02/time-out-tip-dry-eye-blink-reminders <p><a href="/timeout/"><img src="/timeout/images/icon.png" align="right" /></a>People use <a href="/timeout/">Time Out</a> for lots of reasons; to avoid RSI, to get regular exercise, to avoid sore eyes, to remember to eat regularly, to stop work at the end of the day, and more. But one use case that I've seen several people mentioning recently is to help with dry eyes.</p> <p>A nice comment from one example:</p> <blockquote><p> "...my eyes are freakishly dry, way over-the-top compared to the average dry eye patient, and your app has allowed me to use my computer longer without killing my eyes. I can't thank you enough for making it!!" </p></blockquote> <p>People who experience dry eyes can sometimes find that blinking more frequently can help keep the eyes lubricated. That can be hard to remember when focused on work, though. Time Out's default Micro break can help with that, but some people prefer even more frequent reminders.</p> <p>Time Out breaks can currently be configured to occur as much as once per minute, which is a lot for a typical break, but by making the break only last one second, and configuring the other <b>Schedule</b> settings to avoid skipping or delaying it, the break can be a very brief reminder without being too disruptive:</p> <p><a href="/files/2019/timeout/dry-eye/schedule.png" title="Click for full size."><img src="/files/2019/timeout/dry-eye/schedule.png" alt="Time Out schedule page" width="100%" border="0" /></a></p> <p>In the next version of Time Out, I am considering enabling using frequency units of seconds, instead of minutes (and hours, etc). It is currently limited to a minimum of 1 minute, as that seemed like a reasonable minimum, but a very quick break like this every few seconds does have merit. But read on for a way this can be achieved even now.</p> <p>The <b>Appearance</b> options can be set to avoid fading the screen via the <b>None</b> theme, with zero fade-in and fade-out times (set the fade times before changing the theme):</p> <p><a href="/files/2019/timeout/dry-eye/appearance.png" title="Click for full size."><img src="/files/2019/timeout/dry-eye/appearance.png" alt="Time Out appearance page" width="100%" border="0" /></a></p> <p>A great way to very quickly remind yourself to blink is to flash the screen. This can be done via the <b>Flash Screen</b> action. The color and duration of the flash can be tweaked as desired.</p> <p>And if once per minute isn't enough, you can add as many as you want on the <b>Actions</b> page, spaced out by setting the offset <b>After Start</b>, like this to have it flash every 10 seconds:</p> <p><a href="/files/2019/timeout/dry-eye/actions.png" title="Click for full size."><img src="/files/2019/timeout/dry-eye/actions.png" alt="Time Out actions page" width="100%" border="0" /></a></p> <p>I hope this is helpful to people suffering from dry eye, or anyone wanting more frequent reminders.</p> timeouttipsMon, 04 Feb 2019 21:23:49 +0000David Sinclair11513 at http://dejal.orgDejalNews #74: It's back!http://dejal.org/blog/2019/01/dejalnews-74-its-back <p><img src="/files/dejalnews/header.png" alt="DejalNews header" width="100%" border="0" /> </p> <p><b>DejalNews 2019-01</b>, <i>issue #74</i></p> <h4>Welcome</h4> <p>This is <i>DejalNews</i>, an occasional newsletter from <a href="/">Dejal</a>.</p> <p><i><b>If you want to receive these newsletters in your email inbox, head over to the <a href="/subscribe/">DejalNews subscribe page</a> to sign up.</b></i></p> <h4>DejalNews is back!</h4> <p>The previous issue of <i>DejalNews</i> was a bit over a year ago. I didn't intend to take a year off publishing these newsletters, but sometimes things just happen. I want to get back on that horse, so hopefully will resume publishing a newsletter each month. Usually they will cover recent releases and news, but I've got a bit of catching up to do this time.</p> <h4>Simon 4.3.1, Time Out 2.5</h4> <p>Since it's been a while since the previous newsletter, I should mention the updates to my main two apps, <a href="/simon/">Dejal Simon</a> version 4.3.1, and <a href="/timeout/">Time Out</a> version 2.5. If you missed them, take a look at the release notes or <a href="/blog/release">blog</a> for what changed.</p> <h4>Introducing SheetPlanner</h4> <p>An exciting new Mac app was introduced recently: <a href="/consulting/sheetplanner/">SheetPlanner</a>. This app was written by me as a consulting project. It is a pro-level outliner, planner, todo, calendar, and more.</p> <p>Version 1.0 of this app was well-received, and we're working on some great enhancements for version 1.1 and beyond. Check it out!</p> <h4>Summary blog posts</h4> <p>A great resource to catch up with or review what happened in the past year are my traditional end-of-year blog posts:</p> <ul> <li><a href="/blog/2019/01/featured-blog-posts-2018">Featured blog posts of 2018</a>: highlighting a few interesting posts from 2018.</li> <li><a href="/blog/2019/01/dejal-year-review-2018">Dejal year in review: 2018</a>: summarizing updates to Dejal and consulting apps in 2018.</li> <li><a href="/blog/2019/01/looking-ahead-2019">Looking ahead: 2019</a>: trying to predict what's coming up this year.</li> </ul> <h4>Personal blogs</h4> <p>But wait, there's more! Blogs, that is. Perhaps one reason for the hiatus of newsletters is that I've been publishing a lot more on my personal blogs, fulfilling that creative outlet. If you want to learn a bit more about the man behind the apps, my non-Dejal projects and interests, check out my other blogs:</p> <ul> <li><a href="https://dejus.com/">Dejus</a> is my personal blog, where I post a photo every day, and other short tweet-like comments. If you follow one blog, this the the one; everything gets linked from here.</li> <li><a href="https://yellowcottagehomestead.com/">Yellow Cottage Homestead</a> is a blog that has longer posts about goings on around the homestead of my wife and I, featuring a weekly #Caturday post with pictures of the feral cats we care for, plus our chickens, bees, building projects, and other homestead topics. If you want to see what I build when not building apps, this is the place.</li> </ul> <p><i>- David</i></p> DejalNewsMon, 28 Jan 2019 23:40:14 +0000David Sinclair11512 at http://dejal.org#10YearChallenge: Time Outhttp://dejal.org/blog/2019/01/10yearchallenge-time-out <p><a href="/timeout/"><img src="/timeout/images/icon.png" align="right" /></a>There's a recent meme going around called <a href="https://twitter.com/search?q=%2310YearChallenge">#10YearChallenge</a>, where people post pictures (often of themselves) from 2009 and 2019.</p> <p>While I usually don't bother with memes, I thought it'd be fun to look at <a href="/timeout/">Time Out</a> from 2009 vs 2019.</p> <p>Here's what a Time Out break looked like back in 2009, plus you can see the old app icon during the break (no other themes!):</p> <p><a href="/files/2019/2009vs2019/2009-break.png" title="Click for full size."><img src="/files/2019/2009vs2019/2009-break.png" alt="Time Out 2009 break screenshot" width="100%" border="0" /></a></p> <p>Vs 2019:</p> <p><a href="/files/2019/2009vs2019/2019-break.png" title="Click for full size."><img src="/files/2019/2009vs2019/2019-break.png" alt="Time Out 2019 break screenshot" width="100%" border="0" /></a></p> <p>The Timer preferences in 2009:</p> <p><a href="/files/2019/2009vs2019/2009-normal.png" title="Click for full size."><img src="/files/2019/2009vs2019/2009-normal.png" alt="Time Out 2009 timer screenshot" width="401" height="399" border="0" /></a></p> <p>Vs the Schedule prefs in 2019:</p> <p><a href="/files/2019/2009vs2019/2019-schedule.png" title="Click for full size."><img src="/files/2019/2009vs2019/2019-schedule.png" alt="Time Out 2019 schedule screenshot" width="100%" border="0" /></a></p> <p>The Appearance prefs in 2009:</p> <p><a href="/files/2019/2009vs2019/2009-appearance.png" title="Click for full size."><img src="/files/2019/2009vs2019/2009-appearance.png" alt="Time Out 2009 appearance screenshot" width="379" height="260" border="0" /></a></p> <p>Vs 2019:</p> <p><a href="/files/2019/2009vs2019/2019-appearance.png" title="Click for full size."><img src="/files/2019/2009vs2019/2019-appearance.png" alt="Time Out 2009 appearance screenshot" width="100%" border="0" /></a></p> <p>Things can certainly change quite a bit in a decade!</p> historytimeoutMon, 21 Jan 2019 22:22:22 +0000David Sinclair11511 at http://dejal.orgLooking ahead: 2019http://dejal.org/blog/2019/01/looking-ahead-2019 <p>Last week I published my annual <a href="/blog/2019/01/dejal-year-review-2018">Dejal year in review</a> post for 2018. This week, let's look ahead for what's in store for 2019.</p> <p>I am currently working on a complete rewrite of <a href="/pack/">Pack</a>, my simple packing list app. It was originally written in Objective-C, using some legacy techniques and technologies, but I decided to rewrite it from scratch using Swift and modern approaches. It's usually not a good idea to rewrite working code, but this app is small enough, and the code crusty enough, that I deemed it worthwhile. I use this app every time I travel, so I'm keen to keep it fresh and current, and add some great new features... hopefully including iCloud syncing, though we'll see how that goes.</p> <p>Next up I will start on <a href="/timeout/">Time Out</a> version 2.6, with a number of enhancements planned, and several more queued up for future versions. If you have any requests for 2.6 or later, now would be a great time to <a href="/contact/?prod=timeout&amp;ref=summary&amp;subj=Time+Out+2.6+suggestion">get in touch</a>.</p> <p>Fun fact: this week Time Out is the top featured app in the Mac App Store, with <a href="https://itunes.apple.com/story/id1446914963">a great feature story</a>. (That link will take you to the story in the App Store on a Mac or iOS device.)</p> <p>I also have a couple of new apps in various states of planning or prototyping; one for macOS, another for iOS. Handy tools to scratch my own itch, which can sometime be a great way to work on an app, though not necessarily a key to commercial success. I hope to get to one or both of those later in the year.</p> <p>And let's not forget <a href="/simon/">Simon</a>; I have some big enhancements planned for its next release, too.</p> <p>On the <a href="/consulting/">consulting</a> side, I'm continuing to work on <a href="/consulting/sheetplanner/">SheetPlanner</a>, <a href="/consulting/newsblur/">NewsBlur</a>, and other client projects this year, with some great new releases coming up.</p> <p>I've noticed that <a href="/blog/">the Dejal blog</a> was a bit neglected last year, with relatively few posts, and I haven't done a <a href="/subscribe/">DejalNews newsletter</a> for a while, so I want to get back into those; I've set a goal to do one post per week, and one newsletter per month, so please hold me to that! I also want to do some improvements to the website this year. (I guess I satisfied my blogging needs with my <a href="https://dejus.com/">personal</a> and <a href="https://yellowcottagehomestead.com/">homestead</a> blogs, but I don't want to ignore the Dejal one too.)</p> <p>In terms of conferences, last year I attended <a href="http://altconf.com">AltConf</a> in San Jose and <a href="https://swiftbynorthwest.com">Swift by Northwest</a> in Portland. This year I'm considering entering the lottery for <a href="https://developer.apple.com/wwdc/">WWDC</a>, since it'll likely have a strong Mac focus, but plan to attend AltConf again if I don't get in. I'd also like to attend other conferences, to be determined.</p> <p>It's going to be another busy year!</p> summaryMon, 14 Jan 2019 22:10:28 +0000David Sinclair11509 at http://dejal.orgDejal year in review: 2018http://dejal.org/blog/2019/01/dejal-year-review-2018 <p>Happy New Year! </p> <p>As we start a new year, let's review what happened with the <a href="/apps/">Dejal apps</a> in 2018:</p> <table border="0"> <tr> <td valign="top"><a href="/simon/"><img src="/simon/images/icon.png" width="64" height="64" /></a></td> <td>My pro app to monitor websites and servers for changes and failures, <a href="/simon/"><b>Simon</b></a>, had a couple of updates in 2018, to version 4.3.1, including Mojave dark mode, meta refresh options, pause improvements, refinements to services and filters, and more. It continues to be sold both directly and as one of the foundation apps in the popular <a href="https://go.setapp.com/stp124?refAppID=201">Setapp</a> subscription service.</td> </tr> <tr> <td valign="top"><a href="/timeout/"><img src="/timeout/images/icon.png" width="64" height="64" /></a></td> <td>My popular break reminder tool, <a href="/timeout/"><b>Time Out</b></a>, had two significant updates in 2018, including version 2.4, adding a useful statistics chart, options to disable buttons for a few seconds, scheduling enhancements, and other improvements, and version 2.5, which included Mojave dark mode, day-of-week availability options, and other improvements. It continues to be available both directly and via the Mac App Store, where it was recently picked as an app they love, and regularly ranked #1 in the Health &amp; Fitness category.</td> </tr> <tr> <td valign="top"><a href="/pack/"><img src="/pack/images/icon.png" width="64" height="64" /></a></td> <td><a href="/pack/"><b>Pack</b></a>, a simple iPhone app to make it easy to pack for trips, didn't have any updates in 2018, but I am working on a big update (more below). I use it for every trip, and have a number of improvements planned. Try it for your next trip!</td> </tr> <tr> <td valign="top"><a href="/datestamp/"><img src="/datestamp/images/icon.png" width="64" height="64" /></a></td> <td><a href="/datestamp/"><b>Date Stamp</b></a>, an iMessage app to provide customizable date stamp stickers, was updated to version 1.0.1. It may or may not be updated again, but works really well as-is. The iMessage store didn't have a very good start, but is more visible in recent iOS releases. Tell your friends if you like this.</td> </tr> <tr> <td valign="top"><a href="/chickens/"><img src="/chickens/images/icon.png" width="64" height="64" /></a></td> <td><a href="/chickens/"><b>Chicken GIFs</b></a> is a sticker pack featuring many fun animated GIFs of my chickens, which can be used as reactions in messages. It may or may not get any future updates, but is fun as-is.</td> </tr> </table> <h4>Consulting</h4> <p>Dejal also produces macOS and iOS apps for other companies, under the banner of <a href="/consulting/">Dejal Consulting</a>. (I do wonder if I should split it into a separate company... but it's been fine for nearly 30 years.)</p> <table border="0"> <tr> <td valign="top"><a href="/consulting/sheetplanner/"><img src="/consulting/sheetplanner/images/icon.png" width="64" height="64" /></a></td> <td>The big news in 2018 was the release of <a href="/consulting/sheetplanner/">SheetPlanner</a>, a pro-level outliner, planner, todo, calendar, and more. I'm really proud of how this app turned out, and it has been fairly popular on the Mac App Store already. I'm continuing to work on this app, so stay tuned for some great enhancements throughout the year.</td> </tr> <tr> <td valign="top"><a href="/consulting/newsblur/"><img src="/consulting/newsblur/images/icon.png" width="64" height="64" /></a></td> <td>I have also resumed working on the iOS client for <a href="/consulting/newsblur/">NewsBlur</a>, a popular RSS reader, with many great enhancements in version 8, and more to come.</td> </tr> <tr> <td valign="top"><a href="/consulting/"><img src="/consulting/images/icon.png" width="64" height="64" /></a></td> <td>I'm also currently working on a macOS project for another client, that I can't mention yet. More about that in the future.</td> </tr> </table> <p>I am currently fully booked up for the next several months at least, but am always interested in talking with potential new clients. If you have a macOS or iOS project you'd like help with (or a custom Simon enhancement), <a href="/consulting/">check out my consulting page</a> for more information.</p> <h4>Thank you</h4> <p>Thank you and welcome to my new customers, and many thanks to the long-term customers who are still enjoying my apps. I really appreciate your support.</p> summaryMon, 07 Jan 2019 22:43:14 +0000David Sinclair11508 at http://dejal.orgFeatured blog posts of 2018http://dejal.org/blog/2019/01/featured-blog-posts-2018 <p>My blog posts often just cover new <a href="/blog/release">releases</a>, but sometimes I post general-interest or <a href="/blog/development">developer</a>-interest topics. Some highlights from 2018 included:</p> <ul> <li>The previous list of <a href="https://www.dejal.com/blog/2018/01/featured-blog-posts-2017">featured blog posts</a>.</li> <li>A peek behind the curtain, <a href="https://www.dejal.com/blog/2018/01/about-author">about the author</a>, with links to my personal and homestead blogs and social media accounts. Check out <a href="https://dejus.com/">my daily photos</a>!</li> <li>A report on <a href="https://www.dejal.com/blog/2018/03/time-out-2-two-years">Time Out 2, two years on</a>, with numbers and a chart evaluating the supporter durations and purchases.</li> <li>Following the trend to <a href="https://www.dejal.com/blog/2018/05/more-secure-world">support secure connections to the site</a> via <code>https://</code> TLS/SSL.</li> <li>Announcing that <a href="https://www.dejal.com/blog/2018/05/heading-san-jose-wwdc-week">I'd be in San Jose for WWDC week</a>, and <a href="https://www.dejal.com/blog/2018/06/wwdc-week-san-jose">a followup</a> afterwards.</li> <li>And <a href="https://www.dejal.com/blog/2018/10/attending-swift-northwest-conference-portland">attending another conference, Swift by Northwest</a> in Portland.</li> <li>A useful tip for Time Out: <a href="https://www.dejal.com/blog/2018/11/time-out-tips-lunchtime-night-breaks">lunchtime and night breaks</a>.</li> <li>Finally, <a href="https://www.dejal.com/blog/2018/11/introducing-sheetplanner-mac">introduction of a new app, SheetPlanner</a> (written by me as consulting work).</li> </ul> <p>I hope you enjoyed these posts.</p> summaryMon, 07 Jan 2019 21:29:33 +0000David Sinclair11507 at http://dejal.orgIntroducing SheetPlanner for Machttp://dejal.org/blog/2018/11/introducing-sheetplanner-mac <p><a href="/consulting/sheetplanner/"><img src="/consulting/sheetplanner/images/icon.png" align="right" /></a>I'm pleased to announce the release of a new macOS app: <a href="https://sheetplanner.com">SheetPlanner</a>. This is a powerful new app that combines an outliner, todo, spreadsheet, timeline, calendar, and more, enabling you to easily plan projects, manage tasks, organize information, and many other uses. </p> <p>It includes support for multiple types of columns, inline notes and links, sorting, an option to focus on a subset of rows, flexible smart filter options, styles, dark mode, and many more features, yet is very simple to get started.</p> <p>SheetPlanner was written by me over the past 18 months or so, as a <a href="/consulting/">Dejal consulting project</a> for SheetPlanner Software LLC.</p> <p><a href="/files/2018/sheetplanner/planning.png" title="Click for full size."><img src="/files/2018/sheetplanner/planning.png" alt="SheetPlanner planning document screenshot" width="100%" border="0" /></a></p> <p>Start by picking one of the pre-made templates, or an empty document:</p> <p><a href="/files/2018/sheetplanner/templates.png" title="Click for full size."><img src="/files/2018/sheetplanner/templates.png" alt="Template chooser screenshot" width="100%" border="0" /></a></p> <p>Configure columns, the theme, and other options in the Inspector:</p> <p><a href="/files/2018/sheetplanner/theme.png" title="Click for full size."><img src="/files/2018/sheetplanner/theme.png" alt="SheetPlanner theme screenshot" width="100%" border="0" /></a></p> <p>You can show any combination of the Outline, Timeline, Month, Year, and Inspector views, in horizontal or vertical orientation:</p> <p><a href="/files/2018/sheetplanner/vertical.png" title="Click for full size."><img src="/files/2018/sheetplanner/vertical.png" alt="Vertical orientation screenshot" width="100%" border="0" /></a></p> <p>Show a month view to see dates on a calendar:</p> <p><a href="/files/2018/sheetplanner/calendar.png" title="Click for full size."><img src="/files/2018/sheetplanner/calendar.png" alt="Month view screenshot" width="100%" border="0" /></a></p> <p>And/or a year view for a heat map of tasks:</p> <p><a href="/files/2018/sheetplanner/expenses.png" title="Click for full size."><img src="/files/2018/sheetplanner/expenses.png" alt="Year view screenshot" width="100%" border="0" /></a></p> <p>Include inline notes and/or attachments:</p> <p><a href="/files/2018/sheetplanner/inspector.png" title="Click for full size."><img src="/files/2018/sheetplanner/inspector.png" alt="Inspector screenshot" width="100%" border="0" /></a></p> <p>Customize powerful filters to show only matching rows:</p> <p><a href="/files/2018/sheetplanner/sales.png" title="Click for full size."><img src="/files/2018/sheetplanner/sales.png" alt="Editing a filter screenshot" width="100%" border="0" /></a></p> <p>Or edit the preferences:</p> <p><a href="/files/2018/sheetplanner/preferences.png" title="Click for full size."><img src="/files/2018/sheetplanner/preferences.png" alt="Preferences screenshot" width="75%" border="0" /></a></p> <h2>Try it now!</h2> <p>SheetPlanner is available as a free download, and includes a free three-week full-featured trial. The app can be purchased for just $49.99, or continue with a free read-only mode if you're not ready to buy.</p> <p>Visit the <a href="https://sheetplanner.com/">SheetPlanner website</a> to learn more, or <a href="https://itunes.apple.com/app/sheetplanner/id1438761088?mt=12">download from the Mac App Store</a> to try it for yourself!</p> consultingWed, 28 Nov 2018 18:20:14 +0000David Sinclair11501 at http://dejal.orgTime Out tips: lunchtime & night breakshttp://dejal.org/blog/2018/11/time-out-tips-lunchtime-night-breaks <p><a href="/timeout/"><img src="/timeout/images/icon.png" align="right" /></a>On <a href="https://twitter.com/dejal">Twitter</a>, <a href="https://twitter.com/earthabbey">Abbey Jackson</a> asked:</p> <blockquote class="twitter-tweet" data-lang="en"><p lang="en" dir="ltr"><a href="https://twitter.com/dejal?ref_src=twsrc%5Etfw">@dejal</a> Love TimeOut! Just noticed on the appstore screenshots an example that shows &quot;Lunch&quot;. Could you share the set up for a daily lunch break at lunch time (rather than a rolling time frame)</p> <p>&mdash; Abbey Jackson (@earthabbey) <a href="https://twitter.com/earthabbey/status/1062909036486524929?ref_src=twsrc%5Etfw">November 15, 2018</a></p></blockquote> <script async src="https://platform.twitter.com/widgets.js" charset="utf-8"></script><p>Sure! Here's the <b>Schedule</b> page for my <a href="/timeout/">Time Out</a> preferences, showing my <b>Lunchtime</b> break configuration:</p> <p><a href="/files/2018/timeout/lunchtime.png" title="Click for full size."><img src="/files/2018/timeout/lunchtime.png" alt="Lunchtime schedule screenshot" width="100%" border="0" /></a></p> <p>There are two important steps to do this: firstly, set the frequency to <b>Every 1 day</b>, and secondly, use the <b>Available</b> options to set a fixed start time of noon. In my example, I have this break only occur on weekdays. I also have the natural break option set to <b>Continue Countdown</b>, since I want the break to start immediately, not get pushed back due to idle time.</p> <p>Didn't realize that you can set daily breaks? Yep! Click, arrow, or tab to the units of the duration ("Break for") and frequency ("Every") fields to change between various units: seconds, minutes, hours for the duration, minutes, hours, days, weeks, months, years for the frequency.</p> <p>As a bonus, here's my <b>Night</b> break, that tells me to go to bed:</p> <p><a href="/files/2018/timeout/night.png" title="Click for full size."><img src="/files/2018/timeout/night.png" alt="Night schedule screenshot" width="100%" border="0" /></a></p> <p>This is similar, but a longer duration. And yes, I go to bed rather early, as I usually get up at 05:30 (but don't get to my Mac till after breakfast).</p> <p>Hope this helps!</p> http://dejal.org/blog/2018/11/time-out-tips-lunchtime-night-breaks#commentstimeouttipsto2Thu, 15 Nov 2018 16:32:52 +0000David Sinclair11500 at http://dejal.orgTime Out 2.5 releasedhttp://dejal.org/blog/2018/10/time-out-2.5-released <p><a href="/timeout/"><img src="/timeout/images/icon.png" align="right" /></a>I'm pleased to announce the general release of version 2.5 of <a href="/timeout/">Time Out</a>, my popular break reminder tool.</p> <p>The most obvious change in version 2.5 is dark mode support on Mojave (macOS 10.14):</p> <p><a href="/files/2018/timeout/2.5/schedule.png" title="Click for full size."><img src="/files/2018/timeout/2.5/schedule.png" alt="Mojave dark mode schedule screenshot" width="100%" border="0" /></a></p> <p>Isn't that pretty?</p> <p>In addition to Mojave compatibility, this update also includes a new option on the <b>Break Schedule</b> page of the preferences to choose which days of the week a break is available. Eagle-eyed people may have noticed it in the above screenshot:</p> <p><img src="/files/2018/timeout/2.5/schedule-avail.png" alt="Mojave dark mode schedule screenshot" width="100%" border="0" /></p> <p>Using this option, you could indicate that breaks should only occur on weekdays, as above, or only Fridays, or any other combination. The days of the week can combine with a time range, or apply all day on the indicated days. This new feature is available as a reward for current supporters, or you can try it as often as you like, for an hour at a time.</p> <p>(Don't worry, the first day of the week will respect your System Preferences; if you consider that the week starts on Sunday, for example, that'll be first in the control.)</p> <p>Another new supporter option is on the <b>Advanced</b> preferences page: the ability to disable the app switcher, force quit, and shut down panels during a break:</p> <p><img src="/files/2018/timeout/2.5/advanced.png" alt="Mojave dark mode advanced screenshot" width="100%" border="0" /></p> <p>Most people probably don't need this, but if you need a little extra encouragement to avoid skipping breaks, this might be helpful, when combined with existing options to disable the postpone and skip buttons.</p> <p>There are of course a number of other enhancements and fixes. I recommend everyone update to this version.</p> <p>Here are the full release notes:</p> <h4>Mojave dark mode and compatibility</h4> <ul> <li>All of the app content has been updated to support dark mode on macOS 10.14.</li> <li>Built for Mojave (macOS 10.14), but still compatible back to Yosemite (10.10).</li> </ul> <h4>New option to choose which days of the week a break is available</h4> <ul> <li>Renamed the <b>Break Schedule Available</b> options to "Every Day" and "Between", and added a new "All Day" option.</li> <li>The latter two now include buttons for the days of the week, enabling days to be toggled off or on, to indicate on which days to use the break.</li> <li>The difference between them is that "All Day" doesn't have the time fields, and "Between" does.</li> <li>This new feature could be useful to have breaks that are only used on weekends, or working days, or Wednesdays and Fridays, or any other combination.</li> <li>This new option is available as a reward for current supporters. If you were a supporter in the past, but it has expired, you can extend your supporter status to use this feature, or try for an hour at a time.</li> </ul> <h4>New option to disable the app switcher, force quit, and shut down panels during a break</h4> <ul> <li>Added a checkbox on the <b>Advanced</b> page to disable the panels that appear when switching apps via Cmd-Tab, force quit via Cmd-Option-Escape, and sleep, restart, or shut down via Ctrl-Eject (or Ctrl-Power). Defaults off.</li> <li>This new option is also available as a reward for current supporters.</li> </ul> <h4>Other changes</h4> <ul> <li>Can now manually postpone a break for longer than the frequency interval.</li> <li>Fixed playing a sound for the <b>Display Notification</b> break action.</li> <li>Fixed a scheduler issue where a lower priority break may be skipped if a higher priority break has never been done.</li> <li>Removed the Fabric crash reporter, to avoid sending unnecessary data to a third party.</li> </ul> <h4>Want to try it?</h4> <p>If you are using the Mac App Store edition, you can update via the <b>App Store</b> app.</p> <p>If you are using the direct edition, you can use the <b>Check for Updates</b> feature in the app to update.</p> <p>Otherwise, <a href="/download/?prod=timeout&amp;op=show&amp;ref=blog">download Time Out 2.5 now!</a></p> http://dejal.org/blog/2018/10/time-out-2.5-released#commentsreleasetimeoutto2Wed, 17 Oct 2018 16:11:03 +0000David Sinclair11497 at http://dejal.orgTime Out 2.5b2 releasedhttp://dejal.org/blog/2018/10/time-out-2.5b2-released <p><a href="/timeout/"><img src="/timeout/images/icon.png" align="right" /></a>What's this? Another <a href="/timeout/">Time Out</a> beta already? Yep!</p> <p>This second beta of version 2.5 includes a couple much-requested new features for supporters, improvements for Mojave, and a fix for prior OS versions, among other changes.</p> <p>Read on for details:</p> <h4>New option to choose which days of the week a break is available</h4> <ul> <li>Renamed the <b>Break Schedule Available</b> options to "Every Day" and "Between", and added a new "All Day" option.</li> <li>The latter two now include buttons for the days of the week, enabling days to be toggled off or on, to indicate on which days to use the break.</li> <li>The difference between them is that "All Day" doesn't have the time fields, and "Between" does.</li> <li>This new feature could be useful to have breaks that are only used on weekends, or working days, or Wednesdays and Fridays, or any other combination.</li> <li>This new option is available as a reward for current supporters. If you were a supporter in the past, but it has expired, you can extend your supporter status to use this feature, or try for an hour at a time.</li> </ul> <h4>New option to disable the app switcher, force quit, and shut down panels during a break</h4> <ul> <li>Added a checkbox on the <b>Advanced</b> page to disable the panels that appear when switching apps via Cmd-Tab, force quit via Cmd-Option-Escape, and sleep, restart, or shut down via Ctrl-Eject (or Ctrl-Power). Defaults off.</li> <li>This new option is also available as a reward for current supporters.</li> </ul> <h4>Mojave dark mode and compatibility</h4> <ul> <li>Fixed a crash of the previous beta on macOS versions before Mojave, when displaying the status popover. Sorry about that!</li> <li>Fixed some cosmetic visual issues from the previous beta.</li> </ul> <h4>Other changes</h4> <ul> <li>Can now manually postpone a break for longer than the frequency interval.</li> <li>Fixed playing a sound for the <b>Display Notification</b> break action.</li> </ul> <h4>Want to try it?</h4> <p>If you are using the direct edition, you can change your <b>Updates</b> preferences to include beta releases, then use the <b>Check for Updates</b> feature in the app to update.</p> <p>Otherwise, <a href="/download/?prod=timeout&amp;op=show&amp;rel=beta&amp;ref=blog">download 2.5b2 now!</a></p> http://dejal.org/blog/2018/10/time-out-2.5b2-released#commentsreleasetimeoutto2Wed, 10 Oct 2018 03:37:02 +0000David Sinclair11495 at http://dejal.orgAttending Swift by Northwest conference in Portlandhttp://dejal.org/blog/2018/10/attending-swift-northwest-conference-portland <p>I will be attending the <a href="https://swiftbynorthwest.com/">Swift by Northwest conference</a> in Portland on October 18-20. This is a sold-out conference for macOS and iOS developers, with a focus on the Swift programming language, and related topics.</p> <p>I've written a blog post on my personal blog to introduce myself to attendees. Others may also be interested.</p> <p><a href="http://dejus.com/2018/10/09/0928/">Check it out!</a></p> http://dejal.org/blog/2018/10/attending-swift-northwest-conference-portland#commentsconferencestravelTue, 09 Oct 2018 16:55:57 +0000David Sinclair11494 at http://dejal.orgSimon 4.3.1 releasedhttp://dejal.org/blog/2018/10/simon-4.3.1-released <p><a href="/simon/"><img src="/simon/images/icon.png" align="right" /></a><a href="/simon/">Simon</a> version 4.3.1 is now available. This bug-fix update just has a couple of tweaks:</p> <ul> <li>Fixed a crash when generating a remote report.</li> <li>Further tweaks for dark mode on Mojave.</li> </ul> <p>Remember, Simon's price has been temporarily reduced (for the full license and upgrade license), to celebrate version 4.3 (and 4.3.1). Get it while it lasts!</p> <p>Changes in 4.3 included:</p> <ul> <li>Mojave dark mode and compatibility</li> <li>Added the ability to follow or not follow a meta refresh for each test</li> <li>Several improvements to the pause and auto-pause functions</li> <li>A number of refinements of services and filters</li> <li>Updated the default data</li> <li>Plus many other improvements</li> <h4>Get it now!</h4> <p>If you are using the direct edition, you can use the <b>Check for Updates</b> feature in the app to update.</p> <p>If you are using the <a href="https://go.setapp.com/stp124?refAppID=201&amp;stc=site&amp;utm_medium=available_on_setapp_button&amp;utm_source=201&amp;utm_campaign=https://www.dejal.com/blog/">Setapp edition</a>, the app will automatically update shortly.</p> <p>Otherwise, <a href="/download/?prod=simon&amp;op=show&amp;ref=blog">download Simon 4.3.1 now</a>.</p> </ul>http://dejal.org/blog/2018/10/simon-4.3.1-released#commentsreleasesimonMon, 08 Oct 2018 18:33:00 +0000David Sinclair11493 at http://dejal.org

Motorcycle News, Editorials, Product Reviews and Bike Reviews Inside the Women’s Motocross Association Although you’re forgiven if you’ve never heard of the Women’s Motocross Association (WMA), Southern California MX fans may have seen some seriously fast ladies ripping up the incredibly rough Glen Helen track on Saturday (in between men’s Pro motos at the annual outdoors ‘Prequel’). Founded just a bit more than two years ago, the WMA appears to have already taken the role of the world’s premier sanctioning body for women’s professional motocross racing. I had the opportunity to spend some time with a few WMA racers on the Friday morning prior to the Glen Helen race, courtesy of new series sponsor Kawasaki. Seeing these girls in action around the track at Glen Helen, besides reminding me how slow I am on an MX bike, was a revelation about the current level of Pro competition in the WMA series. Of course, none of the WMA racers are going to be out dicing with James Stewart and Ricky Carmichael, but there are some talented MX riders in this series, and the fact that a few of them are physically very small only makes it that much more entertaining to watch them throw a full-size MX bike around on a rough track. As I said, the WMA has quickly become the premier sanctioning body in the world for women’s MX. Besides the fact that the WMA has an AMA charter (the WMA pro class champion is recognized at the AMA Sport Award Banquet), take as evidence the participation of female racers from as far away as New Zealand (it doesn’t get much farther away than that, does it?) who have come to the US to pursue their dream of success in professional MX racing. Doesn’t sound too much different from the men’s AMA Supercross and Motocross, does it? It’s hard not to be impressed by the worldwide prestige the WMA series has attained in the short time since it was started in 2004. Partly due to the influx of fast females from overseas, the 2006 WMA pro field is the strongest that women’s MX has ever seen. In fact, the opening race at Glen Helen on Saturday was won by one of those New Zealand imports, 17-year old phenom Katherine Prumm. In between contesting the Women’s World MX Championship in Europe (where she is in contention for the title), the Kawasaki rider has made time to come to the US for two rounds of the WMA series, hoping to earn a contract to race the series full-time next year. In 2006, WMA races will run in conjunction with four AMA Outdoor Nationals – Hangtown, Washougal, Broome-Tioga, and Steel City. So check out the WMA web site, and if you find yourself in the pits at one of the aforementioned nationals, take the time to walk away from the long autograph lines at the factory semis and go talk to one of the WMA racers. I’m certain that the WMA series will end up with a new fan.

Aripiprazole versus other atypical antipsychotics for schizophrenia. In most western industrialised countries, second generation (atypical) antipsychotics are recommended as first line drug treatments for people with schizophrenia. In this review we specifically examine how the efficacy and tolerability of one such agent - aripiprazole - differs from that of other comparable second generation antipsychotics. To evaluate the effects of aripiprazole compared with other atypical antipsychotics for people with schizophrenia and schizophrenia-like psychoses. We searched the Cochrane Schizophrenia Group Trials Register (November 2011), inspected references of all identified studies for further trials, and contacted relevant pharmaceutical companies, drug approval agencies and authors of trials for additional information. We included all randomised clinical trials (RCTs) comparing aripiprazole (oral) with oral and parenteral forms of amisulpride, clozapine, olanzapine, quetiapine, risperidone, sertindole, ziprasidone or zotepine for people with schizophrenia or schizophrenia-like psychoses. We extracted data independently. For dichotomous data we calculated risk ratios (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis based on a random-effects model. Where possible, we calculated illustrative comparative risks for primary outcomes. For continuous data, we calculated mean differences (MD), again based on a random-effects model. We assessed risk of bias for each included study. We included 12 trials involving 6389 patients. Aripiprazole was compared to olanzapine, risperidone and ziprasidone. All trials were sponsored by an interested drug manufacturer. The overall number of participants leaving studies early was 30% to 40%, limiting validity (no differences between groups).When compared with olanzapine no differences were apparent for global state (no clinically important change: n = 703, 1 RCT, RR short-term 1.00 95% CI 0.81 to 1.22; n = 317, 1 RCT, RR medium-term 1.08 95% CI 0.95 to 1.22) but mental state tended to favour olanzapine (n = 1360, 3 RCTs, MD total Positive and Negative Syndrome Scale (PANSS) 4.68 95% CI 2.21 to 7.16). There was no significant difference in extrapyramidal symptoms (n = 529, 2 RCTs, RR 0.99 95% CI 0.62 to 1.59) but fewer in the aripiprazole group had increased cholesterol levels (n = 223, 1 RCT, RR 0.32 95% CI 0.19 to 0.54) or weight gain of 7% or more of total body weight (n = 1095, 3 RCTs, RR 0.39 95% CI 0.28 to 0.54).When compared with risperidone, aripiprazole showed no advantage in terms of global state (n = 384, 2 RCTs, RR no important improvement 1.14 95% CI 0.81 to 1.60) or mental state (n = 372, 2 RCTs, MD total PANSS 1.50 95% CI -2.96 to 5.96).One study compared aripiprazole with ziprasidone (n = 247) and both the groups reported similar change in the global state (n = 247, 1 RCT, MD average change in Clinical Global Impression-Severity (CGI-S) score -0.03 95% CI -0.28 to 0.22) and mental state (n = 247, 1 RCT, MD change PANSS -3.00 95% CI -7.29 to 1.29).When compared with any one of several new generation antipsychotic drugs the aripiprazole group showed improvement in global state in energy (n = 523, 1 RCT, RR 0.69 95% CI 0.56 to 0.84), mood (n = 523, 1 RCT, RR 0.77 95% CI 0.65 to 0.92), negative symptoms (n = 523, 1 RCT, RR 0.82 95% CI 0.68 to 0.99), somnolence (n = 523, 1 RCT, RR 0.80 95% CI 0.69 to 0.93) and weight gain (n = 523, 1 RCT, RR 0.84 95% CI 0.76 to 0.94). Significantly more people given aripiprazole reported symptoms of nausea (n = 2881, 3 RCTs, RR 3.13 95% CI 2.12 to 4.61) but weight gain (7% or more of total body weight) was less common in people allocated aripiprazole (n = 330, 1 RCT, RR 0.35 95% CI 0.19 to 0.64). Aripiprazole may have value in aggression but data are limited. This will be the focus of another review. Information on all comparisons are of limited quality, are incomplete and problematic to apply clinically. Aripiprazole is an antipsychotic drug with a variant but not absent adverse effect profile. Long-term data are sparse and there is considerable scope for another update of this review as new data emerges from the many Chinese studies as well as from ongoing larger, independent pragmatic trials.

all the information, none of the junk | biotech • healthcare • life sciences Join Us at “Biotech in the Belt-Tightening Era” April 9 in Seattle Payers didn’t have much power in biotech’s old days. For a long time, biotech companies could get away with believing that if they offered patients important new drugs, devices or diagnostics they could essentially impose high prices on U.S. health insurers. Getting data to win over the FDA, physicians, and shareholders was what counted. Those days are over. The Affordable Care Act is heading toward full implementation, and employers everywhere are screaming for an end to runaway healthcare spending. Payers are looking harder than ever to find ways to cut out waste in the system. Life science investors now increasingly want to know how the new products in the pipeline of today will thrive in the cost-constrained environment of tomorrow. How is your biotech company adapting to the new reality? This is one of the big questions every life sciences company needs to be thinking about. So I’m excited to pull together a stellar lineup of speakers to discuss this trend at the next big Xconomy event—“Biotech in the Belt-Tightening Era.” This event will be held the afternoon of April 9 at Northeastern University’s new Seattle office at 401 Terry Avenue North. Here’s who you can expect to hear from: Kim Popovits, CEO of Genomic Health —Kim Popovits, CEO of Genomic Health (NASDAQ: GHDX). This Redwood City, CA-based company has grown into one of the biggest success stories in molecular diagnostics. This company did it by blazing a trail with insurers, persuading them to pay several thousand dollars for a genetic test that can predict whether an individual woman’s breast cancer is likely to recur after surgery, and whether she is likely to benefit from a round of preventive chemotherapy. It took reams of data, and years of persistence. But the company is now building on what it learned from that experience to branch into predictive diagnostic tests for colorectal cancer and prostate cancer patients. —Risa Stack, general manager of GE’s healthmagination program. Stack recently left her job as a go-to life sciences partner at Kleiner Perkins Caufield & Byers to join GE’s $6 billion healthymagination program. The stated purpose of GE’s initiative is to foster technologies that increase access to healthcare while lowering costs. Like when she was at KPCB, she’s looking for good ideas, and figuring how they might fit into GE’s plans. Mitch Gold —Mitch Gold, the founder and chairman of Seattle-based Alpine Biosciences. Gold is best known as the former CEO of Dendreon. He left the company about a year ago, not too long after his company hit an iceberg known as the Center for Medicare and Medicaid Services, which conducted a lengthy public inquiry in 2011 before it decided that yes, it officially would pay $93,000 a patient for Dendreon’s sipuleucel-T (Provenge). That experience greatly influenced Gold’s thinking about his new immunotherapy venture, which has a stated goal of advancing immunotherapies that work on multiple biologic pathways, to “create a more robust, defined, and effective immune response in a more cost-efficient manner.” This will be Gold’s first public appearance discussing his plans for Alpine Biosciences, and how drug pricing considerations have factored into his strategy. Clay Siegall —Clay Siegall, the CEO of Seattle Genetics (NASDAQ: SGEN). Siegall’s company delivered the goods almost two years ago, introducing the first commercially successful “empowered antibody” and the biggest innovation for a couple of rare lymphomas in decades. The company responded by setting a price of $13,500 a dose initially, and increasing it since. Seattle Genetics has so far had good fortune in its dealings with insurers at this price, but I for one am interested in hearing Siegall talk about what kind of prices he believes the company will be able to command for future drugs from its pipeline. —Scott Ramsey, director of the Institute for Cancer Outcomes Research and Evaluation at the Fred Hutchinson Cancer Research Center. Ramsey, was profiled in these pages last year as a “lonely voice asking tough questions on cancer cost effectiveness.” Some in industry may not like to hear what he has to say, but his voice is an influential one that shouldn’t be ignored. Results from ICORE’s studies will end up being published in peer-reviewed journals, and he intends to put data into a free public resource designed to help patients see where the waste is in cancer treatment, and help patients see where they can get bang for their healthcare buck. —Mark Litton, co-founder and chief business officer, Alder Biopharmaceuticals. This Bothell, WA-based company was built on the idea of making better/faster/cheaper antibody drugs. Alder is now gathering the kind of data from clinical trials that it believes it will need to satisfy not just the FDA, but payers who will want to know they’re getting a good value. —Al Luderer, CEO, Seattle-based Integrated Diagnostics. This company, a spinoff from Lee Hood’s group at the Institute for Systems Biology, is preparing to release its first commercial product this spring. It’s a blood-based test that’s supposed to be able to give doctors a clear early warning sign of lung cancer on the move. InDi will surely need to convince physicians this test is worth incorporating into their practice, but the company also started talking to payers before it even designed its all-important prospective clinical trial. I’ll be sure to ask him what he learned from those conversations, and how it influenced the company’s strategy. Chad Robins —Chad Robins, co-founder and CEO, Seattle-based Adaptive Biotechnologies. Robins is running one of the two aggressive startups in the U.S. using high-speed DNA sequencers to help doctors determine when they have truly wiped out a patient’s blood cancer with standard treatment, or when a previously undetectable malignancy is still hanging around there in the blood. Adaptive started out providing its service to researchers, but it is making the push into the bigger diagnostics market this year, which means it must offer a compelling proposition to payers. As you can see, we’ve got a diverse group of speakers coming at this question on both the therapeutics and diagnostics side. I’ll have more to say about the agenda for this event in coming weeks. But now is the best time to get your tickets, as we have a President’s Day discount running for the next week. See you there at Northeastern University Seattle on April 9.

Gross anatomy of the human cardiac conduction system with comparative morphological and developmental implications for human application. The main aim of this review is to provide macroscopic anatomical information on the human cardiac conduction system (CCS) with comparative morphological and developmental implications for future human application. In the elder human CCS, the sinuatrial node (SAN) is almost consistently positioned on the sulcus terminalis and is variable in size and shape with its extent. However, the atrioventricular CCS that is distal to the atrioventricular node (AVN) varies frequently in shape, size, and position with respect to some conventionally used landmarks. From the comparative anatomical viewpoint, there are marked differences between humans and most mammals and birds not only in the position of atrioventricular CCS in relation to surrounding structures but also in the morphology of the atrioventricular CCS. Therefore, experimental data obtained in most mammals and birds are difficult to apply directly to humans. Recent advances in the understanding of CCS development have been introduced for cardiologists, anatomists, and biomedical researchers. Animals whose morphology is similar to that of mature human CCS should be used for experimental and developmental research if the results are intended for human application. Research on the CCS is an exciting and progressive area, and is likely to yield solutions to a number of problems in future.

Life Improvement Fort Bowie Hike Fort Bowie was established in the mid-1800s to protect Apache Pass. Apache Pass was used by the Butterfield Overland Mail Route and became an important spot to protect due to its year-round water supply, Apache Spring. For over 30 years, it was a sight of major military operations until Geronimo surrendered in 1886 and the Chiricahua Indians were removed to Florida and Alabama. Here we are just starting our hike and we can look out towards the pass , which is where the very first V shows on the left. It was a trek of one and a half miles out and one and a half miles back, at elevations ranging from 4,550 to 5,250 feet. We began about three in the afternoon, it was upper 80s in temperature, and it didn’t take long before we were wondering if we had bit off more than we could chew, or hike, as the case may be! The path was totally dirt and mostly smooth, although at times there was some incline and you had to really watch your step. Here we are almost getting to the area where the Butterfield Overland Mail route went through. There was a way-station with an inn (of sorts) where the travelers could stop for the night, which now are just foundation ruins. The fort ruins are way in the distance, just small glimmers of white. We still have a long ways to hike! Here is one of the many varieties of cactus in the area. We are beginning to gain elevation and are very near the spring, as you can tell from the denser and greener foliage. In Arizona, you know there is water when you see large trees. Everywhere else, trees appear to be more scrub brush than what us Easterners think of as trees. Apache Spring, the year-round water source that was the cause of so much strife in the mid- to late-1800s. Some of the local Sonoran Desert vegetation. And here is our goal, the ruins of Fort Bowie! After the cool shade of the springs area, this last section of the hike up was a difficult one. Thankfully there was a Visitor’s Center at the top with air conditioning, and that is where we headed and rested before venturing back out to look at the ruins. Although truthfully, by the time we got there, we had really ceased to care very much about the ruins. We were more than a little fatigued, and beginning to worry about the late hour and whether we would make it back down to the car before dark! Categories Archives I am not a science fiction reader, mostly because I have a very difficult time visualizing other worlds and other world creatures. Mary Doria Russell did an excellent job presenting new species and new worlds in a believable manner. I tru...

Judicial Nominees In Clinton’s 8 years in office, 61 (perhaps 63) of his judicial nominees were blocked by Senate Republicans. In Bush’s 4 years in office, only 10 of his nominees have been blocked. There’s no puzzle here to figure out. The facts are plain. Despite the fact that Clinton’s nominees were more centrist and Bush’s have been more extremist, The Democrats have blocked far fewer nominees than the Republicans did under Clinton. And Clinton didn’t even recycle his nominees; unlike Bush, he didn’t bring back rejects in order to make the other party look more obstructionist. Still, right-wingers shamelessly whine about how the Democrats are uprooting Democracy by not simply out-and-out confirming whomever Bush wants put into lifetime judicial seats, no matter how radical, no matter how questionable. When it’s shown that the GOP was far more obstructionist over Clinton, they switch arguments and say that it’s how the nominations are being blocked that’s important. The Democrats are using the filibuster, and as such, they aren’t even allowing the Congress to vote on the nominees! How evil! But then, under Clinton, Republicans (who had control over both houses of Congress and therefore did not need the filibuster) blocked most of Clinton’s nominees under what was called the “blue slip” system. In this system, a nominee’s home-state senator may indefinitely delay and thereby kill a nomination simply by withholding a blue slip of paper needed by the Judiciary committee for the nomination to go forward. In other words, Republicans didn’t even allow the Congress to vote on the nominees! Both filibusters and the blue slip achieve the same end by the same method: delay a nomination until the Senate gives up and moves on. So any claim by Republicans that the filibuster is somehow dirty is hypocritical to say the least. After Bush took office, the blue slip rule was still in effect–but then Republicans started noticing that Democrats were using it for the same purposes Republicans had! Well, we can’t have that! So in 2003, when Republicans retook their sliver majority in the Senate, they changed the rules (they love doing that, don’t they?) so Democrats couldn’t do what they had been doing. This forced the Democrats to either resort to filibusters, or to become completely powerless. All of this just adds another layer to the GOP hypocrisy. Another layer still: it turns out that Senate Republicans haveused the filibuster to block nominations themselves. In 1995, Clinton nominated Dr. Henry Foster Jr. for a Public Health post. Senators Orrin Hatch, Trent Lott, John Ashcroft, Bob Dole, John McCain and 38 other Republicans successfully filibustered the Senate to shoot down Clinton’s nominee. When Clinton nominated the same man as Surgeon General in 1998, Ashcroft again used the filibuster, though this time unsuccessfully. The GOP similarly used the filibuster to block ambassadorial and judicial nominees as well. So just about every way you can look at it, the Senate Republicans are being massively hypocritical on this issue. They blocked more nominees, and in as many as if not more ways than Democrats. It’s the hit-and-run driver berating the jaywalker for his scofflaw behavior. But rank-and-file Republicans don’t seem to care about this. It’s outrage time, apparently. However, I don’t see this becoming as big an issue in next year’s elections as such things as, say, the deficit, social security, and right to privacy vs. political grandstanding (re: Terry Schiavo). I think there are enough stains on the GOP record so that the voters won’t as easily forget. And blaming others is how the GOP thrives. Republicans have controlled Congress completely for 10 of the 12 years up to 2006 (the other 2 years mostly in complete control) and will have had the White House for 6. When things are going down the toilet, they won’t have anyone to blame but themselves; no one will be buying the idea that everything is still Clinton’s fault. It cuts both ways. Here is an exerpt from a MSNBC article. There are very few who are not hypocritical on this, even the dear democrats. (Since it seems you were not aware.) “Protesting the maneuvers by Republican senators, Sen. Patrick Leahy, D-Vt., told the Senate on March 9, 2000, “Whoever the next president might be, if it is a Republican president, do we start doing the same things to him the Republicans have done to President Clinton?” We now know the answer to Leahy’s question: yes. Leahy and other Democrats are doing to President Bush what the Republicans did to Clinton. Such delays “should not be done in judicial nominations,” Leahy said in 2000. “We should protect the integrity and the independence of our federal courts.” Sen. Russ Feingold, D-Wis., on March 8, 2000 noted “It is indefensible to hold a nomination hostage for his entire second term. It defies the clear constitutional prerogatives of the duly elected president to choose nominees to the bench and the duty of the Senate to say yes or no.” “I plead with my colleagues to move judges with alacrity, vote them up or down,” said Sen. Charles Schumer, D-N.Y. during the Paez saga. “This delay makes a mockery of the Constitution.”

Q: How to access drives other than C: in Ubuntu on Windows In the Windows Subsystem for Linux, I can access the C: drive as /mnt/c. How can I access other drive letters, such as optical discs and network mounts? They do not show up under /mnt for me. A: How can I access other drive letters, such as optical discs and network mounts? At the moment there are limitations on what drives are mounted: In order for a drive to show up under /mnt/ it must meet the following criteria: The drive must be a fixed drive The drive must be formatted to NTFS. This has been raised as an issue: Drives other than C: are not mounted in /mnt #1079. It is still marked as "Open".

