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"William Morgan (architect)\n\nWilliam Newton Morgan, Sr. (",
"December 14, 1930 – January 18, 2016) was an American architect and author, based in Jacksonville, Florida. ",
"Three of his designs are included on the Florida Association of the American Institute of Architects list of Florida's top 100 buildings (The Williamson House in Ponte Vedra Beach; Morgan's residence in Atlantic Beach; and Dickinson Hall at the University of Florida, formerly the Museum of Natural History). ",
"He has written five books including his most recent, Earth Architecture (2008). ",
"In 2012 the University of Florida awarded Morgan an honorary doctor of arts degree as well as the first recipient of its School of Architecture's Lifetime Achievement Award. ",
"Morgan has been described as a pioneer of sustainable design.",
"\n\nMorgan grew up in Jacksonville and graduated with a bachelor's degree from Harvard University before serving in the U.S. Navy during the Korean War. ",
"After the war he returned to Harvard to study architecture. ",
"He studied in Italy on a Fulbright Scholarship (U.S.-Italy Fulbright Commission) and then returned to Jacksonville in 1961 to open his architecture practice in the city where he had grown up.",
"\n\nMorgan's five books cover the architecture of pre-industrial cultures, including those in pre-Columbian North America and Micronesia. ",
"He died in Jacksonville after a long illness on January 18, 2016, aged 85.",
"\n\nWorks\n\nWilliamson House, Ponte Vedra Beach (1966), AIA Florida Award of Merit (1964) and listed on AIA's list of Top 100 buildings in Florida\nMuseum of Science and History (1969), adjacent to Friendship Fountain, formally the Jacksonville Children's Museum\nDickinson Hall (1971) at the University of Florida campus in Gainesville, formerly the Museum of Natural History/ Florida Museum of Natural Sciences. ",
"The earth-bermed concrete building is listed on AIA's Top 100 Buildings in Florida\nPolice Administration Building, Jacksonville \nDaniel State Office Building, Jacksonville (now an annex and parking garage for the Hyatt Regency Riverfront Hotel)\nMorgan home, Atlantic Beach (1974), Morgan's home in Atlantic Beach, influenced by the stepped structure of the Roman seaside town Herculaneum Listed on AIA's Top 100 Buildings in Florida\n\nSee also\nArchitecture of Jacksonville\n\nReferences\n\nCategory:21st-century American architects\nCategory:Writers from Jacksonville, Florida\nCategory:Harvard Graduate School of Design alumni\nCategory:Architects from Jacksonville, Florida\nCategory:20th-century American architects\nCategory:Fulbright Scholars\nCategory:1930 births\nCategory:2016 deaths\nCategory:Jacksonville Modern architecture\nCategory:Brutalist architects"
] |
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"/* -*- mode: c++; coding: utf-8; tab-width: 4; indent-tabs-mode: nil; c-basic-offset: 4; show-trailing-whitespace: t -*-*/\n\n#define BOOST_TEST_MODULE test_wire_basket\n#include <feel/feelcore/testsuite.hpp>\n\n#include <feel/options.hpp>\n#include <feel/feelalg/backend.hpp>\n#include <feel/feeldiscr/functionspace.hpp>\n#include <feel/feelfilters/creategmshmesh.hpp>\n#include <feel/feelfilters/savegmshmesh.hpp>\n#include <feel/feelfilters/domain.hpp>\n#include <feel/feelvf/vf.hpp>\n#include <feel/feelfilters/exporter.hpp>\n#include <feel/feeldiscr/createsubmesh.hpp>\n#include <feel/feeldiscr/projector.hpp>\n\n\nnamespace test_wire_basket\n{\n\nusing namespace Feel;\n/*_________________________________________________*\n * Run\n *_________________________________________________*/\n\ntemplate <uint16_type OrderPoly>\nvoid run()\n{\n\n /* change parameters below */\n const int nDim = 3;\n const int nOrderPoly = OrderPoly;\n double meshSize = doption(_name=\"gmsh.hsize\");\n\n //--------------------------------------------------------------------------------------------------//\n\n typedef Mesh< Simplex<nDim,1,nDim> > mesh_type;\n