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All coordinates and structure factor files are available from the PDB database (accession numbers: 6KR2 and 6KR3). Introduction {#sec001} ============ The flaviviruses are a large group of positive-strand RNA viruses, including dengue virus (DENV), West Nile virus (WNV), Japanese encephalitis virus (JEV), Zika virus (ZIKV), tick-borne encephalitis virus (TBEV), and Omsk hemorrhagic fever virus (OHFV). The majority of flaviviruses are mosquito-borne or tick-borne, sometimes causing human encephalitis or hemorrhagic diseases. The recent ZIKV outbreaks in South and North America, and more recently in Southeast Asia, have intensified the global threats of flaviviruses, in part due to the capabilities of the virus to cause birth defects through maternal-fetal transmission \[[@ppat.1008484.ref001]\]. The flavivirus RNA genome is 10--11 kilo-bases in length, bearing a type 1 cap and lacking a poly-adenine tail. It encodes a large polyprotein that is further processed by viral and host proteases, yielding three structural proteins C/prM/E, and seven nonstructural proteins NS1/NS2A/NS2B/NS3/NS4A/NS4B/NS5 \[[@ppat.1008484.ref002]\]. Being a unique natural fusion of an N-terminal methyltransferase (MTase) and a C-terminal RNA-dependent RNA polymerase (RdRP), the NS5 is the largest and most conserved protein encoded by flaviviruses. The NS5 MTase catalyzes the guanylyltransfer and both the guanine N7 and nucleoside 2′-O methylation steps in the capping process, and is a single-domain module adopting a common S-adenosyl-L-methionine (SAM)-dependent MTase fold \[[@ppat.1008484.ref003],[@ppat.1008484.ref004]\]. The K-D-K-E catalytic tetrad sits in the center of the MTase catalytic cleft, with the methyl donor SAM binding site and the cap binding site residing on the opposite sides. The RdRP module is the central molecular machine governing the viral genome replication, and has an encircled human right hand architecture with palm, fingers, and thumb domains surrounding the active site \[[@ppat.1008484.ref005],[@ppat.1008484.ref006]\]. The fingers domain can be further divided into index, middle, ring, and pinky subdomains according to nomenclatures first used in describing the poliovirus (PV) RdRP ([Fig 1A](#ppat.1008484.g001){ref-type="fig"}) \[[@ppat.1008484.ref007],[@ppat.1008484.ref008]\]. Among the seven viral RdRP catalytic motifs, A/B/C/D/E are within the most conserved palm, and F/G are part of the ring and pinky fingers, respectively. Motifs A/B/C/F contain amino acids highly conserved in all viral RdRPs, and these conserved residues have highly analogous spatial arrangements around the polymerase active site \[[@ppat.1008484.ref009],[@ppat.1008484.ref010]\]. Being an entity bearing two active sites and multiple essential viral enzymatic activities, NS5 has become a very attractive system in flavivirus research, and understanding the interplay between its MTase and RdRP modules is undoubtedly critical. {#ppat.1008484.g001} Among the evidence related to MTase-RdRP crosstalk, high-resolution structures of full-length NS5 are essential in providing direct and informative readout of the interactions between the two modules. To date, two types of global conformations have been observed in full-length NS5 structures \[[@ppat.1008484.ref011]\]. The conformation revealed by the JEV NS5 structure (named JEV-mode hereinafter) features a medium size interface (\~1540 Å^2^, for all interface area values presented in this study, the total buried solvent accessible surface from both side of the interface was accounted) with a conserved hydrophobic core \[[@ppat.1008484.ref008],[@ppat.1008484.ref012]\], and is also observed in recently reported ZIKV, yellow fever virus (YFV), and DENV serotype 2 (DENV2) full-length NS5 crystal structures \[[@ppat.1008484.ref013]--[@ppat.1008484.ref018]\]. In such a conformation, the MTase approaches the RdRP from its backside and interacts with the RdRP middle finger, ring finger, and an index finger helix bearing part of a nuclear localization signal (NLS-helix) \[[@ppat.1008484.ref019]\] ([Fig 1A](#ppat.1008484.g001){ref-type="fig"}). The second conformation was observed in two different crystal forms of DENV serotype 3 (DENV3) NS5 (named DENV3-mode hereinafter) \[[@ppat.1008484.ref020],[@ppat.1008484.ref021]\] ([Fig 1B](#ppat.1008484.g001){ref-type="fig"}). In this case, the MTase also approaches the RdRP from the backside, but it is related to the JEV conformation by an approximately 110° rotation around an axis passing near its center of mass with less than 6 Å translation. The RdRP index and middle fingers are still involved in the interactions in a slightly larger interface (\~1650--1780 Å^2^), and the nature of the interactions is instead primarily polar. Notably, the NTP binding ring finger (motif F) contacts with the MTase are absent in the DENV3 structures and the ring finger itself and the adjacent motif G residues in the pinky finger are largely disordered ([Fig 1B](#ppat.1008484.g001){ref-type="fig"}). Motif G participates in RNA template binding and has been proposed to participate in the translocation step after every phosphoryl transfer reaction \[[@ppat.1008484.ref022],[@ppat.1008484.ref023]\]. Hence, the JEV-mode conformation likely represents a state more suitable for polymerase synthesis from the structural perspective. With two monomer conformation modes and eight crystal forms identified, more than 10 NS5 dimer interfaces can be recognized in the aforementioned NS5 crystal structures with no obvious conservative features. A couple of studies did focus on some of these dimer interface interactions, even though the primary NS5 solution state is monomer \[[@ppat.1008484.ref016],[@ppat.1008484.ref021]\]. Either by probing the inter-molecular interactions, deleting the MTase domain, or mutating the MTase-RdRP linker, multiple *in vitro* polymerase assay-based studies together suggest that the MTase regulates the RdRP catalytic activities, albeit to overall moderate extents \[[@ppat.1008484.ref012],[@ppat.1008484.ref014],[@ppat.1008484.ref016],[@ppat.1008484.ref018],[@ppat.1008484.ref024],[@ppat.1008484.ref025]\]. However, the RdRP assays established in all these studies, no matter in primer-dependent or *de novo* (including dinucleotide driven) format, did not demonstrate the formation of a processive RdRP elongation complex (EC), at least for the majority of the polymerase molecules, and all these assays require the manganese ion (Mn^2+^) for catalysis, albeit in combination with the magnesium ion (Mg^2+^) in some cases. In other words, the mutation-derived effect on RdRP synthesis observed in these studies may only reflect overall changes in non-processive RdRP synthesis activity, while specific alteration of either RdRP initiation or elongation cannot be clearly judged. Furthermore, none of these studies characterized both the JEV- and DENV3-mode monomer conformations to distinguish their differences in RdRP synthesis, except for our previous JEV NS5 study that only probed the JEV-mode conformation \[[@ppat.1008484.ref012]\]. Therefore, the precise mechanism of the regulation and the explicit contribution of either NS5 conformation remain to be clarified. In this work, we report two crystal forms of DENV2 NS5 that reveal two conformational states bearing clear analogies to those observed in the JEV-mode and DENV3-mode NS5 structures, respectively. Virological data further support the conservation and the functional importance of both conformation modes. NS5 constructs bearing mutations specifically probing two modes of MTase-RdRP intra-molecular interfaces were tested in *in vitro* polymerase assays, and only the JEV-mode interface related mutants inhibited polymerase initiation primarily through a three-fold reduction in the Michaelis constant of the initiating NTP (*K*~*M*,*NTP*~), while polymerase EC properties were not much affected by mutations probing both modes of interactions. Collectively, our work demonstrates the conformational conservation and diversity of the flavivirus NS5 and highlights the specific contribution of the JEV-mode conformation to polymerase initiation. Results {#sec002} ======= The first form of DENV2 NS5 structure contains a partially open MTase-RdRP interface and is clearly related to the JEV-mode NS5 structures {#sec003} ------------------------------------------------------------------------------------------------------------------------------------------ With an aim to further understand the conformational diversity of NS5 and related functional relevance, we crystallized and solved the structures of DENV2 NS5 in two different crystal forms at 3.1 Å (form 1) and 2.9 Å (form 2) resolution ([Table 1](#ppat.1008484.t001){ref-type="table"}). Each structure has two NS5 molecules in the crystallographic asymmetric unit, and has the two molecules arranged in a dimer through pseudo two-fold symmetries with highly consistent global conformation (root mean square (RMS) deviation values for superimposable C-α atoms are 0.74 Å and 0.57 Å, respectively; chain A as the reference). Strikingly, the NS5 conformations between the two crystal forms are quite different ([Fig 1C and 1D](#ppat.1008484.g001){ref-type="fig"}). Using a maximum likelihood superpositioning method \[[@ppat.1008484.ref026]\], the RdRP palm and the majority of the fingers domain were identified as the structurally most conserved regions in the superpositioning including these and the representative full-length flavivirus NS5 structures ([Fig 1](#ppat.1008484.g001){ref-type="fig"}). The DENV2 form 1 conformation is clearly related to the JEV-mode conformation with the JEV interface partially opened through a pure 20° rotation along an axis passing the vicinity of the highly conserved GTR residues that were proposed to pivot the MTase movement relative to RdRP \[[@ppat.1008484.ref008],[@ppat.1008484.ref027]\] ([Fig 1A and 1C](#ppat.1008484.g001){ref-type="fig"}; [Fig 2A](#ppat.1008484.g002){ref-type="fig"}). The partial opening of the interface results in the reduction of the interface area to only about 900 Å^2^ or 59% of the JEV interface. Among the six conserved hydrophobic residues forming the interface core in the JEV structure, only three of them (DENV2 NS5 residues W121, F349, and P583) remained as part of the interface. The tip of the ring finger no longer contacts the MTase in the DENV2 form 1 structure, and its electron density becomes weak but still readily traceable and its folding is largely consistent with the JEV conformation ([Fig 1A and 1C](#ppat.1008484.g001){ref-type="fig"}; [Fig 2A](#ppat.1008484.g002){ref-type="fig"}). However, the motif G region in the pinky finger is largely disordered as observed in the DENV3 structures \[[@ppat.1008484.ref020],[@ppat.1008484.ref021]\]. Based on these observations, we propose that the interactions between the MTase residues 113 and 115 and the phenylalanine (residue 465 in DENV2 NS5) in the tip of the RdRP ring finger are essential for maintaining the canonical folding of the ring and pinky fingers, and the folding of the motif G region in the pinky finger is likely dependent on the dynamics of the adjacent ring finger. It is also worth noting that, in addition to ring and pinky fingers, the index finger is also partially disordered in most of the RdRP-only flavivirus NS5 structures \[[@ppat.1008484.ref005],[@ppat.1008484.ref006]\]. These observations together suggest that MTase interaction likely contributes to the folding of RdRP fingers domain, which in turn could affect polymerase properties including RNA binding and subsequent catalytic events. {ref-type="fig"}. For panels A and B, the rotational movements correlate the both structure pairs are indicated.](ppat.1008484.g002){#ppat.1008484.g002} 10.1371/journal.ppat.1008484.t001 ###### X-ray diffraction data collection and structure refinement statistics. {#ppat.1008484.t001g} Crystal form--PDB 1 -- 6KR2 2 --6KR3 --------------------------------------------------------------- ------------------------- ------------------------- **Data collection**[^**1**^](#t001fn001){ref-type="table-fn"} Space group P2~1~ C222~1~ Cell dimensions *a*, *b*, *c* (Å) 87.2, 146.4, 98.4 178.8, 210.0, 157.9 α, β, γ (°) 90, 105.8, 90 90, 90, 90 Resolution (Å)[^2^](#t001fn002){ref-type="table-fn"} 60.0--3.06 (3.17--3.06) 60.0--2.93 (3.03--2.93) R~merge~ 0.160 (0.50) 0.138 (0.55) R~meas~ 0.191 (0.60) 0.153 (0.61) CC~1/2~ 0.933 (0.781) 0.952 (0.832) I / σI 6.8 (2.1) 11.6 (3.0) Completeness (%) 98.3 (99.1) 99.9 (100.0) Redundancy 3.2 (3.2) 5.6 (5.5) **Refinement** Resolution (Å) 3.06 2.93 No. reflections 44,340 63,847 R~work~ / R~free~ [^3^](#t001fn003){ref-type="table-fn"} (%) 22.4 / 27.5 23.3 / 27.0 No. atoms     Protein 12638 12758     Ligand / Ion / Water 52 / 4 / 33 134 / 19 / 47 B-factors (Å^2^)     Protein 27.9 60.3     Ligand / Ion / Water 54.5 / 76.4 / 22.5 59.9 / 93.2 / 52.5 RMS deviations     Bond lengths (Å) 0.011 0.012     Bond angles (°) 1.42 1.25 Ramachandran stat.[^4^](#t001fn004){ref-type="table-fn"} 79.9 / 17.2 / 1.7 / 1.2 83.1 / 15.1 / 1.0 / 0.8 ^1^ One crystal was used for data collection for each structure. ^2^ Values in parentheses are for highest-resolution shell. ^3^ 5% of data are taken for the R~free~ set. ^4^ Values are in percentage and are for most favored, additionally allowed, generously allowed, and disallowed regions in Ramachandran plots, respectively. The second form of DENV2 NS5 structure resembles the DENV3 NS5 structures {#sec004} ------------------------------------------------------------------------- The DENV2 form 2 conformation is instead analogous to the DENV3-mode conformation but contains previously unidentified features. It is related to the DENV3-mode conformation by a 14° rotation along an axis near the interface and the MTase-RdRP linker region (residues 264--273 in DENV2 NS5) and a translation less than 2 Å ([Fig 1B and 1D](#ppat.1008484.g001){ref-type="fig"}; [Fig 2B](#ppat.1008484.g002){ref-type="fig"}). The primarily polar interactions between the NLS-helix and the MTase are largely retained ([Fig 2B](#ppat.1008484.g002){ref-type="fig"}), and interface area is about 1460 Å^2^ and is only reduced for about 11% as compared to the first reported DENV3-mode interface \[[@ppat.1008484.ref020]\]. The rotational movement widens the cleft between the relatively conserved residue pair E67-R68 in the MTase and the RdRP middle finger, creating a pocket that allows the binding of a putative SAH molecule with high occupancy (0.90 and 0.97) in addition to the SAH molecule usually bound in the SAM binding pocket of the MTase ([Fig 1D](#ppat.1008484.g001){ref-type="fig"}; [Fig 2B and 2C](#ppat.1008484.g002){ref-type="fig"}). Usually, SAH can be co-crystallized with the flavivirus MTase at a 1:1 molar ratio with the SAH co-purified with the MTase after its overexpression in bacterial culture \[[@ppat.1008484.ref004],[@ppat.1008484.ref008],[@ppat.1008484.ref020],[@ppat.1008484.ref028]\]. It is possible that the observed NS5 conformation allowed SAH co-purification with NS5 at a higher molar ratio. Such a secondary SAH binding site has not been observed in numerous MTase-containing flavivirus NS5 structures. This binding pocket appears to be not tight enough, as the SAH molecules bind at moderately different positions in the two NS5 proteins in the crystallographic asymmetric unit, and specific interactions between the non-carbon atoms of the SAH and the side chains of the NS5 are largely lacking ([Fig 2B and 2C](#ppat.1008484.g002){ref-type="fig"}). Nevertheless, based on the fact that this secondary SAH binding pocket is created at the MTase-RdRP interface and is reasonably conservative ([Fig 2C](#ppat.1008484.g002){ref-type="fig"}), it might have potential as a target to develop small molecule inhibitors against flaviviruses. The correlation among all four NS5 conformational states and the structural elements that may mediate NS5 conformational dynamics {#sec005} --------------------------------------------------------------------------------------------------------------------------------- The two DENV2 NS5 structures nicely fill the gap of major conformational differences between the JEV-mode and DENV3-mode structures, suggesting a plausible order from JEV-mode to DENV2 form 1, then to form 2, and finally to DENV3-mode, primarily through rotational movements in more or less consistent directions ([Fig 1](#ppat.1008484.g001){ref-type="fig"}; [Fig 3A and 3B](#ppat.1008484.g003){ref-type="fig"}; [S1 Movie](#ppat.1008484.s001){ref-type="supplementary-material"}). Three structural elements may play critical roles in the transitioning among these states. The first is the universally conserved GTR sequence at the C-terminal end of the MTase ([Fig 3C](#ppat.1008484.g003){ref-type="fig"}). This tripeptide sequence was proposed as a pivoting element in the work of the full-length JEV NS5 structure and was proved to be functionally important in both JEV and DENV2 replications \[[@ppat.1008484.ref008],[@ppat.1008484.ref027]\]. The second element is the 10-residue MTase-RdRP linker that overall exhibits low sequence conservation in flaviviruses ([Fig 3C](#ppat.1008484.g003){ref-type="fig"}). A comparison of all full-length NS5 structures demonstrated that the N-terminal half of the linker undergoes a swinging motion with a partial refolding to become helical when transitioning from the JEV-mode conformations to the DENV3-mode ones, while the C-terminal half remains unaffected ([Fig 3A and 3B](#ppat.1008484.g003){ref-type="fig"}). Not surprisingly, mutations in the linker region or linker substitutions using sequences of other flavivirus NS5 have been found to affect NS5 conformation distribution, NS5 enzymatic activities, and virus proliferation \[[@ppat.1008484.ref018],[@ppat.1008484.ref024],[@ppat.1008484.ref029]\], possibly by altering the flexibility of the linker. The third element is the NLS-helix (residues 348--358 in DENV2 NS5) in the RdRP index finger. On one hand, this helix is critical to both the JEV-mode and DENV3-mode of interface interactions by contributing the F349 and R353 residues ([Fig 2A and 2B](#ppat.1008484.g002){ref-type="fig"}; [Fig 3B](#ppat.1008484.g003){ref-type="fig"}). On the other hand, it is at the central region of a long stretch of conserved sequences (residues 341--366 in DENV2 NS5) that may also be related to NS5 nuclear localization, nuclear export, and interaction with another important viral protein NS3 \[[@ppat.1008484.ref019],[@ppat.1008484.ref030],[@ppat.1008484.ref031]\], emphasizing its possible importance when not participating in the intra-molecular MTase-RdRP interactions. We propose that the largely rotational movement of the MTase from the JEV-mode conformations to the DENV3-mode conformations may utilize this highly conserved helix as a guiding track ([S1 Movie](#ppat.1008484.s001){ref-type="supplementary-material"}). At the starting and end points of the movement, the conserved hydrophobic residue patch P113/X115/W121 (the majority of X are L and M) and the conserved polar residue pair E67-R68 provide the anchoring points on the MTase side ([Fig 3B--3D](#ppat.1008484.g003){ref-type="fig"}). On the other hand, both of these stable conformations make the NLS-helix inaccessible to other factors, and the helix may only become solvent exposed at certain stages of virus life cycle. {ref-type="fig"}. The α-carbon atoms of two important patches of residues are shown as blue spheres. C) The sequence logo plot showing the conservation of the two RdRP interacting regions, the GTR-linker region (top panel), and the NLS-helix that is important for both JEV- and DENV3-mode conformational states, the middle and ring finger regions only critical in JEV-mode states (bottom panel). The triangles indicated key residues involved in the intra-molecular interactions. D) A schematic free energy diagram for all four conformational states of flavivirus NS5. The relative free energy was crudely estimated by the solvent accessible surface area occluded by the NS5 intra-molecular interface interactions. E) A list of DENV2 NS5 mutants that were designed based on both the JEV- and DENV3-mode conformations, with abbreviations and full descriptions, including mutation site and mutation type.](ppat.1008484.g003){#ppat.1008484.g003} Virological data support the functional relevance of both the JEV-mode and the DENV3-mode conformations {#sec006} ------------------------------------------------------------------------------------------------------- Previously, we tested the functional significance of the JEV-mode conformation using both JEV and DENV2 systems \[[@ppat.1008484.ref027]\]. When arginine/aspartic acid/serine (R/D/S) mutations were introduced at the six hallmark hydrophobic residue sites, virus proliferation was significantly inhibited (the corresponding mutation sites in DENV NS5 were listed in [Fig 3E](#ppat.1008484.g003){ref-type="fig"}). In order to understand functional relevance of the DENV3-mode conformation, we designed five mutations at the NS5 residues 67 and 68 for each virus system (E67A, E67D, K68A, K68R and E67A/K68A in JEV; E67A, E67D, R68A, R68K and E67A/R68A in DENV2, and correspond to the same mutations with an "M\_" prefix in [Fig 3E](#ppat.1008484.g003){ref-type="fig"}) and compared the mutant constructs with the wild type (WT) viruses ([Fig 4](#ppat.1008484.g004){ref-type="fig"}). The residues 67--68 were chosen as the mutation sites because these two residues are highly conserved among the MTase residues that participate in the DENV3-mode MTase-RdRP interface but are not involved in the JEV-mode interface interactions. We first introduced each mutation into a JEV infectious clone \[[@ppat.1008484.ref032]\]. After viral RNA was transfected into baby hamster kidney cells BHK-21, viral protein expression and virus production were monitored. The expression level of the viral envelope (E) protein in transfected cells was detected by an immunofluorescence assay (IFA) ([Fig 4A](#ppat.1008484.g004){ref-type="fig"}). Both the E67A and K68R mutant viruses produced similar IFA positive cells in comparison with the WT virus (100% IFA positive cells observed at 72 h post transfection (hpt)); The K68A and E67A/K68A mutants showed only around 10% positive cells; the E67D mutant produced very few IFA-positive cells. Virus productions were then quantified by a plaque assay at three time points (48, 72, and 96 h) post transfection. Consistent with the IFA data, the E67A and K68R mutant RNAs yielded similar amounts of viruses as the WT at each time point, the K68A and E67A/K68A mutants moderately impaired virus production, and viruses derived from the E67D mutant RNA-transfected cells were only detected at 72 and 96 hpt ([Fig 4A](#ppat.1008484.g004){ref-type="fig"}). Overall, the results indicated residues 67 and 68 are important for JEV proliferation. We also performed similar analyses using a DENV2 infectious clone ([Fig 4B](#ppat.1008484.g004){ref-type="fig"}) \[[@ppat.1008484.ref033]\]. No IFA-positive cells were observed in the R68A, R68K and E67A/R68A transfected cells; the E67A and E67D produced around 70%-80% IFA-positive cells relative to the WT. Data from the plaque assay indicated that virus production was blocked by the R68A, R68K, and E67A/R68A mutations, while the E67A and E67D mutations had slightly less effect on virus production at each time point post transfection comparing with the WT ([Fig 4B](#ppat.1008484.g004){ref-type="fig"}). Taken together, these virological data suggest that the DENV3-mode conformation is also functionally important and is likely conserved in flaviviruses, consistent with our structural observation of both conformations in DENV2 NS5. {#ppat.1008484.g004} The establishment of effective *in vitro* RdRP assays to characterize both initiation and elongation in DENV2 NS5 {#sec007} ----------------------------------------------------------------------------------------------------------------- We previously tested the JEV-mode interface mutants in JEV NS5 using *in vitro* assays derived from an HCV study \[[@ppat.1008484.ref012],[@ppat.1008484.ref034]\]. While the HCV assays have Mg^2+^ as the only divalent metal ion and allow the formation of processive ECs \[[@ppat.1008484.ref034]\], the JEV assays require Mn^2+^ for RdRP activity and the stability and reactivity of the assembled complexes are far from optimal \[[@ppat.1008484.ref008]\]. When the HCV assay format was used in the DENV2 NS5, the RdRP enzyme behavior is consistent with the HCV enzyme, and therefore the DENV2 assays established in this study can serve as effective systems to assess RdRP catalytic properties and to analyze whether the interface interactions observed in both the JEV-mode and the DENV3-mode conformations modulate RdRP catalysis. Note that dinucleotide-driven assays, such as those in the HCV study \[[@ppat.1008484.ref034]\], have been used in multiple polymerase systems to reasonably mimic the *de novo* initiation process \[[@ppat.1008484.ref035],[@ppat.1008484.ref036]\]. When ATP and UTP were provided as the only NTP substrates, a GG dinucleotide primer (P2) was extended to yield a 9-mer product (P9) as directed by a 30-mer template (T30) after a 45-min incubation ([Fig 5A](#ppat.1008484.g005){ref-type="fig"}). We assessed the reactivity of the P9-containing complex by a single-nucleotide extension assay. Because the complex was in the precipitate form under the low-salt reaction condition (20 mM NaCl) but was soluble under high-salt condition (e.g. 190 mM NaCl), we removed the excess ATP and UTP by centrifugation, pellet wash, and pellet resuspension, and then added CTP to allow the single-nucleotide addition to make a 10-mer product (P10). It turned out that the conversion from P9 to P10 was very rapid and was completed immediately after manual mixing on ice without further incubation ("0 min"; [Fig 5A](#ppat.1008484.g005){ref-type="fig"}, lane 3). Although not accurately determined, the expected catalytic rate constant of the P9-containing polymerase complex is at least magnitudes larger than that determined in the JEV study (0.14 min^-1^ for WT NS5) \[[@ppat.1008484.ref012]\]. This observation strongly suggests that the P9-containing complex of DENV2 NS5 has completed the transition from initiation to elongation and is a *bona fide* EC. Therefore, the production of this P9-containing EC (EC9) can be used to assess the overall process of initiation followed by the transition to elongation. ![Mutations perturbing the JEV-mode interface interactions impaired DENV2 RdRP initiation.\ A) Left: A diagram of construct T30/P2 used in all polymerase assays and related NTP-driven reactions to generate products with different lengths. Middle: reaction flow chart of the P2-driven EC formation (IC2 to EC9) and the subsequent single-nucleotide extension (EC9 to EC10). Right: the EC9 was in a form of precipitate and was able to extend to EC10 upon CTP addition under high-salt condition. B-C) The EC9 formation comparison with the WT NS5 for the JEV-mode (B) and DENV3-mode (C) mutants. The relative intensity of the 9-mer was used to estimate the polymerase activities (the WT value for each time point series was set to 100). D) Comparison of the WT and two representative mutants (R3 for the JEV-mode; M_67A/68A for the DENV3-mode) in the multiple-turnover P3 formation and in the single-turnover P9 formation assays. The pppGGA was synthesized when GTP and ATP were provided as the only NTP substrates using the P2-free T30 template and was used as a migration marker. Note that pppGGA migrated at similar position as pGG, but faster than pGGA since it contains two extra phosphate groups at the 5′ end. A chemically synthesized 9-mer loaded with an equal molar amount to T30 was used as a quantitation standard (STD, lanes 62 and 81). The average intensity of the STD bands was set to 1. Based on previously reported evaluation, the intensity-molar amount starts to deviate from a linear relationship when the relative intensity approaches 4--5 under similar experimental settings \[[@ppat.1008484.ref012]\]. Therefore, the intensity reported in lanes 64--65 and 76--77 are underestimated. The P9 product migrated faster than the chemically synthesized STD RNA due to its 5′-phosphate inherited from the pGG dinucleotide.](ppat.1008484.g005){#ppat.1008484.g005} Perturbing the JEV-mode but not the DENV3-mode intra-molecular interactions impairs the DENV2 NS5 RdRP initiation but not elongation {#sec008} ------------------------------------------------------------------------------------------------------------------------------------ To test the impact on polymerase catalysis brought by the intra-molecular MTase-RdRP interactions, we made two sets of DENV2 NS5 mutants. The first set contains equivalent mutations utilized in the JEV study to perturb the hydrophobic JEV-mode interface \[[@ppat.1008484.ref012]\], and the second set that contains mutations at residues 67--68 was used to probe the polar DENV3-mode interface ([Fig 3E](#ppat.1008484.g003){ref-type="fig"}). We compared the EC9 formation of these mutants with the WT NS5 at three incubation time points. For the WT NS5, only limited 9-mer accumulation was observed beyond the first time point (15 min), and small amount of misincorporation-related 10-mer products became obvious at the last time point (90 min) ([Fig 5B](#ppat.1008484.g005){ref-type="fig"}, lanes 11, 18, and 25; [Fig 5C](#ppat.1008484.g005){ref-type="fig"}, lanes 41, 47, and 53). These observations again suggest that: although the EC9 formation is a slow process due to slow pre-initiation and initiation steps, it likely produces a stable EC that is not turning over to carry out multiple rounds of P9 synthesis. Among the six JEV-mode NS5 mutants, three of them exhibited obvious slower accumulation of P9 products, in particular at shorter incubation time points ([Fig 5B](#ppat.1008484.g005){ref-type="fig"}, compare lanes 15--17, 22--24, 29--31 to the WT lanes). In contrast, all five DENV3-mode NS5 mutants showed very similar trend of P9 accumulation as the WT enzyme ([Fig 5C](#ppat.1008484.g005){ref-type="fig"}). These data together suggest that perturbing the JEV-mode but not the DENV3-mode interactions inhibits the overall process to produce a processive EC. To further dissect the mechanism of inhibition brought by the JEV-mode interface mutations, we compared representative NS5 mutants (R3 for JEV-mode interface and M_67A/68A for DENV3-mode interface) with the WT enzyme in a P2-driven initiation assay to explicitly assess the continuous production of the 3-mer (P3) when ATP was provided as the only NTP substrate, while the P9 synthesis was monitored in parallel for comparison ([Fig 5D](#ppat.1008484.g005){ref-type="fig"}). Here we use a chemically synthesized 9-mer as a quantitation standard (STD; [Fig 5D](#ppat.1008484.g005){ref-type="fig"}, lanes 62 and 81) loaded with an equal molar amount of the T30 template. For the WT, the R3 mutant, and the M_67A/68A mutant, the P9 amount was relatively consistent at the 60 and 90 min time points ([Fig 5D](#ppat.1008484.g005){ref-type="fig"}, compare lanes 67, 73, 79 to lanes 68, 74, 80), suggesting that all three constructs had formed stable ECs and did not turn over to accumulate the P9 products over time. In contrast, the P3 accumulation proceeded continuously during the same period for all three constructs, indicating that the P3-containing complex is an initiation complex (IC) that carried out multiple rounds of synthesis in an abortive fashion ([Fig 5D](#ppat.1008484.g005){ref-type="fig"}, lanes 63--65, 69--71, and 75--77). The R3 mutant had a slower P3 accumulation than the WT and the M_67A/68A mutant had, clearly suggesting that the perturbation of the JEV-mode interface impaired the RdRP initiation process. We next performed two tests regarding the EC9 properties using the WT, R3, and M_67A/68A constructs ([Fig 6](#ppat.1008484.g006){ref-type="fig"}). To test the EC9 reactivity, we compared the P9-to-P10 conversion under high and low CTP substrate concentrations for these constructs ([Fig 6B](#ppat.1008484.g006){ref-type="fig"}). At 300 μM CTP concentration, all three constructs converted the majority of P9 to P10 at "0-min" time point (89--94% converted suggested by intensity-based quantitation) ([Fig 6B](#ppat.1008484.g006){ref-type="fig"}, lanes 12, 14, and 16). When CTP was supplied at 5 μM, the conversion became slower, but all three constructs showed consistent progress of conversion (67--70% and 84--88% converted at "0-min" and at 1 min, respectively) ([Fig 6B](#ppat.1008484.g006){ref-type="fig"}). To test the stability of the EC9, we used NaCl as the challenging agent in a high-salt challenge stability assay similar to those described in previous work characterizing the PV, HCV and the classical swine fever virus (CSFV) RdRPs \[[@ppat.1008484.ref034],[@ppat.1008484.ref037],[@ppat.1008484.ref038]\]. We found that EC9 formed by all three constructs were quite stable and exhibited comparable inactivation rate constants (0.02--0.04 h^-1^, corresponding to half life values of 18--35 h) upon a NaCl challenge at 500 mM concentration ([Fig 6C and 6D](#ppat.1008484.g006){ref-type="fig"}). These data together suggest that the EC9 is highly stable and reactive, and these properties were not much affected by both types of mutations. {#ppat.1008484.g006} The representative R3 mutant perturbing the JEV-mode interface leads to about 4-fold reduction in initiation efficiency and primarily by affecting the initiating NTP binding {#sec009} ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------- To specifically investigate the enzymatic properties of the WT and the two representative mutants during the conversion of the P2 to P3, we measured the relative catalytic rates under different ATP concentrations for each construct ([Fig 7A--7C](#ppat.1008484.g007){ref-type="fig"}), and these data were used to determine the Michaelis constants (*K*~*M*~) of these constructs ([Fig 7D--7F](#ppat.1008484.g007){ref-type="fig"}). By optimizing the reaction time points selection for each NTP concentration and each construct, the 3-mer band intensities were controlled to be within the linear range of the Stains-All based staining method, to facilitate quantitation accuracy (refer to our previous analysis in the JEV study \[[@ppat.1008484.ref012]\]) ([Fig 7A--7C](#ppat.1008484.g007){ref-type="fig"}). It turned out that the *K*~*M*~ value of the R3 mutant is about three times the values of the WT and M_67A/68A mutant (1046 μM vs. 344 μM and 312 μM), indicating that the initiating NTP binding is clearly impaired by the JEV-mode interface mutations ([Fig 7D--7F](#ppat.1008484.g007){ref-type="fig"}). Higher NTP concentrations were not tested in these trials due to a substrate inhibition effect observed in preparatory experiments. We then use the relative catalytic rates determined at 1000 μM for the WT and M_67A/68A mutant, and 1500 μM for the R3 mutant, respectively, to correlate the curve fittings of all three constructs ([Fig 7G](#ppat.1008484.g007){ref-type="fig"}, see [Materials and Methods](#sec014){ref-type="sec"}). The estimated relative specificity constant (rel. *k*~*cat*~*/K*~*M*~) were approximately 0.27 and 1.45 for R3 and M_67A/68A mutants, respectively ([Fig 7G](#ppat.1008484.g007){ref-type="fig"}, using the WT as reference). Taken together, these data suggest that perturbation of the JEV-mode interface clearly impaired DENV2 RdRP initiation mainly by affecting the initiation NTP binding, while perturbation of the DENV3-mode interface only had a moderate effect. {ref-type="sec"}). The STD samples were used as a reference and NTP concentration range was adjusted for each NS5 construct, both for ensuring that all P3 band intensities were within the linear range of the staining method used. D-F) The relative reaction rates (left) and *K*~*M*~ fitting (right) analyses for the WT (D), R3 (E), and M_67A/68A (F) constructs. Left: The adjusted intensity of the 3-mer products as a function of time for WT, R3, and M_67A/68A with five ATP concentrations. (G) An analysis of the relative specificity constants of the R3 and M_67A/68A mutants to the WT. Single-gel based reaction rate correlation analysis (left) for the R3-WT (purple points) and M_67A/68A-WT pairs to correlate three Michaelis-Menten curves for determination of the relative specificity constants (right).](ppat.1008484.g007){#ppat.1008484.g007} In the multiple-turnover P3 accumulation process, either the catalysis of the P2-to-P3 conversion and the dissociation of the P3 product could be rate limiting. Hence, the observed *k*~*cat*~ related differences in the P3 conversion initiation assay could be affected by the variation in the P3 dissociation rates among different constructs. To further validate our judgment, we monitored the P2-driven P9 formation for the WT, R3, and M_67A/68A constructs ([Fig 8](#ppat.1008484.g008){ref-type="fig"}). In this case, the observed difference in the P9 formation is highly dependent on the catalytic rate (presumably the P2-to-P3 conversion step), while not much related by dissociation rates at subsequent steps due to the single-turnover feature of the reaction and the absence of the intermediate products (3-8-mer) in the denaturing gel analyses. When the initiating ATP was supplied at the *K*~*M*~-level concentration of the WT and M_67A/68A mutant (300 μM), the overall conversion rate (P2-to-P9) of the R3 mutant was much slower than those of the other two constructs (0.05 min^-1^ vs. 0.23--0.24 min^-1^). When the ATP concentration was lifted to the *K*~*M*~-level of the R3 mutant (1000 μM), the conversion rate of the R3 was still lower than those of the other two constructs, while the difference between the R3 and WT/ M_67A/68A constructs became smaller (0.11 min^-1^ vs. 0.20--0.27 min^-1^). These data validate the judgment derived from the P3 formation assay and strongly suggest that the JEV-mode interface interactions are critical in NS5 initiation, and in particular, in the initiation NTP binding. {#ppat.1008484.g008} Discussion {#sec010} ========== On the conformation diversity and conformation-function relationship of the flavivirus NS5 {#sec011} ------------------------------------------------------------------------------------------ By solving the DENV2 NS5 crystal structures in two different global conformations and characterizing the functional relevance of both conformations, the work presented here helps the understandings of the conformational diversity and conservation in flavivirus NS5, highlighting the important role of the MTase module, a natural fusion partner of the NS5 RdRP module, in the initiation phase of RNA synthesis. Interestingly, the MTase only facilitates RdRP initiation through the JEV-mode conformation, and this specific mechanism is in agreement with the structural observation that the MTase stabilizes the folding of the NTP-binding ring finger only through this conformation \[[@ppat.1008484.ref008],[@ppat.1008484.ref039]\] ([Fig 1A](#ppat.1008484.g001){ref-type="fig"}). Both conformation modes seem not to apparently contribute to the RdRP catalysis in the elongation phase, supporting our previous proposal that the RdRP may only need the assistance from the MTase in the unstable initiation phase \[[@ppat.1008484.ref012],[@ppat.1008484.ref040]\]. Based on the virological data, both conformation modes are important for virus proliferation. Therefore, the DENV3-mode conformation could contribute to other NS5-involved processes. However, whether and how it is related to the catalysis of the MTase, or to the interactions with other viral proteins or host factors remain to be clarified. Note that, the index finger NLS-helix (residues 348--359 in DENV2 NS5), possibly participating in NS3-binding or NS5 shuttling between cytoplasm and nucleus, was occluded by the MTase in both JEV- and DENV3-mode conformations \[[@ppat.1008484.ref019],[@ppat.1008484.ref030],[@ppat.1008484.ref041]\]. Interestingly, residues in the same helix were found to mediate RANTES ([r]{.ul}egulated on [a]{.ul}ctivation, [n]{.ul}ormal [T]{.ul} cell [e]{.ul}xpressed and [s]{.ul}ecreted, also known as CCL5) expression in TBEV \[[@ppat.1008484.ref031]\]. Therefore, additional functional relevant conformation modes likely exist, as also suggested by the small-angle X-ray scattering and reverse genetics data \[[@ppat.1008484.ref005],[@ppat.1008484.ref042],[@ppat.1008484.ref043]\]. Based on the conformational variation of the N-terminal half of the linker region observed in crystallography, the MTase is able to reach the fingers side without much difficulty. However, a conformational change of the entire linker, or additional rearrangements of the N-terminal extension (NE, residues 274--301) of the RdRP is probably necessary to allow the MTase to reach the front of RdRP as we previously suggested \[[@ppat.1008484.ref008]\]. Naturally fused regions as common regulators of viral RdRPs {#sec012} ----------------------------------------------------------- Although from the same virus family and utilizing the same *de novo* initiation mechanism, the overall structure is quite different for *Flaviviridae* RdRP molecules from representative virus genera. The 66-kD HCV (the type species of the hepacivirus genus) NS5B comprises the RdRP catalytic core and a 21-residue C-terminal membrane anchor. The 82-kD pestivirus NS5B has a 24-residue C-terminal membrane anchor and a \~90-residue unique N-terminal domain (NTD) specifically modulate the RdRP fidelity through intra-molecular interactions with the RdRP palm \[[@ppat.1008484.ref037]\]. The flavivirus NS5 does not have the C-terminal membrane anchor, but is naturally fused to the capping related MTase at its N-terminus. Compared to the NTD-RdRP regulation in pesitivirus NS5B, the crosstalk between the flavivirus MTase and RdRP seems to be more versatile with respect to conformational diversity and functional relevance, as discussed above. While the *Flaviviridae* RdRPs exhibit diversities in global structure and regulatory mechanisms involving the naturally fused regions of the RdRP module, this phenomenon appears to be commonly occurring in viral RdRPs \[[@ppat.1008484.ref044]\]. The *Rhabdoviridae* L proteins contain four additional functional regions including an MTase and a polyribonucleotidyl transferase (PRNTase) \[[@ppat.1008484.ref045]\]; the *Bunyavirales* L proteins include two additional regions with analogy to the PA and PB2 subunits of the *Paramyxorviridae* RdRP complex that participate in the cap-snatching process to generate a capped primer for RdRP synthesis \[[@ppat.1008484.ref046],[@ppat.1008484.ref047]\]; the *Alphatetraviridae* RdRPs contain an MTase and a helicase at the N-terminal region \[[@ppat.1008484.ref048]\]; the *Nidovirales* RdRPs, including the *Coronaviridae* nsp12 and *Arteriviridae* nsp9, contain a \~200-400-residue N-terminal region with the nucleotidyltransferase (NiRAN) function \[[@ppat.1008484.ref049],[@ppat.1008484.ref050]\]. Likewise, viral RdRPs may evolve from common ancestors comprising only the catalytic module with relative independency in carrying out RNA synthesis, similar to the PV 3D^pol^ and HCV NS5B. Co-evolution with versatile host species and the low coding capacity-driven protein function combination may contribute to the structural and functional diversity of current viral RdRPs with respect to regions beyond the RdRP catalytic module. We propose that the functional roles currently offered by these regions, such as the fidelity modulation in pestivirus NS5B and initiation enhancement flavivirus NS5, are likely a result of their co-evolution with the RdRP module through the establishment of specific interactions. Moreover, the RdRP fidelity and initiation enhancement offered by the pesitvirus NS5B NTD and flavivirus NS5 MTase, respectively, is likely not an improvement of a specific function relative to the corresponding RdRP ancestors, but a balance between gaining an extra module and maintaining the levels of key enzymatic properties for the RdRPs. Implications for conformation-based protein function {#sec013} ---------------------------------------------------- Large-scale protein conformational changes are amazing events in biological systems, albeit associated with very different characteristics. Driven by multiple cycles of phosphoryl transfer reactions and accompanied by dramatic changes in protein-nucleic acid interactions, the N-terminal one third of bacteriophage T7 RNA polymerase undergoes a dramatic rearrangement as it makes an irreversible transition from the promoter-bound initiation state to the promoter-free elongation state in the transcription process \[[@ppat.1008484.ref051]--[@ppat.1008484.ref053]\]. By contrast, the observed conformational diversity in flavivirus NS5 has not yet involved continuous events of nucleotide addition, and the energy barrier between different observed states may be low enough to allow a distribution of several states in solution. As both captured by crystallography in multiple virus species, the JEV-mode and DENV3-mode conformations probably represent relatively stable states of apo NS5, thus forming the foundation for further understanding of the NS5 function when it is participating in enzymatic reactions or interactions with essential viral or host factors. The flavivirus NS5 is also a great example that the different interaction modes can be established between regions of a single protein, and are related to different functions of the protein and different processes in the life cycle of the corresponding species. In a broader context, the conformation-based function diversity extends the function capacity beyond the traditional consideration of protein folding, and is therefore an important factor when understanding protein function. Materials and methods {#sec014} ===================== Cloning and protein production {#sec015} ------------------------------ The full-length WT DENV2 NS5 gene within the DNA clone of TSV01 strain (GenBank: AY037116) was cloned into a pET26b vector to yield the pET26b-DENV2-NS5 plasmid. Eleven full-length NS5 constructs with point mutations ([Fig 3E](#ppat.1008484.g003){ref-type="fig"}) were made by using the QuickChange site-directed mutagenesis method and the WT plasmid as the template. NS5 expressing plasmids were transformed into *Escherichia coli* strain BL21-CodonPlus(DE3)-RIL for expression of NS5 constructs with a hexa-histidine tag at the C-terminus. Cells were grown at 30°C overnight in the NZCYM medium containing 25 μg/mL kanamycin (KAN25) and 20 μg/mL chloramphenicol (CHL20) until the optical density at 600 nm (OD~600~) was 1.0. The overnight culture was used to inoculate 1 L of NZCYM medium with KAN25 and CHL20 to reach an initial OD~600~ around 0.025. The cells were grown at 37°C at 220 rpm to an OD~600~ of 1.0 and then cooled to room temperature (r.t.). Isopropyl-β-D-thiogalactopyranoside (IPTG) was added to a final concentration of 0.5 mM, and the cells were grown for an additional 6 h at r. t. or 20 h at 16°C before harvesting. Purification of DENV NS5 and its variants {#sec016} ----------------------------------------- Cell lysis, subsequent purification and storage procedures were as previously described in the JEV NS5 study \[[@ppat.1008484.ref008]\], except that the centrifugation duration to remove cell debris was 1 h, a 50 mM imidazole wash was applied prior to the elution step of the nickel-affinity chromatography, and 5 mM Tris (pH 7.5) was used as the buffering agent in the gel filtration chromatography. Tris-(2-carboxyethyl)phosphine (TCEP) was added to the pooled fractions to a final concentration of 5 mM. The molar extinction coefficient for the DENV NS5 was calculated based on protein sequence using the ExPASy ProtParam program (<http://www.expasy.ch/tools/protparam.html>). The yield is typically 2 mg of pure protein per L of bacterial culture. Protein crystallization and crystal harvesting {#sec017} ---------------------------------------------- The DENV NS5 crystals were grown by sitting drop vapor diffusion at 10 or 16°C using 10--12 mg/mL protein sample. Crystals grew to its final dimension in about 3 weeks with a precipitant/well solution containing 1.7% (vol./vol.) dioxane, 0.085 M bicine (pH 8.8), 4.9% (wt./vol.) PEG2000, and 15% (vol./vol.) glycerol for crystal form 1, and 0.2 M NH~4~I, 8% (vol./vol.) Tacsimate (pH 6.1), and 20% (wt./vol.) PEG3350 for crystal form 2. Crystals were transferred into cryo-stablizer solutions and stored in liquid nitrogen prior to data collection. Crystallographic data processing and structure determination {#sec018} ------------------------------------------------------------ Diffraction datasets were collected at the Shanghai Synchrotron Radiation Facility (SSRF) beamlines BL17U1 (crystal form 1, wavelength 0.9792 Å) and BL18U1 (crystal form 2, wavelengths: 0.9788 Å) at 100 K. Typically, at least 180° of data were collected in 0.4--0.5° oscillation steps. Reflections were integrated, merged, and scaled using HKL2000 or D\*Trek \[[@ppat.1008484.ref054],[@ppat.1008484.ref055]\]. The initial structure solution for crystal form 1 was obtained using the molecular replacement program PHASER \[[@ppat.1008484.ref056]\] and separated MTase and RdRP ensembles derived from JEV and DENV3 NS5 structures (PDB entries 4K6M and 4V0Q) \[[@ppat.1008484.ref008],[@ppat.1008484.ref020]\]. The final model of crystal form 1 was split into three ensembles (MTase, RdRP thumb with index tip, and the rest of RdRP) in the molecular replacement trial to obtain the initial structure solution for crystal form 2. Manual model building and structure refinement were done using Coot and PHENIX, respectively \[[@ppat.1008484.ref057],[@ppat.1008484.ref058]\]. The 3,500 K composite simulated-annealing omit 2F~o~-F~c~ electron density maps were generated using CNS \[[@ppat.1008484.ref059]\]. All NS5 superimpositions were done using the maximum likelihood based structure superpositioning program THESEUS \[[@ppat.1008484.ref026]\]. Relative domain motions were analyzed by DynDom \[[@ppat.1008484.ref060]\]. The occlusion of the solvent accessible area by the MTase-RdRP interactions was analyzed by program SurfRace with a probe radius of 1.4 Å and the 10-residue linker excluded in the calculation \[[@ppat.1008484.ref061]\]. The multiple sequence alignment of NS5 was carried out using 47 available complete NS5 sequences among the flavivirus species documented by the International Committee on Taxonomy of Viruses (ICTV) ([http://www.ictvonline.org](http://www.ictvonline.org/)), and the alignment was then used to generate the sequence logos ([http://weblogo.berkeley.edu](http://weblogo.berkeley.edu/)) and the conservation score projected structural representations. The projection of the conservation score onto structural model was done by the ConSurf server \[[@ppat.1008484.ref062]\]. Cells and antibodies {#sec019} -------------------- BHK-21 cells (American Type Culture Collection (ATCC), CCL-10) was propagated in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum (FBS), 100 units/mL of penicillin and 100 μg/mL of streptomycin in 5% CO~2~ at 37°C. Monoclonal antibody (4G2) against envelope protein of flavivirus was used to detect viral protein expression of both JEV and DENV2. FITC-conjugated goat anti-mouse IgG was used as secondary antibody. Construction of mutant genome-length cDNA of JEV and DENV2 {#sec020} ---------------------------------------------------------- The infectious clones of pACYC-JEV-SA14 \[[@ppat.1008484.ref063]\] and pACYC-DENV2-TSV \[[@ppat.1008484.ref033]\] were used as the backbone to construct recombinant JEV and DENV2 with different NS5 mutations, respectively. All mutations were engineered by fusion PCR. The JEV NS5 mutations were engineered at *BamH*I and *Xba*I restriction sites of pACYC-JEV-SA14. All DENV2 NS5 mutations were inserted into to pACYC-DENV2-TSV by restriction digestion with *Nru*I and *Cla*I. All constructs were verified by DNA sequencing before they were used in the subsequent experiments. Recombinant JEV and DENV2 study with different NS5 mutations {#sec021} ------------------------------------------------------------ The infectious clone of JEV and DENV2 with corresponding NS5 mutations were linearized with *Xho*I and *Cla*I, respectively, and then subjected to *in vitro* transcription using a T7 *in vitro* transcription kit (Thermo Fisher Scientific). Approximately 1 μg of transcribed recombinant genomic RNAs were transfected into BHK-21 cells with reagent DMRIE-C (Invitrogen). Then the cell slides were fixed in cold (-20°C) 5% (vol. to vol.) acetone in methanol at r. t. for 10 min. After washing three times with phosphate buffer saline (PBS) (pH 7.4), the fixed cells were subjected to IFA with 4G2 monoclonal antibody to examine viral envelope expression of both JEV and DENV2. At the same time, the supernatants of RNA-transfected BHK-21 cells were harvested as viral stocks for plaque assay to quantify viral titers and examine plaque morphologies. Briefly, confluent BHK-21 cells (1×10^5^ cells per well, plated 1 day in advance) in 24-well plates were infected with serially 10-fold diluted viral supernatants and incubated at 37°C with 5% CO~2~ for 1 h before the layer of medium containing 1% methylcellulose was added. After 4 days of incubation at 37°C with 5% CO~2~, the cells were fixed in 3.7% formaldehyde and then stained with 1% crystal violet. The viral titer was calculated as plaque formatting unit (PFU) per mL. RNA preparation {#sec022} --------------- The 30-mer template RNA (T30, [Fig 5A](#ppat.1008484.g005){ref-type="fig"}) used for *de novo* polymerase assays was chemically synthesized (Integrated DNA Technologies or Dharmacon) and purified by 12% (wt./vol.) polyacrylamide/7 M urea gel electrophoresis. The target RNA was excised from the gel, electro-eluted by using an Elu-Trap device (GE Healthcare), ethanol precipitated, dissolved in an RNA annealing buffer (RAB: 50 mM NaCl, 5 mM Tris (pH 7.5), 5 mM MgCl~2~), and stored at -80°C after a self-annealing process (a 3-min incubation at 95°C followed by snap-cooling to minimize inter-molecular annealing). A 5′-phosphorylated dinucleotide primer pGG (P2) (Jena Biosciecnes) was mixed with T30 at 5:1 or 20:1 molar ratio to make the T30/P2 construct. *In vitro* polymerase assays {#sec023} ---------------------------- All *in vitro* polymerase assays were based on the dinucleotide (P2)-driven reactions. The standard reaction condition was derived from the JEV NS5 work with the 4 μM of the T30 RNA and 6 μM of NS5 and with a couple of adjustments \[[@ppat.1008484.ref012]\]. Firstly, a manganese-free reaction condition (50 mM Tris (pH 7.5), 20 mM NaCl, 5 mM MgCl~2~, 5 mM DTT) (hereinafter referred as reaction buffer) was established. Secondly, a 5′-phosphorylated dinucleotide (pGG) and the T30 RNA was mixed at a difference ratio. In the assay to characterize the conversion of P2 to the 3-mer product (P3), ATP was supplied as the only NTP substrate and a high P2:T30 ratio (20:1) was used to achieve multiple turnovers within a reasonable duration. For the P9-containing EC (EC9) formation assay to achieve the P2-to-P9 conversion, ATP and UTP were supplied and the P2:T30 ratio was 5:1. For the P9-to-P10 single nucleotide elongation assay, reactions were first carried out as described in the EC9 formation assay. The reaction mixtures were centrifuged at 16,000 g for 5 min, and the pellet was washed twice by the reaction buffer, and was then resuspended in a modified reaction buffer with NaCl concentration lifted to 200 mM. CTP was supplemented to the resuspended mixture to allow the single-nucleotide elongation at 30°C, and the reaction was quenched immediately ("0" min) or at a certain time point after the addition of CTP. The concentrations of NaCl and CTP in the final reaction mixture are 200 mM and 300 μM, respectively, unless otherwise indicated. For all assays, the procedures for denaturing polyacrylamide gel electrophoresis (PAGE), gel staining, and quantitative analyses were performed as previously described \[[@ppat.1008484.ref012]\]. The Stains-All (Sigma-Aldrich)-based staining method is reasonably accurate when quantitating RNA bands with the same length, and in the majority of our experiments we tried to keep the band intensity within the linear range estimated in the previous study by adjusting the range of reaction time points \[[@ppat.1008484.ref012]\]. For the P2-to-P3 conversion assay, 50, 100, 200, 500, and 1000 μM ATP concentrations were used for WT and M-67A/68A, and 200, 400, 600, 1000, and 1500 μM were used for R3. To account for gel-to-gel intensity variations, samples from the same reaction mixture (indicated by the same icon above corresponding lanes in [Fig 7A--7C](#ppat.1008484.g007){ref-type="fig"}) were loaded on different gels to normalize the intensities (e.g. lanes 4/17, 14/27, 24/37 in [Fig 7A](#ppat.1008484.g007){ref-type="fig"}). The normalized intensity was then used to calculate the relative reaction rates ([Fig 7D--7F](#ppat.1008484.g007){ref-type="fig"}, left), which in turn were fitted to the Michaelis-Menten equation ([Fig 7D--7F](#ppat.1008484.g007){ref-type="fig"}, right). To estimate the relative *k*~*cat*~ and specificity constant values of all three constructs, The Michaelis-Menten curves of all three constructs were normalized based on the measurement of the relative reaction rates of each WT-mutant pair in the same gel ([Fig 7G](#ppat.1008484.g007){ref-type="fig"}). For the stability assessment of EC9, the P2-to-P9 conversion was first carried out as described above. The reaction mixture was subsequently centrifuged at 16,000 g for 5 min, and the pellet was washed twice by the reaction buffer and was then resuspended in a modified reaction buffer with NaCl concentration lifted to 500 mM. The resuspension was incubated in 37°C for various duration (0--78 h), and then CTP was added to reach a final concentration of 300 μM to trigger the P9-to-P10 conversion by EC9 that survived the incubation. The fraction of 10-mer intensity values were fitted to a single-exponential decay model to estimate the inactivation rates of all three constructs. Supporting information {#sec024} ====================== ###### A modelled NS5 conformational transition from the JEV-mode to the DENV3-mode. The movie starts with the JEV NS5 structure (PDB entry 4K6M), switches to the first form of DENV2 structure (PDB entry 6KR2), then the second form of DENV2 structure (PDB 6KR3), and finally the DENV3 structure (PDB entry 4V0Q). Three rotation axes related to the MTase movement are indicated by black lines, and one axis related to the RdRP thumb movement is indicated by a grey line. Note that the non-superimposable regions are not included in the structural models. (MP4) ###### Click here for additional data file. We thank Dr. Pei-Yong Shi for providing the cloning material for the DENV2 NS5 gene, Dr. Xiao-Dan Li for construction of the DENV2 NS5 M3 mutant plasmid, Dr. Bo Shu for X-ray diffraction data collection, Liu Deng and Yancheng Zhan for laboratory assistance, Dr. Yunhuang Yang for helpful discussions, synchrotron SSRF (beamlines BL17U and BL18U1 Shanghai, China) for access to beamlines, and The Core Facility and Technical Support, Wuhan Institute of Virology, for access to instruments. 10.1371/journal.ppat.1008484.r001 Decision Letter 0 Diamond Michael S. Section Editor Rey Félix A. Associate Editor © 2020 Diamond, Rey 2020 Diamond, Rey This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 25 Feb 2020 Dear Dr. Gong, Thank you very much for submitting your manuscript \"A conformation-based intra-molecular initiation factor identified in the flavivirus RNA-dependent RNA polymerase\" for consideration at PLOS Pathogens. As with all papers reviewed by the journal, your manuscript was reviewed by members of the editorial board and by two independent reviewers. As you will see, the reviewers provided contradictory reports. After careful consideration, we have editorially sided with reviewer 2.   Flavivirus NS5 is a multifunctional protein, composed of an N-terminal methyl-transferase (MTase) domain and a larger RNA-dependent RNA polymerase (RdRp) C-terminal domains. Multiple structures have been reported previously, some identifying a functional dimeric complex. As a polymerase, the NS5 protein has to adopt several conformation, which are different for initiation of RNA synthesis, for capping the newly synthesized RNA, or for elongation of the latter. In your study, you obtained crystals of DENV2 NS5 adopting two different conformations : one that resembles a structure reported for NS5 from the Japanese encephalitis flavivirus (JEV), in which the MTase domain adopts a "closed conformation" with respect to the RdRp domain, and another in which it adopts an \"open conformation\", similar to the one seen before in a structure of NS5 from the dengue virus serotype 3 (DENV3). As the two MTase/RdRp interfaces are different,  site directed mutagenesis allowed the selective targeting of the two interfaces. The use of these mutants for functional studies in an assay that allows to distinguish RNA initiation from RNA elongation showed that mutations at the interface seen in the open form interfere with the initiation process but do not affect the elongation process. Although there was no effect of the mutants at the interface observed in the closed form, it was considered editorially that it  is the first time that a given conformation of NS5 can be clearly attributed to a specific step in the replication process, and even though no MTase studies were performed, as pointed out by reviewer 1, that this is still a meaningful study. Please prepare and submit your revised manuscript within 30 days. If you anticipate any delay, please let us know the expected resubmission date by replying to this email.  When you are ready to resubmit, please upload the following: \[1\] A letter containing a detailed list of your responses to all review comments, in particular to those raised by reviewer 2, but also, whenever possible, to those raised by reviewer 1, together with a description of the changes you have made in the manuscript.  Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out \[2\] Two versions of the revised manuscript: one with either highlights or tracked changes denoting where the text has been changed; the other a clean version (uploaded as the manuscript file). Important additional instructions are given below your reviewer comments. Thank you again for your submission to our journal. We hope that our editorial process has been constructive so far, and we welcome your feedback at any time. Please don\'t hesitate to contact us if you have any questions or comments. Sincerely, Félix A. Rey Associate Editor PLOS Pathogens Michael Diamond Section Editor PLOS Pathogens Kasturi Haldar Editor-in-Chief PLOS Pathogens ​[orcid.org/0000-0001-5065-158X](http://orcid.org/0000-0001-5065-158X) Michael Malim Editor-in-Chief PLOS Pathogens [orcid.org/0000-0002-7699-2064](http://orcid.org/0000-0002-7699-2064) \*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\* The paper describes the X-ray structure of the NS5 protein of Dengue virus serotype 2. Flavivirus NS5 is a multifunctional protein, composed of an N-terminal methyl-transferase (MTase) domain and a larger RNA-dependent RNA polymerase (RdRp) C-terminal domains. Multiple structures have been reported previously, some identifying a functional dimeric complex. As a polymerase, this protein has to adopt several conformation, which are different for initiation of RNA synthesis, for capping the newly synthesized RNA, and for elongation of the later. Here, the authors have identified two different conformations of NS5 in their crystals: one that resembles a structure reported for NS5 from the Japanese encephalitis flavivirus (JEV), in which the MTase domain adopts a "closed conformation" with respect to the RdRp domain, and another in which it adopts an open conformation, similar to the one seen before in a structure of NS5 from the dengue virus serotype 3 (DENV3). What I found novel is that, as the two MTase/RdRp are different, they used directed mutagenesis to alter the interfaces in the closed or in the open conformation. They used these mutants for functional studies in an assay that allowed them to distinguish RNA initiation from RNA elongation. They found that mutations in the interface seen in the open form interfere with the initiation process but do not alter the elongation process. Although they didn't found a phenotype for the mutants at the interface observed in the closed form, this is the first time that a given conformation of NS5 can be assigned to a particular step in the replication process, and even though no MTase studies were performed, as pointed out by reviewer 1, I found that the authors have still presented a meaningful study. Reviewer Comments (if any, and for reference): Reviewer\'s Responses to Questions **Part I - Summary** Please use this section to discuss strengths/weaknesses of study, novelty/significance, general execution and scholarship. Reviewer \#1: In this manuscript, Wu et al. report the crystal structures Dengue virus type 2 (DENV2) NS5 and show that it exists in two distinct conformations representing both of the previously reported structures of Japanese encephalitis virus (JEV) and DENV3 NS5. These are defined as JEV-mode and DENV3-mode due to closeness of these DENV2 structures to the JEV and DENV3 NS5 structures. Moreover, the authors present additional data by mutational analysis to distinguish the functional differences between the two conformations of DENV2 NS5. They performed in vitro polymerase assays with wild-type (WT) and site-specific NS5 mutants to distinguish the initiation and elongation steps of RNA synthesis as well as cell-based replication using immunofluorescence assays. The authors conclude that the methyltransferase (MTase) of NS5 serves as a unique initiation factor only through NS5 conformation in the JEV-mode. But no MTase assays were performed. Overall, the crystallographic work is well-done. However, their biochemical and virological assays raise several questions. The functional roles of these two conformational states of DENV2 NS5 in viral replication remains unclear. Moreover, another group reported recently that DENV2 NS5 exists in two distinct conformational states (El Sahili, Soh, Schiltz, Gharbi-Ayachi, She, Shi, Lim, Lescar, 2020. J. Virol. 94: e01294-19). These authors in El Sahili et al. provide convincing evidence that it is the inter-domain linker between the MTase and POL domains the functional determinant of the two conformational states of DENV2 NS5. Reviewer \#2: The flaviviral NS5 proteins contain a methyltransferase (MTase) domain followed by an RNA-dependent RNA polymerase (RdRP) domain, both of which have essential functions during viral replication. Structures of the individual domains have been known for over a decade and biochemical approaches have been applied to studying the seemingly independent activities of these domains; this has worked moderately well for the MTase, but not so well for the RdRP due to the presence of a priming loop on the thumb domain that limits RNA binding and has precluded detailed biochemical studies of elongation kinetics the solving of an active elongation complex structure. Over the past few years that have several structure of full length NS5 solved from multiple flaviviruses (JEV, ZIKV, DENV3), and interestingly these have shown different interactions between the MTase and RdRP domains. However, it has not yet been clear if the observed inter-domain interactions are biologically relevant or due to crystal packing effects. The work presented in this manuscript provides a thorough study of MTase-RdRP interactions using structural biology, biochemistry, and virus replication data to address functional roles of the flaviviral methyltransferase (MTase) during the initiation of replication by the RdRP domain. Two new structures of DENV2 NS5 are solved that capture domain orientations which are intermediate between those solved previously for DENV3 and JEV. Structure-based mutagenesis is then used to show that one specific mode of MTase-RdRP interaction (the JEV mode) is important for both the growth of infectious virus and for in vitro initiation by the RdRP domain. These new results provide key insights into understanding the molecular mechanisms whereby flaviviral NS5 initiates replication. Using initiation of a pGG dinucleotide to form pGGA or to extent to a longer 9mer when UTP is also added, the authors use mutations of the show that formation of both products is diminished upon mutation of the JEV-mode interface but not the DENV3 interface, indicating that the JEV-mode is the active form. Furthermore, the researchers demonstrate that mutating the MTase interaction only affects RdRP initiation to form short products (pGG to pGGA), and does not affect on the elongation of a longer 9mer product to a 10mer. This latter elongation step is demonstrated to be very rapidly done by a complex that is stable in high salt, showing that the authors have assembled authentic stalled elongation complexes form a flaviviral polymerase. This is a major breakthrough that sets the stage for future studies of both RdRP biochemistry and elongation complex structure. The core experiments and conclusions are solid and well presented in the manuscript and there are no major concerns with the interpretation of the results. As usual from Gong lab, the illustrations are excellent and the polymerase biochemistry is well done with rigorous interpretations, all the more notable in this work because of the extensive steps taken to normalize Stains-All data across multiple gels. However, there are a few points where additional clarification or grammar corrections would be appreciated, as outlined below. Line 146-149: It may be worth discussing that the ring finger and part of index finger are not resolved in many of the early flaviviral RdRP domain structures (2hcn, 2hfz, 2j7u, 2j7w... see the flaviviral structures at DOI: 10.5281/zenodo.3361874). Might this be because the MTase domain is needed to stabilize the fingers folding, which could have big effects on RNA binding and initiation? The section from lines 162-167 describing SAH binding site is weak and the evidence for an "allosteric" site sounds somewhat circumstantial. Is there any experimental evidence for SAH binding being important, or is it perhaps a crystallization artifact? The section should either be strengthened with experimental data or references, or the idea of "allosteric" should be removed and the observed SAH density instead be described as an interesting structural observation that merits further biochemical validation. Also, was SAH added to the crystallization conditions, or did this SAH co-purify with the protein much as the SAH bound to the MTase domain does? Is there full occupancy of this "allosteric" site and of the native MTase site? Is there any (weak) anomalous density from the sulfur that would definitively identify the SAH? Please explicitly state the actual concentration of polymerase, RNA template and pGG primer used in the biochemical experiments. These are not stated anywhere in the manuscript, where only mole ratios are listed. \*\*\*\*\*\*\*\*\*\* **Part II -- Major Issues: Key Experiments Required for Acceptance** Please use this section to detail the key new experiments or modifications of existing experiments that should be [absolutely]{.ul} required to validate study conclusions. Generally, there should be no more than 3 such required experiments or major modifications for a \"Major Revision\" recommendation. If more than 3 experiments are necessary to validate the study conclusions, then you are encouraged to recommend \"Reject\". Reviewer \#1: In this manuscript, Wu et al. report the crystal structures Dengue virus type 2 (DENV2) NS5 and show that it exists in two distinct conformations representing both of the previously reported structures of Japanese encephalitis virus (JEV) and DENV3 NS5. These are defined as JEV-mode and DENV3-mode due to closeness of these DENV2 structures to the JEV and DENV3 NS5 structures. Moreover, the authors present additional data by mutational analysis to distinguish the functional differences between the two conformations of DENV2 NS5. They performed in vitro polymerase assays with wild-type (WT) and site-specific NS5 mutants to distinguish the initiation and elongation steps of RNA synthesis as well as cell-based replication using immunofluorescence assays. The authors conclude that the methyltransferase (MTase) of NS5 serves as a unique initiation factor only through NS5 conformation in the JEV-mode. But no MTase assays were performed. Overall, the crystallographic work is well-done. However, their biochemical and virological assays raise several questions. The functional roles of these two conformational states of DENV2 NS5 in viral replication remains unclear. Moreover, another group reported recently that DENV2 NS5 exists in two distinct conformational states (El Sahili, Soh, Schiltz, Gharbi-Ayachi, She, Shi, Lim, Lescar, 2020. J. Virol. 94: e01294-19). These authors in El Sahili et al. provide convincing evidence that it is the inter-domain linker between the MTase and POL domains the functional determinant of the two conformational states of DENV2 NS5. Specific comments 1\. Line 71, p. 4: This study focuses only on the polymerase activity of NS5 although the interdomain interaction between MTase and POL domains could impact on both enzyme activities. Why the authors did not perform any MTase assays to study the impact of the two conformations of DENV2 NS5? 2\. Lines 99-101, p. 5: "This statement is not correct. Once initiated de novo, RdRp can continue RNA synthesis until the template is copied. This has been demonstrated for dengue virus type 2 RdRp in many studies using subgenomic RNA templates containing 5'- and 3'-terminal regions and conserved cis-active elements that have been shown to be important for both initiation and elongation steps (see refs. Ackermann and Padmanabhan, 2001; Niyomrattanakit et al. 2010). The statement on line 101 is not accurate because in one study, processivity of RdRp was demonstrated by including heparin after initiation complex is formed to block re-initiation events (Nomaguchi et al. 2003). The statement on line 102 needs to modified to indicate that both Mg++ and Mn++ were used (in refs. 18, 24 and 25 cited in this study). 3\. The effects of mutations on MTase activity were not studied whereas these were examined in ref. 18 cited in this study. 4\. Lines 204, 208, 264: There is no Fig. 3E included in the manuscript. 5\. Lines 235-239 and lines 239-242: Please cite the ref(s) here; 12 or 33?. 6\. One concern with this study is the use of artificial GG dinucleotide primer and template for RdRp initiation and elongation assays. The authors' definition of de novo initiation in mosquito-borne RdRp assays is unconventional and may lead to wrong conclusions regarding the mutational effects in RdRp activities. For example, the catalytic rate constant could not be accurately determined under their conditions (lines 252-257). Reviewer \#2: None \*\*\*\*\*\*\*\*\*\* **Part III -- Minor Issues: Editorial and Data Presentation Modifications** Please use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity. Reviewer \#1: Minor Comments: 1\. Line 144: Which DENV3 structures the authors are referring to here? It would be helpful if the authors label the motif G in Fig. 1. 2\. Lines 160-162: The SAH binding site has been observed and labeled in Klema et al. (ref. 21). 3\. Define "pt" ( line 229) andNS5B NTD (line 403). Reviewer \#2: Line 40: calling differences in prior structures "drastically different global folds" is perhaps an overstatement since the effects are really at the level of relative domain orientations and not protein folding. Line 51: remove "about" as it redundant with giving a range of 10-11 kb for genome length. Line 71: change are to is Line 72: make evidences singular Line 76: typo in hereafter Line 86: in discussing interface areas, please explicitly state if the values presented reflect total buried solvent accessible surface from both sides of the interface, or from only one side of the interface. Also on lines 138, 157 and others. Line 115: Consider deleting "apparently" as the data for this are convincing. Line 120: change in to to. Line 127: arrange should be in past tense (arranged). Line 301: The same high-salt challenge studies are also used in studies of picornaviral polymerases, where they led to the crystallization of elongation complexes. Line 312-316: What really needs to the optimized here is the amount of material loaded on the gel, not necessarily what was used in the reactions, which could be done at higher concentrations and then diluted prior to gel loading (a minor conceptual point, no need to edit the text). Line 316: Change 3-fold to "3-fold higher" Line 375: I do not agree with the statement that the global structural organization is quite different from flaviviral polymerases versus others. Structure comparisons have shown the core polymerase fold and structure to be very similar across all viral polymerases, and certainly among positive strand RNA viruses, with few insertions or topology changes within the core fold. There are added domains, such as the N-terminal MTase and NiRAN domains or C-terminal membrane anchors, but these are additions to the protein and not a reorganization of the protein fold as implied by the manuscript as written. Line 394: I do believe there is convincing evidence that the N-terminal region of nsp9 is a nucleotidylating NiRAN domain. Line 518: Include actual concentrations of macromolecules used in the experiments. Figure 3: Are the stereo panels in A and B flipped right to left? Stereo viewing of these images does not seem to work correctly. Figure 5: In panel D, why is the 9mer STD band higher than the 9mer product band from the polymerase? Effect of the 5' phosphate from pGG primer, perhaps? Line 816: Consider changing to "...in the multiple turnover P3 formation and single turnover P9 formation assays" so as to explain the vast difference in band intensities in the figure legend itself (in addition to the comments already in the text of the manuscript). Line 833: Technically speaking, the experiment in really testing inactivation of the elongation complex and not the dissociation rate of the RNA, although that is probably a valid interpretation in this case. Figure 7: In some cases, linear curve fits to determine initial rates are being applied to data that have clear curvature (panel E-200uM, panel F-50 & 100 uM, panel G-R3). This is a minor point. \*\*\*\*\*\*\*\*\*\* PLOS authors have the option to publish the peer review history of their article ([what does this mean?](https://journals.plos.org/plospathogens/s/editorial-and-peer-review-process#loc-peer-review-history)). If published, this will include your full peer review and any attached files. If you choose "no", your identity will remain anonymous but your review may still be made public. **Do you want your identity to be public for this peer review?** For information about this choice, including consent withdrawal, please see our [Privacy Policy](https://www.plos.org/privacy-policy). Reviewer \#1: No Reviewer \#2: No [Figure Files:]{.ul} While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, [[https://pacev2.apexcovantage.com](https://pacev2.apexcovantage.com/)]{.ul}. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at [<[email protected]>]{.ul}. [Data Requirements:]{.ul} Please note that, as a condition of publication, PLOS\' data policy requires that you make available all data used to draw the conclusions outlined in your manuscript. Data must be deposited in an appropriate repository, included within the body of the manuscript, or uploaded as supporting information. This includes all numerical values that were used to generate graphs, histograms etc.. For an example see here: <http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001908#s5>. [Reproducibility:]{.ul} To enhance the reproducibility of your results, PLOS recommends that you deposit laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see [[http://journals.plos.org/plospathogens/s/submission-guidelines\#loc-materials-and-methods](http://journals.plos.org/plospathogens/s/submission-guidelines)]{.ul} 10.1371/journal.ppat.1008484.r002 Author response to Decision Letter 0 27 Feb 2020 ###### Submitted filename: point_by_point_responses.docx ###### Click here for additional data file. 10.1371/journal.ppat.1008484.r003 Decision Letter 1 Diamond Michael S. Section Editor Rey Félix A. Associate Editor © 2020 Diamond, Rey 2020 Diamond, Rey This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 18 Mar 2020 Dear Dr. Gong, We are pleased to inform you that your manuscript \'A conformation-based intra-molecular initiation factor identified in the flavivirus RNA-dependent RNA polymerase\' has been provisionally accepted for publication in PLOS Pathogens. Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. A member of our team will be in touch with a set of requests. Please note that your manuscript will not be scheduled for publication until you have made the required changes, so a swift response is appreciated. IMPORTANT: The editorial review process is now complete. PLOS will only permit corrections to spelling, formatting or significant scientific errors from this point onwards. Requests for major changes, or any which affect the scientific understanding of your work, will cause delays to the publication date of your manuscript. Should you, your institution\'s press office or the journal office choose to press release your paper, you will automatically be opted out of early publication. We ask that you notify us now if you or your institution is planning to press release the article. All press must be co-ordinated with PLOS. Thank you again for supporting Open Access publishing; we are looking forward to publishing your work in PLOS Pathogens. Best regards, Félix A. Rey Associate Editor PLOS Pathogens Michael Diamond Section Editor PLOS Pathogens Kasturi Haldar Editor-in-Chief PLOS Pathogens ​[orcid.org/0000-0001-5065-158X](http://orcid.org/0000-0001-5065-158X) Michael Malim Editor-in-Chief PLOS Pathogens [orcid.org/0000-0002-7699-2064](http://orcid.org/0000-0002-7699-2064) \*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\* Reviewer Comments (if any, and for reference): 10.1371/journal.ppat.1008484.r004 Acceptance letter Diamond Michael S. Section Editor Rey Félix A. Associate Editor © 2020 Diamond, Rey 2020 Diamond, Rey This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 24 Apr 2020 Dear Dr. Gong, We are delighted to inform you that your manuscript, \"A conformation-based intra-molecular initiation factor identified in the flavivirus RNA-dependent RNA polymerase,\" has been formally accepted for publication in PLOS Pathogens. We have now passed your article onto the PLOS Production Department who will complete the rest of the pre-publication process. All authors will receive a confirmation email upon publication. The corresponding author will soon be receiving a typeset proof for review, to ensure errors have not been introduced during production. Please review the PDF proof of your manuscript carefully, as this is the last chance to correct any scientific or type-setting errors. Please note that major changes, or those which affect the scientific understanding of the work, will likely cause delays to the publication date of your manuscript. Note: Proofs for Front Matter articles (Pearls, Reviews, Opinions, etc\...) are generated on a different schedule and may not be made available as quickly. Soon after your final files are uploaded, the early version of your manuscript, if you opted to have an early version of your article, will be published online. The date of the early version will be your article\'s publication date. The final article will be published to the same URL, and all versions of the paper will be accessible to readers. Thank you again for supporting open-access publishing; we are looking forward to publishing your work in PLOS Pathogens. Best regards, Kasturi Haldar Editor-in-Chief PLOS Pathogens ​[orcid.org/0000-0001-5065-158X](http://orcid.org/0000-0001-5065-158X) Michael Malim Editor-in-Chief PLOS Pathogens [orcid.org/0000-0002-7699-2064](http://orcid.org/0000-0002-7699-2064) [^1]: The authors have declared that no competing interests exist.