typedef FunctionSpace<mesh_type, bases<Lagrange<OrderPoly,Scalar> > > space_type;\n typedef Exporter<mesh_type> export_type;\n // trace\n typedef typename mesh_type::trace_mesh_type trace_mesh_type;\n typedef Exporter<trace_mesh_type> trace_export_type;\n // trace_trace\n typedef typename trace_mesh_type::trace_mesh_type trace_trace_mesh_type;\n typedef Exporter<trace_trace_mesh_type> trace_trace_export_type;\n\n //--------------------------------------------------------------------------------------------------//\n\n auto mesh = createGMSHMesh( _mesh=new mesh_type,\n _update=MESH_CHECK|MESH_UPDATE_FACES|MESH_UPDATE_EDGES|MESH_RENUMBER,\n _desc=domain( _name=( boost::format( \"hypercube-%1%\" ) % nDim ).str() ,\n _addmidpoint=false, _usenames=false, _shape=\"hypercube\",\n _dim=nDim, _h=meshSize,\n _xmin=0., _",
"xmax=1.,",
"\n _ymin=0., _",
"ymax=1.,",
"\n _zmin=0., _",
"zmax=1.,",
"\n _substructuring=true ) );\n\n\n auto backend = backend_type::build( soption( _name=\"backend\" ) );\n auto pi = M_PI;\n auto g = sin( pi*( 2*Px()+Py()+1./4 ) )*cos( pi*( Py()-1./4 ) );\n\n auto Xh = space_type::New(_mesh=mesh);\n double domain_measure = integrate( _range=elements( mesh ),_expr=cst( 1. ) )",
".evaluate()( 0,0 );\n std::cout <<\"domain_measure= \" << domain_measure << std::endl;\n\n auto TXh = Xh->trace( markedfaces( mesh,6 ) ) ;\n double trace_measure = integrate( _range=elements( TXh->mesh() ),_expr=cst( 1. ) )",
".evaluate()( 0,0 );\n std::cout <<\"trace_measure= \" << trace_measure << std::endl;\n\n auto TTXh = TXh->trace();\n auto trace_trace_measure = integrate( _range=elements( TTXh->mesh() ),_expr=cst( 1. ) )",
".evaluate()( 0,0 );\n double trace_trace_integrate_g = integrate( _range=elements( TTXh->mesh() ),_expr=g ).evaluate()( 0,0 );\n std::cout <<\"trace_trace_measure= \" << trace_trace_measure << std::endl;\n\n // projections\n auto projection_g = vf::project( _space=Xh, _range=elements( mesh ),_expr=g );\n auto trace_projection_g = vf::project( _space=TXh,_range=elements( TXh->mesh() ),_expr=g );\n auto trace_trace_projection_g = vf::project( _space=TTXh,_range=elements( TTXh->mesh() ),_expr=g );\n\n // extensions\n double trace_trace_integrate = integrate( _range=elements( TTXh->mesh() ),\n _expr=idv( trace_trace_projection_g ) ).evaluate()( 0,0 );\n double ttmean_g = trace_trace_integrate/trace_trace_measure;\n double mean_g = trace_trace_integrate_g/trace_trace_measure;\n std::cout << \"mean_g= \" << mean_g << std::endl;\n std::cout << \"ttmean_g= \" << ttmean_g << std::endl;\n\n\n auto zero_extension = vf::project( _space=TXh,_range=boundaryfaces( TXh->mesh() ),_expr=idv( trace_trace_projection_g ) );\n auto const_extension = vf::project( _space=TXh,_range=boundaryfaces( TXh->mesh() ),_expr=idv( trace_trace_projection_g )-ttmean_g );\n const_extension += vf::project( _space=TXh, _range=elements( TXh->mesh() ), _expr=cst( ttmean_g ) );\n //auto op_lift = opLift( _domainSpace=Xh,_backend=backend );\n auto op_lift = opLift( _domainSpace=Xh,_backend=backend,_penaldir=100. );",
"\n auto glift = op_lift->project( _expr=idv( const_extension ), _range=markedfaces( mesh,6 ) );\n\n double boundary_error = integrate( _range=markedfaces( mesh,6 ), _expr=idv( glift )-idv( const_extension ) ).evaluate()( 0,0 );\n //auto laplacian_error = integrate( elements( mesh ), trace( hessv( glift ) ) ).evaluate()( 0,0 );\n\n auto const_extention_error1 = integrate( _range=boundaryfaces( TXh->mesh() ),\n _expr=idv( trace_trace_projection_g )-idv( const_extension ) ).evaluate()( 0,0 );\n auto const_extention_error2 = integrate( _range=elements( TXh->mesh() ), _expr=ttmean_g-idv( const_extension ) ).evaluate()( 0,0 );\n\n\n\n std::cout << \"boundary_error= \" << boundary_error << std::endl;\n std::cout << \"const_extention_error1= \" << const_extention_error1 << std::endl;\n std::cout << \"const_extention_error2= \" << const_extention_error2 << std::endl;\n\n BOOST_CHECK_SMALL( boundary_error,1e-4 );\n BOOST_CHECK_CLOSE( domain_measure, 