Low autonomic arousal as vulnerability to externalising behaviour in infants with hostile mothers. Maternal psychopathology and the child's autonomic nervous system functioning are risk factors for aggressive behaviour later in life. While research has shown that maternal psychopathology already affects young children, less is known about the association between autonomic functioning and aggressive behaviour in young children. In addition, maternal psychopathology and autonomic nervous system functioning may interact to determine the risk of aggressive behaviour. In a sample of 375 infants and their mothers, maternal psychiatric symptoms were assessed with the Brief Symptom Inventory and toddler aggressive behaviour with the Child Behaviour Checklist. Infant heart rate was recorded at 14 months. Maternal psychiatric problems, including hostility and depression, were associated with toddler aggressive behaviour. Maternal psychiatric problems interacted with mean heart rate (P=0.01) and HF variability (P=0.03) in their effect on toddler aggressive behaviour. Mothers with high psychiatric problems, in particular, high hostility, were more likely to have toddlers with high aggressive behaviour. Moreover, in the presence of maternal risk factors, low autonomic arousal renders children particularly susceptible to aggressive behaviour.

Calcium efflux from frog twitch muscle fibers. An apparatus is described which collects the effluent from the center 0.7 cm of a single muscle fiber or bundle of muscle fibers. It was used to study the efflux of (45)Ca from twitch muscle fibers. The efflux can be described by three time constants 18 +/- 2 min, 300 +/- 40 min, and 882 +/- 172 min. These kinetics have been interpreted as those of a three-compartment system. The fastest is thought to be on the surface membrane of the muscle and of the T system. It contains 0.07 +/- 0.03 mM Ca/liter of fiber and the Ca efflux is 0.11 +/- 0.04 pM Ca/cm(2). sec. The intermediate rate compartment is thought to represent the Ca in the longitudinal reticulum. It contains approximately 0.77 mM Ca/liter. Only the efflux from this compartment increases during stimulation. The most slowly exchanging compartment is poorly defined. Neither Ca-free nor Ni-Ringer solutions alter the rate of loss from the fastest exchanging compartment. Ni apparently alters the rate of loss from the slowest compartment.

Nitro PDF Reader is one of the best alternatives to Adobe Reader, as it is a simple PDF reader allowing you to view PDF files, edit them or highlight text. It also allows to load multiple documents on Nitro PDF Reader and work on them. Nitro PDF Reader lets you extract images from PDF files like Some PDF Image Extract. Apart from the Image extract, it can also convert the image to PDF. All the options : Create from file, Convert to text and Extract images can be accessed in Home toolbar. One can always choose the destination folder for the extracted items. This freeware Nitro PDF Reader can get your images in TXT, BMP, JPG, GIF, PNG, WMF, EMF or EPS format. If you want the features like Combine files, Edit text and Convert to text; one has to purchase a pro version of Nitro PDF Reader. How to use Nitro PDF Reader to create PDF, convert into a text file, and extract images? Creating PDF, converting into a text file and extracting images from PDF is very simple. Open any PDF file using Nitro PDF Reader and choose any option from its toolbar. Select the location and your job will be done in a few seconds. The download size is approx 55 MB, which is huge. If someone only wants to extract images from PDF file then Some PDF Image Extract can be the better option for them. You can download Nitro PDF Reader from here.

Let me first welcome you to the Debian Users Forum. We hope your visit here will both help and enlighten you in your Debian experience. We do have a few expectations of what you have done already to find your answer.1) We expect that you have used Google or another search engine to find your answer.2) That you have searched the Man pages available on your topic. If you don't know how you may do this, open a terminal and at the prompt enter "man topic" where "topic" represents the topic you are having trouble with.3) Lastly, that you have tried to use the forum search feature to find help on your issue. We are glad to be here to help you, you should however realize that our members and staff are ALL volunteer people just like you. No one gets paid to be here and help. Also our members are from all over the globe and there may be dead times on the forum where no one responds right away. We do try to avoid this though. Thank you for your interest in Debian, I hope you find it as much of a rewarding experience as I do.

The truth is, even though Moonlight will be remembered in trivia games and Wikipedia pages as the best picture of 2016, the people who made it will have to live with not having the moment of their name being read from the card. They were not allowed to deliver uninterrupted speeches. Instead, Barry Jenkins just stood in awe and uttered a few phrases. Even with Moonlight winning, the talent behind the film still didn't get the respect it deserved, calling to mind one of the most iconic lines of Shonda Rhimes' Scandal.

Q: Is there a way to change what Pepper says in Autonomous Life? I would like to change what Pepper the robot says when it is in "default mode", i.e. without having any application launched; thus enabling it to answer some questions the manufacturer didn't include, or to change its answer. I have already tried —to no avail— looking for a solution on Aldebaran's documentation, google researches proved fruitless too. The kind of questions that the robot can be asked are here: http://doc.aldebaran.com/2-5/family/pepper_user_guide/basic_channel_conversation_pep.html it doesn't say how to change the content though. I'm basically expecting the robot to be able to deliver some information without needing to get into application; I'm aware that there are collaborative speeches but this isn't what I am looking for. A: Option 1: You can find the dialoges from Pepper at: /data/home/nao/.local/share/PackageManager/apps/dialog_* e.g. /data/home/nao/.local/share/PackageManager/apps/dialog_goodbye/dlg_goodbye/dlg_goodbye_enu.top You could edit or extend those. Option 2: You could copy the content, edit them as you like and merge it into your own dialog. But you would have to "get into application". If you just want to add something to the default dialoges. Then you could activate your own custom topic in default mode. Given your topic file is named myTopic.top and is placed in /data/home/nao/: import naoqi from naoqi import ALProxy ald = ALProxy("ALDialog", "pepper.local", 9559) myTopic = ald.loadTopic("/data/home/nao/myTopic.top") ald.activateTopic(myTopic) ald.getLoadedTopics("English") Then your custom topic should be listed among the other topics activated in defaut mode. Option 3: Make your own application with your own dialog and just activate all the other topics too.

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Interior Fabrics & Seat Trims When it comes to choosing the finishing touches to your Peugeot 3008 SUV, you can create a look that suits you with our selection of interior fabric and leather seat trims. With our range of finishes you’ll be able to create your own personalised ambience for your new vehicle. 3008 SUV GALLERY Why choose peugeot? Premium Aftercare With Peugeot’s signature AfterCare Program, we’re committed to ensuring that each new car continues to run smoothly into the future. Unique Innovation Welcome to Peugeot where performance and design, including the world first Peugeot i-Cockpit®, have been perfectly combined to deliver exceptional results. Optimal Efficiency At Peugeot, our advanced engines have been designed to deliver high performance while also being energy efficient. With over 80,000kms covered in 16 months, is a man that drives for a living – and his PEUGEOT 508 Allure just keeps on trucking. Behind this heavy vehicle license trainer and assessor is a PEUGEOT story going back to Geoff’s youth; when he built” John Doe With over 80,000kms covered in 16 months, is a man that drives for a living – and his PEUGEOT 508 Allure just keeps on trucking. Behind this heavy vehicle license trainer and assessor is a PEUGEOT story going back to Geoff’s youth; when he built

Report on the 13th International Society of Blood Transfusion Platelet Immunology Workshop. The aim of the 13th International Society of Blood Transfusion Platelet Immunology Workshop was to compare the sensitivity and specificity of the in-house method for the detection of human platelet antigen (HPA) antibodies currently used in participating laboratories with a modified rapid protocol for the monoclonal antibody (mAb) immobilization of platelet antigen (MR-MAIPA) assay. Twenty-eight laboratories from 15 countries participated. A set of four freeze-dried minimum potency reference reagents with known single-specificity HPA antibodies were supplied for testing by titration with both assays and two coded freeze-dried plasma samples were provided for antibody specificity testing. Critical reagents and materials for the MR-MAIPA were provided including lyophilized panel platelets and five capture mAbs. Titration of the reference standards showed that the sensitivity of the MR-MAIPA was the same as the in-house methods. The proposed replacement anti-HPA-1a reference reagent 05/106 gave results that did not differ significantly from the current reference reagent 93/710. The results with the two blinded samples showed that in the first sample, 27 out of the 28 laboratories were able to correctly identify the anti-HPA-1a present when using their respective in-house methods, but only 23 correctly identified the antibody when using the rapid MAIPA method. The results from the second sample, which contained multispecificities, showed that only 50% of the participants correctly identified all five antibodies present using their in-house method. The results for the rapid MAIPA were lower, with only 32% identifying all specificities. The variability in the reconstitution of the freeze-dried platelets may have been one of the contributing factors to the poorer results. The sensitivity of the MR-MAIPA compared favourably with that of the in-house methods. Most laboratories were able to identify anti-HPA-1a alone in Sample 1 but more than half of the participants were not able to correctly assign the specificity of all HPA antibodies present in the second sample. The usefulness of the panel of freeze-dried platelets varied considerably between laboratories.

[Device-assisted behavior therapy of 2 enuretic monozygotic sets of twins]. Two sets of identical twins with enuresis were treated with behavior therapy involving a conditioning apparatus. The surprising similarities in the course and outcome are described and discussed.

Q: New tag should require more privilege I am a relatively new user in Ask Ubuntu site, which is a subsite of the Stack Exchange network. After participating in the Questions and answers in the AU site for a while, I see that, the "tags" are very important in this site. (It is also very important on all SE sites). I often see and feel that, Moderators and Community members have a hard time deleting tags, which were created by users (without having good knowledge about the importance of tags). I also experienced a situation where a user trying to delete ubuntu-netbook tag, created a new one as ubuntu-n accidentally and was unaware of this new tag. (We are requested to delete that tag, because that is no longer important). So, I feel that, tag creation should not be that easy and should go through some approval by moderators before being used in the system. That's why I am proposing this request. We can apply to the system one or more of these methods to prevent unimportant tags being created. We can increase the required reputation level from 300 to 2000. It is now 300 New tags should go through moderator approval before being used. The user can still type a new tag name, but that new tag will only appear in the question after moderator approval I want to hear from community members about this particular request. A: 300 is quite a high enough limit honestly. I mean, if you reach 300 rep, it means you did participate in the community and the site itself (at least a bit). 2K seems like too much for me. Tags are important — yes — but a wrong tag might not create so many problems, and in any case, not that many problems to justify a 2K limit privilege. Another thing: apart from the fact that moderators already have quite a few duties to take care of, adding this one wouldn't have that much effect. Consider that a tag, in order to survive, must be used. If you create a tag and nobody else uses it, the system will purge it. So it's not like a wrong tag is a scar forever. It'll be seen sooner or later, either by the system or by the community: no need for exclusive moderator action.

Forgotten password Niche Jobs Ltd Privacy Policy Nurses.co.uk is a job advertising website run by Niche Jobs Ltd. Niche Jobs Ltd is not an employment agency and does not undertake such activities as would be consistent with acting as an agency. This privacy policy applies only to this website. If you do not accept this privacy policy, you must not use the website. A user will have been deemed to have accepted our Privacy Policy when they register their details on the site, or set up a job alert emails. We are committed to ensuring our user's privacy in accordance with the 1998 Data Protection Act, as well as ensuring a safe and secure user experience. Personal (identifiable) information When users submit identifiable* information to the website they are given the choice as to whether they wish their details to be visible to companies advertising on the website. 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A user may remove their details by selecting the 'Remove my account' option from their account menu, or by requesting the removal of their details via the 'Contact Us' link on the website. A confirmation of this removal will be sent to the user by Niche Jobs Ltd. If you have any questions regarding this privacy policy, you may contact us at: Choose a CV Now add this CV Niche Jobs Ltd Privacy Policy is a job advertising website run by Niche Jobs Ltd. Niche Jobs Ltd is not an employment agency and does not undertake such activities as would be consistent with acting as an agency. This privacy policy applies only to this website. If you do not accept this privacy policy, you must not use the website. A user will have been deemed to have accepted our Privacy Policy when they register their details on the site, or set up a job alert emails. We are committed to ensuring our user's privacy in accordance with the 1998 Data Protection Act, as well as ensuring a safe and secure user experience. Personal (identifiable) information When users submit identifiable* information to the website they are given the choice as to whether they wish their details to be visible to companies advertising on the website. By selecting 'Allow companies to contact me about jobs', this means that a user's information, as it is entered on the website, may be viewed by companies who use our CV Search tool or watchdog function. At no point does Niche Jobs Ltd distribute a user's information to third parties beyond what we may be legally obligated to do. By selecting 'I don't wish to be contacted about jobs by companies looking to hire', this means that a user's information will only be visible to a company advertising on the site if a user applies to a job being advertised by that company. Whilst Niche Jobs Ltd makes every effort to restrict CV access to legitimate companies only, it cannot be held responsible for how CVs are used by third parties once they have been downloaded from our database. Identifiable information is anything that is unique to a user (i.e. email addresses, telephone numbers and CV files). Niche Jobs Ltd may from time to time send email-shots on behalf of third parties to users. Users can unsubscribe from mailshots using the unsubscribe link in the email or by contacting Niche Jobs Ltd via the Contact Us page on the website. Non-identifiable information Niche Jobs Ltd may also collect information (via cookies) about users and how they interact with the site, for purposes of performance measuring and statistics. This information is aggregated, so is not identifiable on an individual user basis. Users may choose to accept or deny cookies from Niche Jobs Ltd, but users should be aware that if cookies are not permitted it may adversely affect a user’s experience of the site. Removal of stored information Niche Jobs Ltd reserves the right to remove user information from the database if that information is deemed obsolete or used in a way that is detrimental to the performance of the website or the reputation of the business as a whole. A user may remove their details by selecting the 'Remove my account' option from their account menu, or by requesting the removal of their details via the 'Contact Us' link on the website. A confirmation of this removal will be sent to the user by Niche Jobs Ltd. If you have any questions regarding this privacy policy, you may contact us at: Pulse are looking for a Qualified ITU Nurse for ad hoc duties at an NHS Hospital in Chelmsford. This Client provides local elective and emergency services to [... Click Apply...] people living in and around the districts of Chelmsford, Maldon and Braintree. 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We are seeking a dedicated and enthusiastic Band 5 Staff Nurse to join our client's busy Cardiac Intensive Treatment Unit based at their NHS Trust site in Harefield, Greater London , a small, attractive exurban community on the green belt fringe of the city. This is a full-time permanent post, but this unit is open to hearing from applicants seeking to negotiate a ... Job Description The successful post holder will assess, plan, deliver and evaluate high standards of critical care nursing. They will be responsible for working within a team, supervising and directing junior staff and deputising for Senior Staff Nurses in their absence. Duties & Responsibilities Demonstrating an ability to record, monitor and interpret a patie ... Looking for regular, consistent work that specifically suits your needs? At Allied Nursing Services, we offer more to nurses than just a job. 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They have multiple facilities covering a broad range of acute specialties, including: surgical, medical, oncology, & critical care units to name a few. This position will offer the successful applicant the opportunity to work within ... We are seeking a committed and experienced Band 6 Senior Staff Nurse to join our client's busy Cardiac Intensive Treatment Unit based at their NHS Trust site in Harefield, Greater London , a small, attractive exurban community on the green belt fringe of the city. This is a full-time permanent post, but this unit is open to hearing from applicants seeking to negotiate a part-time o ... TFS have launched a Surrey team and would like you to be part of it..! 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Apache – “Crystal Clear” (mp3) Texas/Bay Area band Apache‘s sound is pushing upstream in a time when many bands are trying to tattoo a new sonic marker in the rock n’ roll landscape. They write catchy garage rock gems in the 70s glam-rock tradition. You won’t find any traces of grad-school ideology in “Crystal Clear” as Apache celebrates teenage angst through the power of lo-fi rock n’ roll. Find out more about Apache. Visit their artist page on their label, Birdman Records.

namespace ScriptableObjectArchitecture { public static class SOArchitecture_Utility { public const int ASSET_MENU_ORDER_VARIABLES = 121; public const int ASSET_MENU_ORDER_EVENTS = 122; public const int ASSET_MENU_ORDER_COLLECTIONS = 123; public const string VARIABLE_SUBMENU = "Variables/"; public const string COLLECTION_SUBMENU = "Collections/"; public const string GAME_EVENT = "Game Events/"; public const string ADVANCED_GAME_EVENT = GAME_EVENT + "Advanced/"; public const string ADVANCED_VARIABLE_SUBMENU = VARIABLE_SUBMENU + "Advanced/"; public const string ADVANCED_VARIABLE_COLLECTION = COLLECTION_SUBMENU + "Advanced/"; // Add Component Menus public const string ADD_COMPONENT_ROOT_MENU = "SO Architecture/"; public const string EVENT_LISTENER_SUBMENU = ADD_COMPONENT_ROOT_MENU + "Event Listeners/"; } }

Q: how to add opencv to a gui QT application? I created a new widget gui application in QT . and in order to using opencv , I added INCLUDEPATH and LIBS to my projects as following : QT += core gui greaterThan(QT_MAJOR_VERSION, 4): QT += widgets TARGET = testqt4 TEMPLATE = app SOURCES += main.cpp\ widget.cpp INCLUDEPATH += C:/opencv/build/include LIBS += -LC:\opencv\build\x64\vc12\lib -lopencv_world310d HEADERS += widget.h FORMS += widget.ui and I included my desired opencv headers as following : #ifndef WIDGET_H #define WIDGET_H #include <QWidget> #include <opencv2/core/core.hpp> #include <opencv2/highgui/highgui.hpp> .... but when I builded the project I encountered with this error : can anyone help me to fix this error ? thank you . A: Are you using qt creator? It will not update your makefile once you changed your .pro file. Right click on the project folder in Projects view and click "Run qmake" should fix it.

5 Para A Meia-Noite 5 Para A Meia-Noite (5 to Midnight) is a late-night talk show that airs on Thursdays on the Portuguese TV channel RTP1 (formerly on RTP2). Its format is based on several American late-night talk shows. External links References Category:2009 Portuguese television series debuts Category:Portuguese television talk shows Category:2000s Portuguese television series

Timeliners: Revision to yesterday's e-mail - due date is end of July. So proposals by mid-June, first draft report by early/mid-July, discussion throughout. Bob > ---------- > From: Harshbarger, Robert > Sent: Monday, May 21, 2001 5:16 PM > To: Ellingson, Mons; Fotiou, Demetrios; Grow, Lisa; Holden-Baker, Susan; > Smith, Chris; Tilghman, Carmine; Underwood, John; Williams, Bill > Cc: 'Hackney, Mark' > Subject: A3A1 Ad Hoc Review Team > > Yes, that's right, you did raise your hand for this. > > We are to submit to ISAS any recommendation(s) by August ??, 2001 (what > was the date, I didn't write it down). > > Is there benefit to have a face-to-face meeting? Either way, we'll use > e-mail for discussion and maybe a conference call or two. > > First assignment is to read: > * A3A1-Interim is what we are currently running with. > * A3A1-version3-draft2 goes before the NERC BOT June 10-11. > * A3A1-candr contains public comments and responses from NERC IS. > > <<File: a3a1-interim.doc>><<File: a3a1v3d2-0501.doc>><<File: > a3a1candr.doc>> > Questions to keep in mind: > * Are our current timelines as good as it gets? > * Do we want to adopt the Eastern Interconnection's timelines? > * What are the deficiencies of our timelines? > * Will these deficiencies be present under 1.7? > * Which timing requirements could be changed with an reasonable amount > of effort (i.e., tariff items, AGC ramp times, A3A1, etc.)? > > Remember.... > <<File: trainedpros.wav>> > > Bob Harshbarger > OASIS Trading Manager > Puget Sound Energy > (425) 882-4643 voice > (425) 882-4496 fax > (206) 405-5161 pager > (206) 604-3251 cell >

Estimation of biological occupational exposure limit values for selected organic solvents from logartihm of octarol water partition coefficient. For several organic solvents (solvents in short), biological occupational exposure limits (BOELs) have been established for un-metabolized solvents in urine, based on the solvent exposure-urinary excretion relationship. This study was initiated to investigate the possibiliy of estimating a BOEL from the Pow (the partition coefficient between n-octyl alcohol and water), a physico-chemical parameter. Data were available in the literatures for exposure-excretion relationship with regard to 10 solvents for men and 7 solvents for women. Statistical analysis revealed that the slopes (after correction for molecular weights and logarithmic conversion) of the exposure-excretion regression lines linearly correlated (p<0.01) with the log Pow values the respective solvents. No significant difference (p>0.05) was observed between men and women, and it was acceptable to combine the data for the two sexes. Thus the log Pow-log slope relation was represented by a single equation for both sexes. Based on the observations, procedures were established to estimate BOEL values from Pow. Successful estimations of BOELs for styrene, tetrahydrofuran and m-xylene (a representative of xylene isomers) were calculated as examples. The present study proposed promising procedures for estimation of a BOEL from the Pow.

The pursuit of precision pharmaceuticals: divergent effects of beta2 agonist isomers. Beta2 agonists are the most commonly used treatment for acute bronchoconstriction. However, during regular use there is a progressive decline of protective efficacy of bronchodilators. This progressive decline has long been considered anomalous because with short-acting beta agonists, there is no corresponding change in bronchodilator efficacy. Airway hyper-responsiveness is itself a feature of asthma and there maybe however, there may be an increase in airway hyper-responsiveness following regular use of beta2 agonist. Airway hyperresponsiveness could diminish the capacity of beta agonists to protect from or result in paradoxical bronchospasm and there effects of racemic salbutamol. There have been reports of increased morbidity and mortality associated with excessive use of beta(2) agonists. As all beta agonists used clinically are racemates composed of 1:1 mixtures of R and S isomers, conducted on the possible involvement of the isomers in hyper-responsiveness. Hyper-responsiveness cannot be attributed to the R isomer, whose capacity to activate beta adrenoceptors will nullify this effect. In contrast, extensive evidence indicated that the S isomer might cause hyper-responsiveness and potential airway inflammation. Further, the S isomer shows a propensity to activate human eosinophils and alter muscarinic M(2) receptor functions. The S isomer, which makes no contribution to therapeutic efficacy and may exacerbate asthma, might therefore be excluded from asthma therapy.

at is the derivative of n(o) wrt o? -2007 What is the third derivative of 854*p**2 - 5 + 8 - 1319*p**4 - 920*p**2 wrt p? -31656*p Let q be (2/15*6)/((-22)/(-715)). What is the second derivative of -q*o**2 - 91*o**3 + 26*o + 2 + 186*o**3 - 98*o**3 wrt o? -18*o - 52 Find the second derivative of -833*h + 176*h - 267*h + 473*h**3 - h**2 wrt h. 2838*h - 2 Suppose -11*n + 10*n + 6 = 0. What is the third derivative of -1 - 84*s**n + 13745*s - 13745*s - 9*s**2 wrt s? -10080*s**3 Differentiate -6501 + 6866 - 382*s**3 + s**3 wrt s. -1143*s**2 Let z(h) be the third derivative of -195*h**8/112 + h**4/6 + 53*h**3/2 + 1556*h**2. Find the second derivative of z(t) wrt t. -11700*t**3 Let r(f) be the first derivative of 2*f**7/7 - 14*f**6/3 - 7*f**3 + 51*f - 3138. Find the third derivative of r(c) wrt c. 240*c**3 - 1680*c**2 Let n = 270 + -265. Find the third derivative of 69*u**5 - 30*u**2 - 69*u**n - 8*u**6 wrt u. -960*u**3 Let q(o) = -495*o**3 + 5*o + 1713. Let f(h) = -485*h**3 + 4*h + 1715. Let u(r) = 5*f(r) - 4*q(r). What is the first derivative of u(z) wrt z? -1335*z**2 Let o(d) = -2*d**2 - 1. Let c(b) = 300*b**3 - 8*b**2 - 792. Let h(s) = -5*c(s) + 20*o(s). Find the first derivative of h(l) wrt l. -4500*l**2 Let g = 2 - 0. Let d be 8 + ((-3)/g)/(8/16). Find the third derivative of 758*y - 758*y + 2*y**d + 17*y**2 wrt y. 120*y**2 Let u(h) = 16*h - 63*h + 32*h**2 - 86*h - 16. Let c(p) = -31*p**2 + 133*p + 12. Let a(l) = -4*c(l) - 3*u(l). What is the second derivative of a(w) wrt w? 56 Let d(n) = -21*n**2 + 19*n - 2275. Let t(c) = -6*c**2 + 9*c - 1137. Let s(q) = -2*d(q) + 5*t(q). What is the derivative of s(l) wrt l? 24*l + 7 Let f = -113 + 119. Suppose 9*c - 6*c = f. Find the third derivative of -59*r**c + 43*r**4 + 149*r**2 - 64*r**2 wrt r. 1032*r Suppose 6*g - 272 - 40 = 0. What is the first derivative of -51 - 89 + 41 - g*j - 51*j - 51*j wrt j? -154 Find the third derivative of 485*o**4 + 60*o**2 + 589*o**4 + 1657*o**4 - 912*o**2 wrt o. 65544*o Let c(s) be the first derivative of 0*s**2 - 10 - 2/3*s**3 + 5/4*s**4 + 31*s. Find the first derivative of c(m) wrt m. 15*m**2 - 4*m Differentiate 140 + 787 + 607*l**3 + 728*l**3 + 1735*l**3 + 110*l**3 with respect to l. 9540*l**2 Let l(i) = -64*i**5 + 56 - 29 - 27 + 23*i**2 + 3*i. Let y(s) = 704*s**5 - 252*s**2 - 32*s. Let b(j) = 32*l(j) + 3*y(j). Find the third derivative of b(a) wrt a. 3840*a**2 Let i be -7 + (-39)/(-4) + 1*(-2 + 0). Let q(p) be the second derivative of -5*p**2 + 0 - i*p**4 + 19*p + 0*p**3. What is the derivative of q(l) wrt l? -18*l Let a(c) be the third derivative of 1135*c**4/12 - 527*c**3/3 + 1320*c**2. Find the first derivative of a(m) wrt m. 2270 Find the third derivative of 1087*x**4 + x**4 + 1524*x - 444*x - 3*x**2 + x**2 wrt x. 26112*x What is the second derivative of 4*z**2 + 62045*z**3 - 62251*z**3 - 2*z**2 + 2285*z wrt z? -1236*z + 4 Let d(l) = 1790*l**2 - 3740*l + 18. Let u(m) = 3578*m**2 - 7477*m + 42. Let y(x) = -7*d(x) + 3*u(x). What is the second derivative of y(f) wrt f? -3592 Let b(k) = 3*k**2 - 251*k + 372. Let v(p) = 4*p**2 - 268*p + 376. Let f(j) = 2*b(j) - 3*v(j). Differentiate f(d) with respect to d. -12*d + 302 Let k(j) = j**4 - 284*j**3 + 2521*j**2 + 2. Let a(r) = -r**4 + 285*r**3 - 2522*r**2 - 3. Let o(v) = -2*a(v) - 3*k(v). Find the third derivative of o(t) wrt t. -24*t + 1692 Let s(d) = 227*d + 1081. Let h(r) = 456*r + 2163. Let g(x) = 4*h(x) - 9*s(x). What is the first derivative of g(l) wrt l? -219 Let h = 232 - 228. Find the second derivative of 4*l + 14*l**4 - 3 + 12*l**h + 11*l**4 + 0*l wrt l. 444*l**2 Let g(r) = 2111*r**2 - 23*r + 58. Let n(b) = 10560*b**2 - 112*b + 290. Let c(a) = -19*g(a) + 4*n(a). What is the second derivative of c(i) wrt i? 4262 Suppose 143*a - 144*a = -2. Find the third derivative of -k**3 + 1 + 3 + a*k**6 - 6*k**2 + 62*k**3 wrt k. 240*k**3 + 366 Find the third derivative of -5895*s**3 - 1284 - s + 2512 - 1209 + 6*s**2 wrt s. -35370 What is the derivative of 15 + 1393*i - 214*i - 25 + 15 - 7*i wrt i? 1172 Let g(r) be the third derivative of r**5/60 + r**4/12 - 5*r**3/6 - 4*r**2. Let m be g(2). Differentiate 72 - 7*q**3 - 67 - 5*q**m wrt q. -36*q**2 Find the first derivative of -4578*i**2 + 197*i**2 + 501*i**2 - 3221 wrt i. -7760*i Let n(r) = -22*r + 184. Let k be n(7). Differentiate 10 + k + h - 3*h**2 + 12 with respect to h. -6*h + 1 Suppose -2*c + 3*v = -29, -c + v = -6 - 7. Suppose 5*x - 2*n = 7 + 34, 0 = 5*n - c. Differentiate 9*i - x*i + 28 - 13*i**3 + 0*i with respect to i. -39*i**2 Let l(j) = 13456*j**3 - 3706*j**2 + 2*j - 6. Let q(f) = f**3 + f**2 - f + 3. Let o(s) = -l(s) - 2*q(s). What is the third derivative of o(v) wrt v? -80748 Let b = 28 - 23. Let v(r) be the first derivative of -b*r + 7 - r - r**5 + 7*r. Find the first derivative of v(k) wrt k. -20*k**3 Let v(a) = -66*a**5 + 670*a**2 + 4*a. Let n(d) = -67*d**5 + 669*d**2 + 5*d. Let b(g) = 4*n(g) - 5*v(g). What is the third derivative of b(s) wrt s? 3720*s**2 Differentiate -41081*l**3 - 41083*l**3 + 75*l**4 + 693 + 82162*l**3 with respect to l. 300*l**3 - 6*l**2 Let l(k) be the first derivative of 4*k**5/5 - 317*k**4/4 + 1704*k**3 - 2205. What is the third derivative of l(r) wrt r? 96*r - 1902 Let y(g) be the second derivative of -4019*g**5/10 - 3823*g**3/6 - 476*g. What is the second derivative of y(o) wrt o? -48228*o Let h(d) be the second derivative of 0*d**2 - d - 19/20*d**5 + 0*d**3 - 5/3*d**4 - 9. What is the third derivative of h(a) wrt a? -114 What is the third derivative of 6364237*f**2 - 207*f**3 - 6364851*f**2 - 119*f**3 wrt f? -1956 Let n(l) = 8*l**2 - 5*l + 3. Let d be n(2). Suppose 6*u - 5*g - d = u, -22 = -5*u + 4*g. Differentiate 1 + 7 - 2 - 22 + 20*w**u with respect to w. 40*w Let v(d) be the first derivative of 3*d**5/5 + 33*d**4/4 + 13*d + 62. Let j(s) be the first derivative of v(s). What is the third derivative of j(z) wrt z? 72 Let b(y) = -1264*y**2 - 29*y - 534. Let n(l) = 632*l**2 + 16*l + 276. Let m(q) = -6*b(q) - 11*n(q). What is the first derivative of m(s) wrt s? 1264*s - 2 Let n(r) be the second derivative of 0*r**4 + 0*r**5 - 3/10*r**6 - 29/3*r**3 + 1/21*r**7 + 0 + 0*r**2 - 90*r. Find the second derivative of n(k) wrt k. 40*k**3 - 108*k**2 Let p(d) be the first derivative of -41*d**6/6 + 25*d**4/4 + 2*d**3/3 - 1183*d**2 - 4197. What is the third derivative of p(j) wrt j? -2460*j**2 + 150 Let j(i) be the second derivative of -1438*i**5/5 + 204*i**4 - i**2 - 10422*i. Find the third derivative of j(q) wrt q. -34512 Let j(s) = -30 + 25*s - 17*s + s**2 - 1. Let u be j(-11). What is the derivative of 19 - 2*q - u*q - 16*q wrt q? -20 Let c(m) be the third derivative of -5537*m**5/60 - 6187*m**3/6 - 12007*m**2. Differentiate c(r) wrt r. -11074*r Let k(n) be the first derivative of -23*n**2 + 0*n**4 + 0*n + 0*n**5 + 0*n**3 + 169 - 103/3*n**6. Find the second derivative of k(r) wrt r. -4120*r**3 Let q(o) be the second derivative of -5*o**4/12 + 49*o**3/6 + 378*o**2 - 2783*o. Find the first derivative of q(r) wrt r. -10*r + 49 Differentiate -14*d**2 + 5639*d - 2842*d - 2834*d - 1246 wrt d. -28*d - 37 Let l = -326 + 329. What is the first derivative of -3*d**3 - 5*d - 3 - l*d - 81 + 3*d wrt d? -9*d**2 - 5 Let m = -55 + -14. Let i be -4 + 4 + 4 - m. Find the first derivative of -24 + i - 5*o**4 - 2*o**4 wrt o. -28*o**3 Let j(p) = -69*p - 10. Let x be (-18 + 20)*((-6)/4 - 1). Let m(a) = 70*a + 11. Let l(v) = x*j(v) - 4*m(v). What is the first derivative of l(o) wrt o? 65 Let o(b) = -3*b**4 + 7*b**3 - 4*b**2 + 9*b - 928. Let w(f) = -13*f**4 + 28*f**3 - 17*f**2 + 34*f - 3706. Let g(c) = 17*o(c) - 4*w(c). Differentiate g(j) wrt j. 4*j**3 + 21*j**2 + 17 Suppose 309*m = 312*m - 156. What is the derivative of -2*q**2 + 30*q + 56*q - 127 - 112 - 116 + m wrt q? -4*q + 86 Suppose 0 = -2*l - 4*o + 26, -19 = -4*l - 3*o + 8. Let t(r) be the second derivative of -1/6*r**l + 15*r**2 + 21*r + 0. Differentiate t(u) wrt u. -1 Let p(u) = 1033*u - 924. Let c(t) = -2047*t + 1844. Let z(y) = -3*c(y) - 5*p(y). Differentiate z(h) wrt h. 976 Let v(n) be the first derivative of n**3/3 + 304*n**2 - 1062*n - 2605. What is the derivative of v(o) wrt o? 2*o + 608 Suppose -13*y = 14 - 170. Let p = 6 + 9. Differentiate 12 - p + 15 + 16*s**4 + y wrt s. 64*s**3 What is the third der

Axonal transport of neurofilament proteins in IDPN neurotoxicity. The neurofibrillary changes produced by IDPN are the consequence of the ability of the agent to impair the slow axonal transport of neurofilaments. The susceptibility of various neurons to this effect depends upon their neurofilament content; neurofilament-rich large caliber axons are severely affected. In motor neurons the half-velocities of neurofilament proteins are reduced 2-10 fold, while tubulin and other slow component constituents are only mildly altered. Optic nerve fibers are intermediate in vulnerability, and small neurofilament-poor fibers have little change in slow transport. The agent acts directly on the axon, and the transport defect is expressed all along the course of susceptible axons. Similar alterations in neurofilament transport have recently been found with 3,4-dimethyl-2,5-hexanedione, indicating that similar pathogenetic mechanisms can occur with toxic agents other than IDPN.

Selective reduction of hippocampal dentate frequency potentiation in aged rats with impaired place learning. Induction of posttetanic potentiation (PTP) and long-term potentiation (LTP) was analyzed in hippocampal slices obtained from a) young 6-month-old Sprague-Dawley (SD) rats, all of them performing well in the Morris Maze, and b) aged SD 20-month-old and Fischer 344 24-month-old rats showing different degrees of ability in the same test. After the application of an electrical tetanus 1 s, 100 Hz, 50 microA in the stratum radiatum, no significant differences were found in the percent of induction of both PTP and LTP in the CA1 area of hippocampal slices obtained from rats of different strains and ages. After the application of an electrical tetanus 1 s, 100 Hz, 50 microA in the stratum moleculare, a significant difference was found in the percent of dentate PTP induction in hippocampal slices obtained from rats of different ages. Specifically, dentate PTP induction was significantly (p < 0.01) higher in slices obtained from young SD rats, and from old SD rats with a better performance in the Morris maze, escape latency less than 10 s and 150 cm, than in slices obtained from old SD or Fischer 344 rats that had shown poor performance in the Morris Maze. On the contrary, no significant differences were found in the percent of dentate LTP in hippocampal slices obtained from rats of different strains and ages. The data demonstrate that the induction of hippocampal dentate high-frequency PTP is selectively reduced in old rats with impaired Morris Maze performance.

Daily Archives: October 15, 2008 My column for the FT this week (mentioned here two posts ago) states my own view on the implications of the financial crisis for the future of capitalism–namely, that the effects outside finance will be limited, and this is not the end of capitalism as we know it. Here are two other interesting and forcefully expressed opinions. Harold Meyerson in the Washington Post thinks the game is up for “unregulated capitalism”: In 1949, a number of famous writers, among them Arthur Koestler, André Gide, Richard Wright, Stephen Spender and Ignazio Silone, wrote essays explaining why they were no longer communists. The essays were collected in a volume entitled “The God That Failed.” Today, conservative intellectuals might want to consider writing a tome on the failure of their own beloved deity, unregulated capitalism. The fall of the financial system has been so fast and far-reaching that there’s been no time to fully consider its implications for the reigning economic theology of the past 30 years. But with the most right-wing administration in modern American history scurrying to nationalize the banks, the question cannot be elided indefinitely. What exactly do economic conservatives believe now that their god is dead? What’s become of the glories of privatized Social Security? Of the merits of 401(k)s vs. defined-benefit pensions? No wonder we’ve seen a disoriented John McCain wandering the moors howling about Bill Ayers. What’s he supposed to do? Admit that the Reagan-Thatcher faith in unregulated capitalism, to which every GOP presidential candidate was pledging allegiance just last winter, has collapsed? Interesting to see this dismiss the Clinton and Blair administrations as mere extensions of the Reagan-Thatcher order. Actually I agree with Meyerson about that: they were. But I thought that the Democratic narrative upholds the 1990s as an example of how good things can be when intelligent, well-meaning people are in charge. In other words, good government is more a question of competence and good faith than ideology. To abandon that line, you have to consign Clinton and Blair to the trash. I was also a bit puzzled by this: McCain and Barack Obama disagree sharply on the government’s role in bolstering the economy. Obama favors public outlays on alternative energy and education, which would not only create jobs but also make us more competitive globally. What is this, “make us more competitive globally”? Surely that is the old, dead paradigm. Even as the piece reads its last rites, that Reagan-Thatcher way of thinking is stirring back to life. If you are going to dispense with market forces, I don’t think you can afford to care very much about staying competitive globally. The other piece, much more to my own way of thinking, is by Simon Jenkins. For many years (outside the specialist domain of economic commentary) he has been my favourite British pundit, and one of the two or three best I have come across anywhere. Rigorous, liberal (in the old-fashioned sense), open-minded and surprising. See what you think: So this is to be Brown’s Falklands. Victory on Mount All-fall-down. Bonfire of the bonuses. Service in St Paul’s. March-past by the Royal Troop of Derivatives Traders. Anthem to the Bankers’ Brigade. Tomb of the Unknown Arbitrageur. A fortnight is clearly a long time in ideology. What fun historians will have with October 2008. Do you remember the hoary old days when they let Lehmans go bankrupt and refused to guarantee bank deposits? Where were you when a governor of the Bank of England worried about inflation and something called moral hazard? How tables turn. Socialism is now cock of the walk, capitalism mugged by reality. It is rubbish, total rubbish. Market failure has been compounded by brain failure of the discredited profession of economics, overwhelmed by journalistic wish-fulfilment and glee. The banks have not been “nationalised”, just deluged with money. They remain pluralist and competitive institutions, with independent boards. Their workers are not civil servants. Investors retain their shares. The bonus culture will revive. The impresarios of greed have been punished, or at least a few of them. But this is not socialism in our time, just public money hurled at the face of capitalism. Clive Crook’s blog This blog is no longer updated but it remains open as an archive. I have been the FT's Washington columnist since April 2007. I moved from Britain to the US in 2005 to write for the Atlantic Monthly and the National Journal after 20 years working at the Economist, most recently as deputy editor. I write mainly about the intersection of politics and economics. Clive Crook’s blog: A guide Comment: To comment, please register with FT.com. Register for free here. Please also read the FT's comments policy here.Time: UK time is shown on Clive's posts.Follow the blog: Links to the Twitter and RSS feeds are at the top of the blog.Schedule:Clive's column appears in the FT on Mondays and you can read an excerpt of it on this blog.FT blogs: See the full range of the FT's blogs here.