1, 1e-10 );\n BOOST_CHECK_CLOSE( trace_measure, 1, 1e-12 );\n BOOST_CHECK_CLOSE( trace_trace_measure, 4, 1e-12 );\n BOOST_CHECK_SMALL( const_extention_error1,1e-10 );\n BOOST_CHECK_SMALL( const_extention_error2,5e-4 );\n\n\n //-------------------------------------------------------------------------------------------------------\n auto mesh3D = createGMSHMesh( _mesh=new mesh_type,\n _update=MESH_CHECK|MESH_UPDATE_FACES|MESH_UPDATE_EDGES|MESH_RENUMBER,\n _desc=domain( _name=(boost::format( \"Hypercube-%1%\" ) % nDim).str() ,\n _addmidpoint=false,\n _usenames=true, _shape=\"hypercube\", _dim=nDim, _h=meshSize,\n _xmin=0., _",
"xmax=1., _",
"ymin=0., _",
"ymax=1., _",
"zmin=0., _",
"zmax=1.,",
"\n _substructuring=true\n ) );\n\n //auto wirebasket = createSubmesh( mesh3D, markededges(mesh3D,\"WireBasket\") );\n auto Xh3D = space_type::New(_mesh=mesh3D);\n auto Wh = Xh3D->wireBasket();\n FEELPP_ASSERT( Wh->mesh()->numElements() !",
"= 0 )( Wh->mesh()->numElements() ).error( \"invalid wirebasket mesh\" );\n\n saveGMSHMesh(_mesh=Wh->mesh(), _filename=\"wirebasket.msh\");\n auto w = Wh->element();\n auto z = Wh->element();\n\n auto M = backend->newMatrix( _test=Wh, _trial=Wh );\n form2( _trial=Wh, _test=Wh, _matrix=M ) = integrate( _range=elements(Wh->mesh()), _expr=idt(w)*id(z) );\n w.setOnes();\n z.setOnes();\n std::cout << \"measure from mass = \" << M->energy( w, w ) << \"\\n\";\n BOOST_CHECK_CLOSE( M->energy( w, w ), 12., ",
"1e-12 );\n\n // test merkerToDof\n const std::string str = \"WireBasket\";\n auto dft = Xh3D->dof()->markerToDof(str);\n std::cout<<\"nDof= \"<< std::distance(dft.first,dft.second) <<\"\\n\";\n FEELPP_ASSERT( std::distance(dft.first,dft.second) !",
"= 0 )( std::distance(dft.first,dft.second) ).error( \"invalid wirebasket nDof\" );\n\n //-------------------------------------------------------------------------------------------------------\n auto myexporter = exporter(_mesh=mesh,_name=\"Export\" );\n myexporter->step( 0 )->add( \"g\", projection_g );\n myexporter->step( 0 )->add( \"glift\", glift );\n myexporter->save();\n\n auto trace_exporter = exporter(_mesh=TXh->mesh() ,_name=\"Trace_Export\" );\n trace_exporter->step( 0 )->add( \"traceg\", trace_projection_g );\n trace_exporter->step( 0 )->add( \"const_extension\", const_extension );\n trace_exporter->save();\n\n auto trace_trace_exporter = exporter(_mesh=TTXh->mesh() ,_name=\"Trace_Trace_Export\" );\n trace_trace_exporter->step( 0 )->add( \"tracetrace_g\", trace_trace_projection_g );\n trace_trace_exporter->save();\n\n} // run\n\n} //namespace test_wire_basket\n\n\n/*_________________________________________________*\n * Main\n *_________________________________________________*/\n\nFEELPP_ENVIRONMENT_NO_OPTIONS\n\nBOOST_AUTO_TEST_SUITE( wire_basket )\n\nBOOST_AUTO_TEST_CASE( wire_basket1 )\n{\n test_wire_basket::run<2>();\n}\nBOOST_AUTO_TEST_SUITE_END()\n"
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[
"European commission says Britain imposes extra test on people from the EU that does not apply to British citizens\n\nThis article is more than 7 years old\n\nThis article is more than 7 years old\n\nBritain is being taken to court by the European commission over allegations that nationals from EU countries are unfairly denied welfare benefits.",
"\n\nThe commission argues that Britain imposes an extra test on migrants from the EU that does not apply to British citizens, in contravention of EU law.",
"\n\nBritain applies its own test on top of the standard EU test to determine if a migrant is eligible for welfare payments. ",
"The commission believes that, as a result, thousands of migrants may have been denied access to benefits, such as child tax credit and jobseeker's allowance.",
"\n\nDetails of the legal action in the European court of justice will be announced on Thursday.",
"\n\nA British official told the BBC he could not comment about court action until the commission made its decision public.",