Characterization of antigen recognized by the monoclonal antibody (4F2): different molecular forms on human T and B lymphoblastoid cell lines. The monoclonal antibody 4F2 recognizes a disulfide-linked ricin-binding glycoprotein complex (Mr congruent to 125,000) composed of a sialylated heavy subunit (Mr congruent to 85,000 on T cell lines) and an unsialylated light subunit (Mr congruent to 41,000). The antigen (T85,41) recognized by 4F2 on T cell lines is structurally distinct from the antigen (B93, 41) on B cell lines. The heavy subunits, but not the light subunits, from all T cell lines examined were uniformly smaller in size than the heavy subunits from several B cell lines. This reflects differences in carbohydrate rather than protein represent in B93,41 compared with T85,41, because both heavy subunits have a common unglycosylated form (p65) and a common partially glycosylated precursor form (p68). Among non-T, non-B hematopoietic cell lines, the monocytoid line U-937 expressed an antigen that resembles B93,41, whereas the erythroleukemic line K-562 expressed an antigen more similar to T85,41. 4F2 recognizes a protein determinant on the heavy subunit (with or without N-linked glycosylation) and also the unglycosylated heavy subunit retains the ability to associate with light subunit. The light subunit itself contains no detectable N-linked carbohydrate. Unlike the transferrin receptor, synthesis of the antigen recognized by 4F2 on the promyelocytic cell line HL-60 did not diminish upon dimethylsulfoxide-induced differentiation, and thus is not tightly correlated with cell proliferation.

package net.sgoliver.android.controlpers2; import android.content.Context; import android.content.res.TypedArray; import android.util.AttributeSet; import android.view.LayoutInflater; import android.view.View; import android.widget.Button; import android.widget.EditText; import android.widget.LinearLayout; import android.widget.TextView; public class ControlLogin extends LinearLayout { private EditText txtUsuario; private EditText txtPassword; private Button btnLogin; private TextView lblMensaje; private OnLoginListener listener; public ControlLogin(Context context) { super(context); inicializar(); } public ControlLogin(Context context, AttributeSet attrs) { super(context, attrs); inicializar(); // Procesamos los atributos XML personalizados TypedArray a = getContext().obtainStyledAttributes(attrs, R.styleable.ControlLogin); String textoBoton = a.getString( R.styleable.ControlLogin_login_text); btnLogin.setText(textoBoton); a.recycle(); } private void inicializar() { //Utilizamos el layout 'control_login' como interfaz del control String infService = Context.LAYOUT_INFLATER_SERVICE; LayoutInflater li = (LayoutInflater)getContext().getSystemService(infService); li.inflate(R.layout.control_login, this, true); //Obtenemoslas referencias a los distintos control txtUsuario = (EditText)findViewById(R.id.TxtUsuario); txtPassword = (EditText)findViewById(R.id.TxtPassword); btnLogin = (Button)findViewById(R.id.BtnAceptar); lblMensaje = (TextView)findViewById(R.id.LblMensaje); //Asociamos los eventos necesarios asignarEventos(); } public void setOnLoginListener(OnLoginListener l) { listener = l; } private void asignarEventos() { btnLogin.setOnClickListener(new OnClickListener() { public void onClick(View v) { listener.onLogin(txtUsuario.getText().toString(), txtPassword.getText().toString()); } }); } public void setMensaje(String msg) { lblMensaje.setText(msg); } }

The World Bank pioneered global HIV and AIDS financing early in the emergency and remains committed to achieving Millennium Development Goal 6, to halt by 2015 and begin to reverse the spread of HIV and AIDS, through prevention, care, treatment, and mitigation services for those affected by HIV and AIDS. Read More » The objective of the Additional Financing for Total War against HIV and AIDS (TOWA) Project is to assist Kenya to expand the coverage of targeted HIV and AIDS prevention... Show More + and mitigation interventions. Negative measures include: dust, air pollution, noise pollution, water pollution, soil erosion, waste management, and borrow pits. Negative measures include: a) locating this site away from residential area in order to avoid dissipation of noxious emissions to the community; b) locating it away from agricultural areas to avoid contamination of food products by effluents. Having it located in a well drained site preferably downhill or away from any water wells. The site can also be drained to avoid stagnation of storm water that can result in to surface pollution or underground pollution; c) locate site at least 50 meters away from any ground water source; and d) plan the layout of the waste disposal area so that the order of utilizing the excavated pits can be determined. Such plans should be able to inform the construction of future new pits at the site since plan drawings are expected to remain in the records of waste disposal units. Show Less - This environmental assessment for Kenya total war against HIV/AIDS project undertakes a situational analysis of health care waste management through assessment of policy,... Show More + legal and administrative framework in relation to health care waste management. The study also assesses the existing technologies, levels and presence of scavenging and recycling; established the cost benefits of public-private partnership in health care waste management, and finally reviews existing training curricula, identifying unmet needs and proposing appropriate and affordable strategies for the training at various levels. Mitigation measures includes: the need to reduce the volume or contaminated and organic waste through shredding, recycling cremation of human body parts, autoclaving. The segregation of material is crucial in order to facilitate hygienic disposal. Proper and adequate facilities for storage of healthcare wastes. Measures will be taken for effective transportation of healthcare wastes. Capacity will be carried out at all levels from generation to disposal through appropriate training, media and other forums. Community awareness and advocacy. Show Less -

Q: Thomas-Wigner rotation of a stick directly from the Lorentz Transformation I'm trying to better understand Thomas-Wigner rotation. I understand how to calculate it for the case of a perpendicular pair of boosts. But I also want to see the rotation more directly. The effect is purely kinematic. It's all within the Lorentz Transformation (LT). It's therefore possible to see the rotation using a pair of LT boosts on some suitable histories. I'm not seeing the correct outcome when I do this. Is my algorithm (below) correct? Notation used here involves three frames: K boosted along the X-axis to K'. then a second boost along the Y-axis of K' to K''. I examine the histories of the endpoints of a stick. the stick is stationary in K'', and it lies along the X''-axis in K'' I get the histories (worldlines) of the end-points of the stick (simple, because the stick is stationary in K'') I then reverse-boost from K'' to K' to K. (I call this reverse because the usual direction is from K to K' to K'') in K, I find two events, one on each history, that are at the same coordinate-time in K. This is a time-slice across the two histories. A time-slice is needed whenever you need to measure spatial geometry. I take the difference between the two events, to get a displacement 4-vector in K, whose ct-component is 0 this displacement 4-vector gives me the geometry of the stick as seen in K I infer the angle of the stick with respect to the X-axis in K It doesn't work. I see rotation and contraction of the stick. The rotation is in the right direction, but it's way too big. Example data: boost 1 [Y,-0.6c] boost2 [X,-0.8c] length of the stick in K: 0.76837 (length is 1.0 in K'') Rotation of the stick from time-slice of histories in K: -38.6598 degrees Thomas-Wigner angle calculated directly from a formula: -18.92464 degrees The formula is $\tan \theta = - (\gamma1 * \gamma2 * \beta1 * \beta2)/(\gamma1 + \gamma2$) (Although you should concentrate on the algorithm stated above, the actual code is here, if it helps.) A: The algorithm is correct in that it shows the geometry of the stick in frame K. But the geometry of the stick is affected not only by Thomas-Wigner rotation, but also by the regular flattening (length contraction) that happens with all boosts. So there are two effects here, not one. The first is the spatial flattening (length contraction) that happens with all boosts, of course. Spatial flattening changes not only lengths, but angles and shapes. In the present case, it changes the orientation of the stick. The second effect is the Thomas-Wigner rotation. The result I have from the algorithm stated above reflects both of these effects (in the position of the stick as measured in K). (All angles in degrees. All measurements in the K frame.) A:Equivalent-boost direction: 24.2277 from the X-axis. B:Angle of the stick from manual calc in code : 38.6598 from the X-axis A+B: angle of stick: 62.8875 from the direction of equivalent-boost C:Thomas-Wigner rotation from a formula: 18.9246 from the X-axis D: flattening (length contraction) of (A + C) from a formula: 62.8875 from the direction of equivalent-boost (same as above) So it seems to all agree, when the two effects are taken into account. The formula for the change in orientation of a stick (used in D) is: $\tan \theta' = \gamma * \tan \theta$

Q: Error converting data type nvarchar to bigint -when joining two differnet data types I am trying to join two tables. Table1.Column1 where column 1 is a BIGInt. On Table2.Column2 where column 2 is Nvarchar. Here is what I am running Select HspId, CMSid, Cast(CMSId as nvarchar) From Q2IMSSiteHistory2015old inner Join HSP on HSP.CMSid = Q2IMSSiteHistory2015old.POS I am getting the following Error: Error converting data type nvarchar to bigint. Even if I do not cast anything I get the same error. A: Cast the join. Select HspId, CMSid, Cast(CMSId as nvarchar) From Q2IMSSiteHistory2015old inner Join HSP on CAST(HSP.CMSid as nvarchar) = Q2IMSSiteHistory2015old.POS

IN THE COURT OF CRIMINAL APPEALS OF TEXAS NO. WR-17,575-06 RONALD MIXON, Relator v. TRAVIS DISTRICT CLERK, Respondent ON APPLICATION FOR A WRIT OF MANDAMUS CAUSE NO. 100459 IN THE 147TH JUDICIAL DISTRICT COURT FROM TRAVIS COUNTY Per curiam. O R D E R Relator has filed a motion for leave to file a writ of mandamus pursuant to the original jurisdiction of this Court. In it, he contends that he filed an application for a writ of habeas corpus in the 147th Judicial District Court of Travis County, that more than 35 days have elapsed, and that the application has not yet been forwarded to this Court. In these circumstances, additional facts are needed. The respondent, the District Clerk of Travis County, is ordered to file a response, which may be made by: submitting the record on such habeas corpus application; submitting a copy of a timely filed order which designates issues to be investigated, see McCree v. Hampton, 824 S.W.2d 578 (Tex. Crim. App. 1992); or stating that Relator has not filed an application for habeas corpus in Travis County. Should the response include an order designating issues, proof of the date the district attorney's office was served with the habeas application shall also be submitted with the response. This application for leave to file a writ of mandamus shall be held in abeyance until the respondent has submitted the appropriate response. Such response shall be submitted within 30 days of the date of this order. Filed: October 12, 2011 Do not publish

Postprandial sphincter of Oddi myoelectric activity and gallbladder emptying. Feeding initiates gallbladder emptying and bile delivery into the duodenum. It is not yet defined how the sphincter of Oddi regulates flow of bile into the duodenum during gallbladder emptying. The aim of this study was to assess postprandial spike burst activity in the sphincter of Oddi, while quantitating gallbladder emptying with noninvasive radioisotope imaging. Six adult opossums were prepared with bipolar electrodes in the sphincter of Oddi. After 2 weeks of recovery the animals were fasted overnight and positioned under a gamma camera, and myoelectric recordings were begun. After two cycles of the migrating motor complex (MMC), 2 mCi 99Tc-HIDA was infused intravenously and permitted to concentrate in the gallbladder for a period of 30 min. Subsequently, a 30-ml liquid meal, containing 0.9 g protein, 3.5 g carbohydrate, and 3.3 g fat, was instilled into the stomach. Sphincter of Oddi myoelectric activity (spike bursts/min) and gallbladder emptying (expressed as percentage of original 99Tc counts in the gallbladder) were measured at intervals for 120 min following feeding. Feeding resulted in prompt gallbladder emptying. Sphincter of Oddi spike burst activity was not altered significantly in the first 30 min after feeding, suggesting that motor activity in the sphincter of Oddi does not initially influence bile flow. Subsequently, spike burst activity increased progressively, suggesting that sphincter of Oddi motor activity may accelerate bile delivery into the duodenum during later phases of gallbladder emptying.

As compared to conventional cathode-ray tubes (CRTs) primarily used for realizing moving images, LCDs (Liquid Crystal Displays) have a drawback, so-called motion blur, which is the blurring of outline of a movement portion perceived by a viewer when displaying an image with movement. It is suggested that this motion blur arises from the LCD display mode itself (see, e.g., patent document 1 and non-patent document 1). Since fluorescent material is scanned by an electron beam to cause emission of light for display in CRTs, the light emission of pixels is basically impulse-like although slight afterglow of the fluorescent material exists. This is called an impulse-type display mode. On the other hand, in the case of LCDs, an electric charge is accumulated by applying an electric field to liquid crystal and is retained at a relatively high rate until the next time the electric field is applied. Especially, in the case of the TFT mode, since a TFT switch is provided for each dot configuring a pixel and each pixel normally has an auxiliary capacity, the ability to retain the accumulated electric charge is extremely high. Therefore, the light emission is continued until the pixels are rewritten by the application of the electric field based on image information of the next frame or field (hereinafter, represented by the frame). This is called a hold-type display mode. Since the impulse response of the image displaying light has a temporal spread in the above hold-type display mode, temporal frequency characteristics are deteriorated along with spatial frequency characteristics, resulting in the motion blur. That is, since the human eye can smoothly follow a moving object, if the light emission time is long as in the case of the hold type, movement of image seems jerky and unnatural due to a time integration effect. To improve the motion blur in the above hold-type display mode, a frame rate (number of frames) is converted by interpolating an image between frames in a known technology. This technology is called FRC (Frame Rate Converter) and is put to practical use in liquid crystal display devices, etc. Conventionally known methods of converting the frame rate include various techniques such as simply repeating read-out of the same frame for a plurality of times and frame interpolation using linear interpolation between frames (see, e.g., non-patent document 2). However, in the case of the frame interpolation process using the linear interpolation between frames, unnaturalness of motion (jerkiness, judder) is generated due to the frame rate conversion, and the motion blur disturbance due to the above hold-type display mode cannot sufficiently be improved, resulting in inadequate image quality. To eliminate effects of the jerkiness, etc., and improve quality of moving images, a motion-compensated frame interpolation (motion compensation) process using motion vectors has been proposed. In this motion compensation process, since a moving image itself is captured and compensated, highly natural moving images can be acquired without deteriorating the resolution and generating the jerkiness. Since interpolation image signals are generated with motion compensation, the motion blur disturbance due to the above hold-type display mode can sufficiently be improved. Above patent document 1 discloses a technology of motion-adaptively generating interpolation frames to increase a frame frequency of a display image for improving deterioration of spatial frequency characteristics causing the motion blur. In this case, at least one interpolation image signal interpolated between frames of a display image is motion-adaptively created from the previous and subsequent frames, and the created interpolation image signals are interpolated between the frames and are sequentially displayed. FIG. 44 is a block diagram of an outline configuration of an FRC drive display circuit in a conventional liquid crystal display device and, in FIG. 44, the FRC drive display circuit includes an FRC portion 100 that converts the number of frames of the input image signal by interpolating the image signals subjected to the motion compensation process between frames of the input video signal, an active-matrix liquid crystal display panel 103 having a liquid crystal layer and an electrode for applying the scan signal and the data signal to the liquid crystal layer, and an electrode driving portion 104 for driving a scan electrode and a data electrode of the liquid crystal display panel 103 based on the image signal subjected to the frame rate conversion by the FRC portion 100. The FRC portion 100 includes a motion vector detecting portion 101 that detects motion vector information from the input image signal and an interpolation frame generating portion 102 that generates interpolation frames based on the motion vector information acquired by the motion vector detecting portion 101. In the above configuration, for example, the motion vector detecting portion 101 may obtain the motion vector information with the use of a block matching method, a gradient method, etc., or if the motion vector information is included in the input image signal in some form, this information may be utilized. For example, the image data compression-encoded with the use of the MPEG format includes motion vector information of a moving image calculated at the time of encoding, and this motion vector information may be acquired. FIG. 45 is a view for explaining a frame rate conversion process by the conventional FRC drive display circuit shown in FIG. 44. The FRC portion 100 generates interpolation frames (gray-colored images in FIG. 45) between frames with the motion compensation using the motion vector information output from the motion vector detecting portion 101 and sequentially outputs the generated interpolation frame signals along with the input frame signals to perform a process of converting the frame rate of the input image signal from 60 frames per second (60 Hz) to 120 frames per second (120 Hz). FIG. 46 is a view for explaining an interpolation frame generation process of the motion vector detecting portion 101 and the interpolation frame generating portion 102. The motion vector detecting portion 101 uses the gradient method to detect a motion vector 105 from, for example, a frame #1 and a frame #2 shown in FIG. 45. That is, the motion vector detecting portion 101 obtains the motion vector 105 by measuring a direction and an amount of movement in 1/60 second between the frame #1 and the frame #2. The interpolation frame generating portion 102 then uses the obtained motion vector 105 to allocate an interpolation vector 106 between the frame #1 and the frame #2. An interpolation frame 107 is generated by moving an object (in this case, an automobile) from a position of the frame #1 to a position after 1/120 second based on the interpolation vector 106. By performing the motion-compensated frame interpolation process with the use of the motion vector information to increase a display frame frequency in this way, the display state of the LCD (the hold-type display mode) can be made closer to the display state of the CRT (the impulse-type display mode) and the image quality deterioration can be improved which is due to the motion blur generated when displaying a moving image. In the motion-compensated frame interpolation process, it is essential to detect the motion vectors for the motion compensation. For example, the block matching method, the gradient method, etc., are proposed as representative techniques for the motion vector detection. In the gradient method, the motion vector is detected for each pixel or small block between two consecutive frames and this is used to interpolate each pixel or small block of the interpolation frame between two frames. That is, an image at an arbitrary position between two frames is interpolated at an accurately compensated position to convert the number of frames. Patent Document 1: Specification of Japanese Patent No. 3295437 Non-Patent Document 1: Ishiguro Hidekazu and Kurita Taiichiro, “Consideration on Motion Picture Quality of the Hold Type Display with an octuple-rate CRT”, IEICE Technical Report, Institute of Electronics, Information and Communication Engineers, ETD96-4 (1996-06), p. 19-26 Non-Patent Document 2: Yamauchi Tatsuro, “TV Standards Conversion”, Journal of the Institute of Television Engineers of Japan, Vol. 45, No. 12, pp. 1534-1543 (1991)

Boards ...and they made an album called "Efta!"?? I was looking through my downloads, and I saw some random folder I'd never heard of, and I loaded it to iTunes. And now I'm hearing an album in a language I've never heard before, and it's not bad, but I googled them and can't find a single link that mentions them. Or the album. And their last.fm page had 1 listener, with 1 play. So confused.

Product Information Light up your life. Each Pairfum Snow Crystal Tin Candle has its own unique crystal structure in the wax. Envelope yourself and your home with a beautifully pure perfume. A sensuous, intensely feminine floral bouquet with regal iris in harmony with jasmine, rose, lily of the valley and freesia, supported by an intoxicating base of powdery iris, musk, precious woods and crystal amber.

Multivalency in Drug Delivery-When Is It Too Much of a Good Thing? Multivalency plays a large role in many biological and synthetic systems. The past 20 years of research have seen an explosion in the study of multivalent drug delivery systems based on scaffolds such as dendrimers, polymers, and other nanoparticles. The results from these studies suggest that when it comes to the number of ligands, sometimes, to quote Shakespeare, "too much of a good thing" is an apt description. Recent theoretical studies on multivalency indicate that the field may have had a misplaced emphasis on maximizing binding strength where in fact it is the selectivity of multivalent drug delivery systems that is the key to success. This Topical Review will summarize these theoretical developments. We will then illustrate how these developments can be used to rationalize the immunoresponses and drug uptake mechanisms for multivalent systems and show the path forward toward the design of better multivalent drug delivery systems.

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<read><delim>\x3e</delim><match><pcre>.*?88 B ></pcre></match></read> <write><data>10 16\x0a</data></write> <read><delim>\x3e</delim><match><pcre>.*?89 B ></pcre></match></read> <write><data>7 14\x0a</data></write> <read><delim>\x3e</delim><match><pcre>.*?89 B ></pcre></match></read> <write><data>3 1\x0a</data></write> <read><delim>\x3e</delim><match><pcre>.*?89 B ></pcre></match></read> <write><data>1 7\x0a</data></write> <read><delim>\x3e</delim><match><pcre>.*?90 B ></pcre></match></read> <write><data>17 6\x0a</data></write> <read><delim>\x3e</delim><match><pcre>.*?90 B ></pcre></match></read> <write><data>19 15\x0a</data></write> <read><delim>\x3e</delim><match><pcre>.*?90 B ></pcre></match></read> <write><data>8 11\x0a</data></write> <read><delim>User</delim><match><pcre>.*?Game Over Stones Exhausted You are a Winner, User</pcre></match></read> </replay> </pov>

Q: Frequent blow outs in the same location I keep getting blow outs in my front tube and always in the same location: right next to the valve stem. The blow outs look like: On this same tube, there is wear on exactly the other side of the valve stem. I have checked the tire and the wheel and there doesn't appear to be anything sharp enough there. What can cause this? I suspect it's something that I'm doing. I'm tired of buying new tubes, as I hear these flats cannot be patched. If it matters, it's a presta valve and I usually inflate to 110 psi, the maximum. A: Check inside the rim at the point where the punctures occur. Is the rim tape intact? Does a spoke push through when weight is placed on the bike? One of my friends had a problem like this, and it turned out that when he sat on the bike his weight caused the end of a spoke to push through the rim and puncture his tyre. A: A few things come to mind: Using a presta tube on a rim designed for schraeder valves. This would cause wear around the valve stem. See "Can I usea a presta tube in a schraeder rim?" for more details. Worn out rim tape near the valve. Does the tape look worn? Is there some nasty edge or burr under the tape that's getting through? Try replacing the rim tape or doubling it up in the area where you're getting the flats. Tubes getting nicked when you install them. When replacing your front tube, do you put the valve stem in first or last? (first is better) Is it possible that the tube is getting pinched against the rim edge when putting the tire back on? A: The picture of your blow-out doesn't show up for me, so I'm guessing a bit based on your description. Do you use the little nut that comes with the tube and threads down the stem of the presta valve? Typically, you'd thread this nut on and screw it down to the rim after installing and inflating the tube. The nut provides a bit of support for the vavle stem against the rim. If you are using this nut, you may be overtightening it. The symptoms if this is the case will be the valve stem separating from the tube where it joins the tube. If this sounds like your problem, I'd suggest you either don't fit the nut or you only fit the nut after you've inflated the tube in the tyre, and that you make sure you don't tighten the nut too tight.

Q: App service plan pricing details This is the details required to fill for App Service plan section What should we enter for the number of instances while entering the details of the App service plan. How is the number of instances determined. suppose a Web App Bot i depolyed in azure using a free account does not use any Virtual Machine..then does it mean the web apps do not need any Virtual Machines even when moved to production also. When i check the Virtual Machines tab in the Azure portal https://portal.azure.com/ it says no virtual Machines to display. A: The Azure VM is where your web app run. So whatever plan you choose, there's at least one VM instance hosting your web app. How is the number of instances determined. The number of instance is determined by two factors. Pricing tier of your App service plan. It decides the maximum of instance you can use. For Free or Shared pricing tier, web apps run on the same VM with apps belonged to other customers, you only need to input 1 if you want to calculate. Your need. For pricing tier Basic+ (Basic, Standard, Premium), you possess more than one dedicated VM instance(You can check the explicit number in portal or here). Thus you can set the instance number from 1 to Maximum mentioned above, according to your requirement. When i check the Virtual Machines tab in the Azure portal, it says no virtual Machines to display. Virtual Machines tab shows the VM resource you create explicitly, while the VM hosting your web app is managed by Azure automatically. Thus you can't see them.

Q: Calling method from a generic wildcard reference the following code is reduced to the essentials for the question: public class GenericTest { private interface CopyInterface<T extends CopyInterface<T>> { public void copyFrom(T source); } public void testMethod() { CopyInterface<?> target; CopyInterface<?> source; target.copyFrom(source); } } This leads to the following compiler error message: The method copyFrom(capture#1-of ?) in the type GenericTest.CopyInterface is not applicable for the arguments (GenericTest.CopyInterface) GenericTest.java /ACAF/src/de/tmasoft/acaftest/attributes line 14 Java Problem When I use the raw type for the variable target, I just get a raw-type warning. Is there a way to get this compiled without using a raw-type? A: You have to make your testMethod() generic and declare that source and target are of the same type: public <T extends CopyInterface<T>> void testMethod() { T target = ...; //initialize the variable T source = ...; //initialize the variable target.copyFrom(source); }

In a typical computing environment, before documents are sent to a printer for printing they are converted into a printer-ready format by a printer driver executing on a computer. For example, users generally work within an application program on a computer to generate or acquire a document or application file. The application program typically permits the user to view the document, manipulate its content, and print the document by selecting a print command. Selecting the print command cues the application program to initiate the print services of the operating system. The print services present a user interface in the form of a print dialog box that allows the user to select various print options prior to printing the document. When the user selects the print option within the print dialog, the application program uses a particular operating system API (application programming interface) to “draw” the document. The operating system collects the drawing commands and uses the printer driver to convert them to a PDL (page description language) format that is specific to the printer. The printer driver then directs the PDL to the printer where it is rendered as hardcopy output. Although the above process is functional, there are several disadvantages associated with the printer driver. Most operating systems come with various types of printer drivers for the most common types of printers. When a particular driver is installed, the associated printer can be used. One problem is that each printer driver is closely associated with the operating system because the imaging system API used by an application to “draw” a document or application file is particular to the operating system. Therefore, a specific printer driver must be developed for each printer (or closely associated group of printers) to function with the various operating system platforms (e.g., Macintosh, Windows, Linux). Thus, a single printer requires the development of as many printer drivers as there are operating systems with which the printer must function. Costs associated with developing numerous printer drivers for each new printer are significant. Another disadvantage related to the specific nature of printer drivers is their consumption of computing resources. Operating systems must include an ever-increasing number of printer drivers to accommodate the various types of printers. Maintaining the numerous printer drivers on a computer can consume valuable memory resources on the computer. In addition, executing printer drivers consumes valuable computer processing resources. Furthermore, if an operating system does not support or include a particular printer driver, the printer driver is typically available for downloading and installation from various locations on the Internet. However, this takes time, effort, and usually a little more know-how than an average user possesses. Yet another disadvantage associated with operating system specific printer drivers is that they are typically activated by a print command from within an application program. Thus, in order for a user to print an application file associated with a particular application program, the application program must be installed on the user's computer. Therefore, users are not typically able to locate particular application files and generate a hardcopy documents if a copy of the associated application program used to create the application files is not resident on the user's computer. Accordingly, the need exists for a way to print application files from computers that does not involve the use of operating system specific printer drivers installed on every computer.

/** * Copyright (c) 2015-present, Facebook, Inc. All rights reserved. * * You are hereby granted a non-exclusive, worldwide, royalty-free license to * use, copy, modify, and distribute this software in source code or binary * form for use in connection with the web services and APIs provided by * Facebook. * * As with any software that integrates with the Facebook platform, your use * of this software is subject to the Facebook Developer Principles and * Policies [http://developers.facebook.com/policy/]. This copyright notice * shall be included in all copies or substantial portions of the software. * * THE SOFTWARE IS PROVIDED "AS IS", WITHOUT WARRANTY OF ANY KIND, EXPRESS OR * IMPLIED, INCLUDING BUT NOT LIMITED TO THE WARRANTIES OF MERCHANTABILITY, * FITNESS FOR A PARTICULAR PURPOSE AND NONINFRINGEMENT. IN NO EVENT SHALL * THE AUTHORS OR COPYRIGHT HOLDERS BE LIABLE FOR ANY CLAIM, DAMAGES OR OTHER * LIABILITY, WHETHER IN AN ACTION OF CONTRACT, TORT OR OTHERWISE, ARISING * FROM, OUT OF OR IN CONNECTION WITH THE SOFTWARE OR THE USE OR OTHER * DEALINGS IN THE SOFTWARE. * */ package com.facebook.ads.sdk; import java.io.File; import java.lang.reflect.Modifier; import java.lang.reflect.Type; import java.util.Arrays; import java.util.HashMap; import java.util.List; import java.util.Map; import com.google.common.base.Function; import com.google.common.util.concurrent.Futures; import com.google.common.util.concurrent.ListenableFuture; import com.google.common.util.concurrent.SettableFuture; import com.google.gson.JsonObject; import com.google.gson.JsonArray; import com.google.gson.annotations.SerializedName; import com.google.gson.reflect.TypeToken; import com.google.gson.Gson; import com.google.gson.GsonBuilder; import com.google.gson.JsonElement; import com.google.gson.JsonParser; import com.facebook.ads.sdk.APIException.MalformedResponseException; /** * This class is auto-generated. * * For any issues or feature requests related to this class, please let us know * on github and we'll fix in our codegen framework. We'll not be able to accept * pull request for this class. * */ public class Flight extends APINode { @SerializedName("applinks") private CatalogItemAppLinks mApplinks = null; @SerializedName("category_specific_fields") private CatalogSubVerticalList mCategorySpecificFields = null; @SerializedName("currency") private String mCurrency = null; @SerializedName("description") private String mDescription = null; @SerializedName("destination_airport") private String mDestinationAirport = null; @SerializedName("destination_city") private String mDestinationCity = null; @SerializedName("flight_id") private String mFlightId = null; @SerializedName("id") private String mId = null; @SerializedName("images") private List<String> mImages = null; @SerializedName("oneway_currency") private String mOnewayCurrency = null; @SerializedName("oneway_price") private String mOnewayPrice = null; @SerializedName("origin_airport") private String mOriginAirport = null; @SerializedName("origin_city") private String mOriginCity = null; @SerializedName("price") private String mPrice = null; @SerializedName("sanitized_images") private List<String> mSanitizedImages = null; @SerializedName("url") private String mUrl = null; protected static Gson gson = null; Flight() { } public Flight(Long id, APIContext context) { this(id.toString(), context); } public Flight(String id, APIContext context) { this.mId = id; this.context = context; } public Flight fetch() throws APIException{ Flight newInstance = fetchById(this.getPrefixedId().toString(), this.context); this.copyFrom(newInstance); return this; } public static Flight fetchById(Long id, APIContext context) throws APIException { return fetchById(id.toString(), context); } public static ListenableFuture<Flight> fetchByIdAsync(Long id, APIContext context) throws APIException { return fetchByIdAsync(id.toString(), context); } public static Flight fetchById(String id, APIContext context) throws APIException { return new APIRequestGet(id, context) .requestAllFields() .execute(); } public static ListenableFuture<Flight> fetchByIdAsync(String id, APIContext context) throws APIException { return new APIRequestGet(id, context) .requestAllFields() .executeAsync(); } public static APINodeList<Flight> fetchByIds(List<String> ids, List<String> fields, APIContext context) throws APIException { return (APINodeList<Flight>)( new APIRequest<Flight>(context, "", "/", "GET", Flight.getParser()) .setParam("ids", APIRequest.joinStringList(ids)) .requestFields(fields) .execute() ); } public static ListenableFuture<APINodeList<Flight>> fetchByIdsAsync(List<String> ids, List<String> fields, APIContext context) throws APIException { return new APIRequest(context, "", "/", "GET", Flight.getParser()) .setParam("ids", APIRequest.joinStringList(ids)) .requestFields(fields) .executeAsyncBase(); } private String getPrefixedId() { return getId(); } public String getId() { return getFieldId().toString(); } public static Flight loadJSON(String json, APIContext context, String header) { Flight flight = getGson().fromJson(json, Flight.class); if (context.isDebug()) { JsonParser parser = new JsonParser(); JsonElement o1 = parser.parse(json); JsonElement o2 = parser.parse(flight.toString()); if (o1.getAsJsonObject().get("__fb_trace_id__") != null) { o2.getAsJsonObject().add("__fb_trace_id__", o1.getAsJsonObject().get("__fb_trace_id__")); } if (!o1.equals(o2)) { context.log("[Warning] When parsing response, object is not consistent with JSON:"); context.log("[JSON]" + o1); context.log("[Object]" + o2); } } flight.context = context; flight.rawValue = json; flight.header = header; return flight; } public static APINodeList<Flight> parseResponse(String json, APIContext context, APIRequest request, String header) throws MalformedResponseException { APINodeList<Flight> flights = new APINodeList<Flight>(request, json, header); JsonArray arr; JsonObject obj; JsonParser parser = new JsonParser(); Exception exception = null; try{ JsonElement result = parser.parse(json); if (result.isJsonArray()) { // First, check if it's a pure JSON Array arr = result.getAsJsonArray(); for (int i = 0; i < arr.size(); i++) { flights.add(loadJSON(arr.get(i).getAsJsonObject().toString(), context, header)); }; return flights; } else if (result.isJsonObject()) { obj = result.getAsJsonObject(); if (obj.has("data")) { if (obj.has("paging")) { JsonObject paging = obj.get("paging").getAsJsonObject(); if (paging.has("cursors")) { JsonObject cursors = paging.get("cursors").getAsJsonObject(); String before = cursors.has("before") ? cursors.get("before").getAsString() : null; String after = cursors.has("after") ? cursors.get("after").getAsString() : null; flights.setCursors(before, after); } String previous = paging.has("previous") ? paging.get("previous").getAsString() : null; String next = paging.has("next") ? paging.get("next").getAsString() : null; flights.setPaging(previous, next); if (context.hasAppSecret()) { flights.setAppSecret(context.getAppSecretProof()); } } if (obj.get("data").isJsonArray()) { // Second, check if it's a JSON array with "data" arr = obj.get("data").getAsJsonArray(); for (int i = 0; i < arr.size(); i++) { flights.add(loadJSON(arr.get(i).getAsJsonObject().toString(), context, header)); }; } else if (obj.get("data").isJsonObject()) { // Third, check if it's a JSON object with "data" obj = obj.get("data").getAsJsonObject(); boolean isRedownload = false; for (String s : new String[]{"campaigns", "adsets", "ads"}) { if (obj.has(s)) { isRedownload = true; obj = obj.getAsJsonObject(s); for (Map.Entry<String, JsonElement> entry : obj.entrySet()) { flights.add(loadJSON(entry.getValue().toString(), context, header)); } break; } } if (!isRedownload) { flights.add(loadJSON(obj.toString(), context, header)); } } return flights; } else if (obj.has("images")) { // Fourth, check if it's a map of image objects obj = obj.get("images").getAsJsonObject(); for (Map.Entry<String, JsonElement> entry : obj.entrySet()) { flights.add(loadJSON(entry.getValue().toString(), context, header)); } return flights; } else { // Fifth, check if it's an array of objects indexed by id boolean isIdIndexedArray = true; for (Map.Entry entry : obj.entrySet()) { String key = (String) entry.getKey(); if (key.equals("__fb_trace_id__")) { continue; } JsonElement value = (JsonElement) entry.getValue(); if ( value != null && value.isJsonObject() && value.getAsJsonObject().has("id") && value.getAsJsonObject().get("id") != null && value.getAsJsonObject().get("id").getAsString().equals(key) ) { flights.add(loadJSON(value.toString(), context, header)); } else { isIdIndexedArray = false; break; } } if (isIdIndexedArray) { return flights; } // Sixth, check if it's pure JsonObject flights.clear(); flights.add(loadJSON(json, context, header)); return flights; } } } catch (Exception e) { exception = e; } throw new MalformedResponseException( "Invalid response string: " + json, exception ); } @Override public APIContext getContext() { return context; } @Override public void setContext(APIContext context) { this.context = context; } @Override public String toString() { return getGson().toJson(this); } public APIRequestGet get() { return new APIRequestGet(this.getPrefixedId().toString(), context); } public APIRequestUpdate update() { return new APIRequestUpdate(this.getPrefixedId().toString(), context); } public CatalogItemAppLinks getFieldApplinks() { return mApplinks; } public CatalogSubVerticalList getFieldCategorySpecificFields() { return mCategorySpecificFields; } public String getFieldCurrency() { return mCurrency; } public String getFieldDescription() { return mDescription; } public String getFieldDestinationAirport() { return mDestinationAirport; } public String getFieldDestinationCity() { return mDestinationCity; } public String getFieldFlightId() { return mFlightId; } public String getFieldId() { return mId; } public List<String> getFieldImages() { return mImages; } public String getFieldOnewayCurrency() { return mOnewayCurrency; } public String getFieldOnewayPrice() { return mOnewayPrice; } public String getFieldOriginAirport() { return mOriginAirport; } public String getFieldOriginCity() { return mOriginCity; } public String getFieldPrice() { return mPrice; } public List<String> getFieldSanitizedImages() { return mSanitizedImages; } public String getFieldUrl() { return mUrl; } public static class APIRequestGet extends APIRequest<Flight> { Flight lastResponse = null; @Override public Flight getLastResponse() { return lastResponse; } public static final String[] PARAMS = { }; public static final String[] FIELDS = { "applinks", "category_specific_fields", "currency", "description", "destination_airport", "destination_city", "flight_id", "id", "images", "oneway_currency", "oneway_price", "origin_airport", "origin_city", "price", "sanitized_images", "url", }; @Override public Flight parseResponse(String response, String header) throws APIException { return Flight.parseResponse(response, getContext(), this, header).head(); } @Override public Flight execute() throws APIException { return execute(new HashMap<String, Object>()); } @Override public Flight execute(Map<String, Object> extraParams) throws APIException { ResponseWrapper rw = executeInternal(extraParams); lastResponse = parseResponse(rw.getBody(), rw.getHeader()); return lastResponse; } public ListenableFuture<Flight> executeAsync() throws APIException { return executeAsync(new HashMap<String, Object>()); }; public ListenableFuture<Flight> executeAsync(Map<String, Object> extraParams) throws APIException { return Futures.transform( executeAsyncInternal(extraParams), new Function<ResponseWrapper, Flight>() { public Flight apply(ResponseWrapper result) { try { return APIRequestGet.this.parseResponse(result.getBody(), result.getHeader()); } catch (Exception e) { throw new RuntimeException(e); } } } ); }; public APIRequestGet(String nodeId, APIContext context) { super(context, nodeId, "/", "GET", Arrays.asList(PARAMS)); } @Override public APIRequestGet setParam(String param, Object value) { setParamInternal(param, value); return this; } @Override public APIRequestGet setParams(Map<String, Object> params) { setParamsInternal(params); return this; } public APIRequestGet requestAllFields () { return this.requestAllFields(true); } public APIRequestGet requestAllFields (boolean value) { for (String field : FIELDS) { this.requestField(field, value); } return this; } @Override public APIRequestGet requestFields (List<String> fields) { return this.requestFields(fields, true); } @Override public APIRequestGet requestFields (List<String> fields, boolean value) { for (String field : fields) { this.requestField(field, value); } return this; } @Override public APIRequestGet requestField (String field) { this.requestField(field, true); return this; } @Override public APIRequestGet requestField (String field, boolean value) { this.requestFieldInternal(field, value); return this; } public APIRequestGet requestApplinksField () { return this.requestApplinksField(true); } public APIRequestGet requestApplinksField (boolean value) { this.requestField("applinks", value); return this; } public APIRequestGet requestCategorySpecificFieldsField () { return this.requestCategorySpecificFieldsField(true); } public APIRequestGet requestCategorySpecificFieldsField (boolean value) { this.requestField("category_specific_fields", value); return this; } public APIRequestGet requestCurrencyField () { return this.requestCurrencyField(true); } public APIRequestGet requestCurrencyField (boolean value) { this.requestField("currency", value); return this; } public APIRequestGet requestDescriptionField () { return this.requestDescriptionField(true); } public APIRequestGet requestDescriptionField (boolean value) { this.requestField("description", value); return this; } public APIRequestGet requestDestinationAirportField () { return this.requestDestinationAirportField(true); } public APIRequestGet requestDestinationAirportField (boolean value) { this.requestField("destination_airport", value); return this; } public APIRequestGet requestDestinationCityField () { return this.requestDestinationCityField(true); } public APIRequestGet requestDestinationCityField (boolean value) { this.requestField("destination_city", value); return this; } public APIRequestGet requestFlightIdField () { return this.requestFlightIdField(true); } public APIRequestGet requestFlightIdField (boolean value) { this.requestField("flight_id", value); return this; } public APIRequestGet requestIdField () { return this.requestIdField(true); } public APIRequestGet requestIdField (boolean value) { this.requestField("id", value); return this; } public APIRequestGet requestImagesField () { return this.requestImagesField(true); } public APIRequestGet requestImagesField (boolean value) { this.requestField("images", value); return this; } public APIRequestGet requestOnewayCurrencyField () { return this.requestOnewayCurrencyField(true); } public APIRequestGet requestOnewayCurrencyField (boolean value) { this.requestField("oneway_currency", value); return this; } public APIRequestGet requestOnewayPriceField () { return this.requestOnewayPriceField(true); } public APIRequestGet requestOnewayPriceField (boolean value) { this.requestField("oneway_price", value); return this; } public APIRequestGet requestOriginAirportField () { return this.requestOriginAirportField(true); } public APIRequestGet requestOriginAirportField (boolean value) { this.requestField("origin_airport", value); return this; } public APIRequestGet requestOriginCityField () { return this.requestOriginCityField(true); } public APIRequestGet requestOriginCityField (boolean value) { this.requestField("origin_city", value); return this; } public APIRequestGet requestPriceField () { return this.requestPriceField(true); } public APIRequestGet requestPriceField (boolean value) { this.requestField("price", value); return this; } public APIRequestGet requestSanitizedImagesField () { return this.requestSanitizedImagesField(true); } public APIRequestGet requestSanitizedImagesField (boolean value) { this.requestField("sanitized_images", value); return this; } public APIRequestGet requestUrlField () { return this.requestUrlField(true); } public APIRequestGet requestUrlField (boolean value) { this.requestField("url", value); return this; } } public static class APIRequestUpdate extends APIRequest<Flight> { Flight lastResponse = null; @Override public Flight getLastResponse() { return lastResponse; } public static final String[] PARAMS = { "currency", "description", "destination_airport", "images", "origin_airport", "price", "url", }; public static final String[] FIELDS = { }; @Override public Flight parseResponse(String response, String header) throws APIException { return Flight.parseResponse(response, getContext(), this, header).head(); } @Override public Flight execute() throws APIException { return execute(new HashMap<String, Object>()); } @Override public Flight execute(Map<String, Object> extraParams) throws APIException { ResponseWrapper rw = executeInternal(extraParams); lastResponse = parseResponse(rw.getBody(), rw.getHeader()); return lastResponse; } public ListenableFuture<Flight> executeAsync() throws APIException { return executeAsync(new HashMap<String, Object>()); }; public ListenableFuture<Flight> executeAsync(Map<String, Object> extraParams) throws APIException { return Futures.transform( executeAsyncInternal(extraParams), new Function<ResponseWrapper, Flight>() { public Flight apply(ResponseWrapper result) { try { return APIRequestUpdate.this.parseResponse(result.getBody(), result.getHeader()); } catch (Exception e) { throw new RuntimeException(e); } } } ); }; public APIRequestUpdate(String nodeId, APIContext context) { super(context, nodeId, "/", "POST", Arrays.asList(PARAMS)); } @Override public APIRequestUpdate setParam(String param, Object value) { setParamInternal(param, value); return this; } @Override public APIRequestUpdate setParams(Map<String, Object> params) { setParamsInternal(params); return this; } public APIRequestUpdate setCurrency (String currency) { this.setParam("currency", currency); return this; } public APIRequestUpdate setDescription (String description) { this.setParam("description", description); return this; } public APIRequestUpdate setDestinationAirport (String destinationAirport) { this.setParam("destination_airport", destinationAirport); return this; } public APIRequestUpdate setImages (List<Object> images) { this.setParam("images", images); return this; } public APIRequestUpdate setImages (String images) { this.setParam("images", images); return this; } public APIRequestUpdate setOriginAirport (String originAirport) { this.setParam("origin_airport", originAirport); return this; } public APIRequestUpdate setPrice (Long price) { this.setParam("price", price); return this; } public APIRequestUpdate setPrice (String price) { this.setParam("price", price); return this; } public APIRequestUpdate setUrl (String url) { this.setParam("url", url); return this; } public APIRequestUpdate requestAllFields () { return this.requestAllFields(true); } public APIRequestUpdate requestAllFields (boolean value) { for (String field : FIELDS) { this.requestField(field, value); } return this; } @Override public APIRequestUpdate requestFields (List<String> fields) { return this.requestFields(fields, true); } @Override public APIRequestUpdate requestFields (List<String> fields, boolean value) { for (String field : fields) { this.requestField(field, value); } return this; } @Override public APIRequestUpdate requestField (String field) { this.requestField(field, true); return this; } @Override public APIRequestUpdate requestField (String field, boolean value) { this.requestFieldInternal(field, value); return this; } } synchronized /*package*/ static Gson getGson() { if (gson != null) { return gson; } else { gson = new GsonBuilder() .excludeFieldsWithModifiers(Modifier.STATIC) .excludeFieldsWithModifiers(Modifier.PROTECTED) .disableHtmlEscaping() .create(); } return gson; } public Flight copyFrom(Flight instance) { this.mApplinks = instance.mApplinks; this.mCategorySpecificFields = instance.mCategorySpecificFields; this.mCurrency = instance.mCurrency; this.mDescription = instance.mDescription; this.mDestinationAirport = instance.mDestinationAirport; this.mDestinationCity = instance.mDestinationCity; this.mFlightId = instance.mFlightId; this.mId = instance.mId; this.mImages = instance.mImages; this.mOnewayCurrency = instance.mOnewayCurrency; this.mOnewayPrice = instance.mOnewayPrice; this.mOriginAirport = instance.mOriginAirport; this.mOriginCity = instance.mOriginCity; this.mPrice = instance.mPrice; this.mSanitizedImages = instance.mSanitizedImages; this.mUrl = instance.mUrl; this.context = instance.context; this.rawValue = instance.rawValue; return this; } public static APIRequest.ResponseParser<Flight> getParser() { return new APIRequest.ResponseParser<Flight>() { public APINodeList<Flight> parseResponse(String response, APIContext context, APIRequest<Flight> request, String header) throws MalformedResponseException { return Flight.parseResponse(response, context, request, header); } }; } }

1. Introduction =============== The synthesis of metal sulfide nanocrystals has attracted much interest for both fundamental research and technological applications in the past decades \[[@B1-nanomaterials-02-00113],[@B2-nanomaterials-02-00113],[@B3-nanomaterials-02-00113],[@B4-nanomaterials-02-00113],[@B5-nanomaterials-02-00113],[@B6-nanomaterials-02-00113]\]. Metal sulfide nanocrystals have been prepared by a wide range of synthetic methods, one of which involves the direct decomposition of molecular precursors \[[@B7-nanomaterials-02-00113],[@B8-nanomaterials-02-00113],[@B9-nanomaterials-02-00113],[@B10-nanomaterials-02-00113],[@B11-nanomaterials-02-00113],[@B12-nanomaterials-02-00113],[@B13-nanomaterials-02-00113],[@B14-nanomaterials-02-00113]\]. Molecular precursor approach has recently been developed as an efficient route to prepare monodispersed semiconductor nanocrystals \[[@B7-nanomaterials-02-00113],[@B10-nanomaterials-02-00113],[@B15-nanomaterials-02-00113]\] and, in some cases, unique shape-control has been achieved \[[@B9-nanomaterials-02-00113],[@B11-nanomaterials-02-00113],[@B16-nanomaterials-02-00113]\]. One of the earliest precursors used for preparing metal sulfides in the literature is *N*,*N*'-dialkyl dithiocarbamate. In this preparation, the precursor was injected into hot coordination solvents such as trioctylphosphine oxide (TOPO) under nitrogen atmosphere at high temperatures \[[@B7-nanomaterials-02-00113],[@B8-nanomaterials-02-00113],[@B9-nanomaterials-02-00113],[@B10-nanomaterials-02-00113],[@B11-nanomaterials-02-00113]\]. Metal bis(benzylthiolates) \[[@B12-nanomaterials-02-00113]\] and metal salts of alkylxanthate \[[@B17-nanomaterials-02-00113],[@B18-nanomaterials-02-00113],[@B19-nanomaterials-02-00113]\] have also been used as precursors to prepare nanocrystalline sulfides of zinc, cadmium or lead via pyrolysis at 150--400 °C. It was found that Lewis base such as hexydecylamine (HDA), trioctylphosphine (TOP) or tributylphosphine (TBP) could lower the reaction temperature for the alkylxanthate precursors. Recently, there are also several reports on the preparation of ternary and metal sulfide nanocrystals via the decomposition of thiocarboxylate precursors \[[@B20-nanomaterials-02-00113],[@B21-nanomaterials-02-00113],[@B22-nanomaterials-02-00113],[@B23-nanomaterials-02-00113],[@B24-nanomaterials-02-00113]\]. Most of these syntheses, nevertheless, require elevated or refluxing temperatures. In this paper, we report a generalized precursor method operating at room temperature for the synthesis of various metal sulfide nanocrystals. The precursors we use are metal thiobenzoates \[M~x~(SCOC~6~H~5~)~y~ or simply MTB\]. These MTB precursors are air-stable and could be readily prepared from thiobenzoic acid and the corresponding metal salts following the known literature method \[[@B25-nanomaterials-02-00113]\]. We illustrate the generality of this MTB method by preparing four types of semiconductors from both transition and main group metals: Ag~2~S, Cu~2−x~S, In~2~S~3~ and CdS. We discuss in this report the basis of our approach and also attempt to understand the reaction mechanism through theoretical Density Functional Theory (DFT) calculations. With this insightful knowledge, we demonstrate how to manipulate the stability of the precursor, and thus the reaction kinetics, to generate different nanostructures. 2. Experimental Section ======================= 2.1. Synthesis of Precursors and Metal Sulfide Nanocrystals ----------------------------------------------------------- Commercially available compounds such as thiobenzoic acid (Fluka), ether, ethanol, chloroform (all from J. T. Baker), sodium bicarbonate (Dumont), silver nitrate (Merck), indium chloride (Fluka), acetonitrile, cadmium acetate, copper chloride, 2,2'-bipyridine, octylamine, dodecylamine and oleylamine (all from Aldrich) were used as received. All of the MTB precursors used in this paper (M = Ag, Cu, In, Cd; TB = thiobenzoate) were prepared according to literature methods \[[@B25-nanomaterials-02-00113]\]. The products obtained were washed with ethanol, dried, and recrystallized from chloroform or ether. Purity of the crystals was checked with microanalysis and their decomposition profiles were investigated by thermogravimetric analysis (TGA). For the synthesis of silver sulfide nanoparticles, AgTB (3 mmol) was stirred in toluene (5 mL) at room temperature, and then added with 1.8 mmol of an amine. A homogeneous clear brown solution formed quickly and the solution was stirred for a further 3 hours. After that, 10 mL of ethanol was added to induce turbidity in the mixture. The brown or dark brown nanoparticles are isolated by centrifugation, washed several times with ethanol and acetone, and then dried under vacuum. The resulting powder can be easily re-dispersed in toluene, hexane, chloroform and other non-polar solvents. The experimental procedure is similar for the synthesis of copper sulfide nanoparticles, except that the reaction mixture turned blue and was stirred overnight. Dark brown or black copper sulfide nanoparticles were isolated, which can be re-dispersed in non-polar solvents such as toluene, hexane and chloroform. The synthesis of cadmium sulfide nanoparticles is similar to silver sulfide and copper sulfide, except that the reaction mixture turned yellow and was stirred for 4 hours at room temperature. Pale yellow product was separated by centrifugation after adding 10 mL of ethanol. The product isolated, after washing with ethanol and acetone, can be re-dispersed in chloroform, hexane and toluene. For the synthesis of indium sulfide nanoparticles, InTB (0.3 mmol) was stirred in toluene (5 mL) at room temperature, and then 1.2 mmol of octylamine (OA) was injected to give a yellow solution. After stirring for 6 hours, 10 mL of ethanol was added to induce the formation of turbidity. The particles were purified similarly to the previous procedure. For the preparation of oleylamine-capped In~2~S~3~ nanoparticles, it was found necessary to further add 40 µL of propylamine to speed up the reaction. 2.2. Characterizations ---------------------- TGA was recorded on a SDT 2960 Simultaneous DTA-TGA by heating approximately 10 mg of the precursor under inert N~2~ flow (flow rate 90 mL/min) at a heating rate of 10 °C/min. X-ray diffraction (XRD) analysis was carried out on a Siemens D5005 X-ray powder diffractometer with Cu Kα radiation (40 kV, 40 mA). The powdered sample was mounted on a sample holder and scanned with a step size of 2θ = 0.05° in the range of 20° to 90°. UV-Visible spectra were recorded using a Shimadzu UV-2550 UV/Vis spectrophotometer. FT-IR spectra were recorded using a FTS 165 Bio-Rad FTIR spectrophotometer in the range of 4000--400 cm^−1^ on KBr or nujol mulls. Transmission electron microscopy (TEM) images were obtained on a 100 kV JEM-100CXII TEM and 200 kV JEOL 2010F microscope. Samples were prepared by placing a drop of the dispersed nanoparticles onto a copper grid with carbon film, and were allowed to dry in a desiccator. 2.3. Computational Methodology ------------------------------ Calculations were performed using the hybrid density functional B3LYP \[[@B26-nanomaterials-02-00113],[@B27-nanomaterials-02-00113]\] method with the effective core potential LanL2DZ \[[@B28-nanomaterials-02-00113],[@B29-nanomaterials-02-00113],[@B30-nanomaterials-02-00113],[@B31-nanomaterials-02-00113]\] basis set. All reported energies include zero point energy corrections. All calculations were performed using the Gaussian 98 \[[@B32-nanomaterials-02-00113]\] suite of programs. Optimization was performed without any constraints and the optimized structures were verified to be equilibrium structures or transition states from frequency calculations. An equilibrium structure is characterized by all real frequencies while a transition state has one and only one imaginary frequency. 3. Results and Discussion ========================= 3.1. Thermal Behavior of the MTB Precursors ------------------------------------------- The decomposition profiles of the four MTB precursors were investigated and their TGA curves are presented in [Figure 1](#nanomaterials-02-00113-f001){ref-type="fig"} and [Table 1](#nanomaterials-02-00113-t001){ref-type="table"}. The analysis indicated a clear onset of decomposition at \~ 200--300 °C in each case. The residual weight after each complete decomposition was found to be close to the expected remaining weight of the corresponding metal sulfide. The slightly higher measured values are possibly due to the presence of some nonvolatile carbon-containing side-products \[[@B33-nanomaterials-02-00113]\]. {ref-type="table"}.](nanomaterials-02-00113-g001){#nanomaterials-02-00113-f001} nanomaterials-02-00113-t001_Table 1 ###### Decomposition onset and weight of residue obtained from TGA plots in [Figure 1](#nanomaterials-02-00113-f001){ref-type="fig"}. Precursors Decomposition onset (°C) Weight of residue (%) ------------------------ -------------------------- ----------------------- ------ **AgSCOC~6~H~5~** 172 51.4 50.6 **CuSCOC~6~H~5~** 155 36.5 35.4 **In(SCOC~6~H~5~)~3~** 196 33.6 31.0 **Cd(SCOC~6~H~5~)~2~** 163 38.5 35.9 The decomposition pathway is expected to be similar to typical thiocarboxylate compounds as proposed by Hampden-Smith \[[@B33-nanomaterials-02-00113]\]: M (SCOC~6~H~5~)~x~ → MS~x/2~ + x/2 (C~6~H~5~CO)~2~S   (1) Hence, in solvents such as carboxylic acid and TOPO, these complexes were found to decompose to the corresponding metal sulfides at elevated temperatures. In our studies, nevertheless, we have found that the MTB precursors decompose readily at room temperature by reacting with various alkylamines. In [Section 3.2](#sec3dot2-nanomaterials-02-00113){ref-type="sec"} below, we first characterize the sizes and morphologies of the nanoparticles prepared. We then present the DFT results on our proposed mechanism in [Section 3.3](#sec3dot3-nanomaterials-02-00113){ref-type="sec"}. 3.2. Preparation and Characterization of Metal Sulfide Nanoparticles {#sec3dot2-nanomaterials-02-00113} -------------------------------------------------------------------- ### 3.2.1. Silver Sulfide Nanoparticles Ag~2~S is a semiconductor with a narrow band gap of 1.08 eV \[[@B34-nanomaterials-02-00113]\]. When AgTB precursor was stirred with octylamine (OA) in toluene at room temperature, monodispersed Ag~2~S nanocrystals can be isolated after 3 hours ([Figure 2](#nanomaterials-02-00113-f002){ref-type="fig"}a). Typical XRD pattern of the nanoparticles prepared from AgTB is shown in [Figure 2](#nanomaterials-02-00113-f002){ref-type="fig"}d. The diffraction pattern revealed good monoclinic crystallinity and fitted well with the α-phase of bulk Ag~2~S (JCPDS 14-72). This is known to be the stable silver sulfide phase which commonly exists at room temperature. The same α-phase silver sulfide nanocrystals were obtained when the reaction was carried out using other amines such as dodecylamine (DDA) and oleylamine (OLA). TEM analysis showed that spherical nanoparticles with reasonable size distribution were produced at room temperature in all these cases. The Ag~2~S nanocrystals obtained from different amines, however, are slightly different in sizes as shown by the size histograms in [Figure 2](#nanomaterials-02-00113-f002){ref-type="fig"}a--c. Thus, average particle diameters of 9.2 ± 1.9, 8.3 ± 1.5 and 7.5 ± 0.9 nm are obtained for reaction with OA, DDA and OLA respectively. In conclusion, the Ag~2~S particle sizes can be controlled by varying the chain length of the alkylamine used, and longer-chain amines tend to produce smaller-sized particles. {#nanomaterials-02-00113-f002} Typical XPS spectra of the Ag~2~S nanocrystals are shown in [Figure 3](#nanomaterials-02-00113-f003){ref-type="fig"}, with binding energies corrected with reference to the C 1s peak at 284.7 eV. The doublet arising from Ag 3d~5/2~ and 3d~3/2~ was detected at 368.0 and 374.1 eV respectively, while the S 2p photoelectron peak appears at 161.7 eV. These values are close to those of bulk Ag~2~S \[[@B35-nanomaterials-02-00113]\]. There is no O 1s peak (531.0 eV) detected on the spectrum, indicating that there is no by-product such as Ag~2~SO~4~ (368.3 eV) or Ag~2~O (368.4 eV) produced. Peak area analysis of the Ag 3d~5/2~ and S 2p peaks, after accounting for elemental sensitivity factors, gives an elemental ratio of 1.97:1 for Ag to S. {#nanomaterials-02-00113-f003} ### 3.2.2. Copper Sulfide Nanoparticles Similarly, we found that CuTB precursors readily decompose by reacting with alkylamines at room temperature to give uniform Cu~2−x~S nanoparticles. TEM analysis ([Figure 4](#nanomaterials-02-00113-f004){ref-type="fig"}a--c) indicated average diameters of 8.1 ± 1.1, 6.1 ± 0.5 and 5.8 ± 0.4 nm for the nanoparticles produced from OA, dioctylamine (DOA) and OLA, respectively. It is well known that copper sulfides exist in many different phases and compositions (Cu~x~S, x: 1 → 2). Non-stoichiometric copper sulfide is readily formed and has been utilized as superionic conductor or p-type semiconductor. XPS peak area analysis gave an elemental Cu to S ratio of 1.72:1 for our samples, thus corresponding to x \~0.28 in the Cu~2−x~S general formula. The XRD pattern in [Figure 4](#nanomaterials-02-00113-f004){ref-type="fig"}d clearly revealed the rhombohedral structure, which fits well with the standard bulk Cu~2−x~S phase (JCPDS 85-1693). {#nanomaterials-02-00113-f004} While DOA also reacts with CuTB to produce copper sulfide nanoparticles at room temperature, we notice that the growth rate is slightly slower and the particles produced are smaller than those prepared with primary amine (*i.e*., OA). We believe that, since OA is less bulky compared to DOA, it attacks the precursor with less hindrance and thus causes the reaction to occur at a faster rate. In addition, DOA is expected to play a better role to efficiently prevent the nanoparticles from aggregation and thus will tend to produce smaller particles. On the other hand, our experiments confirmed that tri-substituted amine does not result in the formation of Cu~2−x~S, probably due to its bulkiness. ### 3.2.3. Indium Sulfide Nanoparticles β-In~2~S~3~ is an n-type semiconductor with a band gap of 2.0--2.2 eV \[[@B36-nanomaterials-02-00113]\]. It has promising applications in the preparation of green and red phosphors for photoconductors and photovoltaics \[[@B37-nanomaterials-02-00113],[@B38-nanomaterials-02-00113],[@B39-nanomaterials-02-00113]\]. In addition, it can serve as a host for a number of metal ions to form semiconducting and/or magnetic materials. In~2~S~3~ nanocrystals have not received as much attention so far, due to the lack of a straightforward preparation methodology. In this case, we have successfully prepared these nanoparticles by decomposing InTB precursor in alkylamines. Reacting InTB with OA could produce spherical In~2~S~3~ with an average diameter of 3.7 ± 0.6 nm ([Figure 5](#nanomaterials-02-00113-f005){ref-type="fig"}a). However, reaction of InTB with OLA or DOA could not proceed at room temperature until the addition of a trace amount of a short chain amine. Thus, upon adding propylamine into OLA, In~2~S~3~ nanoparticles with average diameter of 2.6 ± 0.4 nm could be isolated ([Figure 5](#nanomaterials-02-00113-f005){ref-type="fig"}b). The In~2~S~3~ nanoparticles prepared from OLA and OA show a UV-Vis absorption onset at 355 nm (3.50 eV) and 437 nm (2.84 eV), respectively ([Figure 5](#nanomaterials-02-00113-f005){ref-type="fig"}c). Compared to the band-gap of bulk In~2~S~3~ (2.2 eV or 564 nm) \[[@B36-nanomaterials-02-00113]\], it is clear that the excitonic transition is blue-shifted due to strong quantum confinement in these In~2~S~3~ nanocrystals. [Figure 5](#nanomaterials-02-00113-f005){ref-type="fig"}d shows the XRD pattern of the as-prepared In~2~S~3~ nanoparticles, confirming the tetragonal β-phase of In~2~S~3~ (JCPDS 32-0456). {#nanomaterials-02-00113-f005} ### 3.2.4. Cadmium Sulfide Nanoparticles CdS is one of the most studied metal sulfides, due to its various applications. When CdTB precursor was mixed with OA, spherical CdS nanoparticles with an average diameter of 5.3 ± 0.7 nm were produced ([Figure 6](#nanomaterials-02-00113-f006){ref-type="fig"}a). No reaction had happened, however, in the sole presence of OLA at room temperature. Again, CdS nanoparticles with an average diameter of 4.4 ± 0.3 nm were obtained upon adding a small amount of propylamine into the OLA ([Figure 6](#nanomaterials-02-00113-f006){ref-type="fig"}b). {#nanomaterials-02-00113-f006} The monodispersity of the prepared CdS nanoparticles is manifested in their absorption spectra, which exhibit a clear distinct band rather than a shoulder or threshold ([Figure 6](#nanomaterials-02-00113-f006){ref-type="fig"}c). The band-edge absorption is blue-shifted, occurring at 432 nm for OA-capped and 424 nm for OLA-capped nanocrystals. These gave an estimated particle diameter of 4.9 and 4.0 nm respectively from the Brus equation, in good agreement with those obtained from TEM analysis. CdS is known to exist in two structures: Cubic zinc blende phase and hexagonal wurtzite phase. In our sample, XRD analysis ([Figure 6](#nanomaterials-02-00113-f006){ref-type="fig"}d) suggested a wurtzite crystal structure (JCPDS 41-1049). This observation is interesting, since CdS nanoparticles with zinc blende structure are often produced in ambient conditions, whereas wurtzite structure is often obtained at high temperatures. 3.3. Proposed Mechanism for the Formation of Nanoparticles from the MTB Precursors {#sec3dot3-nanomaterials-02-00113} ---------------------------------------------------------------------------------- ### 3.3.1. The Role of Amine in the Reaction From the above experimental results, we have confirmed that long chain alkylamines such as OA and OLA can react with the thiobenzoate precursors at room temperature to produce monodispersed metal sulfide nanoparticles. Comparatively short chain amines such as propylamine and ethylamine yield larger particles that precipitate quickly from the reaction mixtures. By mixing a small amount of these shorter chain amines into the long chain amines, on the other hand, enables monodispersed nanoparticles to be isolated again. Thus, the long chain amines are needed in this reaction as capping groups to efficiently prevent aggregation of the nanoparticles. After repeating the reactions using different types of amine, we could also conclude that the types of amine used will affect the rate of formation of the specific nanocrystals. Thus, for OLA and aliphatic amines with chains longer than 14 carbon atoms, In~2~S~3~ nanoparticles cannot be produced at room temperature. Hence, heating was needed to initiate this particular reaction. On the other hand, the reaction can be induced at room temperature when a small amount of shorter chain amines are added into the long chain amine. An important aspect of our findings is that MTB precursors are broken down by amines at room temperature. We have found that in other common capping reagents, e.g., TOPO, thiols or carboxylic acids, the decomposition of MTB precursors can only occur at elevated temperatures. We determined the onsets of these reactions by slowly heating up the MTB precursors in these media, and the results are summarized in [Table 2](#nanomaterials-02-00113-t002){ref-type="table"}. We could hence conclude that the decomposition of thiobenzoates in amines is not a simple pyrolysis process. nanomaterials-02-00113-t002_Table 2 ###### Comparison of the decomposition onsets from TGA and reaction in different media for the various MTB precursors. AgTB CuTB InTB CdTB --------------------------- ---------- ---------- ---------- ---------- Decomposition onset (TGA) 172 °C 155 °C 196 °C 163 °C OA Room T Room T Room T Room T Octanethiol \~85 °C \~90 °C \~130 °C \~115 °C TOPO \~130 °C \~130 °C \~160 °C \~150 °C Octanoic acid \~145 °C \~140 °C \~170 °C \~155 °C In addition to the above, we have also confirmed that tertiary amines such as trioctylamine do not react with the MTB precursors even at reflux conditions. Secondary amines, such as DOA, can produce monodispersed nanoparticles from CuTB and AgTB precursors at room temperature, but not with InTB and CdTB. Thus, it seems that amines with an active hydrogen atom are needed for the reaction to proceed at room temperature. On the basis of all the above observations, we propose a general reaction mechanism as follows. The reaction probably arises from an initial attack of the amine group onto the electron-deficient (*i.e*., electrophilic) carbonyl carbon of the MTB precursor \[[@B40-nanomaterials-02-00113]\], and this is followed by an elimination of an amide to produce the metal sulfides ([Scheme 1](#nanomaterials-02-00113-scheme1){ref-type="scheme"}): {#nanomaterials-02-00113-scheme1} For the InTB and CdTB precursor, the reaction with secondary DOA occurs only at elevated temperatures. We believe this is because the bulkier DOA could not access the carbonyl carbon of these di- and tri-substituted MTB precursors readily. As a comparison, we have also performed reactions with shorter chain secondary amines, such as diethylamine and dipropylamine. It was found that reactions of these secondary amines with MTB can occur readily at room temperature. The particles produced, however, are rather large in size, as expected from our proposition that amines are playing dual roles as the nucleophilic reagent and the capping agent. From these results, it can be seen that properties such as coordination ability, steric hindrance, solubility, as well as stability constants are all important factors in the successful preparation of nano-sized crystals from the MTB precursors. ### 3.3.2. Results of DFT Calculations {#sec3dot3dot2-nanomaterials-02-00113} In order to support the proposed mechanism in [Scheme 1](#nanomaterials-02-00113-scheme1){ref-type="scheme"}, we performed DFT calculations by modeling the reaction between MTB precursors with a simple amine-ethylamine. For all the four types of precursors, B3LYP/LanL2DZ optimized transition state structures were located as shown in [Figure 7](#nanomaterials-02-00113-f007){ref-type="fig"}. The zero-point corrected enthalpy change values and energy barriers are tabulated in [Table 3](#nanomaterials-02-00113-t003){ref-type="table"}. For comparison, important geometric parameters of the optimized ground and transition state structures are presented in [Table 4](#nanomaterials-02-00113-t004){ref-type="table"}. Thus, as can be seen in [Figure 7](#nanomaterials-02-00113-f007){ref-type="fig"}, a transition state structure resembling the nucleophilic addition-elimination mechanism proposed is obtained for all the MTB precursors studied. Clearly, a C-N bond (\~1.5--1.6 Å in [Table 3](#nanomaterials-02-00113-t003){ref-type="table"}) is formed between the nucleophilic amine and the electrophilic carbonyl carbon of MTB in the transition state. A simultaneous elimination of amide is also evident from the lengthening of one C-S bond from \~1.8 Å to \~2.7 Å. We notice also that one of the metal-sulfur bonds is shortened during this addition-elimination process towards the formation of metal-sulfur monomer. In [Table 3](#nanomaterials-02-00113-t003){ref-type="table"}, we noted that the DFT predicted activation energy values are similar, (\~110 kJ mol^−1^) for all the four precursors studied. This low energy barrier is in agreement with our observation that these reactions can occur readily at room temperature. Moreover, all the reactions were predicted to give an exothermic enthalpy ranging from 4 to 33 kJ mol^−1^. The calculations further suggested that reactions of AgTB and CuTB will be fast, partly driven by the large exothermic enthalpy change. {#nanomaterials-02-00113-f007} nanomaterials-02-00113-t003_Table 3 ###### B3LYP/LanL2DZ predicted values of energy barrier and enthalpy change for the ethylamine-mediated decomposition of the respective MTB precursors. Precursor Energy barrier (kJ mol^−1^) Enthalpy change (kJ mol^−1^) -------------- ----------------------------- ------------------------------ Ag(SCOPh) 109.7 −33.3 Cu(SCOPh) 109.2 −27.3 Cd(SCOPh)~2~ 108.0 −6.7 In(SCOPh)~3~ 115.3 −4.0 nanomaterials-02-00113-t004_Table 4 ###### Comparison between the B3LYP/LanL2DZ optimized initial state and transition state structures for the ethylamine-mediated decomposition of the respective MTB precursors. Precursor Bond length in precursor (Å) Bond length in transition state structures (Å) -------------- ------------------------------ ------------------------------------------------ ------- ------- ------- ------- Ag(SCOPh) 2.540 1.820 2.398 2.660 1.603 1.061 Cu(SCOPh) 2.348 1.812 2.173 2.669 1.601 1.060 Cd(SCOPh)~2~ 2.632 1.803 2.454 2.801 1.564 1.102 In(SCOPh)~3~ 2.725 1.777 2.373 2.608 1.628 1.035 ^a^Length of the shortened M-S bond; ^b^N-H bond length of ethylamine = 1.017 Å. In order to further elucidate the role of different amines, we also performed B3LYP/LanL2DZ calculations for reactions mediated by different amines. Using a AgTB precursor as the example, transition state structures similar to that shown in [Figure 7](#nanomaterials-02-00113-f007){ref-type="fig"}a were obtained and the calculation results are summarized in [Table 5](#nanomaterials-02-00113-t005){ref-type="table"}. Similarly, the formation of a new C-N bond, lengthening of the C-S bond and shortening of the Ag-S bond are predicted. It is important to highlight that DFT calculations predicted the bond dissociation energy of AgS-COPh as 266.0 kJ mol^−1^, while that of Ag-SCOPh was predicted as 206.4 kJ mol^−1^. Thus, our studies suggest that the stronger S-C bond is broken instead of the weaker Ag-S bond in the presence of amine. In [Table 5](#nanomaterials-02-00113-t005){ref-type="table"}, variations between different amines was predicted to be rather similar, except that the energy barrier is slightly smaller and the exothermic enthalpy is larger in the case of OA and had, as compared to DOA. All these DFT results provided good support to our experimental observations and the proposed mechanism. nanomaterials-02-00113-t005_Table 5 ###### B3LYP/LanL2DZ calculated results for the various amine-mediated decomposition of AgTB. Amine ^a^ N-H bond length (Å) Energy barrier (kJ mol^−1^) Enthalpy (kJ mol^−1^) Bond length in transition state structures (Å) ----------- --------------------- ----------------------------- ----------------------- ------------------------------------------------ ------- ------- ------- EA 1.017 109.7 −33.3 2.398 2.660 1.603 1.061 OA 1.017 107.6 −35.1 2.399 2.670 1.600 1.061 HDA 1.017 107.0 −36.2 2.398 2.680 1.599 1.061 DOA 1.019 108.8 −22.1 2.393 2.945 1.573 1.060 ^a^EA = Ethylamine, OA = Octylamine, HDA = Hexadecylamine, DOA = Dioctylamine;^b^Bond lengths in AgTB precursor: Ag-S = 2.540 Å, C-S = 1.820 Å. ### 3.3.3. FT-IR Analysis of the Reaction Mixtures In order to further support the proposed mechanism, we monitored the reaction at room temperature using FTIR analysis. Reaction mixtures of the respective MTB precursor with OA were concentrated through rotary evaporation and their FTIR spectra were measured. [Figure 8](#nanomaterials-02-00113-f008){ref-type="fig"} shows a typical FTIR spectrum of such reaction mixture, together with the spectra of pure OA and the precursor for comparison. The FTIR spectrum of pure AgTB shows two strong bands at 1602 and 1573 cm^−1^, arising from C=O stretching. These are slightly lower in frequency as compared to υ(C=O) in thiobenzoic acid, due to its strong coordination to the metal ions \[[@B41-nanomaterials-02-00113]\]. Lower frequency peaks at 915, 901 and 647 cm^−1^ resulting from the C-S bending vibration and O-C-S deformation were also observed in the pure AgTB spectrum. On the other hand, the FTIR spectrum of pure OA shows a pair of fairly strong asymmetric and symmetric stretching of primary N-H bands at 3376 and 3292 cm^−1^, and also another N-H bending mode at 1610 cm^−1^. In comparison, the reaction mixture AgTB + OA gives a IR peak of the C=O group at 1641 cm^−1^ ([Table 6](#nanomaterials-02-00113-t006){ref-type="table"}). This position is characteristic of the −C=O bond stretching in amides \[[@B41-nanomaterials-02-00113]\]. Besides, secondary amides often exhibit a relatively strong bending band at about 1543 cm^−1^, attributed to a combination of a C-N stretching band and an N-H bending band. Meanwhile, the doublet of N-H is replaced by a single sharp band at 3310 cm^−1^, typical of the N-H stretching frequency of a secondary amine or an amide. Clearly, the N-H bending mode, existing at 1610 cm^−1^ in pure OA, has disappeared in the reaction mixture. {#nanomaterials-02-00113-f008} nanomaterials-02-00113-t006_Table 6 ###### A comparison of IR spectral bands of AgTB, OA and the mixture of AgTB + OA. Sample Peak Assignments \* (cm^−1^) ----------- ------------------------------ ------ ------ ------ ----- ----- OA 3376 2923 1610 \- \- \- 3292 2861 AgTB \- 3049 \- 1602 915 647 1573 901 AgTB + OA 3310 2928 \- 1641 \- \- 2853 1543 \* υ~s~: stretching; δ~s~: N-H bending; δ: deformation. Thus, the above FTIR analysis confirms the attack of the OA molecule onto the carbonyl carbon of the AgTB precursors to form an intermediate secondary amide adduct. In addition, it was also found that the vibrational peaks of C-S bending and O-C-S deformation detected in AgTB had disappeared from the mixture. This further confirms the breaking down of these bonds as suggested by DFT calculations in [Section 3.3.2](#sec3dot3dot2-nanomaterials-02-00113){ref-type="sec"}. 3.4. Stability of Precursor and Its Influence on the Formation of Nanoparticles ------------------------------------------------------------------------------- In summary, we described above a general precursor method that can be used to prepare metal sulfides at room temperature. Since the injection of reagent is carried out at ambient conditions, special handling techniques are thus not necessary during preparation. In addition, there is just one parameter to monitor once the type of amine is chosen, *i.e.*, the relative amine-to-precursor ratio. This particular simplicity has allowed us to advantageously adopt the method in the preparation of homogeneous nanoparticles/polymer composites, for example, for electrode applications \[[@B42-nanomaterials-02-00113]\]. With a good understanding of the reaction mechanism, we propose to modify the stability of the precursors for controllable growth and crystal engineering. It is known that the growth of colloidal nanocrystals is controlled by a balance between nucleation and growth processes \[[@B43-nanomaterials-02-00113],[@B44-nanomaterials-02-00113]\]. A successful synthetic scheme should start with a burst of nucleation events followed by a controllable growth stage, without either prolonged nucleation or ripening. In addition, anisotropic growth is favored by a sustained high monomer concentration. Hence, as a rule of thumb, a good precursor should be stable enough to prevent individual nucleation to occur, while sufficiently easy to break down to ensure a steady supply of monomers. We illustrate below our attempt to modify the stability of a AgTB precursor to achieve controllable formation of nanoparticles. By dissolving AgTB in trioctylphosphine (TOP) prior to the addition of amine, we found that heating to a temperature greater than 80 °C was required to produce Ag~2~S nanoparticles. In addition, we could obtain β-phase Ag~2~S as the kinetically-driven product by optimizing the reaction temperature and amine-to-precursor ratio \[[@B22-nanomaterials-02-00113]\]. Thus, TOP acts as the stabilizing reagent to AgTB in this case. We performed DFT calculations on complexes of AgTB coordinated to PH~3~ molecules (as a simpler analog of TOP) and the results are shown in [Figure 9](#nanomaterials-02-00113-f009){ref-type="fig"}. In [Table 7](#nanomaterials-02-00113-t007){ref-type="table"}, DFT calculations predicted that three PH~3~ groups could be coordinated to AgTB, with an overall stabilization of \~109 kJ mol^−1^. nanomaterials-02-00113-t007_Table 7 ###### B3LYP/LanL2DZ predicted effect of PH~3~ coordination to AgTB. Structure ^a^ Complex Energy + ZPE (Hartree ^b^) Enthalpy stabilization (kJ mol^−1^) --------------- ---------------- ---------------------------- ------------------------------------- \- AgTB −500.73344 \- \- PH~3~ −8.24658 \- 1 AgTB(PH~3~) −509.01069 −80.5 2a AgTB(PH~3~)~2~ −517.26284 −95.1 2b AgTB(PH~3~)~2~ −517.26420 −98.7 3 AgTB(PH~3~)~3~ −525.51484 −109.4 ^a^ The fully optimized structures are shown in [Figure 9](#nanomaterials-02-00113-f009){ref-type="fig"}; ^b^ 1 Hartree = 2625.502 kJ mol^−1^. {#nanomaterials-02-00113-f009} In addition, we have also located the transition states for the proposed amine-mediated nucleophilic attack onto the complexes by DFT calculations. We modeled the reaction using ethylamine attacking onto three different precursors: AgTB, AgTB(PH~3~) and AgTB(PMe~3~). The optimized transition state structures and their important geometrical parameters are compared in [Figure 10](#nanomaterials-02-00113-f010){ref-type="fig"} and [Table 8](#nanomaterials-02-00113-t008){ref-type="table"}. The DFT predicted energy barriers are 109.7 kJ mol^−1^, 124.1 kJ mol^−1^ and 128.6 kJ mol^−1^ for these three precursors respectively. The slightly higher barrier (\~14--19 kJ mol^−1^) predicted for reactions involving AgTB(PH~3~) and AgTB(PMe~3~) is in agreement with our experimental observations. Thus, we demonstrated that the desired control over nucleation and growth can be achieved through optimizing the delicate balance between the amount of activator (amine) and stabilizer (TOP). We have indeed found this to be general and applicable to most of the MTB precursors studied. For instance, we have varied the type of activator (from OA to dodecanethiol) and stabilizer (from TOP to tributylphosphite) to produce Cu~2−x~S of different crystalline phases \[[@B23-nanomaterials-02-00113]\]. By further changing the activator to difunctional amine such as ethylenediamine, dendritic Cu~2−x~S crystals were produced, giving well-defined snowflakes and blossom-like shapes \[[@B24-nanomaterials-02-00113]\]. {#nanomaterials-02-00113-f010} nanomaterials-02-00113-t008_Table 8 ###### Important B3LYP/LanL2DZ geometrical parameters for the various transition state (T.S) structures, compared with those in the precursor complex (P) and ethylamine (EA). Precursor complex (P) Bond length (Å) ----------------------- ----------------- ------- ------- ------- ------- ------- ------- AgTB 2.540 2.398 1.820 2.660 1.603 1.017 1.061 AgTB(PH~3~) 2.495 2.382 1.822 2.716 1.585 1.079 AgTB(PMe~3~) 2.496 2.390 1.822 2.731 1.579 1.087 4. Conclusions ============== In summary, we have reported here a simple route to prepare various types of metal sulfide nanoparticles readily from metal thiobenzoate precursors under ambient conditions. Such a simple and specific process may be utilized for the production of nanostructures and nanocomposites, and for applications such as nanofabrication and nanopatterning at ambient temperature. Principles we have demonstrated in this report include: (1) by choosing a suitable capping agent that can initiate an attack onto the functionality of the precursor, a relatively less stable intermediate may be generated and this can lead to breaking down of the precursor at room temperature. We believe this also explains why precursors such as metal dithiocarbamate or metal alkylxanthate could react with amine to generate the corresponding semiconductors at temperatures well-below their decomposition onsets \[[@B12-nanomaterials-02-00113],[@B15-nanomaterials-02-00113]\]; (2) by choosing a suitable coordination group, stability of the precursor may be optimized such that the decomposition can be moved to a kinetically-controlled regime. We believe this general principle can be used to guide the preparation of other types of metal chalcogenides from suitable precursors. This research work is supported by the National University of Singapore research grant R-143-000-167-112.

Q: WIndows 10 UWP - How can I determine if a Key press is a letter or number? Windows 10 UWP: Example: On UWP grid, a button1.content = 1 and a textbox. Using mouse to press button1.content, 1 is shown in the textbox.text. How to simulate numeric keypad (1) and 1 is shown in the textbox.text? A: You can use TextBlock.Text to set the text to TextBlock. If you want to know the key press, you should add KeyDown in Grid <Grid KeyDown="Grid_OnKeyDown"></Grid> And add the following code private void Grid_OnKeyDown(object sender, KeyEventArgs e) { var str = e.Key.ToString(); if (char.IsDigit(str[0])) { //is digit } // is letter } You can use TextBlock.Text = xx to set the TextBlock.

119 F.Supp.2d 485 (2000) Jean Patrick MICHEL, Petitioner v. IMMIGRATION AND NATURALIZATION SERVICE, Respondent No. 4:CV-99-1879. United States District Court, M.D. Pennsylvania. November 3, 2000. Sandra L. Greene, York, PA, for petitioner. Kate L. Mershimer, Assistant United States Attorney, Harrisburg, PA, for respondent. MEMORANDUM McCLURE, District Judge. BACKGROUND: On October 22, 1999, petitioner Jean Patrick Michel, acting pro se, commenced this action by filing a document denominated "Motion for bond/relief under 28 U.S.C. [§] 2241." Michel is a native and citizen of Haiti who is currently a detainee of the Immigration and Naturalization Service (INS). He is subject to a final order *486 of deportation issued December 3, 1997, but INS has not been able to effectuate the deportation, apparently due to slow action on the part of Haiti. Succinctly stated, Michel seeks release on bond pending his removal. Before the court is the report and recommendation of U.S. Magistrate Judge Thomas M. Blewitt, which recommends that the petition be denied. DISCUSSION: I. STANDARD A district court is required to review de novo those portions of a magistrate judge's report to which objections are made. Commonwealth of Penna. v. United States, 581 F.Supp. 1238, 1239 (M.D.Pa.1984); 28 U.S.C. § 636(b)(1). When no objections are filed to the report of a magistrate judge, a court has discretion to review that report as it deems appropriate. A magistrate judge's finding or ruling on a motion or issue properly becomes the holding of the court unless objections are filed. Thomas v. Arn, 474 U.S. 140, 106 S.Ct. 466, 88 L.Ed.2d 435 (1985). However, the district court may not grant a motion for summary judgment, Fed.R.Civ.P. 56, or a motion to dismiss under Fed.R.Civ.P. 12(b)(6) solely because the motion is unopposed; such motions are subject to review for merit. Stackhouse v. Mazurkiewicz, 951 F.2d 29, 30 (3d Cir. 1991); Anchorage Associates v. Virgin Islands Board of Tax Review, 922 F.2d 168, 174 (3d Cir.1990). Michel has filed objections to the report and recommendation which we review de novo. II. STATEMENT OF FACTS AND PROCEDURAL HISTORY Michel is a native and citizen of Haiti who entered the United States on September 11, 1971, as a lawful permanent resident. In October, 1997, INS issued an order to show cause alleging that Michel had been convicted twice in 1994 of criminal possession of stolen property, and was therefore removable under 8 U.S.C. § 1227(a)(2)(A)(ii). An immigration judge found Michel removable, a decision upheld by the Board of Immigration Appeals (BIA) on October 27, 1998. However, the Court of Appeals for the Second Circuit issued a stay of removal during the pendency of an appeal to that court. The Second Circuit has since affirmed the final order of removal and lifted the stay. Michel v. I.N.S., 206 F.3d 253 (2d Cir.2000). See also 8 U.S.C. § 1229b(c)(6). The removal is based on Michel's two convictions for crimes of moral turpitude. While the appeal was pending, Michel requested release on a $15,000.00 bond. The District Director in New York denied the request and notified Michel that he had the right to appeal to the BIA. No appeal from the denial was filed. Originally, Michel was released on bail by an immigration officer. However, the immigration judge revoked bail, stating that Michel was ineligible. Michel has remained in custody while INS attempts to effect his deportation to Haiti. Although Haiti accepts deportees from the United States, the process is slow. Given the above recitation, the issues before this court are limited. Michel is not one of those aliens subject to removal whose native country will not accept him, so that he is not likely to be subject to permanent detention. Also, there is no question regarding deportability, as any such question is answered by the Second Circuit's affirmance of the order of removal. Further, Michel may not petition for a waiver of deportation because he previously has received such a waiver. 206 F.3d at 257. The sole question is whether a resident alien who is subject to removal for committing crimes of moral turpitude has the right to be released on bond because his native country moves slowly to accept him. As recited by the magistrate judge, Michel has stated the issue as whether the failure to release him from custody on bond after the expiration of the 90-day *487 removal period violated his right to due process. Report and Recommendation at 3 (quoting Petitioner's Amended Reply to Respondent's Brief at 1). III. JURISDICTION As a preliminary matter, we note that INS argued before the magistrate judge that the court lacked jurisdiction over the denial of bond pursuant to 8 U.S.C. § 1226(e). The undersigned judge so held in Jacques v. Reno, 73 F.Supp.2d 477 (M.D.Pa.1999). In Chi Thon Ngo v. I.N.S., 192 F.3d 390 (3d Cir.1999), our Court of Appeals held, though without analysis, that the district court had jurisdiction over a petition for a writ of habeas corpus under § 2241. Id. at 393 (citing Sandoval v. Reno, 166 F.3d 225, 237-238 (3d Cir.1999); DeSousa v. Reno, 190 F.3d 175, 182 (3d Cir.1999)). The petitioner in Chi Thon Ngo was an excludable alien who was subjected to exclusion proceedings for lack of a valid immigrant visa and for conviction of crimes of moral turpitude and aggravated felonies. Id. at 392. He claimed to be eligible for release because his country of origin would not accept him. Id. at 393. The statutory provision on which we relied in Jacques, § 1226(e), also would apply to proceedings involving a petitioner like that in Chi Thon Ngo. It follows, then, that the Third Circuit necessarily has abrogated Jacques to the extent we found that our jurisdiction to entertain a petition for a writ of habeas corpus had been repealed by § 1226(e).[1] We turn, then, to the merits of the petition. IV. RELEASE ON BOND As noted, Michel claims to be entitled to release on bond or under an order of supervision because the 90-day period for removal has expired. The claim is asserted as arising under the Due Process Clause of the Fifth Amendment. Once an alien is ordered "removed," INS[2] is afforded a 90-day period in which to effect removal. 8 U.S.C. § 1231(a)(1)(A). The alien is subject to detention during the removal period. Sec. 1231(a)(2). After expiration of the 90-day period, the alien may be released under specified conditions. § 1231(a)(3). While aliens such as Michel who are deportable under § 1227(a)(2)(A)(ii) must be detained pending a final order of removal, 8 U.S.C. § 1226(c)(1)(B), inadmissible aliens, aliens removable under 8 U.S.C. § 1227(a)(1)(C), (a)(2), or (a)(4), and aliens determined to be a risk to the community or unlikely to comply with the removal order may be detained after expiration of the 90-day period. § 1231(a)(6). See also 8 C.F.R. §§ 241.1 et seq. (regulations governing post-hearing detention and removal, including continued detention and conditions of release). Michel argues, however, that this statutory language violates his right to substantive due process because it requires that he be kept in prolonged detention, i.e. deprives him of his fundamental right to liberty, without an adequate governmental interest justifying the intrusion. The basic *488 disagreement between the parties is the extent to which Michel's asserted liberty interest is cognizable under the substantive component of the Due Process Clause. This disagreement also is reflected in opinions by judges of this court on which the parties rely. In Sombat Map Kay v. Reno, 94 F.Supp.2d 546 (M.D.Pa.2000), Judge Rambo found that a deportable alien whose country of origin would not accept him was entitled to release on conditions. Judge Caldwell disagreed, finding that periodic review of an alien's continued detention satisfied the Due Process Clause. Cuesta Martinez v. I.N.S., 97 F.Supp.2d 647 (M.D.Pa.2000). We begin with some of the case law leading to those decisions, as well as opinions issued thereafter which put the decisions into context. (A) Other Authority In Chi Thon Ngo, the petitioner was a native of Viet Nam who was paroled into the United States in 1982. He was convicted in state court for firearm possession and for attempted robbery in unrelated events. He was ordered to be deported in 1995 because he lacked a valid visa, he committed a crime involving moral turpitude, and he committed two crimes for which the sentences imposed were greater than five years. Important in the analysis was the fact that the petitioner was paroled into the country, meaning that he had not been admitted formally and was considered to have the status of an applicant for admission, despite his lengthy residence in the United States. Id. at 392 and n. 1. The petitioner claimed that Viet Nam's refusal to take him back meant that he was subject to virtually indefinite detention. Id. at 392-393. The Third Circuit first reviewed the applicable provisions of the Immigration and Nationality Act, both before and after amendment through the Antiterrorism and Effective Death Penalty Act of 1996 (AEDPA), Pub.L. No. 104-132, 110 Stat. 1214, and the Illegal Immigration Reform and Immigrant Responsibility Act of 1996 (IIRIRA), Pub.L. No. 104-208, 110 Stat. 3009. Because both versions of the statutes granted INS the authority to detain or release on conditions, there was no need to determine which version applied. Id. at 394-395. There are conflicting constitutional and policy considerations at issue in that Congress has attempted to insulate the national community from potentially dangerous criminal aliens, and aliens released from custody have a great potential to abscond, but those aliens have due process rights. Id. at 395. The problem was to find a way of satisfying these conflicting interests. The Third Circuit first noted that the exclusion of aliens is a matter generally for the political branches and that, in many instances, the exercise of the power over naturalization and immigration would be unacceptable if applied to citizens. Id. at 395-396. Still, an alien is a "person" entitled to substantive due process protection and, in some circumstances, procedural due process. Id. at 396. The Third Circuit then reviewed a number of cases involving the detention of excludable aliens in which courts found no substantive due process violation. The one exception was a case decided before INS promulgated regulations relating to periodic parole review for Mariel Cubans. Also, one case involved a deportable alien whose continuing detention was upheld, subject to the same regulations. Id. at 396-397. The Third Circuit summarized these holdings as follows: ... [T]here is no constitutional impediment to the indefinite detention of an alien with a criminal record under a final order of exclusion, deportation, or removal if (1) there is a possibility of his eventual departure; (2) there are adequate and reasonable provisions for the grant of parole; and (3) detention is necessary to prevent a risk of flight or a threat to the community. Id. at 397. Therefore, while recognizing that the "entry fiction" is precisely that, a fiction, *489 and that detention indeed is tantamount to punishment, the Third Circuit concluded that continued detention for lengthy periods was permissible as long as adequate provisions for parole are available. Id. at 397-398. Its holding was limited to excludable aliens, with no views expressed on the applicability of the same principles in cases involving deportable aliens. Id. at 398 n. 7. Because the regulations governing parole review for the Mariel Cubans satisfied the Due Process Clause if applied properly, and negotiations were underway with Viet Nam (so that detention could not be said to be permanent), INS was given 30 days to conduct the necessary parole review or the petitioner would be released. Id. at 398-399. For present purposes, the upshot of Chi Thon Ngo is that, at least as applies to excludable aliens, prolonged detention does not violate due process as long as the type of review described therein is provided. The question becomes whether the same principle will apply to deportable aliens. One of the cases cited by Judge Rambo in Sombat Map Kay is Binh Phan v. Reno, 56 F.Supp.2d 1149 (W.D.Wash.1999) (en banc).[3] In that case, the five judges of the Western District of Washington sat en banc to review five "lead cases" so that they would have a common framework for analyzing due process claims in a large number of immigration cases then pending. Id. at 1151. In an opinion by Chief Judge Coughenour, the court first reviewed the statutory and regulatory framework, determined that it had jurisdiction under § 2241, and rejected a government argument that administrative exhaustion was required before the court should entertain the claims. Id. at 1151-1153. It then turned to the petitioners' due process arguments. Initially, the court noted that all aliens have liberty interests under the Fifth Amendment, but that excludable aliens are limited in that interest to the procedure explicitly authorized by Congress due to the entry fiction. Id. at 1153-1154. However, because lawfully admitted aliens develop ties that go with permanent residence, their constitutional status changes, and they are entitled to greater protection under the Due Process Clause. Id. at 1154. See also id. at 1154 n. 6 (referring to the foregoing principle as the "assimilation doctrine"). Having noted that the first question in substantive due process analysis is a careful description of the asserted right, the court rejected the government's description of the right as the right to be released into the United States pending removal. Rather, the right is the fundamental interest in liberty generally. Id. at 1154. Because the described right is fundamental, the questioned government action is subject to "strict scrutiny," meaning that "a deprivation will comport with due process only if it is narrowly tailored to serve a compelling government interest." Id. at 1154-1155 (citation omitted). Applying this standard, the court looked at the asserted government goals in detaining deportable criminal aliens and whether the detention is excessive in light of those goals. It also examined the goals in the context of the government's (or at least the political branches') usual plenary authority over immigration matters. It rejected a more deferential standard because *490 there was no need to extend such deference beyond the deportation order, as the governmental interests asserted (prevention of flight and protection of the public) are domestic, and not foreign policy, matters. Id. at 1155. The court concluded that, balanced against the likelihood that the government would effectuate removal and the dangerousness of the individual alien, the detention of an alien did not comport with substantive due process when there is no realistic chance that the alien will be removed. Id. at 1155-1156. Diametrically opposed to Binh Phan is Zadvydas v. Underdown, 185 F.3d 279 (5th Cir.1999), reh'g en banc denied, cert. granted, ___ U.S. ____, 121 S.Ct. 297, ___ L.Ed.2d ____ (2000). The petitioner in that case had a complicated history relating to his country of origin because his parents were "displaced persons" in Germany in the aftermath of World War II. Both parents were from historically disputed territory which, at various times, was independent Lithuania, territory of Nazi Germany, or part of the Soviet empire. In addition, Germany requires birth of German blood for citizenship, as opposed to birth on its territory (as would apply in the United States). The complications arising from this parentage prevented easy resolution of the problem of finding a country willing to accept the petitioner after removal from the United States. In addition, the Dominican Republic, the country of origin of the petitioner's wife, did not respond to inquiry from INS. Regardless, the petitioner had been admitted lawfully to the United States but had committed offenses which left him subject to a final order of deportation. He was detained by INS as a flight risk. Id. at 283-284. The Fifth Circuit also reviewed the statutory and regulatory context of the petition and found jurisdiction. Id. at 285-288. It then reviewed precedent concerning the sovereign's power to control immigration matters, describing this power as "essentially plenary." Id. at 288-289. While aliens have rights as "persons" for purposes of the Fifth Amendment, those rights are limited by the sovereign's plenary powers. Thus, while an illegal alien cannot be sentenced to hard labor without due process, id. at 289 (citing Wong Wing v. United States, 163 U.S. 228, 16 S.Ct. 977, 41 L.Ed. 140 (1896)), the constitutional rights of aliens may be restricted when they conflict with the sovereign's plenary power. Id. (citing, inter alia, Kleindienst v. Mandel, 408 U.S. 753, 92 S.Ct. 2576, 33 L.Ed.2d 683 (1972) (citizens had First Amendment interest in listening to communist agitator, but government could exclude agitator; by implication, agitator's interest in speech did not outweigh plenary power)). The Fifth Circuit then distinguished Wong Wing, in which the alien was summarily punished to a year at hard labor and thereafter to removal from the United States. The Supreme Court itself noted in that opinion that detention pending deportation is not the same as detention as punishment for being illegally present in this country because the former is necessary to the deportation proceedings. Zadvydas at 289 (quoting Wong Wing at 980; removal proceedings "would be in vain" if the alien could not be detained). The Fifth Circuit then restated the principle that excludable aliens could be detained for an indefinite period of time pending removal, citing its prior holding in a case involving Mariel Cubans. Id. at 290 (citing Gisbert v. U.S. Attorney General, 988 F.2d 1437 (5th Cir.1993)). It rejected the petitioner's argument that, as a deportable alien, he had greater substantive rights than an excludable alien. The difference in rights applies to the procedural protections applicable to the decision to deport, as compared to the decision to exclude, and does not affect substantive rights once there has been a decision to deport or exclude. Id. Next, the court engaged in an analysis of whether the petitioner's detention in fact could be considered permanent, and *491 determined that it could not, at least not until potential avenues for finding a country which would accept him were exhausted. Id. at 291-294. It then returned to the question of a deportable alien's substantive rights. With respect to excludable aliens, when they seek to enter this country, they are requesting a privilege rather than asserting a right. Exclusion therefore is not a deprivation of rights but a denial of a privilege, which, in combination with the deference due in immigration matters, means that the decision is not subject to procedural limitations. Moreover, most substantive rights are constrained by the government's need to control immigration. Id. at 294. To the extent that substantive rights are infringed in a manner unconnected to the immigration power, an excludable alien may assert such rights. This would include the right to be free from malicious infliction of cruel treatment. Id. at 295. In contrast, resident aliens are entitled to procedural due process prior to removal. This right arises from their continued presence in the country and the ties that naturally arise therefrom. Still, the plenary power is not extinguished, and the fact that the standard for evaluating the procedures used is lower than would be applied in the case of a citizen demonstrates the continued viability of the plenary power. Id. (also collecting cases). Nothing in the case law reviewed, however, indicated that a deportable alien has greater substantive rights than excludable aliens when the right asserted and the government interest asserted are the same. Id. In the circumstances presented here, the national interest in effectuating deportation is identical regardless of whether the alien was once resident or excludable. When a former resident alien is—with the adequate and unchallenged procedural due process to which his assertion of a right to remain in this country entitles him—finally ordered deported, the decision has irrevocably been made to expel him from the national community. Nothing remains but to effectuate this decision. The need to expel such an alien is identical, from a national sovereignty perspective, to the need to remove an excludable alien who has been finally and properly ordered returned to his country of origin.... Whether the party to be deported is an excludable or a former resident, the United States has properly made its decision and earnestly wishes—if for no other reason than to save the cost of detention—to deport the detainee. And deportation itself is not punishment.... Id. at 296 (citations omitted). The Fifth Circuit continued by pointing out that the fact that deportation cannot be effected immediately is not a ground for distinguishing between deportable and excludable aliens. In both instances, the government's interest is in preventing crimes against the populace and preventing flight which would defeat the deportation decision. The court emphasized that society must tolerate levels of recidivism from citizens but need not be so generous to non-citizens. Also, the legitimacy of the government's concern about flight is reflected in the fact that the event has occurred with some frequency. Id. at 296-297. To the extent that a resident alien has an interest greater than that of an excludable alien, that interest is in the procedural protections honored in making the deportation decision, and that difference disappears once the final decision is made. Id. at 297. For these reasons, the Fifth Circuit concluded that INS could detain deportable aliens subject to the same limitations (good faith efforts to effect deportation, along with reasonable parole and periodic review procedures) as apply to the detention of excludable aliens subject to prolonged detention. Id. The court specifically rejected the conclusions reached by the Western District of Washington. Id. at 297 n. 20. *492 Even more recently, the Tenth Circuit addressed the same issues in Duy Dac Ho v. Greene, 204 F.3d 1045 (10th Cir.2000). The petitioners (two cases were consolidated on appeal) were both natives and citizens of Viet Nam who entered the United States lawfully but were subjected to final orders of removal for having committed aggravated felonies. Id. at 1048. The district court granted petitions under § 2241 after reading the governing statutes as not authorizing continued detention and concluding that continued detention violated the petitioners' substantive due process rights. Id. at 1049-150. For reasons not relevant to this discussion, the Tenth Circuit concluded that it had jurisdiction and that the statutes permitted indefinite detention. Id. at 1050-1057. In addressing the substantive due process argument, the court first noted that it was not bound by a prior opinion in which the constitutional analysis was viewed properly as dicta. Id. at 1057. The court next characterized the asserted right not as a general right to be free of incarceration without a criminal trial, but as a right to be at large in the United States, the very right denied them by the final orders of removal. The rationale was that their petition in effect was a request to be readmitted to the United States. Id. at 1058. Although aliens present in the United States are persons for purposes of the Fifth Amendment, the petitioners' heightened constitutional status was stripped by the final orders of deportation and they stood as applicants for admission, with no greater expectations than first-time applicants. Id. at 1058-1059. Addressing the argument of one petitioner who claimed greater rights as a former lawful resident alien, the Tenth Circuit relied on Zadvydas and found no distinction between former resident aliens and excludable aliens. Id. at 1059. It therefore concluded that the petitioners had no due process right, substantive or procedural, of which they were deprived through the denial of "their application for entry," and the district court's judgment was reversed. Id. at 1060. One judge dissented in Duy Dac Ho, essentially for the reasons recited in Binh Phan. Duy Dac Ho at 1060-1063. The final case to be taken into consideration is Kim Ho Ma v. Reno, 208 F.3d 815 (9th Cir.2000). In that case (an appeal of one of the five lead cases in Binh Phan), the Ninth Circuit concluded that the Immigration and Nationalization Act does not confer authority on INS to detain indefinitely any alien subject to removal whose country of origin will not permit repatriation. We believe that § 1231(a)(6) plainly allows detention where it states that specified aliens "may be detained beyond the removal period..." Moreover, in Chi Thon Ngo (at 394-395), the Third Circuit held that § 1231(a) authorizes indefinite detention of excludable aliens, and the same provision applies to deportable aliens. It follows that the Third Circuit's statutory analysis directly contradicts Kim Ho Ma and the principles discussed therein cannot be said to be the law of this circuit. We therefore address Kim Ho Ma no further. It also should be noted that the Supreme Court has granted petitions for certiorari in Zadvydas and Kim Ho Ma, and has consolidated the cases. Zadvydas v. Underdown, ___ U.S. ____, 121 S.Ct. 297, ____ L.Ed.2d ____ (2000). While further guidance on the issue before us therefore appears forthcoming, we do not defer disposition of the pending matter because we resolve it in favor of INS. That is, we conclude that Michel is subject to continued detention with periodic review. In effect, the status quo is maintained thereby, a result which would not differ if we awaited the Supreme Court's disposition of Zadvydas. We therefore do not do so. (B) Opinions of Other Middle District Judges As noted, in Sombat Map Kay, Judge Rambo concluded that the detention of a deportable alien whose country of origin *493 would not accept him violated his right to substantive due process. Her reasoning essentially parallels that of Binh Phan. She began with a review of the relevant statutes and regulations, as well as general substantive due process principles. Sombat Map Kay at 548-549. She then rejected INS's position that the right at issue was release into the national community, deciding instead that the asserted right was to be free from restraint behind bars. Id. at 549. Because the fundamental right to liberty was at issue, strict scrutiny applies. Id. at 549-550. Examining the interests at issue, Judge Rambo agreed that the government asserted three legitimate regulatory purposes: executing the petitioner's removal, preventing flight before removal, and preventing danger to the community. The latter two derived solely from the first, but still could be considered compelling. Id. at 550. She also recognized the sovereign authority to control the borders through immigration laws, but found the principle inapposite. That is, the petitioner sought to be released from detention pending removal and could not be considered "at the border" in the sense in which the entry fiction normally applies. Id. at 550-551. Also, the plenary power applies to exclusion and deportation of aliens, not to their detention, so that "the government's interests are not at their maximum level, and the government's power is not plenary." Id. at 551 (also citing Binh Phan for the principle that the interests at stake are domestic, not international, matters). While recognizing that the petitioner's conviction was for a serious offense, and that he had admitted other serious acts, Judge Rambo noted that, when the likelihood of deportation is low or nonexistent, the government's primary purpose in detention "is nonsensical, and the other derivative purposes cannot support indefinite detention." Id. She then pointed out that length of detention is an important factor in strict scrutiny analysis. Id. at 551-552. At some point, the length of detention exceeds any regulatory need and becomes merely punitive in nature. Id. at 552. Judge Rambo then concluded the strict scrutiny analysis by pointing out that the petitioner had not committed any acts subjecting him to discipline while detained and had completed several programs. His family had indicated it would provide him with a home and other assistance if released. It appeared, then, that the risk of flight or dangerousness was low, and he had been detained for some two years with little chance of repatriation at any time in the foreseeable future. Judge Rambo therefore concluded that the prolonged detention was excessive. Id. at 552-553. Turning to INS's argument that Chi Thon Ngo was binding, Judge Rambo distinguished the case as limited to excludable aliens, as specified therein. Sombat Map Kay at 553 and n. 9 (citing Chi Thon Ngo at 398 n. 7). She then reviewed authority supporting the proposition that aliens who have been admitted to the country have greater constitutional status than excludable aliens. Once again, that status is premised on the "entry fiction," which has no applicability beyond the stage at which a determination is made concerning admission. Id. at 553-554. Judge Rambo then rejected the holdings of Duy Dac Ho and Zadvydas as essentially expanding the entry fiction to deportable aliens. Also, the court in Zadvydas did not identify the level of analysis (strict scrutiny, rational basis, or some intermediate level) which it was applying. Sombat Map Kay at 554-556. Finally, Judge Rambo found it inappropriate to expand the entry fiction beyond the context for which it was created, i.e. permitting detention of aliens physically present in the country pending a determination of admissibility. Rather, language employed by the Third Circuit in Chi Thon Ngo supported her reasoning by taking length of detention into consideration. Sombat Map Kay at 556-557. She therefore granted the writ of habeas corpus, directing INS to release the petitioner *494 subject to conditions, absent a showing within 90 days that removal was likely in the foreseeable future. Id. at 557. In Cuesta Martinez, Judge Caldwell disagreed with Judge Rambo and followed Zadvydas. After a discussion of the applicable terminology, he turned to INS's contention that Chi Thon Ngo applied, despite the stated limitation on its holding. Judge Caldwell first noted that the petitioner's position was based on Binh Phan and then noted Judge Rambo's reliance thereon, continuing with a summary of the holding in Sombat Map Kay. Cuesta Martinez at 649-650. He also pointed out the contrary holdings in Zadvydas and Duy Dac Ho, and several district court opinions which followed Binh Phan. Cuesta Martinez at 650. Judge Caldwell emphasized that aspect of the reasoning in Zadvydas equating the status of both excludable aliens and aliens subject to a final order of deportation. Of importance is the fact that neither has any further right to remain in the United States, as all that remains is to effectuate repatriation. The interest from a national sovereignty perspective is identical. Cuesta Martinez at 650-651 (quoting Zadvydas at 296). In contrast, the principles underlying Binh Phan are derived from Landon v. Plasencia, 459 U.S. 21, 103 S.Ct. 321, 74 L.Ed.2d 21 (1982), which established the assimilation doctrine discussed above. That doctrine, however, is inapplicable once a final order of removal issues because it applies to the procedural protection afforded a deportable alien, and the alien's ties to this country are severed by the final order. Cuesta Martinez at 651. Judge Caldwell then distinguished another case cited in Sombat Map Kay, Leng May Ma v. Barber, 357 U.S. 185, 78 S.Ct. 1072, 2 L.Ed.2d 1246 (1958). That case dealt with an alien paroled into the country who sought discretionary withholding of deportation based on persecution in her home country. The Supreme Court held that the parole did not allow her to assert that right, which was available to deportable aliens. The opinion simply has nothing to say about the rights of deportable aliens whose right to remain has been terminated. Cuesta Martinez at 652. The next issue addressed was the purported failure of the court in Zadvydas to recognize that the law acknowledges an "acquired constitutional status" based on the fact of admission. Cuesta Martinez at 652 (quoting Thien Van Vo v. Greene, 63 F.Supp.2d 1278, 1283 (D.Colo.1999)). Judge Caldwell pointed out that the entry fiction ultimately derives from statutory, not constitutional, authority. The purpose is to determine what immigration proceeding is available to the alien based on his status as deportable or excludable, while constitutional analysis seeks to determine what liberty interest may be asserted. The interest (freedom from confinement) would be the same regardless of the alien's status as deportable or excludable. Judge Caldwell therefore agreed with the analysis of Zadvydas and concluded that the Chi Thon Ngo approach would be appropriate for analyzing the claim before him. Cuesta Martinez at 652. Examining the parole reviews provided to the petitioner, Judge Caldwell concluded that INS was in substantial compliance with the procedure prescribed by the Third Circuit. To the extent it was not, there were good reasons (INS was awaiting a psychological report before providing written notification). The writ of habeas corpus was denied without prejudice to the petitioner's right to bring a future action based on future events. Id. at 652-653. (C) Our Determination Having reviewed these cases, we conclude that Judge Caldwell and the Fifth Circuit have the better of the argument. Rather than merely state as much or reiterate the holdings of the cases consistent with this view, we set forth our reasons for disagreeing with Judge Rambo and the Western District of Washington in some detail. *495 Initially, we have some difficulty with the manner in which Judge Rambo reached her ultimate conclusion which is unrelated to the deportable/excludable distinction. After determining that the petitioner's right to be free from confinement outweighed the government's interest in effecting removal, as well as concluding that the derivative interests in public safety and flight risk failed as a matter of law once the interest in effecting removal was outweighed, Judge Rambo proceeded to examine the individual petitioner's dangerousness and flight risk. Sombat Map Kay at 552. However, once there was a determination that INS cannot detain a deportable alien if removal is not likely, the only questions are whether removal is likely and whether INS in fact is detaining the alien. The reasons for detention already had been found constitutionally inadequate, and any further balancing would be of no consequence. See Cuesta Martinez at 650 ("In these circumstances, the alien's liberty interest in being free from incarceration outweighs as a matter of law the government's interest in detention, even if there is evidence that the alien is a risk to the community, or possibly a flight risk."; citing Sombat Map Kay). Apart from that problem, however, we disagree with the view expressed in Binh Phan and its progeny that the right at issue is the freedom from incarceration. The fact of the matter is that, because no other country will accept the alien, the only place to which the alien may be released is the United States. However, as a result of the final order of removal, there is no right to be at large in the United States. In fact, there is no general right for non-citizens to be at large within the United States, and even the right of citizens to be at large is subject to limitations. See generally Zadvydas at 297 n. 19 (examples of citizens detained for protection of the public). As stated above, an alien's entry into the United States (and therefore the state of being at large within our national community) is a privilege, not a right. Stated differently, to say that there is a right to freedom from incarceration necessarily implies a right to the opposite, i.e. that there is a right to be at large in the community. Since the necessary obverse does not exist for aliens, it is improper and an oversimplification to characterize the right as simply the freedom from incarceration. Rather than finding that failing to distinguish between excludable and deportable aliens after a final order of removal improperly expands the entry fiction, we believe that making this distinction improperly expands the assimilation doctrine. The cases granting heightened constitutional status to aliens once admitted to the United States all refer to the process that is due before a final order of removal may issue. The idea is that an alien who has lived in this country for an extended period of time will have established ties through employment, family, friends, etc., which should not be taken away lightly. INS therefore is required to evaluate the case more carefully and with greater procedural protections than would apply to an alien subject to exclusion, who presumably would not have the ties to the community to the extent a resident alien would have. However, once the order of removal becomes final, the resident alien no longer has a right to participation in our society and the ties which may have been established are no longer a significant consideration. Giving the former resident alien greater substantive rights expands the assimilation doctrine to cases to which it has not applied previously and into a context for which it was not intended. That the assimilation doctrine is not subject to expansion is reflected in Chi Thon Ngo, in which the petitioner had been paroled into the United States in 1982. Presumably, such a person would establish the same sorts of community ties as a person formally admitted, yet he still was considered excludable for purposes of the applicable *496 proceedings, and did not have any heightened constitutional status for purposes of release pending removal. Conversely, we do not see how failing to distinguish between deportable and excludable aliens in this context is necessarily an expansion of the entry fiction at all. Rather, it is an equation of the liberty interest on the part of the two "classes" of aliens. That is, neither has a right to be in the United States and is subject to repatriation at the earliest possible opportunity. The only difference in their circumstances was that the deportable alien was once a resident, and the interest to which that residence gave rise has been honored through greater procedural protections prior to the removal order. Once honored, the interest is extinguished for purposes of any further constitutional analysis, and the difference in circumstances no longer exists. The two are identical for purposes of any further due process analysis. This holding is not an expansion of the entry fiction; it is a limitation on the assimilation doctrine, which (as Judge Caldwell pointed out) had no constitutional basis to begin with, but ultimately derived from immigration law. Another way of viewing this matter is to compare the asserted right to the right to personal liberty enjoyed by citizens. Reduced to its basic form, the holding of the cases finding a deportable/excludable alien distinction for substantive due process purposes is that a deportable alien subject to a final order of removal may not be detained by INS if there is no chance that removal will be effected in the foreseeable future. That is, the alien has an absolute right to parole under these conditions, despite having been afforded all necessary procedural protections before a final determination was made to deport the alien. A citizen charged with a serious criminal offense, however, may be held without bail pending trial despite not having been afforded all of the necessary procedural protections before a final determination of guilt may be made. This conclusion flies in the face of logic. Another way to view this matter is to take an example, albeit an extreme example. Suppose that a resident alien was arrested for an attempt to murder a prostitute, an offense which would render him deportable. While INS has custody, it is discovered that the alien is Jack the Ripper. Great Britain, after determining that its interest in pursuing criminal prosecution is outweighed by the danger of having such a person within its borders, might well decline extradition or repatriation. The logic of Binh Phan and its progeny would lead to a determination that the Ripper has an absolute right to be at large within our borders once his criminal sentence expires, a plainly unacceptable result. While our example tends to the extreme, we use it only to point out there are people, such as aliens subject to a final order of removal, who have no right to be at large in the United States and as to whom the governmental interest in protecting the public outweighs any right against prolonged detention. Viewed from this perspective, the governmental interest cannot be seen as derivative of the interest in effecting the removal. Rather, it is an independent and important interest; actually, one of the (if not the single) most important of governmental interests. In this context, we note our disagreement with Binh Phan and its progeny that the matter is entirely domestic. While a foreign nation's refusal to accept return of its nationals may be said to diminish the international or foreign relations aspect of the matter, the fact remains that the person in detention is an alien, not a citizen, and is subject to removal as soon as possible and with no right to be in the United States. The matter remains one of immigration law and not domestic law, and the plenary power remains in effect. We also disagree with the characterization of detention pending removal as necessarily punitive. In Chi Thon Ngo, the *497 Third Circuit noted that characterizing prolonged detention as anything but punishment would be "puzzling to petitioner, who remained in jail under the same conditions as before the state released him, although his status had technically changed from that of a state inmate to an INS `detainee.'" Id. at 397-398. Referring to the legal fiction that the detained alien is "free," the court added, "It is similarly unrealistic to believe that these INS detainees are not actually being `punished' in some sense for their past conduct." Id. at 398. See also Sombat Map Kay at 550 n. 7 (quoting the latter statement). The problem with relying on this quotation for a finding that detained aliens are being punished is that the "some sense" does not refer to the constitutional sense, or at least in a sense that the Constitution is being violated. That is, it is only when detention no longer satisfies a rational, non-punitive purpose that the detention becomes unconstitutional punishment. Zadvydas at 297 and n. 19. For all of these reasons, we agree with Judge Caldwell, the Fifth Circuit, and the Tenth Circuit that there is no reason to distinguish between deportable and excludable aliens for purposes of detention pending removal. The reasoning of Chi Thon Ngo therefore applies in cases involving deportable aliens subject to a final order of removal. Such aliens may be detained by INS subject to periodic review for parole, including a thorough review of the alien's risk of flight and/or danger to the community. (D) Other Due Process Argument In addition to the deportable/excludable distinction discussed above, Michel argues that an analysis of the sufficiency of the parole review procedure has not been made. Actually, a more thorough argument would be that the procedures fail such a test. Regardless, the Third Circuit undertook such an analysis in Chi Thon Ngo, which is binding on us. The analysis suggested by Michel would be superfluous. Because of the conclusion we reach, we do not examine the effect of the fact that Haiti is simply slow to accept deportees, as opposed to nations which do not accept deportees. That is, Michel's situation is one of a slower process than normal, but there is no basis for a conclusion that removal will not be effected or is highly unlikely to be effected. Since INS is providing periodic review under these circumstances, the distinction is not material. V. REMOVAL PERIOD Michel adds an argument that the magistrate judge misapplied the removal period provision. The statute provides in part: Except as otherwise provided in this section, when an alien is ordered removed, the Attorney General shall remove the alien from the United States within a period of 90 days (in this section referred to as the "removal period"). . . . . . The removal period begins on the latest of the following: (i) The date the order of removal becomes administratively final. (ii) If the removal order is judicially reviewed and if a court orders a stay of the removal of the alien, the date of the court's final order. (iii) If the alien is detained or confined (except under an immigration process), the date the alien is released from detention or confinement. 8 U.S.C. § 1231(a)(1)(A), (B). In reciting the procedural history of the case, the magistrate judge indicated that the BIA dismissed Michel's appeal on October 27, 1998, rendering the removal order administratively final and establishing January 25, 1999, as the end of the 90-day removal period. However, the Second Circuit issued a stay on February 9, 1999, and vacated the stay when it affirmed the BIA on February 4, 2000. Report and Recommendation at 2. According to Michel, the *498 magistrate judge's later conclusion that he had only recently fallen within the release provisions of § 1231 is incorrect. This argument is based on a premise that there can be only one removal period, and that the magistrate judge was incorrect in reading the statute to allow the removal period to restart after the stay was vacated. Actually, that is the only rational reading of the statute. According to Michel's reading, once the removal order became final and the removal period began, that was the only period of time which could be designated as the removal period. However, the statute provides that the removal period begins on the latest of several dates. The passing of one date does not stop the operation of the statute. In a sense, the only way to apply the statute to a given situation is retrospectively. That is, the removal period begins when the removal order becomes final. If a court issues a stay, the removal period begins when the stay is lifted. Therefore, the only way to determine when the removal period begins, or began, is to look at what events already have occurred. If there is another potential event, there is another potential beginning date for the removal period. The only sensible reading of this provision is that INS is required to effectuate the removal within 90 days of certain events, but will have another 90 days if another one of the designated events occurs at a later date. The obvious reason for this is that INS's authority to effect the removal is suspended due to the occurrence of the later event (such as a stay order). In Michel's case, the magistrate judge correctly determined that the removal period began on February 4, 2000, so that the instant petition is premature. VI. CONCLUSION Based on the foregoing, we conclude that a deportable alien subject to a final order of removal may be detained by INS beyond the 90-day removal period. An alien subject to such detention is entitled to periodic review for purposes of release on conditions as described in Chi Thon Ngo. The time for such review begins on the date that the order becomes administratively final, the date on which any stay ordered by a court is vacated, or the date on which the alien is released from detention or confinement for other than immigration process. The beginning date of the 90-day removal period is not altered by the fact that one of these events may have occurred at an earlier time. An order consistent with this memorandum will issue. ORDER For the reasons stated in the accompanying memorandum, IT IS ORDERED THAT: 1. The report and recommendation (record document no. 18) of the magistrate judge is adopted as the holding of the court, as supplemented hereby. 2. Petitioner Jean Patrick Michel's exceptions (record document no. 19) to the report and recommendation are construed as objections to the report and recommendation under LR 72.3 of the Local Rules for the Middle District of Pennsylvania, and are overruled. 3. Michel's petition (record document no. 1) for a writ of habeas corpus pursuant to 28 U.S.C. § 2241 is denied. 4. The clerk is directed to close the file. NOTES [1] We noted in Jacques that our analysis might be in conflict with that applied in cases decided by the Third Circuit, which in turn we felt were in conflict with Reno v. American-Arab Anti-Discrimination Committee, 525 U.S. 471, 119 S.Ct. 936, 142 L.Ed.2d 940 (1999). However, the Third Circuit precedent was distinguishable, and we therefore were able to resolve Jacques so as to avoid any conflict with Third Circuit decisions. Jacques at 481-482. In DeSousa, the Third Circuit read American-Arab far more narrowly than we did in Jacques. We do not believe that we have any further authority to read American-Arab as we see fit, but must do so in light of DeSousa. See also Liang v. I.N.S., 206 F.3d 308 (3d Cir.2000). [2] Although the governing statutes refer to the authority and duties of the Attorney General, responsibility for immigration matters has been delegated to INS, and so we refer to INS for present purposes. Also, we refer to the codified version of the statutes for ease of reference and reading. [3] In Kim Ho Ma v. Reno, 208 F.3d 815 (9th Cir.2000), the Court of Appeals for the Ninth Circuit conducted a statutory analysis and determined that INS lacks authority to detain an alien beyond the 90-day removal period if the alien cannot be returned to his or her native land due to the absence of a repatriation agreement. Ma was one of the cases consolidated for en banc review in Binh Phan, and has been consolidated with Zadvydas v. Underdown (discussed later in this opinion) for review by the Supreme Court on certiorari. For present purposes, then, Binh Phan has been abrogated and Ma represents the law of the Ninth Circuit. The reasoning of Binh Phan, however, has been adopted by a number of district courts and it remains an important opinion. See Cuesta Martinez at 650 (collecting cases). It is for this reason that we undertake our examination of Binh Phan.