"\n\nBut the official said the British test was vital to ensure benefits were paid only to people living legally in Britain."
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[
"Influence of surgical complications on graft and patients' survival after a kidney transplantation according to donors' age.",
"\nThe aim of this study was to determine a frequency and a type of early and late surgical complications in kidney transplantation, their impact on renal graft survival among 80 patients, 54 (67.5%) males and 26 (32.5%) females who had undergone a living and cadaveric kidney transplant at the Surgery Center in Tuzla in the period from 15.09.1999 until 31.12.2008. ",
"The subjects were divided into two groups according to donor age, younger and older than 55. ",
"A significantly higher incidence of early rather than late surgical complications was observed in an experimental group (p=0.001, and p=0.77, respectively). ",
"There was a statistically significant difference in the length of graft survival (p=0.004) and the number of deaths (p=0.038). ",
"Older age of kidney graft donor had an impact on the occurrence of early surgical complications and no influence on the occurrence of late surgical complications. ",
"Fatal outcome after kidney transplantation was significantly higher in patients who received grafts of elderly people."
] |
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[
"The present invention relates generally to feedthrough filter capacitor EMI filters. ",
"More particularly, the present invention relates to a hybrid EMI filter substrate and/or flex cable assembly which embodies embedded shielded flat-through/feedthrough filters and/or energy dissipating circuit elements. ",
"This invention is applicable to a wide range of connectors, terminals and/or hermetic seals that support lead wires as they ingress/egress into electronic modules or shielded housings. ",
"In particular, the present invention applies to a wide variety of active implantable medical devices (AIMDs).",
"\nFIGS. ",
"1-40 provide a background for better understanding the significance and novelty of the present invention.",
"\nFIG. ",
"1 illustrates various types of active implantable and external medical devices 100 that are currently in use. ",
"FIG. ",
"1 is a wire formed diagram of a generic human body showing a number of implanted medical devices. ",
"100A represents a family of hearing devices which can include the group of cochlear implants, piezoelectric sound bridge transducers and the like. ",
"100B represents a variety of neurostimulators and brain stimulators. ",
"Neurostimulators are used to stimulate the Vague nerve, for example, to treat epilepsy, obesity and depression.",
"\nBrain stimulators are pacemaker-like devices and include electrodes implanted deep into the brain for sensing the onset of the seizure and also providing electrical stimulation to brain tissue to prevent the seizure from actually occurring. ",
"The lead wires associated with a deep brain stimulator are often placed using real time MRI imaging. ",
"100C shows a cardiac pacemaker which is well-known in the art. ",
"100D includes the family of left ventricular assist devices (LVAD's), and artificial hearts, including the recently introduced artificial heart known as the Abiocor. ",
"100E includes an entire family of drug pumps which can be used for dispensing of insulin, chemotherapy drugs, pain medications and the like. ",
"Insulin pumps are evolving from passive devices to ones that have sensors and closed loop systems. ",
"That is, real time monitoring of blood sugar levels will occur. ",
"These devices tend to be more sensitive to EMI than passive pumps that have no sense circuitry or externally implanted lead wires. ",
"100F includes a variety of bone growth stimulators for rapid healing of fractures. ",
"100G includes urinary incontinence devices. ",
"100H includes the family of pain relief spinal cord stimulators and anti-tremor stimulators. ",