1. Field of the Invention The present invention relates to an earpiece/wire organizer and method for using same to house and maintain wires in an untangled manner; and more particularly, to a wire organizer that provides a sleeve constructed with a plurality of mating spine pieces coated with an interlocking self-adhering surface appointed to releasably engage with itself. 2. Description of the Prior Art Typical earphone or headset constructions comprise a main audio wire which is adapted to connect to a jack integrated within an electronic, audio or optical device. In one form of these organizers, left and right wires connect with the main audio wire to form a “Y”-type construct which delivers audio from an electronic device such as a music device, mp3 player, and/or cellular phone. The left and right wires, or upper legs of the Y, are associated with left and right ear buds which, when worn, allow the user to hear music or sound transmitted from the electronic device. Other earphone or headphone devices involve a single wire attached to a first ear bud and a second ear bud. A microphone jack may additionally be included to transmit audio from the user to the electronic device, and to another user's electronic device; such wiring arrangements are used in the mobile phone industry. In practice, headphone wires are stored in a pocketbook, gym bag, pocket or the like. Unfortunately, the wires forming the headphones tend to tangle and knot making it difficult to quickly connect and use the ear piece with the electronic device or transmission device. This entanglement can be very annoying. Oftentimes untangling of the wires can be difficult and time consuming. Even still, frequent entanglement and untangling can cause eventual damage to the left and right wires, impacting sound quality. Various devices are currently provided for organizing wires. However, none of the devices provide the ability to compress and elongate the wires in a manner which maintains severability of the wires and prevents entanglement thereof. Several of the wire organizer devices heretofore disclosed and utilized involve coverings or jackets constructed with a unilateral elongated body having edges appointed with engageable zipper elements. Exemplary of these types of jacket coverings, are the following patents. U.S. Pat. No. 2,585,054 to Stachura discloses a flexible sheet of electrically conductive material having meeting but separable closure edges with engageable tooth and groove zipper elements adapted to encircle a conductor; and U.S. Pat. No. 5,391,838 to Plummer discloses a rectangular casing with inner and outer surfaces and edges having a conventional zipper provided there along so that the casing may be closed to form a removable tube around conductors to be shielded. These devices are generally separate from the wires and merely operate to wrap around or encase the wires in order to neatly store same when the zipper elements on the edges of the elongated body are engaged. Organization of the wires by application of these jacket-like devices results from bundling within the jacket covering; the wires themselves are not provided with integrated organization means. The wires located within the jacket are not maintained in a separate yet joined manner. Consequently, they may be subject to tangling within the jacket. When the jacket is removed, the wires must be untangled from one another. Other wire organizers involving zip-up devices are generally constructed with zip-up mechanisms integrated along bodies of wires operable to releasably join the wires upon engagement of a zipper or sliding element. For example: U.S. Pat. No. 5,949,026 to DeFlorio discloses a pair of tangle resistant electrical test leads attached to a nonconductive slide fastener, such as a nylon zipper, that co-joins cords by engaging the slide fastener or zipper; U.S. Pat. No. 6,909,050 to Bradford discloses an electrical cable system including a first electrical cable and a second electrical cable constructed to releasably join to form a co-joined cable by strip and groove mating; U.S. Patent Application Publication No. 2005/0069147 to Pedersen discloses a headset wire for a portable electronic device including a zipper used to releasably join or separate pairs of wires; Foreign Patent Publication No. EP 1509062 to Fung et al. discloses a headphone apparatus appointed with a zipper slider for sliding along cords of the headphone and thereby joining or disjoining two cords; Foreign Patent Publication No. JP 07211146 to Tateno discloses a stereophonic earphone cable having a fastener on a side of each the left and right earphone cables and a chuck or slider to co-join the cables; and Foreign Patent Publication No. JP 2004056636 to Kihachiro discloses a headphone apparatus integrated with a slider type fastener over substantially the entire length of each cable so that each branch cable can be co-joined. These integrated zip-up devices, as well as aforediscussed jacket constructs, fail to provide a sleeve surface that enables scrunching or compression and elongation or lengthening of the wires. As such, the co-joined and bundled wires cannot be compressed for enhanced compact storage. Coiling of the co-joined wires and/or jacket containing the bundled wires may be an option to achieve a more orderly neat maintenance; however, this would subject the co-joined wires and/or jacket of the bundled wires to tangling. Another broad categorical type of apparatus for organizing wires involves devices having a member for pulling two wires together without lengthwise co-joining of the wires. For example: U.S. Pat. No. 6,374,126 to MacDonald et al. discloses a hands-free earpiece headset configured such that a second earpiece is integrally mounted and stowed against a first earpiece. The headset further includes a sliding member which is configured to slidably advance and retract about the first and second cords for organization of same. Foreign Patent Publication No. JP 10308992 to Masuda et al. discloses a device having two left headset wires that are appointed to be completely contained in a cylindrical bag which slidably engages to house the wires therein when the headset is being carried. These types of organization apparatuses fail to provide compression or elongation of the enclosed wire in an orderly, tangle free manner. The wires are not co-joined together, but are merely housed in close proximity with engagement of the slide or bag, respectively. As a result, the wires are subject to entangling with one another, especially within the bag assembly storage structure. Various wire organizing devices involve a spool type member engageable with associated wires for stowage thereof. For example: U.S. Pat. No. 4,802,638 to Burger et al. discloses a cord stowage device that includes a spool having opposed ends with cup-shaped members and a channel through which a cable slidably passes, cavities shaped to receive earphones therein for storage are also provided on the outside of the cup-shaped members; U.S. Pat. No. 7,077,693 to Symons discloses a cable management device having a body with an axis and at least one planar flange and cable retainer for allowing removable attachment of a cable during axial winding in a single plane via a spool; and U.S. Patent Application Publication No. 2005/0123164 to Yao et al. discloses a mobile device cord holder constructed with retaining regions defining a cord holding area appointed to hold a cord in a non-tangling manner as the wire is wrapped or spooled around the cord holding area. Wires associated with these spool type devices do not engage with one another to form a single/co-joined wire. Nor do these spool type devices provide the functionality of compressing or elongating the wires. Instead the wires are merely spooled within the device for storage. As the wires wrap around the spool, the wires are prone to tangling. Notwithstanding the efforts of prior art workers to construct an earpiece or wire organizer that prevents or mitigates entanglement of wires during storage and carrying, there remains a need in the art for an earpiece or wire organizer that can be readily engaged by simply scrunching or compressing and pulling or elongating wires together with a single hand motion. Specifically, there is a need in the art for an earpiece or wire organizer that includes a sleeve appointed to house a substantial portion of a wire. Further, there is a need in the art for an earpiece or wire organizer that provides a sleeve constructed with mating spine pieces coated with an interlocking self-adhering surface that attaches to itself to releasably engage the mating spine pieces with one another in a stacked relationship. Moreover, there is a need in the art for an earpiece or wire organizer that provides a sleeve constructed with mating spine pieces coated with an interlocking self-adhering surface that attaches to itself to releasably engage the mating spine pieces, and thereby compress and elongate a wire housed within the sleeve.

Introduction ============ Porcine reproductive and respiratory syndrome (PRRS), first reported in 1987 in the USA, is a global infectious disease that has resulted in widespread economic loss in the swine industry. PRRS is characterized by reproductive failure in pregnant sows (*e.g.* abortions and stillbirths), respiratory distress in pigs of different ages, and severe immune suppression \[[@B13],[@B16]\]. The PRRS virus (PRRSV) is the recognized causative agent of this syndrome. Two different genotypes of PRRSV have been described: European or type 1, and North American or type 2 \[[@B6],[@B21]\]. In China, most isolated strains are of type 2 \[[@B3]\]. PRRSV is an enveloped, positive, single-stranded RNA virus in the genus *Arterivirus*, which belongs to the family Arteriviridae within the order Nidovirales \[14\].The PRRSV genome is 15 kb in length and contains at least 10 open reading frames (ORFs). Of these, ORF1a and ORF1b represent nearly 75% of the viral genome and encode two large polyproteins (pp), pp1a and pp1ab, respectively. These pps can be hydrolyzed into at least 16 small nonstructural proteins (Nsps). Of these 16 Nsps, at least 14 are involved in viral genome replication and transcription \[[@B10]\]. The Nsp1, Nsp2, and Nsp7 proteins elicit a strong immune response in pigs. Fourteen days after pigs are infected with PRRSV, anti-PRRSV Nsp7 antibodies can be detected, and high levels of antibodies in pigs can last for up to 202 days \[[@B2]\]. A diagnosis of PRRSV is important for its prevention and control. The laboratory diagnostic tests commonly used at present include reverse transcriptase polymerase chain reaction (PCR), quantitative real-time PCR \[[@B19],[@B22]\], and four serological detection methods \[[@B1],[@B4],[@B5],[@B20]\]: the indirect fluorescence assay (IFA), the immunoperoxidase monolayer assay (IPMA), the serum neutralization test (SN), and the enzyme-linked immunosorbent assay (ELISA). In recent years, by using the PRRSV N protein as an antigen, the commercial IDEXX ELISA kit (IDEXX Laboratories, USA) has been widely used for the detection of PRRSV antibodies. Recently, an ELISA kit that uses recombinant Nsp7 protein as the antigen has been introduced, and the concurrence rate between that kit and the IDEXX ELISA assay has been reported to be up to 97.6% \[[@B2]\]. Although traditional laboratory tests offer good sensitivity and specificity, these detection methods require professional and technical personnel and specialized equipment. In addition, there are many methodological aspects that must be constantly improved and complemented. In developing countries, vaccination is an important strategy for preventing and controlling PRRSV. To monitor the titer of anti-PRRSV antibodies after vaccination in order to confirm the effectiveness of the vaccination, quick and easy techniques suitable for field testing are needed. Compared with the traditional detection methods, an immunochromatographic strip method has the advantages of being easy to use, providing an answer rapidly and at a low cost, and not requiring specialized equipment or technical personnel, thus such a method is suitable for field testing for antigens or antibodies. In this study, we developed an immunochromatographic test strip for detecting anti-PRRSV antibodies and conducted a preliminary field study of the strip. Materials and Methods ===================== Serum samples ------------- Pigs were experimentally inoculated with either of two strains of PRRSV having differing levels of virulence, HN07-1 and BJ-4, in order to provide positive test serum samples. HN07-1 strain was isolated during an atypical PRRSV outbreak in Henan Province, China in 2007 \[[@B17]\]. The BJ-4 strain was a typical North American (VR2332)-like PRRSV isolated in 1996 in China \[[@B17]\]. The field sera for antibody testing were collected from several swine herds (all sampled pigs were more than 2-weeks-old) within Henan Province, China. Positive serum samples for porcine circovirus-2 (PCV-2), pseudorabies virus (PRV), classical swine fever virus (CSFV), porcine parvovirus (PPV), and foot-and-mouth disease virus (FMDV) were collected and stored in the Henan Provincial Key Laboratory of Animal Immunology, Henan Academy of Agricultural Sciences. Preparation of recombinant Nsp7 protein of PRRSV ------------------------------------------------ For the expression of a recombinant Nsp7 proteins in *Escherichia* (*E.*) *coli*, reverse transcriptase PCR was performed on viral genomic RNA from PRRSV isolate BJ-4, obtained from Dr. Hanchun Yang of China Agricultural University. To amplify the Nsp7 gene the following oligonucleotide primers were used: forward primer, 5′-CGC**GGATCC**TCTCTGACTGGTGCCCTCGCTATG-3′ and reverse primer, 5′-CCG**CTCGAG**TTCCCATTGAACTCTTCCAT-3′ (restriction sites in bold font). The amplified gene was then ligated into the pET-28a vector. The recombinant plasmid was transformed to *E. coli* BL21-competent cells. Single colonies were obtained and tested by PCR and sequencing, and a positive clone was grown at 37℃ in LB broth supplemented with 100 µg/mL ampicillin to an optical density of 0.8 at 600 nm. Expression of the recombinant protein was induced by 100 mM isopropyl-β-D-thiogalactopyranoside (IPTG, TAKARA Bio, China) for 8 h at 37℃. Cells were then harvested by centrifugation (7000 × g for 30 min). Purification of recombinant Nsp7 protein ---------------------------------------- The recombinant Nsp7 protein was purified by immobilized-metal affinity chromatography (IMAC) using a polyhistidine tag and further purified by a gel filtration column Superdex200 (GE Healthcare, Sweden). The cell pellet was suspended and lysed by sonication on ice. The lysate was centrifuged at 16,000 × g for 30 min, and the supernatant was collected and transferred to a Ni-NTA His Band Resin column pre-equilibrated with binding buffer (500 mM NaCl, 20 mM Tris, 5 mM imidazole). More than five column-volumes of washing buffer (500 mM NaCl, 20 mM Tris, 20 mM imidazole) was added to remove the nonspecific binding proteins. The target protein was eluted with elution buffer (500 mM NaCl, 20 mM Tris, 400 mM imidazole). The purity and relative concentration of the recombinant Nsp7 was determined by SDS-PAGE. The protein was further fractionated by gel filtration on a column of Superdex200 in a buffer of 50 mM Tris, 150 mM NaCl by using the Bio-Rad BioLogic system (Bio-Rad Laboratories, USA). The protein of interest was collected in different fractions according to its different states of aggregation. The final protein products were examined by SDS-PAGE before storing at −80℃. Western blot ------------ For western blot analysis, 4 µg purified recombinant Nsp7 protein were subjected to 15% SDS-PAGE gel and transferred to polyvinylidene difluoride membranes. The membrane was washed with phosphate-buffered saline-Tween20 (PBST) and blocked with 5% skimmed milk. After washing three times with PBST, the membranes were reacted with PRRSV-positive sera; a PRRSV-negative serum were used as a negative control. After incubating at 37℃ for 1 h, the resulting blot was treated with secondary antibody horseradish peroxidase-conjugated rabbit-anti-pig IgG (Abbkine; WuHan AmyJet Scientific, China) for 1 h. As the substrate for color development, 3-amino-9-ethylcarbazole (AEC) was used. The antigenicity of the separated protein fractions compared by ELISA --------------------------------------------------------------------- The antibody binding capability of the monomer, dimer, and larger aggregate of the recombinant Nsp7, which were separated by Superdex200 gel filtration column, were compared by indirect ELISA assay. The separated proteins were diluted to the appropriate concentration in 50 mM sodium carbonate bicarbonate buffer (pH 9.6). After incubation for 14 h at 4℃, antigen-coated plates were washed five times with phosphate-buffered saline (PBS) containing 0.05% Tween 80 then blocked with 5% skimmed milk powder dissolved by PBST for 1 h at 37℃. Then, appropriate dilutions in PBST of PRRSV-positive HN07-1, PRRSV-positive BJ-4, and PRRSV-negative pig sera were incubated in the antigen-coated wells at 37℃ for 30 min. Secondary antibody horseradish peroxidase-conjugated rabbit-anti-pig IgG was added at a final dilution of 1:2,000, and the mixture incubated for a further 30 min at 37℃. Finally, 3′,3′,5′,5′-tetramethylbenzidine was added as a substrate. Color development was stopped with 2 M H~2~SO~4~, and the OD value at 450 nm was read on a spectrophotometer. Conjugation of antigen with colloidal gold ------------------------------------------ Colloidal gold with an average particle diameter of approximately 20 to 25 nm was obtained by reduction of a HAuCl4 solution with 1% trisodium citrate. Three milliliters of 1% trisodium citrate (w/v) was added to 100 mL of 0.01% HAuCl~4~·3H~2~O solution (w/v) with stirring. Then the mixture was heated to 100℃ for 20 min. The colloidal gold solution was then cooled to room temperature and stored at 4℃. The colloidal gold-labeled antigen was prepared according to a previously reported method \[[@B23]\]. Briefly, 4 mL of purified protein (0.2 mg/mL) was incubated with 80 mL of colloidal gold solution for 30 min at room temperature with the pH adjusted to 9.4. After the addition of 1 mL of 3% casein solution, the mixture was incubated at room temperature for a further 10 min, and the resulting suspension was centrifuged 25,000 × g at 4℃ for 30 min. Finally, the colloidal gold-labeled antigen was suspended in 4 mL of 0.02 M sodium borate buffer (containing 2% bovine serum albumin \[BSA\], 1% sucrose, 0.1% NaN~3~) and stored at 4℃. Preparation of the conjugate pad and sample pad ----------------------------------------------- Ten percent BSA was sprayed onto a fiberglass conjugate pad by using a XYZ-3000 dispensing platform (BioDot, USA). The pad was then dried at 42℃ for 45 min. Conjugate solution was dispensed onto the modified fiberglass at a speed of 25 µL/cm (about 2 µg per pad) by using the dispensing platform. After drying for 1 h at 42℃, the pad was then stored in a desiccator at room temperature. The sample pad was saturated with a buffer containing 20 mM sodium borate, 2.0% (w/v) sucrose, 2.0% (w/v) BSA, and 0.1% (w/v) NaN~3~ then dried and stored as described above. Pig anti-Nsp7 antibody preparation ---------------------------------- Two-month-old pigs were injected intramuscularly with 100 µg recombinant Nsp7 protein of PRRSV in 2.5 ml of an oil-in-water emulsion per pig. The injection was repeated two times at two-week intervals. Fifteen days after the third immunization, blood containing a high titer of anti-Nsp7 antibody was collected from the immunized pigs. Porcine anti-Nsp7 IgG was salted out from the hyperimmune sera through successive treatment with 50%, 40%, and 33% saturated ammonium sulfate and dialyzed with 0.01 M PBS. ELISA was carried out to determine the titer of anti-Nsp7 protein IgG. The ELISA plate was coated with 0.2 µg/mL Nsp7 protein at 37℃ for 2 h. After washing with PBST five times and blocking with 5% skimmed milk, the anti-Nsp7 protein IgG was two-fold serially diluted with physiological saline and added to the ELISA plate. The anti-Nsp7 IgG titer level was up to 1:20,000. The purified Nsp7 IgG was aliquoted into tubes (1 mL/tube) and stored at −80℃. Immobilization of capture reagents ---------------------------------- Staphylococcal protein A (SPA; Sigma Chemical, USA) at 1.5 mg/mL and porcine anti-Nsp7 IgG at 1 mg/mL were sprayed by using Quanti 3000 Biojets (BioDot) attached to a XYZ Biostrip Dispenser (BioDot) onto a nitrocellulose filter membrane (HiFlow Cellulose Membrane; Millipore, USA) to form zones of 300 mm × 25 mm at the test line (T line) and quality control line (C line), respectively. The T and C lines were in the middle of the membrane, and 5 mm apart from each other. The flow rate of the liquid was 180 sec/4 cm on the membrane, the use level was 1 µL/cm, and forced air drying was carried out at 40℃ for 1 h. The membrane was then sealed in plastic with desiccant and kept at room temperature. Assembly principle and use of test strips ----------------------------------------- Assembly of the test strips used the same method as is previous descriptions \[[@B24],[@B25],[@B26]\]. The strip assembly consists of a sample pad, a conjugate pad, a nitrocellulose membrane (NC membrane), and an absorbent pad. The NC membrane was adhered to the center of the plastic solid support, and the absorbent pad and conjugate pad were adhered to upper and lower sides, respectively of the cellulose nitrate membrane with a 1 mm overlap. The main card was cut to the required width with a paper cutting machine. Each strip was packed in a plastic block and then sealed into a plastic bag with desiccant. When stored at room temperature, the strip\'s period of validity is one year. For testing, serum samples were diluted 1/200 in physiological saline. The 100 µL diluted sample was added to the sample pad and allowed to migrate to the absorbent pad. If the serum sample to be tested contained PRRSV specific antibodies, these antibodies will form a "gold-labeled antigen-antibody" complex with the gold-labeled antigen on the conjugate pad. The complex, while migrating to the NC membrane, binds to SPA, thereby showing a red line in the T line area. Some of the gold-labeled antigen and some of the gold-labeled antigen-antibody complex migrates further to react with the anti-Nsp7 antibody, showing another red line in the C line area. Negative samples do not produce a red line in the T area, whereas the C line will always show a red line whether or not the serum contains anti-PRRSV antibodies. Cross-reactivity and detection limit of the immunochromatographic strip test ---------------------------------------------------------------------------- Cross-reactivity of the strip was evaluated with 18 PRRSV-positive sera (individual S/P ratios were 0.98, 1.37, 1.57, 1.66, 1.66, 1.70, 1.71, 1.72, 1.75, 1.77, 1.78, 1.80, 2.00, 2.28, 2.46, 2.611, 2.75, and 2.79), 10 standard PRRSV-free/negative sera (S/P \< 0.4) from PRRSV-free and non-vaccinated pigs and 32 CSFV-, FMDV-, PCV-2-, PRV-, and PPV-infected serum samples. The detection limit of the strip was evaluated by using PRRSV-positive sera. The titers of the sera were determined by using a commercial ELISA Kit (IDEXX PRRS X3 ELISA kit; IDEXX Laboratories, USA) as the reference standard. Physiological saline solution was used to dilute sera from 1:100 to 1:3,200. The diluted sera were tested with the test strip and the intensity of the T line was scanned with a BioDot TSR3000 film scanner to provide a numerical value. The whole process was repeated three times by three different operators. Comparison of the strip with other methods ------------------------------------------ The strip and the commercial IDEXX PRRS X3 ELISA kit were simultaneously used to test and evaluate 1034 sera obtained from several swine herds in Henan Province, China. A comparison of the results obtained by the two methods was used to evaluate the effectiveness of the test strip. To further evaluate the immunochromatographic test strip for detection, anti-PRRSV antibody sera were collected at intervals after infection. Piglets from PRRSV-free, specific pathogen-free herds were experimentally inoculated with two PRRSV strains of differing virulence, HN07-1 and BJ-4. Groups of three animals were inoculated with HN07-1 or BJ-4 and a further three uninfected piglets were sham-inoculated with a control cell culture supernatant. Blood samples were collected at 0, 7, 14, 21, 28, and 35 days after infection. Sera from these blood samples were simultaneously tested by the immunochromatographic test strip and two reference standard methods: the IDEXX PRRS X3 ELISA kit and the IPMA. A similar experiment was undertaken to evaluate sera from PRRSV-vaccinated pigs. Five piglets were intramuscularly vaccinated with highly pathogenic porcine reproductive and respiratory syndrome virus vaccine (HuN4-F112) following the manufacturer\'s instruction, which were produced by Harbin WEIKE Biological Technology Development Company (batch No. 2014001). Sera were collected at 3, 7, 14, 21, and 28 days post vaccination, and tested with the strip and the IDEXX PRRS X3 ELISA kit. The IPMA was performed according to standard methods. Marc-145 cells were inoculated into 96-well cell plates and cultured in Dulbecco\'s modified Eagle medium (DMEM; Shanghai Bioleaf Biotech, China) containing 10% fetal bovine sera (Shanghai Bioleaf Biotech) at 37℃ in 5% CO~2~ atmosphere for 24 h. When the cells had grown to cover over 90% of the available area, serum samples to be assayed were diluted 1:100 with PBS, and 100 µL of each dilution were transferred to paired wells of HN07-1-infected and HN07-1-uninfected Marc-145 cells. The plates were incubated at 37℃ for 1 h and washed three times with PBST, the secondary antibody, horseradish peroxidase-conjugated rabbit-anti-pig IgG, was added at a final dilution of 1:2,000 in PBST. After washing 3 times, the monolayers were stained with AEC. The plates were observed with a light microscope, and wells containing distinctly stained individual cells were scored as positive. Results ======= Expression and purification of the Nsp7 protein in *E. coli* ------------------------------------------------------------ After IPTG induction, the *E. coli* BL21 (DE3) carrying pET28a-Nsp7 plasmid was shown by using SDS-PAGE to express a recombinant protein with a molecular weight *circa* 34 kDa. The expressed protein was present in the soluble, as well as in the insoluble, fraction of the bacterial cell pellet. After sonication treatment, the completely soluble target protein was dissolved in phosphate buffer solution and purified by Ni-chelation chromatography. The purified protein was up to 90% pure as determined by SDS-PAGE and western blot analysis revealed that the purified protein reacted with anti-PRRSV sera, confirming its antigenicity ([Fig. 1](#F1){ref-type="fig"}). The target protein self-aggregated and was further fractionated by using molecular sieve chromatography. The different assemblages, referred to as the "larger aggregate", the "dimer", and the "monomer" were then identified by SDS-PAGE ([Fig. 2](#F2){ref-type="fig"}). Specific immunogenicity of larger aggregate, dimer, and monomer Nsp7 -------------------------------------------------------------------- The immunogenicity of the Nsp7 larger aggregate, the dimer, and the monomer assemblages were examined by ELISA. The Nsp7 larger aggregate and dimer proteins showed some reactivity with PRRSV-negative sera. The Nsp7 monomer reacted strongly with pig sera against both classical and atypical PRRSV but reacted weakly with negative sera ([Fig. 3](#F3){ref-type="fig"}). Thus, the monomer was selected for use as the colloidal gold-labeled antigen probe for further study. Cross-reactivity of the immunochromatographic strip --------------------------------------------------- Serum samples after 200-fold dilution with physiological saline solution were applied to the immunochromatographic test strip. The combination of antigen and antibody forms an "antigen-antibody complex" which binds to SPA and gives a red line (positive serum) in the test region; no red indicates a negative serum. As a product quality control check, the C line will always show a red line, regardless of whether anti-PRRSV antibodies are present. Cross-reactivity of the immunochromatographic test strip was evaluated with 60 reference serum samples, including 18 PRRSV standard positive sera, 10 negative sera samples, and 32 serum samples positive for CSFV, FMDV, PRV, PCV-2, and PPV. As shown in [Fig. 4](#F4){ref-type="fig"}, the positive sera appeared as two visible red bands at the T and C line positions on the strip, while the negative sera and other sera appeared as only one red band at the C line position. As shown in [Table 1](#T1){ref-type="table"}, the strip gave 18 positive results from the 18 PRRSV-positive samples, and all of the 10 PRRSV-negative samples and the serum samples positive for other non-PRRSV pathogens showed negative results on the immunochromatographic strip. The results indicated that the specificity of the immunochromatographic strip was 100% (42/42). The detection limit of the immunochromatographic strip ------------------------------------------------------ To evaluate the detection limit of the immunochromatographic strip, the PRRSV standard positive sera (S/P ratios were 2.428 and 2.715) were two-fold serially diluted with physiological saline from 1:100 to 1:3,200. A red band could be seen clearly at the T line position when the dilution of the serum sample was 1:3,200 or less, indicating that the strip has a high sensitivity for detecting small amounts of anti-PRRSV antibodies. The strip test lines were scanned with a BioDot TSR3000 membrane strip reader and showed that the G/D×A-ROD×pixel of PRRSV-positive sera for HN07-1 and BJ-4 diluted 1:100, 1:200, 1:400, 1:800, 1:1600, 1:3200 were 95.3926, 118.0526, 187.4653, 114.9801, 78.9306, 52.1133 and 44.6651, 49.7877, 103.5346, 105.3718, 65.5187, 36.0817, respectively. The highest G/D×A-ROD×pixel of the negative/control sera was 13.7273, which was very weak and could not be seen by the naked eye ([Table 2](#T2){ref-type="table"}). The results indicated that the strip had a high sensitivity for detecting PRRSV antibodies and could detect antibodies in serum samples at low concentrations. Comparison of the strip with other methods for detection of experimental infection in pigs ------------------------------------------------------------------------------------------ A comparison of the serological reactivity of the strip with the commercial IDEXX PRRS X3 ELISA test and the IPMA was performed by using serum samples that were collected from pigs experimentally infected with isolates HN07-1 and BJ-4 ([Table 3](#T3){ref-type="table"}). All sera collected prior to 7 days postinoculation were negative in the strip test, ELISA, and IPMA results. At 14 days postinoculation, all samples were detected as seropositive (S/P \> 0.4) by the IDEXX ELISA. The strip test detected seroconversion at 14 days post inoculation in pig numbers 10 and 26. At 21 days postinoculation, all samples were identified as positive by all three methods. In summary, 33 of 36 (91.7%) IDEXX results agreed with the results obtained by the strip and 32 of 36 (88.9%) IPMA results were in agreement with the strip. Comparison of postvaccination PRRSV antibody detection by the strip and IDEXX PRRS X3 ELISA ------------------------------------------------------------------------------------------- All sera collected prior to 7 days post vaccination were negative in both the strip and the IDEXX PRRS X3 ELISA results. At 14 days post vaccination, both the strip and ELISA detected seroconversion in the vaccinated pigs, but both tests also recorded animals which were negative. However, at 21 days postvaccination all serum samples were positive in both tests ([Table 4](#T4){ref-type="table"}). Comparison of the strip with the IDEXX PRRS X3 ELISA for the detection pigs infected in the field ------------------------------------------------------------------------------------------------- To further demonstrate the usefulness and reliability of the immunochromatographic strip for detecting the serum antibody responses of pigs infected with field strains of the virus a 1034 field serum samples were tested in parallel with the strip and IDEXX PRRS X3 ELISA ([Table 5](#T5){ref-type="table"}). According to the formula TP/(TP + FN) and TN/(TN + FP): TP, true positive, TN, true negative, FP, false positive, and FN, false negative, which was used to calculate the sensitivity and specificity of the test, the corresponding values were 93.04% (682/733) and 88.70% (267/301), respectively. Discussion ========== Serological testing for antiviral antibodies is a standard diagnostic and surveillance method for determining whether pigs have been exposed to PRRSV. Currently, the IDEXX PRRSV ELISA kit, which is based on the antigen PRRSV N protein, is widely used for determining the viral infection status of swine herds. The recombinant Nsp7 protein of PRRSV has also been used as an antigen in indirect ELISA tests to detect the antibodies against PRRSV \[[@B2]\]. These ELISA methods require professional/technical personnel and are time-consuming. The proposed immunochromatographic test strip described here is simple, easy to operate, cost efficient, and provides rapid results, which is ideal for wide application, including developing countries. As mentioned, PRRSV has European and North American types. Nucleotide sequences within the same genotype have some variability, whereas the nucleotide sequences between the two different genotypes differ significantly \[[@B11],[@B12]\]. The amino acid sequence identity of the Nsp7 protein in the European-type PRRSV is within 96.7% to 97.4%, whereas that in the North American type is within 84.9% to 100%. However, the amino acid sequence identity of Nsp7 protein between the European and North American types overlapped by only 45% \[[@B8],[@B9],[@B15],[@B18]\]. PRRSV isolates in China are mainly of the North American type, and the BJ-4 strain is a North American type. Thus, we selected the Nsp gene from the BJ-4 strain, a typical North American (VR2332)-like PRRSV, for the preparation of the recombinant antigen for the detection of serum antibodies for the diagnosis of PRRSV infection in China. The developed immunochromatographic strip that uses the recombinant Nsp7 antigen of the BJ-4 strain can detect antibodies against the atypical PRRSV isolate HN07-1, which has been the dominant virus in China after 2006. Recombinant Nsp7 protein has a number of practical advantages. First, it is expressed in a soluble form, which is convenient for protein purification. The Nsp7 protein is sufficiently immunogenic for antibodies against the Nsp7 protein to be detected 14 days after PRRSV infection, and these antibodies remain at elevated levels for 202 days \[[@B2]\]. Therefore, the recombinant Nsp7 protein can be used as the target antigen for detecting anti-Nsp7 antibodies in serological testing. The immunochromatographic strip for detecting PRRSV antibodies on the basis of N protein was developed in 2008 \[[@B7]\]. The movement to eliminate PRRSV may require a variety of serological diagnostic technologies that can accurately detect persistent infection in pigs. In this study, we used a gold-labeled recombinant Nsp7 protein to bind the anti-PRRSV antibodies. This gold-labeled antigen-antibody complex can be captured by SPA and the result is then seen as a red line indicating the presence of PRRSV antibodies. The Nsp7 recombinant protein was further purified by gel filtration to yield the monomer form because aggregates of the protein were found to nonspecifically bind IgG. We observed cross reaction of the Nsp7 large aggregate and dimer protein with PRRSV-negative sera, and the Nsp7 monomer reacted strongly and specifically with porcine antibodies against both classical and atypical PRRSV. On this basis, the monomer was selected for a colloidal gold-labeled antigen probe to increase the specificity of the test strip. The developed test strips have high sensitivity in the detection of antibodies against PRRSV and exhibit no cross reaction with antibodies of other pathogens such as FMDV, PRV, CSFV, PPV, PCV-2, and negative PRRSV sera. We also used the test strips to screen 1034 clinical sera from several swine herds in Henan Province and then compared our results with those from the commercial IDEXX PRRS X3 ELISA kit. The results showed that the sensitivity and specificity of the strip were 93.04% and 88.70%. We used the test strips to detect antibodies in pigs experimentally infected with both classical and atypical PRRSV and compared the results with those of the IDEXX PRRS X3 ELISA kit and the IPMA. The overall coincidence rate was 91.7% and 88.9%, respectively. Post vaccination test results from piglets demonstrated that the strip and the IDEXX PRRS X3 ELISA assay had a high coincidence rate (92%). Considering all of the results, the test strip shows comparable performance to the reference ELISA and should be considered of similar value to the ELISA kit in clinical applications. In summary, the chromatographic strip developed in this study is a simple, sensitive, and serologically-specific detection method. The study results show that the strip accurately identifies antibodies against PRRSV in experimentally infected swine sera, field-infected porcine sera, and sera from piglets after vaccination. Results using the new method are well within the ranges achieved by the commercial IDEXX ELISA assay and the IPMA test. However, the strip cannot distinguish antibodies induced by vaccination from those resulting from viral infection. Further investigation to develop an antibody differentiation test is required. This work was supported by grants from China Agriculture Research System (CARS-36), the Pig Industry Technology System Innovation Team Project of Henan Province (S2012-06), and the Special Fund for Agro-scientific Research in the Public Interest (201203039). We would like to thank Professor Gregson from IoN University for revising the paper. **Conflict of Interest:** The authors declare no conflict of interests. {#F1} {#F2} {#F3} {#F4} ###### Specificity of the immunochromatographic strip with 200-fold diluted porcine sera  PRRSV, porcine reproductive and respiratory syndrome virus; PCV-2, porcine circovirus-2; PCV-1, porcine circovirus-1; CSFV, classical swine fever virus; PRV, pseudorabies virus. ###### G/D×area, and G/peak of the relative optical density (ROD) of test lines of the standard porcine reproductive and respiratory syndrome virus samples^\*^  ^\*^Standard sera samples were tested by using the immunochromatographic test strips and the test lines were scanned with a TSR3000 membrane strip reader. G/D×A indicates graph/density×area, which means density value of the sampled outline, multiplied by its area. G/peak indicates graph peak density, maximum density value of sampled line points. ROD means relative optical density, inverse of gray level value with a logarithmic transformation. ###### Detection porcine reproductive and respiratory syndrome virus (PRRSV) antibodies in swine sera at different days after infected with PRRSV HN07-1 or BJ-4: test strip vs. IDEXX PRRS 3X ELISA kit and immunoperoxidase monolayer assay (IPMA)  ELISA, enzyme-linked immunosorbent assay. ###### Detection of porcine reproductive and respiratory syndrome virus antibodies in swine sera at different days after vaccination using the strip and the IDEXX PRRS 3X ELISA kit  ELISA, enzyme-linked immunosorbent assay; −, Negative; + positive. Samples with S/P ratio \> 0.4 were considered positive. ###### Comparison of results from the strip and the IDEXX PRRS X3 ELISA from pigs infected with field virus  ELISA, enzyme-linked immunosorbent assay. [^1]: ^†^The first two authors contributed equally to this work.

Rod Andrews The Rt. Rev Rodney Osborne Andrews is a retired Anglican bishop. Born on 11 November 1940, educated at the University of Saskatchewan and ordained in 1965 he was involved in parish work and native ministry within the Diocese of Calgary until 1984. He was a military chaplain in the Diocese of Montreal after which he was Archdeacon of Algoma until 2000. He was Rector of St Alban’s, Richmond and University Chaplain at UBC until 2004 when he became the Bishop of Saskatoon. He resigned his See in 2010. Bishop Rodney holds an airline transport pilot’s licence and is currently a flight instructor. References Category:1940 births Category:University of Saskatchewan alumni Category:Anglican bishops of Saskatoon Category:21st-century Anglican bishops Category:Living people Category:Canadian military chaplains

Search Knowledgebase Rabies Rabies is a disease caused by a virus that can affect the nervous system (brain and spinal cord) of any kind of mammal, including humans. Rabies-infected animals can spread the disease through their saliva or brain matter. Signs of rabies in animals may include excessive saliva or sometimes foaming at the mouth, paralysis, or behavioral changes in a pet (shyness when the pet used to be friendly) or no fear of humans in a wild animal. After rabies symptoms appear, the disease progresses quickly and is very difficult to cure. Getting postexposure prophylaxis shots (PEP) before symptoms occur usually gets rid of the virus before it can cause serious damage. Rabies is nearly always fatal if not treated before symptoms appear. People who believe they may have been exposed to the rabies virus should seek medical attention immediately. This information does not replace the advice of a doctor. Healthwise, Incorporated disclaims any warranty or liability for your use of this information. Your use of this information means that you agree to the Terms of Use. How this information was developed to help you make better health decisions.

Nanoscale mechanobiology of cell adhesions. Proper physiological functions of cells and tissues depend upon their abilities to sense, transduce, integrate, and generate mechanical and biochemical signals. Although such mechanobiological phenomena are widely observed, the molecular mechanisms driving these outcomes are still not fully understood. Cell adhesions formed by integrins and cadherins receptors are key structures that process diverse sources of signals to elicit complex mechanobiological responses. Since the nanoscale is the length scale at which molecules interact to relay force and information, the understanding of cell adhesions at the nanoscale level is important for grasping the inner logics of cellular decision making. Until recently, the study of the biological nanoscale has been restricted by available molecular and imaging tools. Fortunately, rapid technological advances have increasingly opened up the nanoscale realm to systematic investigations. In this review, we discuss current insights and key open questions regarding the nanoscale structure and function relationship of cell adhesions, focusing on recent progresses in characterizing their composition, spatial organization, and cytomechanical operation.

Q: How to automate an installation of Phusion Passenger and Nginx? When the command: ./passenger-install-nginx-module is run, it asks a bunch of questions when logged in to the server. The aim is to automate this process, how can this be done if it requires specific answers during the installation? A: Depending on the version of Phusion Passenger, it should ether be possible to do yes | passenger-install-nginx-module (for version 2.0.x) or passenger-install-nginx-module --auto for versions greater than 2.1.

[Effect of adrenaline, noradrenaline and acetylcholine on rabbit and human uterine activity in vivo (author's transl)]. Effects of estrogen (abbr. as E), Estrogen + Progesterone (E + P) and autonomic nerve trophic drugs on uterus were investigated in rabbit and human in vivo and the following results were obtained. 1) Spontaneous contraction in cornu and cervix of E treated rabbit were stronger than in those during pregnancy or treated with E + P. 2) 10(-5) g/kg Adrenaline caused a uniform response pattern in cornu and cervix of E treated rabbit, and the pattern could be divided into three phases. Phase I is supposed to be the contraction response through the alpha receptor, and phase II is presumed as the response that comprises a part of element identical with alpha adrenergic response, while phase III is the relaxation response through the beta 2 receptor. 3) Acetylcholine (ACh) 10(-3) g/kg and Neostigmine 10(-5) g/kg caused augmentation of contraction both in cornu and cervix of rabbit, but this effect was blocked by Atropine, suggesting the presence of parasympathetic control in cornu and cervix. 4) In human corpus and cervix, Phenylephrine and ACh augmented contraction but Terbutaline had reducing contraction, showing the similar phenomenon found in rabbit. From this, it was proven that the similar autonomic nerve controls could be present both in rabbit and human.

When Unix was being developed in 1969 based on a filesystem, the concept of device drivers was already well defined, when it was also viewed as an extension of the same filesystem. Also the model of a portable operating system was already decided early on when it was broken into two main components; the device independent component (the logical layer of the device) which required it to be written in a high-level language such as C and the hardware-dependent (the physical layer of the device) component in which the device driver model maps the low-level data structures of the physical device to high level data structures of the logical device. Therefore the Unix filesystem has no explicit device associated with the way the information is laid down as it deals with data as a block entity and has no knowledge of how a block is composed, in an effort to make the OS kernel as portable as possible. This model which was also adopted by Posix (portable-operating-system-interface-for-unix) continued to this day, especially in the world-wide use of the GNU/Linux system in all professional applications. Though current (2012) OS models such as Unix, Linux, and GUI (Graphical-User-Interface) such as Windows, and Android use a number of hardware-abstraction-layer (HAL) in the virtual-file-system (VFS), block device, the driver codes specific to a hardware can exist in the kernel as the Kernel-Mode-Driver-Framework (KMDF), or by loadable module which is called upon only when needed. Also another method, the User-Mode-Driver-Framework (UMDF) moves driver codes outside the kernel. Nevertheless, the OS at some point will need to execute the physical driver codes which exist in the visible memory space that requires device-specific control. In effect, this makes the kernel hardware-dependent rendering it not only unportable, but unusable to an upgrade of the same platform. Though the HAL insulates an OS from vendor-specific hardware, the HAL still resides in the OS memory space. This has two major impediments: first, the system processor cannot run another process when it is executing the physical driver codes or parallel processing (not multitasking), and second, a device manufacturer must supply the physical device driver. That is why the need for specific kernel upgrades even for the most basic change of computer devices such as video and sound. There is then a need for the HAL to move to the device end itself and implementing FIFOs which is the subject of this patent. When this happens, a correspondingly beneficial effect emerges which creates a new model requiring the device to be treated as a homogenous device. It does not only stop at this, but other spin-offs are created as well; with the addition of FIFOs for every device ports, traditional computer components can be removed as well; the DMA engine, multi-arbiters, multi-bus, and an I/O bus such as the PCI. A very similar invention was initiated by the I2O (intelligent-I/O) Special Interest Group (I2OSIG) which published the I2O specification in 1996. The steering committee members included HP, Intel, Microsoft, Novell, Adaptec, 3Com and more than sixty other members which included corporations such as Acer, ARM, Dell, Fujitsu, Samsung, Seagate, Siemens and Western Digital among many others. The only similarity is that the HAL is also moved outside the OS address space and into the device end itself. But the FIFO oriented view was not included which made the two inventions diverged radically, making the I2O a far more complex implementation with its message passing interface and protocol.

Q: VS2010 repeatedly showing animated icon Visual Studio 2010 is repeatedly showing this animated icon in the bottom right next to the "Ln" every 2 seconds. And even if VS is minimized, it makes my cursor briefly show an hourglass every time. Can someone tell me what this icon stands for? Edit: Showing the icon during a build also. Build icon is on left, mystery icon in middle. A: The icon seems to be related to Intellisense. I noticed that vcpkgsrv.exe was starting and exiting quickly over and over. Although I had a large project.sdf file, Intellisense was not working in my project. I found this KB from Microsoft related to VS2010 Intellisense issues on XP (I'm running XP). When I installed the hotfix, the problem went away. http://support.microsoft.com/kb/2526044

The Century of Warfare Worldwide Conflict From 1900 to the Present Day Based on a TV series scheduled for spring 1995, this book provides a comprehensive overview of warfare in the 20th century in all its forms. Describing the causes of wars in the international arena, their course and how peace was made, it also traces the awesome developments in weapons technology and features stills from contemporary World War I film.

// Copyright 2014 The Chromium Authors. All rights reserved. // Use of this source code is governed by a BSD-style license that can be // found in the LICENSE file. #ifndef COMPONENTS_DATA_REDUCTION_PROXY_CORE_BROWSER_DATA_REDUCTION_PROXY_SETTINGS_TEST_UTILS_H_ #define COMPONENTS_DATA_REDUCTION_PROXY_CORE_BROWSER_DATA_REDUCTION_PROXY_SETTINGS_TEST_UTILS_H_ #include <map> #include <memory> #include <string> #include "components/data_reduction_proxy/core/browser/data_reduction_proxy_settings.h" #include "components/prefs/testing_pref_service.h" #include "net/log/test_net_log.h" #include "net/url_request/test_url_fetcher_factory.h" #include "net/url_request/url_request_test_util.h" #include "testing/gmock/include/gmock/gmock.h" #include "testing/gtest/include/gtest/gtest.h" class PrefService; class TestingPrefServiceSimple; namespace data_reduction_proxy { class DataReductionProxyTestContext; class MockDataReductionProxyConfig; template <class C> class MockDataReductionProxySettings : public C { public: MockDataReductionProxySettings<C>() : C() { } MOCK_METHOD0(GetOriginalProfilePrefs, PrefService*()); MOCK_METHOD0(GetLocalStatePrefs, PrefService*()); MOCK_METHOD1(RecordStartupState, void(ProxyStartupState state)); }; class DataReductionProxySettingsTestBase : public testing::Test { public: static void AddTestProxyToCommandLine(); DataReductionProxySettingsTestBase(); DataReductionProxySettingsTestBase(bool allowed, bool fallback_allowed, bool promo_allowed); ~DataReductionProxySettingsTestBase() override; void AddProxyToCommandLine(); void SetUp() override; template <class C> void ResetSettings(bool allowed, bool fallback_allowed, bool promo_allowed, bool holdback); virtual void ResetSettings(bool allowed, bool fallback_allowed, bool promo_allowed, bool holdback) = 0; void ExpectSetProxyPrefs(bool expected_enabled, bool expected_at_startup); void CheckMaybeActivateDataReductionProxy(bool initially_enabled, bool request_succeeded, bool expected_enabled, bool expected_restricted, bool expected_fallback_restricted); void CheckOnPrefChange(bool enabled, bool expected_enabled, bool managed); void InitWithStatisticsPrefs(); void InitDataReductionProxy(bool enabled_at_startup); void CheckDataReductionProxySyntheticTrial(bool enabled); bool SyntheticFieldTrialRegistrationCallback(const std::string& trial_name, const std::string& group_name) { synthetic_field_trials_[trial_name] = group_name; return true; } base::MessageLoopForIO message_loop_; std::unique_ptr<DataReductionProxyTestContext> test_context_; std::unique_ptr<DataReductionProxySettings> settings_; base::Time last_update_time_; std::map<std::string, std::string> synthetic_field_trials_; }; // Test implementations should be subclasses of an instantiation of this // class parameterized for whatever DataReductionProxySettings class // is being tested. template <class C> class ConcreteDataReductionProxySettingsTest : public DataReductionProxySettingsTestBase { public: typedef MockDataReductionProxySettings<C> MockSettings; void ResetSettings(bool allowed, bool fallback_allowed, bool promo_allowed, bool holdback) override { return DataReductionProxySettingsTestBase::ResetSettings<C>( allowed, fallback_allowed, promo_allowed, holdback); } }; } // namespace data_reduction_proxy #endif // COMPONENTS_DATA_REDUCTION_PROXY_CORE_BROWSER_DATA_REDUCTION_PROXY_SETTINGS_TEST_UTILS_H_

41 So.3d 224 (2010) ODUM v. STATE. No. 2D10-1573. District Court of Appeal of Florida, Second District. July 28, 2010. Decision without published opinion Affirmed.

Government Fleet News SEAL BEACH, CA – CleanScapes, Inc., a newly-designated City of Seattle, Wash., solid waste contractor, has awarded Clean Energy Fuels Corp. a contract for up to 10 years to build and operate a compressed natural gas (CNG) station and provide fuel for CleanScapes’ 40 new CNG-powered refuse trucks. FRANKLIN, KY – After the ground breaking on an electric car plant for Integrity Automotive, residents and city officials in Simpson County have shown their support by ordering three electric trucks from ZAP. LUBBOCK, TEXAS – High gas prices are changing the look of city vehicles. The City of Lubbock expects to start replacing full-size trucks with smaller ones beginning in the 2008-09 fiscal year, which starts Oct. 1. JACKSON, MS – Mississippi needs to adopt guidelines that limit how many new vehicles agencies buy each year, a state auditor’s report says. The report found that Mississippi averages one state-owned vehicle for every three or four employees ANAHEIM, CA - Myers Select Material Handling is doing their part to contribute to a cleaner environment. The forklift servicing company recently presented its hydrogen-combustion forklift at "The Future is Green" conference in Long Beach, Calif. BUFFALO, NY – As global positioning comes to the Erie County fleet, officials are looking at $650,000 a year in fuel and maintenance costs, with only $150,000 in start up costs to place the units in 200 county vehicles. BUFFALO, NY – In tough economic times, should elected officials have 24 hour access to a city-owned car? It’s a debate that includes Buffalo Mayor Byron Brown, the Buffalo School Superintendent, the candidates for District Attorney, and even several federal workers below the cabinet level. RIDGEWOOD, NJ – As part of the Propane Education and Research Council (PERC) event —Ken Smith Motors, Inc. will make its ultimate bi-fuel hybrid propane conversion system viewable to the public as Bergen County will start to utilize the system.

%HOMWARP Warp image by an homography % % OUT = HOMWARP(H, IM, OPTIONS) is a warp of the image IM obtained by % applying the homography H to the coordinates of every input pixel. % % [OUT,OFFS] = HOMWARP(H, IM, OPTIONS) as above but OFFS is the offset of the % warped tile OUT with respect to the origin of IM. % % Options:: % 'full' output image contains all the warped pixels, but its % position with respect to the input image is given by the % second return value OFFS. % 'extrapval',V set unmapped pixels to this value (default NaN) % 'roi',R output image contains the specified ROI in the input image % 'scale',S scale the output by this factor % 'dimension',D ensure output image is DxD % 'size',S size of output image S=[W,H] % 'coords',{U,V} coordinate matrices for im, each same size as im. % % Notes:: % - The edges of the resulting output image will in general not be % be vertical and horizontal lines. % % See also HOMOGRAPHY, ITRIM, INTERP2. % Copyright (C) 1993-2011, by Peter I. Corke % % This file is part of The Machine Vision Toolbox for Matlab (MVTB). % % MVTB is free software: you can redistribute it and/or modify % it under the terms of the GNU Lesser General Public License as published by % the Free Software Foundation, either version 3 of the License, or % (at your option) any later version. % % MVTB is distributed in the hope that it will be useful, % but WITHOUT ANY WARRANTY; without even the implied warranty of % MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE. See the % GNU Lesser General Public License for more details. % % You should have received a copy of the GNU Leser General Public License % along with MVTB. If not, see <http://www.gnu.org/licenses/>. function [w,foffs] = homwarp(H, im, varargin) % the result of a warp can have negative pixel coordinates or very % large coordinates, well away from the origin. opt.full = false; opt.extrapval = NaN; opt.size = []; opt.roi = []; opt.scale = 1; opt.dimension = []; opt.coords = []; opt = tb_optparse(opt, varargin); [w,h] = isize(im); if opt.roi % opt.box is specified in standard ROI format l = opt.roi(1,1); t = opt.roi(2,1); r = opt.roi(1,2); b = opt.roi(2,2); box = [l r r l; t t b b]; else % bounding box in the input image is the full extent box = [1 w w 1; 1 1 h h]; end % map the box vertices in input image to vertices in output image Hbox = homtrans(H, box); % determine the extent of the image after warping xmin = min(Hbox(1,:)); xmax = max(Hbox(1,:)); ymin = min(Hbox(2,:)); ymax = max(Hbox(2,:)); % we want the pixel coordinates to map to positive values, determine the minimum if opt.full offs = floor([xmin, ymin]); % and prepend a translational homography that translates the output image H = [1 0 -offs(1); 0 1 -offs(2); 0 0 1] * H; end sz = round([xmax-xmin+1, ymax-ymin+1]); % we can specify the maxmimum dimension of the resulting image if ~isempty(opt.dimension) s = opt.dimension / max(sz); H = diag([s s 1]) * H; Hbox = homtrans(H, box); % determine the extent xmin = min(Hbox(1,:)); xmax = max(Hbox(1,:)); ymin = min(Hbox(2,:)); ymax = max(Hbox(2,:)); % we want the pixel coordinates to map to positive values, determine the minimum offs = floor([xmin, ymin]); % and prepend a translational homography that translates the output image H = [1 0 -offs(1); 0 1 -offs(2); 0 0 1] * H; sz = round([xmax-xmin+1, ymax-ymin+1]); end if isempty(opt.coords) [Ui,Vi] = imeshgrid(im); else Ui = opt.coords{1}; Vi = opt.coords{2}; end % determine size of the output image if ~isempty(opt.size) [Uo,Vo] = imeshgrid(opt.size); else if opt.full [Uo,Vo] = imeshgrid(sz); else [Uo,Vo] = imeshgrid(im); end end % warp the coordinates of the output pixels UV = homtrans(inv(H), [Uo(:) Vo(:)]'); U = reshape(UV(1,:), size(Uo)); V = reshape(UV(2,:), size(Vo)); % interpolate for each color plane for p=1:size(im,3) imh(:,:,p) = interp2(Ui, Vi, idouble(im(:,:,p)), U, V, 'linear', opt.extrapval); end if nargout > 0 w = imh; else idisp(imh); end if nargout > 1 && opt.full foffs = offs; end

4 -3 times 29382214 -88146642 What is 985361 times 39? 38429079 -5 times 20072.87 -100364.35 Calculate 6070*-22887. -138924090 Product of -12.2 and -1.61505. 19.70361 -2 * -10.53138 21.06276 0.5 times -4534778 -2267389 Calculate -691*150.21. -103795.11 What is the product of -477.757 and -0.3? 143.3271 2248 * 268.3 603138.4 -845.7*-2439 2062662.3 What is the product of -3.2 and -18760.3? 60032.96 Product of 4629201.11 and -4. -18516804.44 Multiply 36 and -36070. -1298520 Product of 1667.716 and 0. 0 Product of 4630.7 and -0.1493. -691.36351 Calculate -0.4*37.0153. -14.80612 Calculate -8.9*-0.063629. 0.5662981 0.0655 * 157.5 10.31625 -1.9 * -5514266 10477105.4 What is -0.179 times -30851? 5522.329 -1*0.1800356 -0.1800356 What is the product of 27.20519 and -10.2? -277.492938 287.8731 * 0.3 86.36193 -61717748 times 0.5 -30858874 What is -4819156 times -6? 28914936 What is the product of -5.99 and -0.147497? 0.88350703 Work out 0.11 * -0.03324126. -0.0036565386 Multiply 0.9599 and -3202. -3073.5998 Multiply -5 and -74969. 374845 1.36776 * -0.062 -0.08480112 What is 779.6 times -0.6735? -525.0606 Product of 136189.1 and -0.79. -107589.389 Calculate 1910*25.5124. 48728.684 Work out -0.034 * -476548. 16202.632 -0.5 times 4046327 -2023163.5 15250831 * -4 -61003324 -0.2*0.662406 -0.1324812 -1698*0.97995 -1663.9551 Work out 47 * 21.9007. 1029.3329 Product of 170556 and -464. -79137984 Product of -0.1 and -3609.7914. 360.97914 Product of -982077678 and -0.2. 196415535.6 -0.1 * -4761303 476130.3 -77091228 times 0 0 Calculate 0.3*-119969093. -35990727.9 -4989.5769*0.4 -1995.83076 141 times -199631 -28147971 Multiply -0.01926143 and 0.4. -0.007704572 Product of 2.822 and -2613. -7373.886 Calculate 46*-864.885. -39784.71 Work out -69 * -120925.73. 8343875.37 Multiply 6.19 and 2864. 17728.16 What is 381355 times 375? 143008125 Product of 0 and -696.945. 0 4075431.5 times 6 24452589 -645.19486*-5 3225.9743 0.5 * -1043164 -521582 Calculate -967018488*1. -967018488 Work out -22.76 * -35.64. 811.1664 -4334*225 -975150 Calculate -388*-238107. 92385516 -17*0.0209303 -0.3558151 -44 * -627519 27610836 What is the product of 0.82566 and 0.8? 0.660528 0.4 times -1.18521736 -0.474086944 Work out -5.698 * 4866. -27726.468 -351.71642 * -1 351.71642 Product of 2113381 and -26. -54947906 -0.021457 * 9.758 -0.209377406 Work out -22256 * -3.01. 66990.56 Multiply -22.841 and 6414. -146502.174 -2 * -3703.786 7407.572 Multiply 19.97181 and -0.01. -0.1997181 0.462 * -275.284 -127.181208 Calculate 616*-1.544. -951.104 What is the product of -0.6 and -3428.548? 2057.1288 Work out 2209204 * 71. 156853484 Product of 7888.2 and -0.052. -410.1864 Product of -3 and 898651. -2695953 Calculate 17417.3*0.26. 4528.498 What is 275 times -6713.35? -1846171.25 Product of 0.075 and 244301. 18322.575 -7075701.7 * -0.4 2830280.68 What is the product of 0.0209 and -4.544? -0.0949696 Calculate 326.52038*0.1. 32.652038 What is the product of -8906 and 297? -2645082 -88 times 35062.1 -3085464.8 What is the product of -0.3 and 1379635? -413890.5 Multiply -54 and -453271. 24476634 0.00861*-194 -1.67034 What is -0.01 times 313.7463? -3.137463 Calculate -813856.7*20. -16277134 What is the product of 3473 and -14335? -49785455 -163.8733*12.8 -2097.57824 12476360 times -0.02 -249527.2 Product of 0.0225312329 and -5. -0.1126561645 Product of -0.07726 and 0.033052. -0.00255359752 0.12*-880018 -105602.16 -30*-522396 15671880 What is the product of -2014.573 and -0.4? 805.8292 What is the product of -11.4 and 262458.5? -2992026.9 What is the product of 3230.425 and 2.4? 7753.02 Product of 176 and 4.2044. 739.9744 Multiply 80251 and -142. -11395642 Work out 819 * -117230. -96011370 689297697 times 5 3446488485 -2.3 times -878880 2021424 Calculate -167613185*-0.5. 83806592.5 112498*-208 -23399584 What is the product of 133786745 and -3? -401360235 -120100 times 0.17 -20417 218.74055*-0.01 -2.1874055 Multiply -2133256 and 0.8. -1706604.8 Multiply -53.4 and 0.11009. -5.878806 Multiply 1081283 and -80. -86502640 Work out 10592248 * -0.5. -5296124 Calculate 187240.7*-0.1. -18724.07 21.8 times -12.132 -264.4776 Product of -71223 and -1.13. 80481.99 0.3 times -0.6411778 -0.19235334 Work out 915.3 * 290.2. 265620.06 Calculate -0.0706625*0.1. -0.00706625 Product of -1 and -323457804. 323457804 -0.2 * 14872440 -2974488 3 times -0.189040812 -0.567122436 Calculate 82.8700174*-5. -414.350087 What is -27.29 times 36? -982.44 Work out -1875.0484 * -17. 31875.8228 1866637 times 105 195996885 Multiply 0.24705272 and -0.13. -0.0321168536 0.03*6125825 183774.75 Product of -81586071 and 0.3. -24475821.3 What is the product of -0.4 and -179389558? 71755823.2 Product of 2 and 1020.15. 2040.3 What is the product of 0.285 and -51452? -14663.82 Calculate -4.7331*149. -705.2319 -1024.1 times -6299 6450805.9 -0.11636 * -29549 3438.32164 What is 96877723 times 3? 290633169 0.044*-77225 -3397.9 133*-457 -60781 -0.048089 * -6774 325.754886 Product of -2 and 2298681. -4597362 Product of 3975366 and -0.09. -357782.94 What is the product of -0.2387 and -40202.6? 9596.36062 215.3 * 6665 1434974.5 What is 1277069 times 18? 22987242 -9952360*-66 656855760 Calculate 26*-3123989. -81223714 Calculate 196809.3*-0.52. -102340.836 -24898897 times 35 -871461395 Calculate -52*-1.23987. 64.47324 Multiply 0.3 and -19.5210619. -5.85631857 Product of -0.65 and -0.454036. 0.2951234 What is -9604760 times -0.9? 8644284 Work out 16 * 414093. 6625488 Calculate -89.1*23.591. -2101.9581 Calculate -35961357*0.4. -14384542.8 Multiply 5 and -0.28188. -1.4094 -924 times -75123 69413652 Product of -37567914 and 27. -1014333678 Calculate 4.6*-18.717981. -86.1027126 What is -9924.09 times 2.4? -23817.816 -2478 * -16.736 41471.808 What is -18.6002 times -100? 1860.02 Work out -3 * 2722.6177. -8167.8531 -27939 times -77 2151303 Work out 2165844 * -0.07. -151609.08 What is -25432.54 times -3? 76297.62 What is the product of -18252.002 and 1? -18252.002 -1058718*1 -1058718 0.05*-2985.238 -149.2619 What is the product of 0.359102797 and -1? -0.359102797 Multiply 79731.9 and -0.1. -7973.19 Calculate -6057*13.802. -83598.714 -1.1 * 56255 -61880.5 6137618 times 2 12275236 62 * -3042584 -188640208 -0.6 * 0.03215237 -0.019291422 What is the product of 2.0384363 and 0.3? 0.61153089 0.316*114295 36117.22 -3.7 * -434113 1606218.1 -0.02923 * 2921 -85.38083 Multiply -2.6 and 1.2361021. -3.21386546 Product of 292.8 and 0.216. 63.2448 Product of -1138 and 98.965. -112622.17 0 * 980.4292 0 Work out -4427 * -65863. 291575501 What is 866712 times -0.1? -86671.2 Multiply -434 and -0.1535. 66.619 What is -26 times -0.174879? 4.546854 What is 51122915 times -16? -817966640 Multiply 0.02 and 75350. 1507 -959 * -30239 28999201 What is 2.08 times -4.7859? -9.954672 Multiply 774878511 and -0.3. -232463553.3 What is 11.5461 times -36.1? -416.81421 Work out -387586604 * 0.5. -193793302 Work out 964 * 118.92. 114638.88 Work out 0.1325181 * -35. -4.6381335 Calculate 24.99*-499136. -12473408.64 1709*0.552 943.368 What is the product of 0.2 and -22.80329? -4.560658 What is the product of 19293 and 46.6? 899053.8 Multiply 7 and 19.2499. 134.7493 74595 * 67 4997865 269 * 44707 12026183 Calculate 347.8*28527. 9921690.6 Multiply 1.69 and 1568.4. 2650.596 -4360084 times 0.36 -1569630.24 Multiply 0.44 and -0.0493279. -0.021704276 What is the product of -33 and 2326.635? -76778.955 Work out -523335 * -178. 93153630 What is the product of -1.31 and 28907.5? -37868.825 4213*-14062 -59243206 0.221 * -289038 -63877.398 What is -5 times -4875478? 24377390 1.54752*2.9 4.487808 1.1*79054267 86959693.7 Product of -41641 and -36. 1499076 Multiply -0.05 and -723136. 36156.8 Calculate -47458427*-0.06. 2847505.62 Multiply -38.7 and 0.20636. -7.986132 What is -1157 times -60819? 70367583 Multiply 100 and -7623.8. -762380 -32955.9 times -10.7 352628.13 Work out -234 * 36882. -8630388 -3 * 571516.74 -1714550.22 What is the product of -242 and -2.6335? 637.307 Product of -531.17232 and 9. -4780.55088 Work out 128765 * 10. 1287650 -621 times 0.00038 -0.23598 What is the product of -1921937 and 76? -146067212 29158.2081*0.2 5831.64162 What is -1.89629 times 2.8? -5.309612 -0.72 * -1370222 986559.84 Product of -0.00448364

Cochylimorpha nomadana Cochylimorpha nomadana is a species of moth of the family Tortricidae. It is found in China (Xinjiang), Afghanistan, Iran, Russia (the Caucasus and south-eastern part of European Russia), Armenia, Kazakhstan, Turkmenistan and Uzbekistan. The wingspan is 22–31 mm. Adults have been recorded from wing from July to August. References Category:Moths described in 1874 Category:Cochylimorpha Category:Moths of Asia

Intracerebroventricular administration of superFIT and its enantiomer to rats: evidence for in vivo acylation of [3H]DADL binding sites. SuperFIT is an high affinity acylating ligand derived from fentanyl. Previous studies suggested that a selective acylation of delta receptors (J. Med. Chem. 29:1087-1093, 1986) resulted from exposure of membranes to this and structurally related compounds. We report in this preliminary study that intracerebroventricular administration of either superFIT or its enantiomer 18 to 24 hours prior to sacrifice decreased the subsequent binding of [3H]DADL to both its higher and lower affinity binding sites.

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If your packing for a cruise be sure to include essentials like medicines to prevent sea sickness and your travel documents. Watch this About.com video for a helpful checklist when packing for a cruise. Sea sickness can be remedied with different medications, herbal supplements, or just by adjusting your body to the boat’s motions. Watch this About.com video to see how you can remedy sea sickness before it ruins your day. Japanese is a difficult language to learn but practicing Japanese in short phrases makes the process easier. Watch this language video from About.com to learn how to say “Isn’t that terrible” in Japanese Traveling anytime soon? From reward programs and noise canceling headphones to laptops, chargers and batteries, Technology Guru, Veronica Belmont gets you ready for your next trip with all the must haves for an enjoyable travel experience!

JFortune – Life ft. Track (Warri 2Pac) & Princess Venessa Earlier this year 2018 Jfortune a.k.a Goodman released two mind blowing singles “Getting Famous” and “The Book”. And now he’s back with another hiphop vibes on his visit to warri. its titled “LIFE” featuring Track (warri 2pac) and Princess Vanessa, mix by ID Cleff.

FDA Approves Eloctate for Patients with Hemophilia A The U.S. Food and Drug Administration today approved Eloctate, Antihemophilic Factor (Recombinant), Fc fusion protein, for use in adults and children who have Hemophilia A. Eloctate is the first Hemophilia A treatment designed to require less frequent injections when used to prevent or reduce the frequency of bleeding. Eloctate is approved to help control and prevent bleeding episodes, manage bleeding during surgical procedures, and prevent or reduce the frequency of bleeding episodes (prophylaxis). Eloctate consists of the Coagulation Factor VIII molecule (historically known as Antihemophilic Factor) linked to a protein fragment, Fc, which is found in antibodies. This makes the product last longer in the patient's blood. “The approval of this product provides an additional therapeutic option for use in the care of patients with Hemophilia A," said Karen Midthun, M.D., director of the FDA's Center for Biologics Evaluation and Research. Hemophilia A is an inherited, sex-linked, blood clotting disorder, which primarily affects males, and is caused by defects in the Factor VIII gene. Hemophilia A affects 1 in every 5,000 males born in the United States. People with Hemophilia A can experience repeated episodes of serious bleeding, mainly into the joints, which can be severely damaged by the bleeding. The safety and efficacy of Eloctate were evaluated in a clinical trial of 164 patients that compared the prophylactic treatment regimen to on-demand therapy. The trial demonstrated that Eloctate was effective in the treatment of bleeding episodes, in preventing or reducing bleeding and in the control of bleeding during and after surgical procedures. No safety concerns were identified in the trial. Eloctate received orphan-drug designation for this use by the FDA because it is intended for treatment of a rare disease or condition. Eloctate is manufactured by Biogen Idec, Inc., Cambridge, Mass. The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation's food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

Background ========== Human immunodeficiency virus type-1 (HIV-1) is characterized by extensive genetic heterogeneity. Molecular epidemiologic studies have demonstrated that globally, the most prevalent forms of HIV-1 are subtypes (clades) C, B and A \[[@B1]-[@B3]\]. Subtype C, which accounts for almost 50% of all HIV-1 infections globally, predominates in sub-Saharan Africa and India \[[@B1]-[@B3]\]. Subtype B is the main genetic form in the Americas, Australia and western Europe; subtype A predominates in areas of central and eastern Africa (Kenya, Uganda, Tanzania and Rwanda) and in eastern Europe \[[@B1]-[@B3]\]; and subtype D is distributed mainly in east Africa, including Uganda \[[@B1]\]. HIV-1 subtypes differ by as much as 20-25% at the genetic level \[[@B2]\], and have varying biological characteristics, including differences in disease progression, pathogenicity, transmissibility and co-receptor usage \[[@B1],[@B2],[@B4]-[@B7]\]. Studies of HIV-1 co-receptor tropism, which have been conducted primarily in populations where subtype B infections predominate, have demonstrated a relationship between HIV-1 co-receptor use and disease stage. In general, early stages of infection and disease are characterized by greater prevalence of only C-C chemokine type 5 (CCR5)-tropic (R5) HIV-1, which has been associated with slower progression to AIDS \[[@B8]-[@B12]\]. The emergence of C-X-C chemokine receptor type 4 (CXCR4)-using virus (X4) has been associated with greater treatment experience and higher risk of death, and coincides with more rapid CD4^+^T-cell depletion and disease progression \[[@B6],[@B8],[@B9],[@B12],[@B13]\]. Some variants of HIV-1 can use either co-receptor (dual/mixed-tropic \[DM\] HIV-1); these can be found in all stages of infection, but are more common in infections of longer duration, with lower CD4^+^cell counts and higher viral loads \[[@B12]-[@B14]\]. Despite the emergence of X4-using variants in some patients, only R5 infection typically persists in the majority of patients. Nearly 50% of patients who die of HIV-1 disease have only R5 HIV-1 detectable at the time of their death, indicating that CCR5 remains a critical co-receptor throughout the course of HIV infection \[[@B12],[@B15]\]. Although HIV-1 co-receptor usage and its relationship to disease stage have been studied in the developed world, where subtype B predominates, such relationships are less well understood for subtypes A, C and D. The R5 phenotype is predominant in subtype C HIV-1 infections, whereas X4-using virus has been reported infrequently, even in advanced disease. R5-using virus is more common in subtype A than subtype D HIV-1 infections, and a high proportion of subtype D infections shows D/M tropism throughout the course of disease \[[@B16]-[@B24]\]. However, some of these previous studies have been limited by small sample sizes. The introduction of the CCR5 antagonist, maraviroc, for HIV-1 therapy \[[@B25]\] has increased interest in the epidemiology of tropism and relationships with HIV-1 subtype. A greater understanding of the tropism of non-B subtype HIV-1 is key for the optimal use of CCR5 antagonists in the treatment of these infections in the developing world, and HIV-1 prevention strategies, such as topical microbicides and systemic pre- or post-exposure prophylaxis. In addition, this information will be important for management of clinic populations in the developed world that include individuals with non-B subtype infections who have migrated from endemic countries \[[@B26]\]. HIV-1 tropism can be determined by genotypic and phenotypic methods. While genotypic assays may have lower specificity and sensitivity, retrospective analyses have found that they are comparable to phenotypic tropism assays for prediction of response to treatment with CCR5 antagonists, in populations pre-screened with a phenotypic assay \[[@B27],[@B28]\]. The clinical development programme for maraviroc, the first-in-class CCR5 antagonist, used the Trofile^®^phenotypic assay (Monogram Biosciences, South San Francisco, California) \[[@B29]-[@B31]\], which determines tropism via the expression of full-length *env*genes of multiple viruses isolated from patient plasma and can detect 10% of X4 variants with 100% sensitivity. More recently, a Trofile^®^assay with enhanced sensitivity to improve detection of low-level X4-using variants has been developed that can detect 0.3% of these variants with 100% sensitivity. Otherwise, assay validation performance characteristics are equivalent between the original and enhanced Trofile^®^assays \[[@B31]\]. The enhanced Trofile^®^assay has been validated in a number of studies by re-testing the co-receptor tropism of clinical samples that were initially determined using the original assay \[[@B31]-[@B34]\]: in a re-analysis of samples from the Phase 3 MERIT study, which evaluated the efficacy of maraviroc in treatment-naïve patients with CCR5-tropic virus, 15% of enrolled patients (n = 106/721) were reclassified as having D/M virus with the enhanced assay \[[@B34]\]. The aim of this study was to estimate the prevalence of R5-, D/M-, and X4-tropic HIV-1 among isolates obtained from patients with HIV-1 subtype C infection from India and South Africa, and with subtype A/A1 and D infection from Uganda, and to explore the demographic and clinical characteristics associated with R5 infection. In addition, the study examined the ability of the Trofile^®^assay to determine tropism of non-B subtypes of HIV-1, which previously had not been explored in a large study. Methods ======= Study design ------------ HIV-1-infected, antiretroviral therapy (ART) treatment-naïve (TN) and treatment-experienced (TE) viremic patients were recruited into this prospective, cross-sectional, epidemiologic study from HIV clinics in South Africa (four sites), Uganda (one site), and India (seven sites) in 2007 and 2008. Sites were selected if they had considerable experience with both HIV management and HIV research. The study protocol was approved by the institutional review board at each site. Both TN and TE adults (aged 18 years or older) were eligible for enrolment in India and Uganda. In South Africa, where the MERIT study had previously been conducted in TN patients \[[@B35]\], only TE adults were eligible for inclusion in the present study. No patients were recruited from any other study. Patients who had received less than 10 days of ART were considered to be TN; those who had experienced failure of at least one three-drug ART regimen were considered to be TE. To maximize the external validity and generalizability of the study, only one member of a known infection cluster (i.e., only one member of a family affected by HIV) was eligible for enrolment. Study procedure --------------- At a single visit, the study was explained to patients, and verbal and written informed consent were obtained prior to conduct of any study procedures. Demographic, and HIV clinical history and treatment data were collected; blood was drawn and analyzed for CD4^+^and CD8^+^T cells using BD FACS™ CAP (Becton Dickinson and Company, Franklin Lakes, New Jersey), and for HIV-1 RNA levels using Amplicor HIV-1 Monitor™ UltraSensitive Assay (Roche Diagnostics, Indianapolis, Indiana). For individuals with viral loads exceeding 500 copies/mL, HIV-1 subtype was determined based on reverse transcriptase and protease gene sequence (Monogram Biosciences). *Pol*subtyping was performed by generating three distinct sets of partial-length nucleotide sequences from patient-derived reverse transcriptase and protease genes. Genetic sequence comparison was determined by the Basic Local Alignment Search Tool algorithm, and subtype was resolved by a customized software package that was validated against the publically available tool on the National Center for Biotechnology Information web site at the National Institutes of Health. Samples determined to be HIV-1 subtypes of interest (A/A1 and D in Uganda; C in South Africa and India) were further tested for viral tropism. HIV-1 co-receptor tropism was determined using the original Trofile^®^assay \[[@B29],[@B30]\] for samples collected from patients in South Africa and Uganda. The Indian cohort was enrolled after the South African and Ugandan cohorts, thus Indian patients were tested using the newly available enhanced Trofile^®^assay, which had replaced the original assay. Samples were prepared for both the original and enhanced assays in the same way: 1 mL plasma samples underwent centrifugation and viral RNA was isolated, purified and subjected to polymerase chain reaction (PCR) amplification of the entire HIV envelope gene (*env*). Co-transfection of HIV *env*expression vectors and HIV-1 genomic vectors produced pseudoviruses containing full length *env*genes derived from patient virus populations. Tropism was determined by measuring the ability of the pseudovirus population to efficiently infect target cells co-expressing CD4 with either the CXCR4 or CCR5 co-receptor \[[@B29],[@B31]\]. For commercial Trofile^®^testing, up to 3 mL of plasma and up to three attempts at RNA PCR amplification are performed for each patient specimen. For this study of non-subtype B specimens, however, only a single attempt at amplification was made with 1 mL samples and primers that were optimized on subtype B specimens (hereafter referred to as \"standard primers\"). In the event that samples yielded a non-reportable tropism result, re-testing was performed using modified primers that were optimized for subtypes A, C and D but retained high performance for subtype B (hereafter referred to as \"optimized primers\"). All re-testing with optimized primers was performed using the same version of Trofile^®^that was used for the initial 1 mL test. Thus for South African and Ugandan specimens, all re-testing was performed with the original assay, and for Indian specimens, all re-testing was performed with the enhanced assay. Sample size and statistical analysis ------------------------------------ The study goal was to include at least 171 patients with reportable tropism results in each country, subtype and treatment experience stratum to provide approximately 5% precision for estimating prevalence of R5 in TN patients (anticipated to be 85%) and 7.5% precision for estimating prevalence of R5 in TE patients (anticipated to be 50%). Demographic and HIV disease characteristics were summarized by country, subtype and treatment experience strata. The prevalence of R5, X4, and D/M HIV-1 among patients with reportable tropism results was estimated in each stratum. The relationship between R5 infection and the following variables was examined in univariate logistic regression analyses: age (per year); gender; CD4^+^cell count (per 50 cells/mm^3^); HIV-1 RNA level (per 10,000 copies/mL); ART experience status; time since HIV diagnosis (months); mode of transmission; and Centers for Disease Control and Prevention (CDC) HIV disease category. CD4^+^count and HIV-1 RNA level were also analyzed using quartiles. Variables significantly associated with tropism in univariate analyses (p \< 0.05) were entered into multivariate logistic regression analyses, in which two-way interactions between all covariates were examined categorically. Backward elimination from a saturated model was used to determine the final predictive model. Results ======= Patients -------- The demographic and clinical characteristics of patients with reportable HIV-1 tropism results are summarized in Table [1](#T1){ref-type="table"}. All but four patients in South Africa and Uganda identified themselves as African: three self-identified as mixed race, and one as Caucasian. All but one patient in India (who self-identified as Asian) identified themselves as Indian. In all countries, nearly all patients reported heterosexual contact as the mode of HIV transmission. ###### Demographics and clinical characteristics of patients with reportable tropism results India South Africa Uganda ---------------------------------------------------- --------------- --------------- ----------------- --------------- ------------- --------------- --------------- **Age:**mean (SD) 36 (8.2) 39 (7.5) 37 (7.9) 38 (8.7) 38 (8.7) 35 (8.4) 33 (8.3) **Gender:**% male 65% 82% 41% 32% 31% 35% 22% **Time since HIV diagnosis**(months): mean (SD) 23 (36.2) 68.4 (43.7) 48.9 (31.5) 37.7 (35.4) 62.8 (48.1) 32.6 (26.6) 46.6 (19.0) **Number of treatment failures:**mean (SD) NA 1.5 (1.6) 1.3 (0.58)\* NA 1.2 (0.4) NA 1.0 (0.2) **Absolute CD4^+^cell count (cells/μL):**mean (SD) 155.7 (128.5) 114.0 (110.1) 204.0 (146.1)\* 334.3 (178.9) 83.4 (64.8) 361.0 (198.0) 109.3 (124.2) **CD4^+^count:**range 3-775 6-504 1-681 5-1171 8-223 10-1255 1-589 **Viral load (log~10~copies/mL):**mean (SD) 5.52 (5.46) 5.40 (5.42) 5.09 (5.55) 5.27 (5.33) 5.60 (5.20) 5.11 (5.19) 5.15 (5.22) **Log viral load: r**ange 3.16-5.88 3.16-5.88 3.04-6.63 3.40-5.88 3.13-5.86 3.33-5.85 3.07-5.88 NA, not available; SD, standard deviation; TE, treatment-experienced; TN, treatment-naïve.\* Missing 1; n = 204. Haemophilia/coagulation disorder and/or blood transmission were reported as transmission factors by three patients (1.5%) in South Africa and two patients (1.1%) in India. Four patients (one in South Africa, one in Uganda, and two in India) reported other unspecified risk behaviours. Risk was not reported or identified by 21 patients (8.8%) in India, two patients (1.0%) in South Africa, and one patient (0.9%) in Uganda. Most patients in South Africa and Uganda were female; most Indian patients were male. Indian patients had lower mean CD4^+^counts than South African and Ugandan patients; however, mean viral loads were consistent across the three countries (Table [1](#T1){ref-type="table"}). TE patients were more likely (53-79%) to have CDC category C AIDS-defining events than TN patients (12-42%), regardless of country (Figure [1](#F1){ref-type="fig"}). Across treatment experience, the proportions of patients with CDC category C HIV disease were higher in India (79% of TE and 42% of TN patients) than in South Africa or Uganda (Figure [1](#F1){ref-type="fig"}). {#F1} Subtype analysis ---------------- Samples for subtype analysis were collected from 307 patients (95 TE, 212 TN) in India, 678 (96 TE, 582 TN) in Uganda, and 297 (all TE) in South Africa. All samples with HIV-1 RNA exceeding 500 copies/mL were submitted for subtype testing. HIV-1 subtype could not be determined in 2.9%, 2.4%, and 5.9% of samples from India, Uganda, and South Africa, respectively, due to samples compromised by collection or handling problems and/or atypical genetic sequences (inability to generate HIV-1 pseudoviruses due to a rare genetic sequence within the patient\'s virus that is cleaved by the restriction enzyme used in the assay). Recruitment of TE patients with reportable tropism in Uganda and India, where HIV treatment is limited, was a challenge and required reducing the numbers of patients in these strata. TN samples were submitted for subtyping up until the enrolment goal of at least 171 patients had been reached. Subtype C was predominant in India (overall, 280 \[91%\]: 202 \[95%\] TN and 78 \[82%\] TE patients) and South Africa (275 \[93%\] TE patients). The predominant subtypes in Uganda were A/A1 (overall, 324 \[48%\]: 285 \[49%\] TN and 39 \[41%\] TE patients) and D (overall, 203 \[30%\]: 167 \[29%\] TN and 36 \[38%\] TE patients). Other subtypes representing ≥ 1% of the Ugandan cohort were A/D (8%), AE (2.4%), C (2.2%), and Complex (1.5%). Tropism ------- Samples from patients with subtype C virus from India and South Africa and subtypes A/A1 and D from Uganda that were initially tested for co-receptor tropism using a single 1 mL aliquot of patient plasma yielded the following reportable results, respectively, when RNA amplification was performed with the standard primers: 240 (86%), 205 (75%), 236 (81%) and 136 (67%) (Figure [2](#F2){ref-type="fig"}). After re-testing all South African, Ugandan and Indian non-reportable samples using optimized primers for RNA amplification, the reportable rate improved to 90-97% in the different strata. {#F2} Overall, most patients with reportable tropism results had only R5 HIV-1, but the proportion with R5 virus varied substantially by country, subtype and treatment experience (Figure [3](#F3){ref-type="fig"}). The proportion with only R5 virus ranged from 30% among TE Ugandan patients infected with subtype D to 97% among TN Indian patients infected with subtype C. D/M-tropic HIV-1 was less frequent, ranging from 3% among TN subtype C-infected patients in India to 65% among TE patients from Uganda with subtype D infection. X4 HIV-1 was rare and found in only eight TE patients from South Africa, and in two TN subtype A-infected patients and one TE subtype D-infected patient from Uganda. {#F3} Although co-receptor tropism varied according to country in TE patients with subtype C infection, R5 tropism was consistently high in TN patients with subtype C. R5 tropism was identified in 97% of TN patients with subtype C from India (Figure [3](#F3){ref-type="fig"}) and, in the MERIT study of maraviroc \[[@B35]\], a similar analysis identified R5 tropism in 94% of 293 TN patients with subtype C, of whom a large majority (92%) were South African. Variables significantly associated with tropism appear in Figure [4](#F4){ref-type="fig"}. Higher CD4^+^count was associated with an increased likelihood of R5 tropism in patients from both India and South Africa (Figures [4A](#F4){ref-type="fig"} and [4B](#F4){ref-type="fig"}). Additionally, in South African patients, older age and higher HIV-1 viral load predicted R5 tropism (Figure [4B](#F4){ref-type="fig"}). Among Ugandan patients infected with subtype A/A1 HIV-1, higher CD4^+^counts were associated with R5 tropism and CDC category B disease was negatively associated with R5 tropism (Figure [4C](#F4){ref-type="fig"}), whereas among patients infected with subtype D, only higher CD4^+^counts predicted R5 tropism (Figure [4D](#F4){ref-type="fig"}). {#F4} Discussion ========== In this study, CCR5 was the predominant co-receptor used in non-B subtype HIV-1 in ART-naïve individuals from India and Uganda, and in TE individuals from South Africa. In contrast to prior reports, this study evaluated a large number (n = 817) of both TN and TE patients infected with non-B subtypes (C, A, D). There were difficulties recruiting TE patients in India and Uganda, which may indirectly reflect the availability of ART, estimated by the World Health Organization to reach only 31% of HIV-infected persons in these countries \[[@B36]\]. Most (83%) study subjects with reportable tropism results had only R5 HIV-1 detectable, including 90% of TN and 72% of TE patients. However, tropism distribution varied by subtype, CD4^+^cell count and treatment experience, which can be considered a marker of advanced disease. Indian subjects with subtype C virus were almost exclusively infected with R5 regardless of their CD4^+^count, HIV-1 disease status, or treatment experience. The prevalence of R5 virus was similarly high in TN South African patients with subtype C infection but, while most common and relatively well-preserved, was somewhat lower in the South African TE cohort of this study (71%). The difference observed between R5 prevalence in India and South Africa may be a result of differences in CD4+ cell count. Compared with the Indian cohort, there was a higher proportion of individuals in the South African cohort with a D/M phenotype (25%) despite similar time since HIV diagnosis and similar exposure to prior therapies. Exclusive use of X4 was rare (4%). Our findings are consistent with previous reports of subtype C strains from India and elsewhere, where R5 HIV-1 is maintained even in advanced stages of disease. For example, some similarities can be observed between the findings of the present study and a previous study that assessed co-receptor tropism of HIV-1 strains in China: mainly that R5 tropism was seen exclusively in subtype C infections, and remained stable over time \[[@B24]\]. These data highlight the persistence of CCR5 tropism even in long-term infections, possibly related to differences within the *env*variable loops \[[@B37]\], and contrasts with other subtypes, especially subtype B, where X4 HIV-1 is more frequent during later stages of infection \[[@B6],[@B8]-[@B10],[@B16],[@B18],[@B21],[@B37]-[@B40]\]. The distribution of HIV-1 subtypes in India and South Africa was consistent with published epidemiologic data \[[@B6]\]. However, this study found more subtype diversity within the Ugandan cohort than previously reported \[[@B41],[@B42]\]. Despite the existence of multiple subtype variations in Uganda, the predominant subtypes were A/A1 (49.0%) and D (28.7%), and there were no marked differences in demographics or HIV disease characteristics. Among Ugandan subjects with subtype A/A1 virus, R5 infection predominated in TN individuals but was reduced in TE individuals, similar to the pattern seen with subtype B. While subtype D TN patients were predominantly R5, X4-using virus (D/M and X4) was detected in nearly 70% of the small number of TE patients. This agrees with earlier reports, where Ugandan individuals infected with subtype D virus showed predominantly D/M tropism \[[@B6],[@B16]-[@B19],[@B21],[@B22]\]. Multivariate analyses of other cohorts have identified higher CD4^+^cell count as a predictor of R5 infection in both TN and TE patients with subtype B and C HIV-1 infections \[[@B43],[@B44]\]. In the present study, multivariate analysis identified CD4^+^count as a significant predictor of CCR5 tropism for subtypes C, A/A1, and D. In Ugandan patients with subtype A/A1, R5 use was negatively associated with the presence of CDC category B disease, with a negative trend for category C. This study provided an opportunity to assess the ability of the Trofile^®^assay to provide results in different non-B subtype HIV-1 viral subtypes collected in developing countries. While initial testing using standard amplification primers with just a single 1 mL aliquot of patient plasma yielded a lower reportable rate (67-86%) than that expected from experience with subtype B virus, non-reportable samples that were re-tested with the original Trofile^®^assay (South Africa and Uganda) or enhanced assay (India) using modified primers optimized for non-B subtype virus, yielded a much higher percentage of reportable results (90-97%), and the distribution of R5 and non-R5 HIV-1 did not change. These improvements in amplification primers - which also retain high performance for subtype B specimens and are currently the primers used regularly for RNA amplification in the Trofile assay - may be advantageous when Trofile testing is used in clinical populations where non-subtype B virus is common \[[@B45]\]. Globally, these data offer guidance on the potential use of CCR5 antagonists and tropism tests in resource-poor clinical settings. Since HIV transmission appears to be mostly associated with R5 HIV-1 regardless of subtype \[[@B46]-[@B48]\] and a large majority of chronic HIV-1 infections in India and South Africa are R5, CCR5 antagonists may have a role in prevention efforts: for example, use as microbicides or in pre- and post-exposure prophylaxis. Combining a CCR5 antagonist with another ARV agent active against all or X4-using viruses may improve the potential utility of CCR5 antagonists in ARV-based HIV-1 prevention strategies. In the context of evaluating patients for CCR5 antagonist therapy, the high proportions of R5 HIV-1 in both TN (97%) and TE (94%) patients in India suggests that alternative methods for determining co-receptor status could be explored in this setting. Tropism could potentially be tested using genotypic or phenotypic co-receptor tropism tests and/or virologic response to short-term CCR5 antagonist monotherapy. Conclusions =========== This study examined the correlates of HIV-1 co-receptor tropism in virus from individuals with non-B subtype HIV-1 infection from India, Uganda and South Africa. While only R5 virus was detectable in the majority of TN individuals infected with subtypes C, A and D, infection with only R5 virus was maintained, albeit at lower levels, in TE individuals. However, R5 prevalence varied by subtype: patients with subtype C, especially in India, were almost exclusively infected with R5, while subtype D patients were more frequently infected with D/M viruses. The high prevalence of R5 HIV-1 in subtype C infections makes a CCR5 antagonist an attractive option for ART-based prevention strategies in areas where subtype C predominates. While a higher CD4^+^cell count was highly correlated with CCR5 use regardless of subtype, a further understanding of HIV-1 co-receptor use in individuals and populations infected with non-subtype B HIV-1 is still needed. Given the heterogeneity of HIV-1 co-receptor use in non-subtype B HIV-1, there remains a need for prospective determination of HIV-1 tropism prior to the initiation of CCR5 antagonist therapy in geographic locations where the burden of infection is greatest. Competing interests =================== Quazi Ataher and Simon Portsmouth are employees of Pfizer Inc. and own Pfizer stock. Sybil Eng, Anna Greenacre and Randy Tressler were employees at Pfizer Inc. at the time that this study was conceived and conducted. Randy Tressler currently owns Pfizer stock and is eligible for a Pfizer pension. Laura Napolitano is an employee of Monogram Biosciences and its parent company, LabCorp, and owns LabCorp stock. Andrew Kambugu has received honoraria from Abbott. Robin Wood has received advisory fees from Merck, GlaxoSmithKline, Abbot and Tibotec. Sharlaa Badal-Faesen declares that she has no competing interests. Authors\' contributions ======================= QA conducted analyses of clinical samples and led manuscript preparation. LAN led and performed the standard and optimized primer data analysis. SP and SE participated in data interpretation. AG conducted statistical analyses of study data. AK, RW and SBF participated in study design, enrolled study subjects and collected clinical samples for analysis. RT conceived of the study, and participated in its design and in data interpretation. All authors reviewed and edited the manuscript. Acknowledgements and funding ============================ The study was supported by funding from Pfizer Inc. Editorial assistance was provided by William Hatch of Health Interactions and Lynsey Stevenson of Complete Medical Communications, and funded by Pfizer Inc. The authors thank the study participants, as well as the investigators: Dr JK Maniar, Jaslok Hospital and Research Centre, Mumbai; Dr GD Ravindran, St. John\'s Medical College & Hospital, Bangalore; Dr Tripathi, Chattrapati Shahuji Maharaj Medical University (Upgraded King George\'s Medical College), Lucknow; Dr S Pujari, Ruby Hall Clinic, Pune; Dr N Kumarasamy, YRG Center for AIDS Research & Education, Chennai; Dr AR Pazare, Seth GS Medical College & King Edward Memorial Hospital, Mumbai; Dr N Khippal, S.M.S. Medical College and Hospital, Jaipur; and staff at the participating study sites. We also thank Monogram Process Development for its role in the construction and implementation of optimized primers at its own expense. Jeannette M Whitcomb, of Monogram Biosciences, initiated the plan to re-test study specimens with optimized primers and led the optimization of the Trofile^®^assay primers. Carmeliza Santos, also of Monogram Biosciences, managed all initial testing and re-testing procedures and data reporting for this study. The Monogram Biosciences Clinical Reference Laboratory performed all assays.

Creating history, India's first unmanned spacecraft mission to moon, the Chandrayaan-1, has entered lunar orbit. This is the first time that an Indian built spacecraft has broken away from the Earth's gravitational field and reached the moon.

Fenofibrate-induced hepatotoxicity: A case with a special feature that is different from those in the LiverTox database. We report a special case of fenofibrate-induced acute severe DILI with sudden onset and rapid recovery, which is different from those in the LiverTox database. The acute severe DILI occurred within only 4 days after fenofibrate initial treatment for hypertriglyceridemia. Liver enzyme levels eventually declined to normal within two weeks after the discontinuation of fenofibrate. Early detection of elevated hepatic enzymes after fenofibrate initial treatment helps physicians to avoid delayed diagnosis and subsequent treatment.

Alcohol expectancies pre-and post-alcohol use disorder treatment: Clinical implications. Modification of elevated positive expectations of alcohol consumption (alcohol outcome expectancies; AOEs) is a key feature of Cognitive Behaviour Therapy (CBT) approaches to Alcohol Use Disorders (AUDs). Despite extensive research supporting the efficacy of CBT for AUD, few studies have examined AOE change. This study aimed to assess AOE change following completion of CBT for AUD and its association with drinking behaviour. One-hundred and seventy-five patients who completed a 12-week CBT program for AUD were administered the Drinking Expectancy Questionnaire (DEQ) at pre-treatment assessment and upon completion of treatment. Abstinence was achieved by 108 (61.7%) of completing patients. For patients who lapsed, the mean proportion of abstinent days was 93%. DEQ scales assessing expectations of positive alcohol effects on tension reduction, assertiveness, and cognitive enhancement were significantly lower post-treatment (p<0.001). Expectations of negative effects on mood were higher post-treatment (p<0.001). The largest AOE change occurred on the tension reduction scale. Greater percentage of abstinent days over treatment was associated with lower pre-and post-treatment tension reduction expectancy scores (p<0.05). Drinking during treatment was associated with smaller changes in expectations of negative effects of alcohol on mood (p<0.05). Individuals who completed CBT treatment for AUD showed significant AOE change. Tension reduction and affective change expectancies may be particularly important for abstinence and useful markers of lapse risk.

// // CSSlider.m // AppSlate // // Created by Taehan Kim on 12. 01. 26.. // Copyright (c) 2012년 ChocolateSoft. All rights reserved. // #import "CSSlider.h" @implementation CSSlider -(id) object { return ((UISlider*)csView); } //=========================================================================== #pragma mark - -(void) setMinimumBarColor:(UIColor*)color { if( [color isKindOfClass:[UIColor class]] ) [((UISlider*)csView) setMinimumTrackTintColor:color]; } -(UIColor*) getMinimumBarColor { return ((UISlider*)csView).minimumTrackTintColor; } -(void) setMaximumBarColor:(UIColor*)color { if( [color isKindOfClass:[UIColor class]] ) [((UISlider*)csView) setMaximumTrackTintColor:color]; } -(UIColor*) getMaximumBarColor { return ((UISlider*)csView).maximumTrackTintColor; } -(void) setThumbColor:(UIColor*)color { if( [color isKindOfClass:[UIColor class]] ) [((UISlider*)csView) setThumbTintColor:color]; } -(UIColor*) getThumbColor { return ((UISlider*)csView).thumbTintColor; } -(void) setMinimumValue:(NSNumber*)number { if( [number isKindOfClass:[NSNumber class]] ) [((UISlider*)csView) setMinimumValue:[number floatValue]]; else if( [number isKindOfClass:[NSString class]] ) [((UISlider*)csView) setMinimumValue:[(NSString*)number length]]; } -(NSNumber*) getMinimumValue { return @( ((UISlider*)csView).minimumValue ); } -(void) setMaximumValue:(NSNumber*)number { if( [number isKindOfClass:[NSNumber class]] ) [((UISlider*)csView) setMaximumValue:[number floatValue]]; else if( [number isKindOfClass:[NSString class]] ) [((UISlider*)csView) setMaximumValue:[(NSString*)number length]]; } -(NSNumber*) getMaximumValue { return @( ((UISlider*)csView).maximumValue ); } -(void) setThumbValue:(NSNumber*)number { CGFloat toValue; if( [number isKindOfClass:[NSNumber class]] ) toValue = [number floatValue]; else if( [number isKindOfClass:[NSString class]] ) toValue = [(NSString*)number length]; else{ EXCLAMATION; return; } if( toValue > ((UISlider*)csView).maximumValue ) toValue = ((UISlider*)csView).maximumValue; if( toValue < ((UISlider*)csView).minimumValue ) toValue = ((UISlider*)csView).minimumValue; [((UISlider*)csView) setValue:toValue animated:YES]; } -(NSNumber*) getThumbValue { return @( ((UISlider*)csView).value ); } -(void) setContinuosChange:(NSNumber*)boolVal { if( [boolVal isKindOfClass:[NSNumber class]] ) [((UISlider*)csView) setContinuous:[boolVal boolValue]]; } -(NSNumber*) getContinuosChange { return@( ((UISlider*)csView).continuous ); } #pragma mark - -(id) initGear { if( !(self = [super init]) ) return nil; csView = [[UISlider alloc] initWithFrame:CGRectMake(0, 0, 400, MINSIZE)]; [csView setBackgroundColor:[UIColor clearColor]]; [csView setUserInteractionEnabled:YES]; csCode = CS_SLIDER; isUIObj = YES; [((UISlider*)csView) setMinimumValue:0]; [((UISlider*)csView) setMaximumValue:10]; [((UISlider*)csView) setValue:5]; [((UISlider*)csView) setContinuous:NO]; [((UISlider*)csView) setMinimumTrackTintColor:[UIColor darkGrayColor]]; [((UISlider*)csView) setMaximumTrackTintColor:[UIColor whiteColor]]; [((UISlider*)csView) setThumbTintColor:[UIColor whiteColor]]; [((UISlider*)csView) addTarget:self action:@selector(valueChanged:) forControlEvents:UIControlEventValueChanged]; DEFAULT_CENTER_D; NSDictionary *d0 = ALPHA_D; NSDictionary *d1 = MAKE_PROPERTY_D(@"Value", P_NUM, @selector(setThumbValue:),@selector(getThumbValue)); NSDictionary *d2 = MAKE_PROPERTY_D(@"Minimum Value", P_NUM, @selector(setMinimumValue:),@selector(getMinimumValue)); NSDictionary *d3 = MAKE_PROPERTY_D(@"Maximum Value", P_NUM, @selector(setMaximumValue:),@selector(getMaximumValue)); NSDictionary *d4 = MAKE_PROPERTY_D(@"Minimum Bar Color", P_COLOR, @selector(setMinimumBarColor:),@selector(getMinimumBarColor)); NSDictionary *d5 = MAKE_PROPERTY_D(@"Maximum Bar Color", P_COLOR, @selector(setMaximumBarColor:),@selector(getMaximumBarColor)); // NSDictionary *d6 = MAKE_PROPERTY_D(@"Thumb Color", P_COLOR, @selector(setThumbColor:),@selector(getThumbColor)); NSDictionary *d7 = MAKE_PROPERTY_D(@"Continuos Change", P_BOOL, @selector(setContinuosChange:),@selector(getContinuosChange)); pListArray = @[xc,yc,d0,d1,d2,d3,d4,d5,d7]; NSMutableDictionary MAKE_ACTION_D(@"Changed Value", A_NUM, a1); NSMutableDictionary MAKE_ACTION_D(@"Minimum Value", A_NUM, a2); NSMutableDictionary MAKE_ACTION_D(@"Maximum Value", A_NUM, a3); actionArray = @[a1, a2, a3]; return self; } -(id)initWithCoder:(NSCoder *)decoder { if( (self=[super initWithCoder:decoder]) ) { [((UISlider*)csView) addTarget:self action:@selector(valueChanged:) forControlEvents:UIControlEventValueChanged]; } return self; } #pragma mark - Gear's Unique Actions -(void) valueChanged:(id) sender { SEL act; NSNumber *nsMagicNum; CGFloat myValue = ((UISlider*)sender).value; // 1. value changed act = ((NSValue*)((NSDictionary*)actionArray[0])[@"selector"]).pointerValue; if( nil != act ){ nsMagicNum = ((NSDictionary*)actionArray[0])[@"mNum"]; CSGearObject *gObj = [USERCONTEXT getGearWithMagicNum:nsMagicNum.integerValue]; if( nil != gObj ){ if( [gObj respondsToSelector:act] ) [gObj performSelector:act withObject:@(myValue)]; else EXCLAMATION; } } // 2. did min value act = ((NSValue*)((NSDictionary*)actionArray[1])[@"selector"]).pointerValue; if( nil != act && myValue == ((UISlider*)sender).minimumValue ) { nsMagicNum = ((NSDictionary*)actionArray[1])[@"mNum"]; CSGearObject *gObj = [USERCONTEXT getGearWithMagicNum:nsMagicNum.integerValue]; if( nil != gObj ){ if( [gObj respondsToSelector:act] ) [gObj performSelector:act withObject:@(myValue)]; else EXCLAMATION; } } // 3. did max value act = ((NSValue*)((NSDictionary*)actionArray[2])[@"selector"]).pointerValue; if( nil != act && myValue == (NSUInteger)((UISlider*)sender).maximumValue ) { nsMagicNum = ((NSDictionary*)actionArray[2])[@"mNum"]; CSGearObject *gObj = [USERCONTEXT getGearWithMagicNum:nsMagicNum.integerValue]; if( nil != gObj ){ if( [gObj respondsToSelector:act] ) [gObj performSelector:act withObject:@(myValue)]; else EXCLAMATION; } } } #pragma mark - Code Generatorz // If not supported gear, return NO. -(BOOL) setDefaultVarName:(NSString *) _name { return [super setDefaultVarName:NSStringFromClass([self class])]; } -(NSString*) sdkClassName { return @"UISlider"; } -(NSString*) addTargetCode { return [NSString stringWithFormat:@" [%@ addTarget:self action:@selector(%@ValueChanged) forControlEvents:UIControlEventValueChanged];\n",varName,varName]; } -(NSString*) actionCode { NSMutableString *code = [[NSMutableString alloc] initWithFormat:@"-(void)%@ValueChanged\n{\n",varName]; SEL act; NSNumber *nsMagicNum; act = ((NSValue*)((NSDictionary*)actionArray[0])[@"selector"]).pointerValue; if( act ) { nsMagicNum = ((NSDictionary*)actionArray[0])[@"mNum"]; CSGearObject *gObj = [USERCONTEXT getGearWithMagicNum:nsMagicNum.integerValue]; const char *sel_name_c = sel_getName(act); NSString *selNameStr = [NSString stringWithCString:sel_name_c encoding:NSUTF8StringEncoding]; if( [selNameStr hasSuffix:@"Action:"] ) { [code appendFormat:@" %@\n",[gObj actionPropertyCode:selNameStr valStr:[NSString stringWithFormat:@"%@.value",varName]]]; } else [code appendFormat:@" [%@ %@@(%@.value)];\n",[gObj getVarName],@(sel_name_c),self.getVarName]; } act = ((NSValue*)((NSDictionary*)actionArray[1])[@"selector"]).pointerValue; if( act ) { nsMagicNum = ((NSDictionary*)actionArray[1])[@"mNum"]; CSGearObject *gObj = [USERCONTEXT getGearWithMagicNum:nsMagicNum.integerValue]; const char *sel_name_c = sel_getName(act); NSString *selNameStr = [NSString stringWithCString:sel_name_c encoding:NSUTF8StringEncoding]; if( [selNameStr hasSuffix:@"Action:"] ) { [code appendFormat:@" %@\n",[gObj actionPropertyCode:selNameStr valStr:[NSString stringWithFormat:@"%@.value",varName]]]; } else [code appendFormat:@" if( %@.minimumValue == %@.value )[%@ %@@(%@.value)];\n",self.getVarName,self.getVarName,[gObj getVarName],@(sel_name_c),self.getVarName]; } act = ((NSValue*)((NSDictionary*)actionArray[2])[@"selector"]).pointerValue; if( act ) { nsMagicNum = ((NSDictionary*)actionArray[2])[@"mNum"]; CSGearObject *gObj = [USERCONTEXT getGearWithMagicNum:nsMagicNum.integerValue]; const char *sel_name_c = sel_getName(act); NSString *selNameStr = [NSString stringWithCString:sel_name_c encoding:NSUTF8StringEncoding]; if( [selNameStr hasSuffix:@"Action:"] ) { [code appendFormat:@" %@\n",[gObj actionPropertyCode:selNameStr valStr:[NSString stringWithFormat:@"%@.value",varName]]]; } else [code appendFormat:@" if( %@.maximumValue == %@.value )[%@ %@@(%@.value)];\n",self.getVarName,self.getVarName,[gObj getVarName],@(sel_name_c),self.getVarName]; } [code appendString:@"}\n"]; return code; } @end

1912 Mürefte earthquake The 1912 Mürefte earthquake occurred at 03:29 local time on 9 August. It had an estimated magnitude of 7.8 and a maximum intensity of X (Extreme) on the Mercalli intensity scale, causing 216 casualties. See also List of earthquakes in 1912 List of earthquakes in Turkey References External links 1912 Mürefte Category:1912 in the Ottoman Empire 1912

Lazy Journal SKU: £28.00 £28.00 Unavailable My Lazy Journal is made from recycled materials including an old hardback book and envelopes. It is for the person who doesn't know what to write in a journal since its pages are already completed for you. There are thirty six pages which are covered with a range of written narratives.Further pictures of this Journal can be seen on the art journals pageof this website.The price includes postage and packing.

Creosote gall midge Creosote gall midges are a species of gall-inducing flies in the Asphondylia auripila group (Diptera: Cecidomyiidae). This group consists of 15 closely related species of flies which inhabit creosote bush (Zygophyllaceae: Larrea tridentata) sensu lato. They have partitioned the plant ecologically with different gall midge species inhabiting the leaves, stems, buds, and flowers of creosote bush. Each species induces a uniquely shaped gall but the insects are otherwise morphologically very similar and very difficult to tell apart. Their life cycle begins when the female oviposits into the part of the plant which her species prefers, she inserts her egg along with a fungal spore from a mycangia (a small pocket to store fungal spores). A gall forms and the fungal mycelium grows to line the inside of the gall, when the egg hatches the developing larva feeds upon the fungus. Adult emergence is timed with periods of plant growth associated with winter, spring, or summer rain fall. In contrast to many other groups of plant-feeding insects (which form new species through changes to new host plants) the evolution of new species in the A. auripila group seems to be a result of colonizing new parts of the same plant and/or colonization of new seasons of plant growth. List of species The Asphondylia genus has over 60 described species. Within the genus the creosote gall midge species form a species group, the A. auripila group. Species described this far (by host-plant part) include: Asphondylia clavata – leaf gall Asphondylia pilosa – leaf gall Asphondylia villosa – leaf gall Asphondylia barbata – leaf gall Asphondylia digitata – leaf gall Asphondylia discalis – leaf gall Asphondylia silicula – leaf gall Asphondylia fabalis – leaf gall Asphondylia bullata – stem gall Asphondylia resinosa – stem gall Asphondylia foliosa – stem gall Asphondylia auripila – stem gall Asphondylia rosetta – stem gall Asphondylia florea – flower gall Asphondylia apicata – bud gall References Gagne, R.J, and Waring, G. 1990. The Asphondylia (Cecidomyiidae: Diptera) of creosote bush (Larrea tridentata) in North America. Proc. Entomol. Soc. Wash. 92:649–671. Category:Cecidomyiidae

Linotype machine The Linotype machine ( ) was a "line casting" machine used in printing sold by the Mergenthaler Linotype Company and related It was a hot metal typesetting system that cast blocks of metal type for individual uses. Linotype became one of the mainstay methods to set type, especially small-size body text, for newspapers, magazines, and posters from the late 19th century to the 1970s and 1980s, when it was largely replaced by phototypesetting and computer typesetting. The name of the machine comes from the fact that it produces an entire line of metal type at once, hence a line-o'-type, a significant improvement over the previous industry standard, i.e., manual, letter-by-letter typesetting using a composing stick and shallow subdivided trays, called "cases". The linotype machine operator enters text on a 90-character keyboard. The machine assembles matrices, which are molds for the letter forms, in a line. The assembled line is then cast as a single piece, called a slug, from molten type metal in a process known as hot metal typesetting. The matrices are then returned to the type magazine from which they came, to be reused later. This allows much faster typesetting and composition than original hand composition in which operators place down one pre-cast glyph (metal letter, punctuation mark or space) at a time. The machine revolutionized typesetting and with it especially newspaper publishing, making it possible for a relatively small number of operators to set type for many pages on a daily basis. Ottmar Mergenthaler invented the linotype in 1884. History In 1876, a German clock maker, Ottmar Mergenthaler, who had emigrated to the United States in 1872, was approached by James O. Clephane and his associate Charles T. Moore, who sought a quicker way of publishing legal briefs. By 1884 he conceived the idea of assembling metallic letter molds, called matrices, and casting molten metal into them, all within a single machine. His first attempt proved the idea feasible, and a new company was formed. Improving his invention, Mergenthaler further developed his idea of an independent matrix machine. In July, 1886, the first commercially used Linotype was installed in the printing office of the New York Tribune. Here it was immediately used on the daily paper and a large book. The book, the first ever composed with the new Linotype method, was titled, The Tribune Book of Open-Air Sports. Initially, the Mergenthaler Linotype Company was the only company producing linecasting machines, but in time, other companies would begin manufacturing. The Intertype Company produced the Intertype, a machine closely resembling the Linotype, and using the same matrices as the Linotype, started production around 1914. Where Mergenthaler prided themselves on intricately formed cast-iron parts on their machine, Intertype machined many of their similar parts from steel and aluminum. Major newspaper publishers retired Linotype and similar "hot metal" typesetting machines during the 1970s and 1980s, replacing them with phototypesetting equipment and later computerized typesetting and page composition systems. , the last-known newspaper still using linotype in the United States, and possibly the world, is The Saguache Crescent. Overview The linotype machine consists of four major sections: Magazine Keyboard Casting mechanism Distribution mechanism The operator interacts with the machine via the keyboard, composing lines of text. The other sections are automatic; they start as soon as a line is completely composed. Some linotype machines included a paper tape reader. This allowed the text to be typeset to be supplied over a telegraph line (TeleTypeSetter). It also allowed for several tape perforator operators to prepare paper tape to be processed by a single linotype machine, essentially decoupling the typing speed of the operators from the operating speed of the linotype machine. Design Matrices Each matrix contains the letter form for a single character of a font of type; i.e., a particular type design in a particular size. The letter form is engraved into one side of the matrix. For sizes up to 14 points, and in some matrices of size 16 to 24 points, the matrix has two letter forms on it, the normal and auxiliary positions. The normal position has the upright (Roman) form of a given character, and on the auxiliary, the slanted (Italic) form of that character will be used, but this can also be the boldface form or even a different font entirely. The machine operator can select which of the two will be cast by operating the auxiliary rail of the assembler, or, when setting entire lines of italics, by using the flap, which is a piece that can be turned under a portion of the first elevator column. This is the origin of the old typesetting terms upper rail for italic and lower rail for Roman characters. These terms have persisted in phototypesetting technology even though the mechanics of the auxiliary rail do not exist there. The character on a Linotype matrix, when viewed, is not inverted as a letter for conventional movable type would be, and the letter is incised below the surface rather than raised above it. This is because the matrix is not used directly to print onto the paper—rather, it is used as part of a mold from which a metal slug will be cast. The slug has its features reversed: therefore, the matrix does not. Magazine section The magazine section is the part of the machine where the matrices are held when not in use, and released as the operator touches keys on the keyboard. The magazine is a flat box with vertical separators that form "channels", one channel for each character in the font. Most main magazines have 90 channels, but those for larger fonts carried only 72 or even 55 channels. The auxiliary magazines used on some machines typically contained 34 channels or, for a magazine carrying larger fonts, 28 channels. The magazine holds a particular font of type; i.e., a particular type design in a particular size. If a different size or style was needed, the operator would switch to a different magazine. Many models of the Linotype machine could keep several magazines (as many as four) available at a time. In some of these, the operator could shift to a different magazine by raising or lowering the stack of magazines with a crank. Such machines would not allow mixing fonts within a single line. Others, such as the Models 25 and 26 allowed arbitrary mixing of text from two magazines within the same line, and the Model 9 extended this capability to mixing from up to four magazines within a single line. Escapement In a linotype machine, the term escapements refers to the mechanisms at the bottom of the magazine that release matrices one at a time as keys are pressed on the keyboard. There is an escapement for each channel in the magazine. Maintenance and lubrication To keep the matrices circulating smoothly throughout the machine, it is necessary that oil not be allowed anywhere near the matrix path. If oil is found in the matrix's path (due to careless maintenance or over-lubrication of nearby parts), it combines with dust, forming a gummy substance that is eventually deposited in the magazine by the matrices. The most common result is that the matrix will not be released from the magazine at its usual speed, and almost always results in a letter or two arriving out of sequence in the assembler — a "matrix transposition". When these machines were in heavy use, it was not uncommon for an operator to set type at the rate of over 4,000 ems per hour, with the fastest operators being able to exceed 10,000 ems per hour (approximately 10 to 30 words per minute in today's units) so careful lubrication and regular cleaning were essential to keep these machines operating at their full potential. Keyboard and composing section In the composing section, the operator enters the text for a line on the keyboard. Each keystroke releases a matrix from the magazine mounted above the keyboard. The matrix travels through channels to the assembler where the matrices are lined up side by side in the order they were released. When a space is needed, the operator touches the spaceband lever just to the left of the keyboard. This releases a spaceband from the spaceband box. Spacebands are stored separately from the matrices because they are too big to fit in the magazine. Once enough text has been entered for the line, the operator depresses the casting lever mounted on the front right corner of the keyboard. This lifts the completed line in the assembler up between two fingers in the "delivery channel", simultaneously tripping the catch holding it in position. The spring-operated delivery channel then transports the line into the casting section of the machine, and engages the clutch that drives the casting section and the subsequent transfer into the distribution section. The operator is now finished with the line; the remaining processing is automatic. While the line is being cast, the operator can continue entering text for the next line. Keyboard The keyboard has 90 keys. The usual arrangement is that black keys on the left were for small letters, white keys on the right were for capital letters, and blue keys in the center for numbers, punctuation marks, spaces, small caps and other items. There is no shift key of the kind found on typewriters. The arrangement of letters corresponds roughly to letter frequency, with the most frequently used letters on the left. The first two columns of keys are: e, t, a, o, i, n; and s, h, r, d, l, u. A Linotype operator would often deal with a typing error by running the fingers down these two rows, thus filling out the line with the nonsense words etaoin shrdlu. This is known as a "run down". It is often quicker to cast a bad slug than to hand-correct the line within the assembler. The slug with the run down is removed once it has been cast, or by the proofreader. The linotype keyboard has the same alphabet arrangement given twice, once for lower-case letters, the keys in black, on the left side of the keyboard, and once for upper-case letters, the keys in white, located on the right side of the keyboard. The blue keys in the middle are punctuation, digits, small capital letters and fixed-width spaces. In proper keyboard operation, an experienced operator's left hand operates only the spaceband key and the left column of keys. The operator's right hand strokes the remaining keys on the entire keyboard. The keys of the keyboard are connected by vertical pushrods to the escapements. When a key is pressed, the corresponding escapement is actuated, which releases a matrix from the magazine. With one exception, each key corresponds directly to a channel in the standard (90 channel) magazine. The one exception is the lower-case letter e: that letter is used so often that the 90 channel magazine actually has 91 channels, with two channels (the leftmost two) both used for the letter e. Similarly, the 72 channel magazine actually has 73 channels, with the leftmost two being used for lower-case e. Alternate lines release matrices alternately from the two e channels in the magazine. On machines that support multiple magazines, there is a shifting mechanism that controls which magazine is currently connected to the keyboard. In most machines, this is done by raising or lowering the stack of magazines. Spaceband box In justified text, the spaces are not fixed width; they expand to make all lines equal in width. In linotype machines this is done by spacebands. A spaceband consists of two wedges, one similar in size and shape to a type matrix, one with a long tail. The wide part of the wedge is at the bottom of the tail, so pushing the tail up expands the spaceband. Due to their size, spacebands are not held in the magazine, but in a spaceband box and released one at a time by pressing the spaceband lever at the left edge of the keyboard. Assembler Matrices released from the magazine, and spacebands released from the spaceband box, drop down into the assembler. This is a rail that holds the matrices and spacebands, with a jaw on the left end set to the desired line width. When the operator judges that the line is close enough to full, he raises the casting lever on the bottom of the keyboard to send the line to the casting section of the linotype machine. The remaining processing for that line is automatic; as soon as the finished line has been transferred to the casting section, the operator can begin composing the next line of text. Casting section The casting section of the machine operated intermittently, when triggered by the operator at the completion of a line. The full casting cycle time was less than nine seconds. Motive power for the casting section came from a clutch-operated drive running large cams (the keyboard and distributor sections ran all the time, since distribution may take much longer; however, the front part of the distributor completed its job before the next line of matrices was distributed). The construction of the machine was such that both the return of the former line to the magazine and the composition of the next line could occur while the current line was being cast, enabling very high productivity. Older machines typically had a 1/3 hp 850 or 1140 revolution per minute motor geared to the main clutch wheel, the inner shaft engaging this wheel while the casting cycle was in operation. An external leather belt on this wheel ran a second jackshaft, which powered the distributor and keyboard matrix conveyor and escapements through additional belting off this shaft. Gas fired pots, such as in the illustration below, were most common in the earlier years, with the pot being thermostatically controlled (high flame when under temperature and low flame when up to temperature), and then a second smaller burner for the mouth and throat heating, with the more modern installations running on 1500 watt electric pots with an initially rheostat controlled mouth and throat heaters (several hundred watts on the electric models). The temperature was precisely adjusted to keep the lead and tin type metal liquified just prior to being cast. Newer machines, and the larger machines above 36 EM Matrix size typically used the more standardized 1/2 horsepower motor after v-belts came into common use in the 1930s. The large machines also had the so-called 'double pot', with either larger gas burners, or else 2250 watt pot heaters and larger mouth and throat heaters. The most modern Linotypes had the mouth and throat heaters thermostatically controlled, an improvement over the manual rheostat adjustment, or gas flame adjustment. The Linotype company would even supply kerosene heaters and line-shaft operated machines, in locales without electricity. The casting section receives completed lines from the assembler, and uses these to cast the type slugs that are the product of the linotype machine. The casting section is automatic: once it is activated by the operator sending a completed line by raising the casting lever, a series of cams and levers move the matrices through the casting section and control the sequence of steps that produce the slug. The casting material is an alloy of lead (85%), antimony (11%), and tin (4%), and produces a one-piece casting slug capable of 300,000 impressions before the casting begins to develop deformities and imperfections, and the type must be cast again. The continuous heating of the molten alloy causes the tin and antimony in the mixture to rise to the top and oxidize along with other impurities into a substance called "dross" which has to be skimmed off. Excessive dross formation leads to the alloy softening as the proportion of lead increases. The mixture must then be assayed and tin and antimony added back (in the form of a specially proportioned alloy) to restore the original strength and properties of the alloy. Justification From the assembler, the assembled line moves via the first elevator to the justification vise. The vise has two jaws (1 and 2 in the illustration) which are set to the desired line width. The spacebands are now expanded to justify the line. When the line is justified, the matrices fit tightly between the vise jaws, forming a tight seal which will prevent the molten type metal from escaping when the line is cast. Justification is done by a spring-loaded ram (5) which raises the tails of the spacebands, unless the machine was equipped with a Star Parts automatic hydraulic quadding attachment or Linotype hydraquadder. If the operator did not assemble enough characters, the line will not justify correctly: even with the spacebands expanded all the way, the matrices are not tight. A safety mechanism in the justification vise detects this and blocks the casting operation. Without such a mechanism, the result would be a squirt of molten type metal spraying out through the gaps between the matrices, creating a time-consuming mess and a possible hazard to the operator. If a squirt did occur, it was generally up to the operator to grab the hell bucket and catch the flowing lead. It was so called because the bucket would often "go to hell", or melt, while holding the molten lead that was still extremely hot. Also, in conjunction with possible hazards facing an operator, toxic lead fumes were possible, as they were the result of melting the lead ingots for casting. Mold disk and crucible The justification vise holds the assembled line against the face of the mold disk. The mold disk has rectangular openings which correspond to the line length and point thickness of the slugs (cast lines) to be made. Mold liners fit into these openings for specific slug dimensions. The maximum line length of the typical linecaster is 30 picas. A less common variant was fitted with 42 pica molds, though these are now rare to non-existent. Directly behind the mold disk is the crucible, which contains molten type metal at an optimal 535°. At the moment before casting, the mold disk moves forward on its slide. Studs in the mold disc engage with blocks on the vise so that the mold disc seats gently, yet tightly and squarely against the line of matrices held in the first elevator jaws and between the vise jaws. The vise jaws compress the line of matrices so molten metal is prevented from squeezing between the mats on cast. The crucible tilts forward, forcing the mouthpiece tightly against the back of the mold. The plunger in the well of the crucible quickly descends, forcing the molten metal up the crucible throat and injecting it into the mold cavity through the array of orifices in the mouthpiece. The jets of molten metal first contact against the casting face of the matrices, and then fills the mold cavity to provide a solid slug body. These have character shapes punched into them, so the result is a cast slug with the character shapes of the line on its top face. The mold disk is sometimes water-cooled, and often air-cooled with a blower, to carry away the heat of the molten type metal and allow the cast slugs to solidify quickly. When casting is complete, the plunger is drawn upward, pulling the metal back down the throat from the mouthpiece. The pot pulls backward away from the mold. The mold disk retracts from the vise studs which held it in perfect relation to the mold, thus breaking the slug away from the matrices. The mold disc then rotates counter-clockwise. In its travel, the slug base is trimmed by the back knife for height to paper (.918") and then returns to its neutral position in front of the ejector blades and aligned with the knife block assembly a pair of honed knives with a fixed knife, and a knife which is set to the point thickness of the mold liners being cast with. The knives are set to dead parallel. The fixed knife on the left bears against the smooth side of the slug (the mold body face of the slug) as it brushes next to it, and the right knife trims the ribs on the slug (the mold cap face of the slug). The disk stops when the mold is vertical, on the right, directly in front of the ejector. The ejector is a stacked series of narrow blades that push the completed slug from the mold aperture in the mold disk. The blades are narrow enough to pass through a mold set to 6-points in thickness with .004" clearance between the fixed mold face and the left side of the blades. The blades are each 2 picas in width and the number of blades engaged on ejection are set based on the line length being cast. All blades are engaged for a 30 pica slug, fewer are engaged as the measure of the slug body is narrowed by the use of progerssively longer mold liners. This prevents the ejector blades from striking the back of a mold liner on narrow slugs. As the slug is pushed from the mold, the slug passes a set of knife edges in the knife block, which trims off any small irregularities in the casting and produces a slug of exactly the desired point thickness. From there, the slug drops into the galley tray which holds the lines in the order in which they were cast. Distribution mechanism The most significant innovation in the linotype machine was that it automated the distribution step; i.e., returning the matrices and space bands back to the correct place in their respective magazines. This is done by the distributor. After casting is completed, the matrices are pushed to the second elevator which raises them to the distributor at the top of the magazine. The space bands are separated out at this point and are returned to the spaceband box. The matrices have a pattern of teeth at the top, by which they hang from the distributor bar. Some of the teeth are cut away; which pattern of teeth is cut away depends on the character on the matrix; i.e., which channel in the magazine it belongs in. Similarly, teeth are cut away along portions of the distributor bar. The bar on the elevator has all teeth, so it will hold any matrix (but not the space bands, which have no teeth at all). Distributor bar and matrix teeth coding As the matrices are carried along the distributor bar by the distributor screws, they will hang on only so long as there are teeth to hold them. As soon as the matrix reaches the point where each of its teeth corresponds to a cut-away tooth on the distributor bar, it is no longer supported and will drop into the matrix channel below that point. The pattern of teeth is a 7-bit binary code, with the innermost pair of teeth at the bottom of the notch being the most significant bit. The codes count up from the left side of the main magazine. Code 0 (no teeth) is for spacebands, which are not carried up to the distributor. Code 1 is skipped (no reason for this is given in the Linotype manual). Codes 2 through 92 are for the 91-channel main magazine, and the codes above that are for the auxiliary magazine, if one is installed on the machine. The widest auxiliary magazine has 34 channels, so its rightmost channel is code 125. Code 126 is unused while code 127 is used for pi matrices (described below). Pi matrices In typesetting, it is sometimes necessary to use characters that are uncommon or obscure enough that it does not make sense to assign them to a magazine channel. These characters are referred to as pi characters or sorts ("pi" in this case refers to an obscure printer's term relating to loose or spilled type). Footnote marks, rarely used fractions, and mathematical symbols are examples of pi characters. In the linotype machine, a pi matrix has all teeth present (code 127, no teeth cut away) so it will not drop from the distributor bar and will not be released into either the main or the auxiliary magazine. Instead, it travels all the way to the end and into the flexible metal tube called the pi chute and is then lined up in the sorts stacker, available for further use. See also Ottmar Mergenthaler Monotype System Monotype Corporation Lanston Monotype Saguache Crescent Etaoin shrdlu Notes References Basil Kahan: Ottmar Mergenthaler – The Man and his Machine; Oak Knoll Press, New Castle (DE), 2000 – External links Linotype: The Film – In Search of the Eighth Wonder of the World (Doug Wilson, 2012) is a feature-length documentary centered around the Linotype type casting machine. "Farewell, Etaoin Shrdlu". short film about history of Linotype and transition to modern methods. New York Times, 2016-10-14. The Printing (Holmes Burton Films Inc., 1947) documentary about linotype tech. in printing industry Metal Type—"For Those who Remember Hot Metal Typesetting" Intertype Book of Instruction is a complete manual on the operation and maintenance of the Intertype linotype machines Linotype Machine on Woodsidepress.com Linecast typesetting service at linotypesetting.com Typesetting: Linotype vocational instruction film: partand part 2. 1/13/1894;The Linotype a Machine To Supersede Typesetting The 1966 Automatically Controlled Elektron (ACE) Linotype, Teletype, Intertype and more Linotype machine patents Category:Printing Category:Typography Category:American inventions

// Copyright 2009 The Go Authors. All rights reserved. // Use of this source code is governed by a BSD-style // license that can be found in the LICENSE file. // +build !gccgo #include "textflag.h" // // System call support for AMD64, OpenBSD // // Just jump to package syscall's implementation for all these functions. // The runtime may know about them. TEXT ·Syscall(SB),NOSPLIT,$0-56 JMP syscall·Syscall(SB) TEXT ·Syscall6(SB),NOSPLIT,$0-80 JMP syscall·Syscall6(SB) TEXT ·Syscall9(SB),NOSPLIT,$0-104 JMP syscall·Syscall9(SB) TEXT ·RawSyscall(SB),NOSPLIT,$0-56 JMP syscall·RawSyscall(SB) TEXT ·RawSyscall6(SB),NOSPLIT,$0-80 JMP syscall·RawSyscall6(SB)

describe('jsdoc/src/astNode', () => { const astBuilder = require('jsdoc/src/astbuilder'); const astNode = require('jsdoc/src/astnode'); const babelParser = require('@babel/parser'); const env = require('jsdoc/env'); const Syntax = require('jsdoc/src/syntax').Syntax; function parse(str) { return babelParser.parse(str, astBuilder.parserOptions).program.body[0]; } // create the AST nodes we'll be testing const arrayExpression = parse('[,]').expression; const arrowFunctionExpression = parse('var foo = () => {};').declarations[0].init; const assignmentExpression = parse('foo = 1;').expression; const binaryExpression = parse('foo & foo;').expression; const experimentalObjectRestSpread = parse('var one = {...two, three: 4};').declarations[0].init; const functionDeclaration1 = parse('function foo() {}'); const functionDeclaration2 = parse('function foo(bar) {}'); const functionDeclaration3 = parse('function foo(bar, baz, qux) {}'); const functionDeclaration4 = parse('function foo(...bar) {}'); const functionExpression1 = parse('var foo = function() {};').declarations[0].init; const functionExpression2 = parse('var foo = function(bar) {};').declarations[0].init; const identifier = parse('foo;').expression; const literal = parse('1;').expression; const memberExpression = parse('foo.bar;').expression; const memberExpressionComputed1 = parse('foo["bar"];').expression; const memberExpressionComputed2 = parse('foo[\'bar\'];').expression; const methodDefinition1 = parse('class Foo { bar() {} }').body.body[0]; const methodDefinition2 = parse('var foo = () => class { bar() {} };').declarations[0].init.body .body[0]; const propertyGet = parse('var foo = { get bar() {} };').declarations[0].init.properties[0]; const propertyInit = parse('var foo = { bar: {} };').declarations[0].init.properties[0]; const propertySet = parse('var foo = { set bar(a) {} };').declarations[0].init.properties[0]; const thisExpression = parse('this;').expression; const unaryExpression1 = parse('+1;').expression; const unaryExpression2 = parse('+foo;').expression; const variableDeclarator1 = parse('var foo = 1;').declarations[0]; const variableDeclarator2 = parse('var foo;').declarations[0]; it('should exist', () => { expect(astNode).toBeObject(); }); it('should export an addNodeProperties method', () => { expect(astNode.addNodeProperties).toBeFunction(); }); it('should export a getInfo method', () => { expect(astNode.getInfo).toBeFunction(); }); it('should export a getParamNames method', () => { expect(astNode.getParamNames).toBeFunction(); }); it('should export an isAccessor method', () => { expect(astNode.isAccessor).toBeFunction(); }); it('should export an isAssignment method', () => { expect(astNode.isAssignment).toBeFunction(); }); it('should export an isFunction method', () => { expect(astNode.isFunction).toBeFunction(); }); it('should export an isScope method', () => { expect(astNode.isScope).toBeFunction(); }); it('should export a nodeToString method', () => { expect(astNode.nodeToString).toBeFunction(); }); it('should export a nodeToValue method', () => { expect(astNode.nodeToValue).toBeFunction(); }); describe('addNodeProperties', () => { let debugEnabled; beforeEach(() => { debugEnabled = Boolean(env.opts.debug); }); afterEach(() => { env.opts.debug = debugEnabled; }); it('should return null for undefined input', () => { expect( astNode.addNodeProperties() ).toBe(null); }); it('should return null if the input is not an object', () => { expect( astNode.addNodeProperties('foo') ).toBe(null); }); it('should preserve existing properties that are not "node properties"', () => { const node = astNode.addNodeProperties({foo: 1}); expect(node).toBeObject(); expect(node.foo).toBe(1); }); it('should add a non-enumerable nodeId if necessary', () => { const node = astNode.addNodeProperties({}); const descriptor = Object.getOwnPropertyDescriptor(node, 'nodeId'); expect(descriptor).toBeObject(); expect(descriptor.value).toBeString(); expect(descriptor.enumerable).toBeFalse(); }); it('should not overwrite an existing nodeId', () => { const nodeId = 'foo'; const node = astNode.addNodeProperties({nodeId: nodeId}); expect(node.nodeId).toBe(nodeId); }); it('should add an enumerable nodeId in debug mode', () => { let descriptor; let node; env.opts.debug = true; node = astNode.addNodeProperties({}); descriptor = Object.getOwnPropertyDescriptor(node, 'nodeId'); expect(descriptor.enumerable).toBeTrue(); }); it('should add a non-enumerable, writable parent if necessary', () => { const node = astNode.addNodeProperties({}); const descriptor = Object.getOwnPropertyDescriptor(node, 'parent'); expect(descriptor).toBeDefined(); expect(descriptor.value).toBeUndefined(); expect(descriptor.enumerable).toBeFalse(); expect(descriptor.writable).toBeTrue(); }); it('should not overwrite an existing parent', () => { const parent = {}; const node = astNode.addNodeProperties({parent: parent}); expect(node.parent).toBe(parent); }); it('should not overwrite a null parent', () => { const node = astNode.addNodeProperties({parent: null}); expect(node.parent).toBeNull(); }); it('should add an enumerable parentId in debug mode', () => { let descriptor; let node; env.opts.debug = true; node = astNode.addNodeProperties({}); descriptor = Object.getOwnPropertyDescriptor(node, 'parentId'); expect(descriptor).toBeObject(); expect(descriptor.enumerable).toBeTrue(); }); it('should provide a null parentId in debug mode for nodes with no parent', () => { let node; env.opts.debug = true; node = astNode.addNodeProperties({}); expect(node.parentId).toBeNull(); }); it('should provide a non-null parentId in debug mode for nodes with a parent', () => { let node; let parent; env.opts.debug = true; node = astNode.addNodeProperties({}); parent = astNode.addNodeProperties({}); node.parent = parent; expect(node.parentId).toBe(parent.nodeId); }); it('should add a non-enumerable, writable enclosingScope if necessary', () => { const node = astNode.addNodeProperties({}); const descriptor = Object.getOwnPropertyDescriptor(node, 'enclosingScope'); expect(descriptor).toBeObject(); expect(descriptor.value).toBeUndefined(); expect(descriptor.enumerable).toBeFalse(); expect(descriptor.writable).toBeTrue(); }); it('should not overwrite an existing enclosingScope', () => { const enclosingScope = {}; const node = astNode.addNodeProperties({enclosingScope: enclosingScope}); expect(node.enclosingScope).toBe(enclosingScope); }); it('should not overwrite a null enclosingScope', () => { const node = astNode.addNodeProperties({enclosingScope: null}); expect(node.enclosingScope).toBeNull(); }); it('should add an enumerable enclosingScopeId in debug mode', () => { let descriptor; let node; env.opts.debug = true; node = astNode.addNodeProperties({}); descriptor = Object.getOwnPropertyDescriptor(node, 'enclosingScopeId'); expect(descriptor).toBeObject(); expect(descriptor.enumerable).toBeTrue(); }); it('should provide a null enclosingScopeId in debug mode for nodes with no enclosing scope', () => { let node; env.opts.debug = true; node = astNode.addNodeProperties({}); expect(node.enclosingScopeId).toBeNull(); }); it('should provide a non-null enclosingScopeId in debug mode for nodes with an enclosing ' + 'scope', () => { let enclosingScope; let node; env.opts.debug = true; node = astNode.addNodeProperties({}); enclosingScope = astNode.addNodeProperties({}); node.enclosingScope = enclosingScope; expect(node.enclosingScopeId).toBe(enclosingScope.nodeId); }); }); describe('getInfo', () => { it('should throw an error for undefined input', () => { function noNode() { astNode.getInfo(); } expect(noNode).toThrow(); }); it('should return the correct info for an AssignmentExpression', () => { const info = astNode.getInfo(assignmentExpression); expect(info).toBeObject(); expect(info.node).toBeObject(); expect(info.node.type).toBe(Syntax.Literal); expect(info.node.value).toBe(1); expect(info.name).toBe('foo'); expect(info.type).toBe(Syntax.Literal); expect(info.value).toBe(1); }); it('should return the correct info for a FunctionDeclaration', () => { const info = astNode.getInfo(functionDeclaration2); expect(info).toBeObject(); expect(info.node).toBeObject(); expect(info.node.type).toBe(Syntax.FunctionDeclaration); expect(info.name).toBe('foo'); expect(info.type).toBe(Syntax.FunctionDeclaration); expect(info.value).toBeUndefined(); expect(info.paramnames).toBeArrayOfSize(1); expect(info.paramnames[0]).toBe('bar'); }); it('should return the correct info for a FunctionExpression', () => { const info = astNode.getInfo(functionExpression2); expect(info).toBeObject(); expect(info.node).toBeObject(); expect(info.node.type).toBe(Syntax.FunctionExpression); expect(info.name).toBe(''); expect(info.type).toBe(Syntax.FunctionExpression); expect(info.value).toBeUndefined(); expect(info.paramnames).toBeArrayOfSize(1); expect(info.paramnames[0]).toBe('bar'); }); it('should return the correct info for a MemberExpression', () => { const info = astNode.getInfo(memberExpression); expect(info).toBeObject(); expect(info.node).toBeObject(); expect(info.node.type).toBe(Syntax.MemberExpression); expect(info.name).toBe('foo.bar'); expect(info.type).toBe(Syntax.MemberExpression); }); it('should return the correct info for a computed MemberExpression', () => { const info = astNode.getInfo(memberExpressionComputed1); expect(info).toBeObject(); expect(info.node).toBeObject(); expect(info.node.type).toBe(Syntax.MemberExpression); expect(info.name).toBe('foo["bar"]'); expect(info.type).toBe(Syntax.MemberExpression); }); it('should return the correct info for a Property initializer', () => { const info = astNode.getInfo(propertyInit); expect(info).toBeObject(); expect(info.node).toBeObject(); expect(info.node.type).toBe(Syntax.ObjectExpression); expect(info.name).toBe('bar'); expect(info.type).toBe(Syntax.ObjectExpression); }); it('should return the correct info for a Property setter', () => { const info = astNode.getInfo(propertySet); expect(info).toBeObject(); expect(info.node).toBeObject(); expect(info.node.type).toBe(Syntax.FunctionExpression); expect(info.name).toBe('bar'); expect(info.type).toBeUndefined(); expect(info.value).toBeUndefined(); expect(info.paramnames).toBeArrayOfSize(1); expect(info.paramnames[0]).toBe('a'); }); it('should return the correct info for a VariableDeclarator with a value', () => { const info = astNode.getInfo(variableDeclarator1); expect(info).toBeObject(); expect(info.node).toBeObject(); expect(info.node.type).toBe(Syntax.Literal); expect(info.name).toBe('foo'); expect(info.type).toBe(Syntax.Literal); expect(info.value).toBe(1); }); it('should return the correct info for a VariableDeclarator with no value', () => { const info = astNode.getInfo(variableDeclarator2); expect(info).toBeObject(); expect(info.node).toBeObject(); expect(info.node.type).toBe(Syntax.Identifier); expect(info.name).toBe('foo'); expect(info.type).toBeUndefined(); expect(info.value).toBeUndefined(); }); it('should return the correct info for other node types', () => { const info = astNode.getInfo(binaryExpression); expect(info).toBeObject(); expect(info.node).toBe(binaryExpression); expect(info.type).toBe(Syntax.BinaryExpression); }); }); describe('getParamNames', () => { it('should return an empty array for undefined input', () => { const params = astNode.getParamNames(); expect(params).toBeEmptyArray(); }); it('should return an empty array if the input has no params property', () => { const params = astNode.getParamNames({}); expect(params).toBeEmptyArray(); }); it('should return an empty array if the input has no params', () => { const params = astNode.getParamNames(functionDeclaration1); expect(params).toBeEmptyArray(); }); it('should return a single-item array if the input has a single param', () => { const params = astNode.getParamNames(functionDeclaration2); expect(params).toEqual(['bar']); }); it('should return a multi-item array if the input has multiple params', () => { const params = astNode.getParamNames(functionDeclaration3); expect(params).toEqual([ 'bar', 'baz', 'qux' ]); }); it('should include rest parameters', () => { const params = astNode.getParamNames(functionDeclaration4); expect(params).toEqual(['bar']); }); }); describe('isAccessor', () => { it('should return false for undefined values', () => { expect( astNode.isAccessor() ).toBeFalse(); }); it('should return false if the parameter is not an object', () => { expect( astNode.isAccessor('foo') ).toBeFalse(); }); it('should return false for non-Property nodes', () => { expect( astNode.isAccessor(binaryExpression) ).toBeFalse(); }); it('should return false for Property nodes whose kind is "init"', () => { expect( astNode.isAccessor(propertyInit) ).toBeFalse(); }); it('should return true for Property nodes whose kind is "get"', () => { expect( astNode.isAccessor(propertyGet) ).toBeTrue(); }); it('should return true for Property nodes whose kind is "set"', () => { expect( astNode.isAccessor(propertySet) ).toBeTrue(); }); }); describe('isAssignment', () => { it('should return false for undefined values', () => { expect( astNode.isAssignment() ).toBeFalse(); }); it('should return false if the parameter is not an object', () => { expect( astNode.isAssignment('foo') ).toBeFalse(); }); it('should return false for nodes that are not assignments', () => { expect( astNode.isAssignment(binaryExpression) ).toBeFalse(); }); it('should return true for AssignmentExpression nodes', () => { expect( astNode.isAssignment(assignmentExpression) ).toBeTrue(); }); it('should return true for VariableDeclarator nodes', () => { expect( astNode.isAssignment(variableDeclarator1) ).toBeTrue(); }); }); describe('isFunction', () => { it('should recognize function declarations as functions', () => { expect( astNode.isFunction(functionDeclaration1) ).toBeTrue(); }); it('should recognize function expressions as functions', () => { expect( astNode.isFunction(functionExpression1) ).toBeTrue(); }); it('should recognize method definitions as functions', () => { expect( astNode.isFunction(methodDefinition1) ).toBeTrue(); }); it('should recognize arrow function expressions as functions', () => { expect( astNode.isFunction(arrowFunctionExpression) ).toBeTrue(); }); it('should recognize non-functions', () => { expect( astNode.isFunction(arrayExpression) ).toBeFalse(); }); }); describe('isScope', () => { it('should return false for undefined values', () => { expect( astNode.isScope() ).toBeFalse(); }); it('should return false if the parameter is not an object', () => { expect( astNode.isScope('foo') ).toBeFalse(); }); it('should return true for CatchClause nodes', () => { expect( astNode.isScope({type: Syntax.CatchClause}) ).toBeTrue(); }); it('should return true for FunctionDeclaration nodes', () => { expect( astNode.isScope({type: Syntax.FunctionDeclaration}) ).toBeTrue(); }); it('should return true for FunctionExpression nodes', () => { expect( astNode.isScope({type: Syntax.FunctionExpression}) ).toBeTrue(); }); it('should return false for other nodes', () => { expect( astNode.isScope({type: Syntax.NameExpression}) ).toBeFalse(); }); }); describe('nodeToString', () => { it('should be an alias to nodeToValue', () => { expect(astNode.nodeToString).toBe(astNode.nodeToValue); }); }); describe('nodeToValue', () => { it('should return `[null]` for the sparse array `[,]`', () => { expect( astNode.nodeToValue(arrayExpression) ).toBe('[null]'); }); it('should return the variable name for assignment expressions', () => { expect( astNode.nodeToValue(assignmentExpression) ).toBe('foo'); }); it('should return the function name for function declarations', () => { expect( astNode.nodeToValue(functionDeclaration1) ).toBe('foo'); }); it('should return undefined for anonymous function expressions', () => { expect( astNode.nodeToValue(functionExpression1) ).toBeUndefined(); }); it('should return the identifier name for identifiers', () => { expect( astNode.nodeToValue(identifier) ).toBe('foo'); }); it('should return the literal value for literals', () => { expect( astNode.nodeToValue(literal) ).toBe(1); }); it('should return the object and property for noncomputed member expressions', () => { expect( astNode.nodeToValue(memberExpression) ).toBe('foo.bar'); }); it('should return the object and property, with a computed property that uses the same ' + 'quote character as the original source, for computed member expressions', () => { expect( astNode.nodeToValue(memberExpressionComputed1) ).toBe('foo["bar"]'); expect( astNode.nodeToValue(memberExpressionComputed2) ).toBe('foo[\'bar\']'); }); // TODO: we can't test this here because JSDoc, not Babylon, adds the `parent` property to // nodes. also, we currently return an empty string instead of `<anonymous>` in this case; // see `module:jsdoc/src/astnode.nodeToValue` and the comment on `Syntax.MethodDefinition` // for details xit('should return `<anonymous>` for method definitions inside classes that were ' + 'returned by an arrow function expression', () => { expect( astNode.nodeToValue(methodDefinition2) ).toBe('<anonymous>'); }); it('should return "this" for this expressions', () => { expect( astNode.nodeToValue(thisExpression) ).toBe('this'); }); it('should return the operator and nodeToValue value for prefix unary expressions', () => { expect( astNode.nodeToValue(unaryExpression1) ).toBe('+1'); expect( astNode.nodeToValue(unaryExpression2) ).toBe('+foo'); }); it('should throw an error for postfix unary expressions', () => { function postfixNodeToValue() { // there's no valid source representation for this one, so we fake it const unaryExpressionPostfix = (() => { const node = parse('+1;').body[0].expression; node.prefix = false; return node; })(); return astNode.nodeToValue(unaryExpressionPostfix); } expect(postfixNodeToValue).toThrow(); }); it('should return the variable name for variable declarators', () => { expect( astNode.nodeToValue(variableDeclarator1) ).toBe('foo'); }); it('should return an empty string for all other nodes', () => { expect( astNode.nodeToValue(binaryExpression) ).toBe(''); }); it('should understand and ignore ExperimentalSpreadProperty', () => { expect( astNode.nodeToValue(experimentalObjectRestSpread) ).toBe('{"three":4}'); }); }); });

875 F.2d 862 Unpublished DispositionNOTICE: Sixth Circuit Rule 24(c) states that citation of unpublished dispositions is disfavored except for establishing res judicata, estoppel, or the law of the case and requires service of copies of cited unpublished dispositions of the Sixth Circuit.Gloria COOLEY, Plaintiff-Appellant,v.SECRETARY OF HEALTH AND HUMAN SERVICES, Defendant-Appellee. No. 88-1465. United States Court of Appeals, Sixth Circuit. April 10, 1989. Before BOYCE F. MARTIN, Jr. and MILBURN, Circuit Judges, and JOHN D. HOLSCHUH, District Judge*. PER CURIAM. 1 The Secretary of Health and Human Services ("Secretary") found that claimant Gloria Cooley ("Cooley") became disabled on May 23, 1984. Cooley appeals the Secretary's determination of her onset date, arguing she is entitled to an earlier date. For the reasons that follow, we affirm the finding of disability, but reverse the district court's determination of Cooley's onset date. I. 2 Cooley applied for disability insurance benefits on March 25, 1982. Her application was denied initially and upon reconsideration. She requested a hearing before an Administrative Law Judge ("ALJ"), which was held on September 10, 1984. On November 15, 1984, the ALJ issued an opinion finding Cooley not disabled. This became the final decision of the Secretary. Cooley then filed for judicial review in the district court. 3 On November 6, 1985, the district court remanded the case to the Secretary for a new evaluation under the revised mental impairment standards of the Social Security Disability Benefits Reform Act of 1984 (Pub.L. No. 98-460). The ALJ conducted two more hearings, on May 19 and July 22, 1986. On January 8, 1987, the ALJ found Cooley disabled by an anxiety-related disorder pursuant to 20 C.F.R. Pt. 404, Subpt. P, App. 1, Sec. 12.06, with an onset date of May 23, 1984. He characterized Cooley as suffering from post-traumatic stress disorder, aggravated by personality and anxiety problems. He found that she was never capable of returning to her past relevant work after she was injured in April 1981, but she could do unskilled work between April 1981 and May 23, 1984. The Appeals Council adopted the ALJ's recommendations. 4 Cooley continued to object to the 1984 onset date and reinstated her action for judicial review. Both Cooley and the Secretary moved for summary judgment. The matter was referred to the magistrate, who recommended granting Cooley's motion for summary judgment. The magistrate believed the medical evidence established that Cooley's ability to concentrate became substantially impaired in April 1981. Therefore, the hypothetical question relied upon by the ALJ which assumed she could concentrate did not accurately portray her impairment, and the vocational expert's response to the deficient question was not evidence that Cooley could perform unskilled work between April 1981 and May 1984. 5 The district court rejected the magistrate's recommendation and affirmed the Secretary's decision that Cooley became disabled on May 23, 1984. The district court did not address the magistrate's concerns with the ALJ's hypothetical question. Cooley then filed a timely appeal with this court. 6 Cooley was born April 5, 1946, and was thirty-five years old when she was injured on April 6, 1981, while working as a health instructor at M.L. King High School in Detroit. According to the injury report she filed with the Board of Education, Cooley was monitoring a hallway when she heard a commotion in a girls' restroom. She went into the restroom, found several boys and girls, and turned to find another teacher to help her with the situation. The students rushed to leave, and Cooley's head and body were squeezed and smashed several times as she became trapped between a brick wall and a door that was repeatedly thrown open by fleeing students. Cooley reported suffering bruises on her face and body. Later, in August 1981, when she underwent the first of numerous physical and neurological examinations, she reported that she lost consciousness during the restroom incident. Cooley's mental and emotional condition deteriorated significantly between April 1981 and May 1984. 7 Cooley testified that since the restroom incident she has been unable to think clearly, and has become forgetful to the point where she lives according to routines and lists. She experiences speech, reading and vision difficulties; becomes fatigued and overwhelmed frequently and easily; and has remained severely depressed, withdrawn and is frightened by other people and her inability to think and speak clearly and coherently. Cooley's complaints and symptoms are documented in an extensive medical history. 8 Between June 1981 and May 1983, Cooley was examined by several neurologists, ophthalmologists, psychiatrists and psychologists, dentists, an ear, nose and throat physician, and a speech therapist. She was hospitalized from May 23, 1984, through June 20, 1984, because of the increasing severity of her impairments and her withdrawal from normal life activities. At admission, she was anxious, easily overwhelmed, depressed and fearful.1 II. A. 9 Our scope of review is limited to the inquiry of whether the Secretary's findings are supported by "substantial evidence." Richardson v. Perales, 402 U.S. 389, 401 (1971). Substantial evidence is "such relevant evidence as a reasonable mind might accept as adequate to support a conclusion." Consolidated Edison Co. v. NLRB, 305 U.S. 197, 229 (1938). In reviewing for substantial evidence, we must examine the record taken as a whole. Duncan v. Secretary of Health & Human Servs., 801 F.2d 847, 852 (6th Cir.1986). 10 Because the ALJ found that Cooley was never capable of returning to her past relevant work, the burden shifted to the Secretary to show by substantial evidence that she could perform work that existed in the national economy. See Buress v. Secretary of Health & Human Servs., 835 F.2d 139, 142 (6th Cir.1987) (per curiam); Varley v. Secretary of Health & Human Servs., 820 F.2d 777, 779 (6th Cir.1987). The theoretical ability to engage in some type of work is not enough; the Secretary must make "a finding supported by substantial evidence that [the claimant] has the vocational qualifications to perform specific jobs." O'Banner v. Secretary of Health, Educ. & Welfare, 587 F.2d 321, 323 (6th Cir.1978). "Substantial evidence may be produced through reliance on the testimony of a vocational expert in response to a 'hypothetical question,' but only 'if the question accurately portrays [the claimant's] individual physical and mental impairments.' " Varley, 820 F.2d at 779 (quoting Podedworny v. Harris, 745 F.2d 210, 218 (3d Cir.1984)). B. 11 Cooley asserts the Secretary did not show by substantial evidence that she could perform specific jobs. The pertinent part of the ALJ's opinion provides: 12 While the evidence of record does suggest the existence of a mental impairment going back to 1981, the undersigned finds that, given the minimal clinical findings in the record prior to May of 1984, the claimant's mental impairment, while severe, did not preclude her from performing a full range of unskilled work. While the testimony from the vocational expert and the medical findings in the record indicate that the claimant could not have performed her teaching job at that time and that her mental impairment probably precluded her from using or transferring her vocational skills, there is nothing in the record indicating that the claimant's mental impairment would have impacted upon her ability to perform unskilled work prior to May of 1984. The undersigned further finds that prior to May 1984, the claimant could have performed those unskilled ... jobs identified by the vocational expert, and that these jobs existed in significant numbers in the local economy. 13 J.A. at 232-33 (emphasis supplied). 14 Striking in the above passage is the ALJ's declaration that "there is nothing in this record indicating" that Cooley could not perform unskilled work prior to May 1984. This statement reflects a mistaken view of the case. As Buress and Varley make clear, the focus is not on what is absent from the record, but what evidence is in the record to prove that Cooley had the vocational qualifications to perform specific jobs. 15 The Secretary's proof of Cooley's residual functional capacity consisted of the testimony of vocational expert Michael Rosko, to whom the ALJ posed two hypothetical questions. The first question satisfies the Varley standard of accuracy, as the ALJ asked Rosko to consider a hypothetical forty-year-old woman who suffered through Cooley's undisputed physical and mental impairments--severe daily headaches, depression, withdrawal, impatience, irritability, frequent crying, hurling things about the house, insomnia, low self-esteem, nightmares, fear of teenagers, fear of telephone calls, frequent anxiety, seizures, poor memory, indecision, unpredictable moods, easily frustrated and overwhelmed, and severely impaired concentration. Assuming these impairments, the vocational expert testified it would be very difficult for the hypothetical woman to return to her past relevant work and that the impairment of her concentration "would probably preclude all jobs--skilled and unskilled for this hypothetical person." 16 Cooley attacks the second hypothetical question, in which the vocational expert was asked to assume the same impairments as above, except the woman's impairments did not substantially interfere with her concentration. He testified this second hypothetical woman could not return to her past relevant work, but "there would be some unskilled jobs that generally fall within the parameters of this hypothetical question." He testified there were approximately 20,000 strictly sedentary, unskilled jobs in the Detroit metropolitan area which she could perform, but if she tired easily and needed to lie down, she could not perform these jobs. 17 Cooley argues the second question is deficient because there is no evidence in the record that her concentration was intact between April 1981 and May 1984. She criticizes the question as failing to portray her individual physical and mental impairments accurately as required by Varley, and asserts it cannot serve as substantial evidence. We agree. A review of the medical evidence in this case indicates that from the beginning of the record, one of the most frequently discussed and documented of Cooley's impairments is her inability to concentrate, her inability to remember, her inability to focus sufficiently to utter complete sentences without needing to stop and reflect midway through. 18 We find other defects in the second hypothetical question as well. For example, the vocational expert assumed the hypothetical woman's continual and severe headaches were controlled by medication. But there is no evidence that Cooley's headaches have ever been controlled or relieved. Similarly, the vocational expert testified that the hypothetical woman could not perform unskilled jobs if she tired easily and needed to lie down during the day. It is undisputed that Cooley is easily overwhelmed, both mentally and physically, and must lie down often because of fatigue. 19 In our analysis it may appear that we are weighing evidence or resolving conflicts therein, which would be outside our scope of review. But the Varley inquiry of whether the Secretary produced substantial evidence that Cooley had retained the qualifications to perform specific jobs demands evaluation of the second hypothetical question, its failure to accurately portray Cooley's physical and mental impairments, and the resulting deficiency in the Secretary's evidence. The hypothetical questions the Secretary relies upon for substantial evidence must adhere to the claimant's actual mental and physical impairments; in this case, the second hypothetical question did not.2 III. 20 For the foregoing reasons, the judgment of the district court is REVERSED, and this case is REMANDED with the instruction that Cooley's onset date of disability be fixed at April 6, 1981. * Honorable John D. Holschuh, United States District Judge for the Southern District of Ohio, sitting by designation 1 The deterioration of Cooley's mental abilities is also documented. In November 1981, she scored in the normal range of intellectual ability, with a full-scale IQ of 95, a performance IQ of 86, and a verbal IQ of 103. By September 1984, her intellectual abilities had declined to the below average range, with a full-scale IQ of 87, a performance IQ of 80, and a verbal IQ of 95. By February 1986, Cooley's intellectual abilities had deteriorated to the point where she could score only in the borderline range on intelligence tests, with a full-scale IQ of 72, a performance IQ of 67, and a verbal IQ of 78 2 Because we find the Secretary's decision lacked substantial evidence, we need not address Cooley's alternate argument that she was rendered disabled by an organic brain disorder rather than an anxiety-related disability

You are here: Nicholas Mills, MD Profile Asante Service Location Asante Ashland Community Hospital Asante Rogue Regional Medical Center Gender: Male Primary Specialty Obstetrics & Gynecology Specialties Obstetrics & Gynecology Robotic Assisted Surgery Biography Nicholas Mills, MD earned his undergraduate degree in chemistry from University of Colorado. He attended medical school at The Ohio State University College of Medicine and then completed his residency in 2011 at nearby Riverside Methodist Hospital in Columbus, Ohio. Dr. Mills’ training has prepared him to manage all areas of women’s health care. He has special interests in caring for women with a history of preterm birth. Following a preterm delivery, the decision to become pregnant again can be a daunting task for couples. Dr. Mills understands this and is ready to help his patients. He prides himself in listening and sharing the emotional burden with these families while identifying areas to improve their pregnancy outcomes. Dr. Mills also has strong interest in gynecology and excellent training in minimally invasive surgery. He aims to guide patients to the therapy that achieves their treatment goals while limiting the physical impact on their lives. From urinary incontinence procedures to treatment for dysfunctional bleeding, Dr. Mills can help patients improve their quality of life with the latest procedures and surgical techniques. He comes to Medford joined by his wife Lyndsey, and children Emerson and Carter. In his free time, he and his family enjoy time outside, hiking, running, and golf. Office Information Doctor's Contact Information Locations Asante's online provider directory, ("Find A Doctor"), is provided for reference purposes only. Providers are responsible for the accuracy of the information submitted. As such, Asante cannot guarantee that the physician information presented is complete or accurate. Asante recommends that you contact your healthcare provider directly for the most accurate and up-to-date information. Providers who would like to report inaccurate information on their profile may contact [email protected], information will be routed to the appropriate Hospital credentialing staff. Asante Moments High-Quality Healthcare for Everyone As the largest healthcare provider in nine counties, Asante provides comprehensive medical care to more than 580,000 people throughout Southern Oregon and Northern California. Our facilities include Asante Ashland Community Hospital in Ashland, Asante Rogue Regional Medical Center in Medford, Asante Three Rivers Medical Center in Grants Pass, Asante Physician Partners and additional healthcare partnerships throughout the region.

Dependent source In the theory of electrical networks, a dependent source is a voltage source or a current source whose value depends on a voltage or current elsewhere in the network. Dependent sources are useful, for example, in modelling the behavior of amplifiers. A bipolar junction transistor can be modelled as a dependent current source whose magnitude depends on the magnitude of the current fed into its controlling base terminal. An operational amplifier can be described as a voltage source dependent on the differential input voltage between its input terminals. Practical circuit elements have properties such as finite power capacity, voltage, current, or frequency limits that mean an ideal source is only an approximate model. Accurate modelling of practical devices requires using several idealized elements in combination. Classification Dependent sources can be classified as follows: Voltage-controlled voltage source: The source delivers the voltage as per the voltage of the dependent element. Voltage-controlled current source: The source delivers the current as per the voltage of the dependent element. Current-controlled current source: The source delivers the current as per the current of the dependent element. Current-controlled voltage source: The source delivers the voltage as per the current of the dependent element. Dependent sources are not necessarily linear. For example, MOSFET switches can be modeled as a voltage-controlled current source when and . However, the relationship between the current flowing through it and is approximately: In this case, the current is not linear to , but rather approximately proportional to the square of . As for the case of linear dependent sources, the proportionality constant between dependent and independent variables is dimensionless if they are both currents (or both voltages). A voltage controlled by a current has a proportionality factor expressed in units of resistance (ohms), and this constant is sometimes called "transresistance". A current controlled by a voltage has the units of conductance (siemens), and is called "transconductance". Transconductance is a commonly used specification for measuring the performance of field effect transistors and vacuum tubes. See also Circuit theory Ground (electricity) Mathematical methods in electronics Open-circuit voltage Lumped-element model Distributed-element model Series and parallel circuits Superposition theorem SPICE Topology (electronics) Trancitor Mesh analysis References Category:Power supplies Category:Electrical power control

SubDir HAIKU_TOP src tests system network posixnet ; UsePrivateHeaders private shared ; UnitTestLib posixnettest.so : PosixNetTestAddon.cpp GetAddrInfo.cpp SocketTests.cpp : be $(TARGET_NETWORK_LIBS) [ TargetLibstdc++ ] ;

MiR-125b-5p suppressed the glycolysis of laryngeal squamous cell carcinoma by down-regulating hexokinase-2. Laryngeal squamous cell carcinoma (LSCC) is the most common form of laryngeal carcinoma with poor prognosis. Exploring novel factors involved in the progression of LSCC is quite necessary for understanding the mechanisms and designing therapeutic strategies for LSCC. In this study, we showed that miR-125b-5p was significantly down-regulated in LSCC tissues and cell lines. The decreased expression of miR-125b-5p was associated with the tumor differentiation, metastasis and high clinical stage of the LSCC patients. Overexpression of miR-125b-5p suppressed the proliferation and induced apoptosis of LSCC cells. Bioinformatics analysis predicted hexokinase-2 (HK2), an essential enzyme involved in the glycolysis of cancer cells, as one of the downstream targets of miR-125b-5p. Further molecular studies showed that highly expressed miR-125b-5p bound the 3'-UTR of HK2 and decreased both the mRNA and protein levels of HK2. Consistent with the function of HK2 in glycolytic metabolism, overexpression of miR-125b-5p significantly suppressed the glucose consumption and lactate production of LSCC cells. Notably, restoration the expression of HK2 attenuated the inhibitory effect of miR-125b-5p on the glycolysis of LSCC cells. The inverse correlation between the expression of miR-125b-5p and HK2 in LSCC tissues further supported the involvement of miR-125b-5p-HK2 axis in the progression of LSCC. Collectively, these finding suggested the miR-125b-5p-HK2 pathway as a novel mechanism in regulating the glycolysis and progression of LSCC.

[Influence of qualitatively different fats on the level of cholesterol and phospholipids in the blood serum and liver on rats in choline-protein insufficiency]. The effect of lard and sunflower oil making part of a cirrhogenic ration with a high content of fat and deficient protein and choline on the level of total and esterified cholesterol and phospholipids in the blood serum and liver was studied. The experiments lasted for 150 and 210-240 days. Changes in the level of cholesterol and phospholipids in the blood serum and liver of the rats were noted to occur from the first days of developing fat dystrophy (fatty degeneration) of the liver, these changes gaining in intensity with lengthening of the test periods and progressive development of the pathological process. The quality of the fat influenced the extent of the upset cholesterol and phospholipids metabolism, since the saturated fat which accelerated and intensified the development of lipohepatosis and cirrhosis caused a significantly greater accumulation of the cholesterol ethers in the liver and reduction of these ethers, as well as of phospholipids in the serum. An addition of choline to the rations prevented the development of lipohepatosis, but failed to avert upsets of the lipids metabolism.

The Mayor walked through the three possible routes and numerous possible future extensions. He broke down how successful systems in cities such as Seattle, Portland, and Tacoma have started with routes similar in length to the proposed for the Milwaukee Streetcar system (2 to 3 miles). The public is invited to attend an open house to review and comment on the proposed routes on October 8th, 2009 from 3 p.m. to 7 p.m. at the Zeidler Municipal Building at 841 N. Broadway. Keep in mind that this is a starter system, limited by the availability of funds. The plan is that once something is in the ground, expansions will be a lot easier. Mayor Barrett himself describes the plan as a “trojan horse” designed to be expanded. We invite you to vote in the below poll for your favorite route (and leave a message in the comments why), here is some quick food for thought from us. You’re also invited to buy a streetcar t-shirt, and wear it to the event on October 8th to show your support. Alignment #1 This route seems positioned for success because it connects likely riders (urban residents) with jobs. The Third Ward and downtown are filled with “creative class” jobs, and downtown and the lower East Side are filled with “creative class” workers. Likewise this streetcar would connect service industry workers with numerous restaurants, bars, and retail locations, saving money for the people who need it most. The jog up to Brady is more valuable than the jog further south in the Third Ward. Adding access for thousands of residents by connecting to Brady is more desirable than getting to the front door of more jobs in the Third Ward. It seems likely that if riders were dropped off by the iconic Milwaukee Public Market they would likely walk to the jobs located south of St. Paul in the Third Ward. Development potential along this route is good, although secondary to the potential for riders. This is key in this author’s viewpoint for making the starter system successful. Connection to the Intermodal Station is essential for regional transit (Amtrak, KRM, Megabus, Greyhound, etc). The 4th Street jaunt at the west end of the route seems likely to be underutilized, with likely only convention attendees and a few hotel guests using the leg. It might be better waiting until funds are available to make the 4th Street leg go further north. Alignment #2 The Water Street leg seems to pass less housing than Alignment #1 would. On the flip side it would likely pass more jobs, and more bars. It seems that a better balance would yield better ridership for the starter system. The potential Brady Street leg is intriguing, but likely a disappointment in terms of development. The Water Street portion could see more accelerated development, because of the line’s construction (The North End’s development would likely be accelerated). The Brady Street portion would draw riders, however, future growth may be difficult because of neighborhood politics including the East Village Neighborhood Conversation Overlay District that limit heights and thereby inhibits density beyond a certain level. Additionally, Brady Street itself is a historic district, which could limit the possibility of new development as well. Long-term development potential from the line on Brady Street is likely fairly limited (compared to other potential routes). Connection to the Intermodal Station is essential for regional transit (Amtrak, KRM, Megabus, Greyhound, etc). The 4th Street jaunt at the west end of the route seems likely to be underutilized, with likely only convention attendees and a few hotel guests using the leg. It might be better waiting until funds are available to make the 4th Street leg go further north. The alignment is less connected with the Third Ward, a large center of jobs, and is even further disconnected with the growing number of apartments at the east and southern areas of the Third Ward. Alignment #3 The alignment misses a large portion of East Town, the most jobs-dense portion of the city. The alignment serves many major entertainment hubs (Bradley Center, US Cellular Arena, Milwaukee Theater, Turner Hall Ballroom, Midwest Airlines Convention Center), which are likely to generate high ridership, but only on a handful of days. The alignment misses the Third Ward completely, a large jobs center, and an increasingly dense population center. The potential Brady Street leg is intriguing, but likely a disappointment in terms of development. The Water Street portion could see more accelerated development because of the line’s construction (The North End’s development would likely be accelerated). The Brady Street portion would draw riders, however, future growth may be difficult because of neighborhood politics including the East Village Neighborhood Conversation Overlay District that limit heights and thereby inhibit density beyond a certain level. Additionally, Brady Street itself is a historic district, which could limit the possibility of new development as well. Long-term development potential from the line on Brady Street is likely fairly limited (compared to other potential routes). The leg from Ogden to Brady would be important to generate ridership on the route, but it’s hard to imagine many people riding it to work daily. The route has the greatest development potential of the three routes, with all of the Park East covered. Unfortunately, that comes with the trade-off of likely the lowest ridership. If the goal is to build a starter system with the greatest number of riders possible, this is the worst option. 33 thoughts on “Milwaukee Streetcar Routes Unveiled by Mayor Barrett” Seems that the first option would have the highest projected ridership? Gotta go with whatever fetches the highest ridership with the starter system, the purpose of transit is for people to ride it, and that should help with extensions when the time comes. I’d say option 2 would be the best since it is most centrally located in the downtown to serve both east town and west town. Though I read that the streetcar may not have it’s own dedicated lane or have street lights turn green automatically for the streetcar? If that is true then don’t even bother with the system, it’s going to be no different than the bus in that it will get caught in traffic, like a bus, travel and a low average speed, and not run on a set schedule. #1 looks best. Connects intermodal station with U.S. Bank Center (this is critical, it’s the largest office building in the state), NW Mutual HQ, Fed courthouse, Cathedral Square, Third Ward, MSOE, Metromarket, Mil. Public Market, close to 411 E. Wisconsin and Pfister, and connects all of that with densely populated east side. I agree with Nathaniel, If people don’t ride and the system is not immediately successful, it will be crucified by the likes of Talk Radio. A streetcar system has been blocked for years, so it needs to hit the ground running if it comes about. The public must get behind it or it will be shelved for another 15 years. I like #1 for the simple fact that it goes through the central business district, while incorporating some entertainment venues. An even better route would start at the intermodal station, go north on 4th to Wisconsin Avenue, then east along Wisconsin Avenue to Jackson/Van Buren, then north to Ogden, then east to Farwell. Why not run this thing on Wisconsin Avenue, which is downtown’s main street? I think option 1 with the extension would be great, and I would actually trade the extension for the small segment that goes from the station to Wisconsin since that segment will be very underutilized. @Andrew, I think there is a lot of consternation with the BRT folks from the county about having both lines on the same street (which to me seems ridiculous, but it is what it is). Might be a congestion/speed of service issue with Wisconsin too (not sure). Hopefully #1 is what is built, with the extension to Brady. This brings together a nice mix of tourist destinations, jobs, housing, and nightlife. Hopefully if KRM and the county’s BRT plans move forward there will be easy transfers(no extra fees/thoughtful placement). Great news. At a glance, I prefer route number 1, though I agree that the 4th street leg seems unnecessary. You’d be quicker walking the 0.30 miles from the intermodal station to the convention center than waiting for a streetcar. Also, this route passes under 794 via Van Buren and Jackson. It seems this routing would severely limit the potential for tidying up the knot of highway ramps at this location or implementing a surface level boulevard. Perhaps a crossing closer the river would be better in this regard? Is the trade-off worth it? I see many of your arguements for route 1, but remember that we also have a proposed COMET system that would, if built, run norh on Prospect and south on Farewell with stops along that corridor. So, do we want duplication? You need to look at the systems together. Or is this proposal replacing the COMET…I thought it was the new route for the downtown circular streetcar OK, after further review route 1 looks the best option considering the current land use, but 2 could lead to new development along the water street corridor and park east. I am torn….to with what will work now or what could create more growth in a under utilized area of the downtown. regardless of where the route is they MUST have a dedicated lane for the vehicle and they must have the street lights turn green for the vehicle so that it’s movement is not stoped for traffic lights. This mode needs to be significantly quicker than the existing buses and in needs to be on time at stops or it won’t be used. I think option 1 hits the greatest number of commuters and would provide walkable access to all the entertainment destinations available downtown. One question that will hopefully be answered at the meeting is how many cars will run on this line? Personally, I would hope there will be no schedule, instead you can expact that a train will be along every 5-10 mins. Unfortunately, given the length of this starter system, if it has a schedule like our current buses it would probably still be easier to make the 30 min walk downtown rather than wait 30 min for a ride. I voted for #1 as the best of the lot but I think that the first route should definitely include going all the way to UWM period. Otherwise I don’t think it will be successful as it could be. I know that it would take more $ but then an unsuccessful route is wasting what we have and puts a pall on further development. For maximum economic development as well as school/job ridership I would include route north of Brady that would include Downer and Oakland shopping centers, that mirrors the “30” and “15” routes that are the most successful of the present bus routes. This would be the “Dream Route” for a successful first run of the street cars in Milwaukee. I think option #1 is the best of the three but it really needs to run at least North Ave. I really can’t imagine that the streetcar is going to blaze though the short route in a way that will far surpass the bus system. I live a few blocks of North and the 30 only takes 20/25 min for me to get to work (4th & Wis) and the 15 about 5 min less. I know people who live along the proposed route that drive and I really don’t forsee then giving up cars for this. Its the people on the fringes of downtown (less economically well off) who really need quick and fast transit versus people who live in 400k condos or pay 2k a month in rent. I know we have to start somewhere, but I think the starting point needs to be a bit larger. If the line could be extended at least to North Ave, that would capture a large number of UWM students, especially since UWM is running those shuttles between the Kenwood campus and North Ave. Yes, it would require a transfer to get downtown where the 15 and 30 wouldn’t, but unlike the 30 or 15, it would allow you to get to the Intermodal station with luggage. Better would be all the way to UWM. I think what hasn’t been made clear here is that there is only enough money for about 2 miles. Of course it would be great to get to North Avenue or UWM. It would also be great to get to Marquette, Bay View, Bronzeville and many other locations but there is only enough money for 2 miles. I lived on the Eastside (Prospect and Brady area) for many years, in the Third Ward for a year, attended UWM for undergrad and grad school, worked downtown for two years and honestly, I don’t think I would have ever ridden the proposed streetcar. I owned a car but often tried to survive without it by using the 15/30 buses. My thought is that “Milwaukee Urbanites” will adapt to this system if it perhaps connects UWM to Marquette and runs through the Third Ward / Downtown / East Town / Brady / North / probably a few other locations… otherwise the bus seems more convenient. Maybe we’re “building a bridge halfway over the river” because that’s all the money we have? (I know not the best analogy) and I could be totally wrong about this… maybe there are enough people who regularly need to go between East Town and Downtown for this too work. I think Urban Milwaukee staff should create a different poll, such as: if you are a “Milwaukee Urbanite” would you use the streetcar? Y / N Also, I’m wondering if any transportation engineering types have weighed in on this. And one more thing… thank you Urban Milwaukee. Someday I plan to move back to Milwaukee but I feel like I’m not missing anything because of your site. Michael, one of the benefits of a streetcar is that it won’t just attract us urbanites, it will attract almost everyone. There are a lot of people who live on the lower east side who now drive to the Third Ward or downtown. I know that sounds crazy, but it’s true. The bus is not appealing to them for a number of reasons (confusing, infrequency of service, misconceptions, etc.). The beauty of enhanced transit options like a streetcar is that they can help increase transit ridership as a whole, because they appeal to a larger group of potential users. From a transportation engineering standpoint: Granted, never underestimate an American’s willingness to shell out $$ to be moved 4 blocks without walking, but still, this leg doesn’t seem to make much sense. From a political/marketing standpoint: There’s zero chance this thing gets build WITHOUT being paraded around in front of the convention center. And there’s the end of discussion for that leg! In addition to the convention center, it might be important for the streetcar to make an appearance on Downtown’s main drag west of the river. Something else I have been wondering about…I’m assuming the streetcar line and the vehicles themselves will need some sort of maintenance shed. Looking at alternative 1, it seems to me that one of the best places for this building to go would be in the 4th and Clybourn Area. I assumed that was another reason why that particular little jaunt. Any other ideas where it could go? I have to go with the consensus on #1. Simply because of projected ridership and the fact that #3 just leads to sports arenas and a empty and unused mall and #2 seems to follow only nightlife not linking any of the East town residences to third ward and downtown Have you guys (Dave and Jeramey) heard anything more about a locally preferred alternative? I know that milwaukeeconnector.com gave a timetable with a “locally preferred alternative approved” in December 2009 to January 2010. Would the City Common Council be in charge of choosing this alternative? The City engineering department?