"100H also includes an entire family of other types of neurostimulators used to block pain. ",
"1001 includes a family of implantable cardioverter defibrillator (ICD) devices and also includes the family of congestive heart failure devices (CHF). ",
"This is also known in the art as cardio resynchronization therapy devices, otherwise known as CRT devices. ",
"100J illustrates an externally worn pack. ",
"This pack could be an external insulin pump, an external drug pump, an external neurostimulator or even a ventricular assist device. ",
"100K illustrates the insertion of an external probe or catheter. ",
"These probes can be inserted into the femoral artery, for example, or in any other number of locations in the human body. ",
"100L illustrates one of various types of EKG/ECG external skin electrodes which can be placed at various locations. ",
"100M are external EEG electrodes placed on the head.",
"\nFIG. ",
"2 is a prior art unipolar discoidal feedthrough capacitor, which has an active internal electrode plate set 102 and a ground electrode plate set 104. ",
"The inside diameter termination surface 106 is connected electrically to the active electrode plate set 102. ",
"An outside diameter termination surface 108 is both solderable and electrically conductive, and it is connected to the outside diameter of electrode plate sets 104.",
"\nFIG. ",
"3 is a cross-section of the discoidal feedthrough capacitor of FIG. ",
"2 shown mounted to a hermetic seal 112 of an active implantable medical device (AIMD). ",
"In prior art discoidal feedthrough capacitor devices, the lead wire 114 is continuous. ",
"The hermetic seal 112 is attached to, typically, a titanium housing 116, for example, of a cardiac pacemaker. ",
"An insulator 118, like alumina ceramic or glass, is disposed within a ferrule 120 and forms a hermetic seal against body fluids. ",
"The terminal pin or lead wire 114 extends through the hermetic seal 112, passing through aligned passageways through the insulator 118 and the capacitor 110. ",
"A gold braze 122 forms a hermetic seal joint between the terminal pin 114 and the insulator 118. ",
"Another gold braze 124 forms a hermetic seal joint between the alumina insulator 118 and the titanium ferrule 120. ",
"A laser weld 126 provides a hermetic seal joint between the ferrule 120 and the housing 116. ",
"The feedthrough capacitor 110 is shown surface mounted in accordance with U.S. Pat. ",
"No. ",
"5,333,095, and has an electrical connection 128 between its inside diameter metallization 106 and hence the active electrode plate set 102 and lead wire 114. ",
"There is also an outside diameter electrical connection 130 which connects the capacitor's outside diameter metallization 108 and hence the ground electrodes 104 to the ferrule 120. ",
"Feedthrough capacitors are very efficient high frequency devices that have minimal series inductance. ",
"This allows them to operate as EMI filters over very broad frequency ranges. ",
"Referring once again to FIG. ",
"3, one can see that another way to describe a prior art discoidal feedthrough capacitor 110 is as a three-terminal capacitor. ",
"Three-terminal devices generally act as transmission lines. ",
"Referring to FIG. ",
"3, one can see that there is a current “I” that passes into lead wire 114. ",
"For a prior art AIMD, on the body fluid side there is generally an implanted lead which can undesirably act as an antenna which can pick up energy from environmental emitters. ",
"This energy is known as electromagnetic interference (EMI). ",
"Cell phones, microwave ovens and the like have all been implicated in causing interference with active implantable medical devices. ",
"If this interference enters lead wire 114 at point X (FIG. ",
"3), it is attenuated along its length by the feedthrough capacitor 110. ",
"Upon exiting, the undesirable high frequency EMI has been cleaned off of the normal low frequency (LF) circuit current (such as pacemaker pacing pulses or biologic frequency sensors) so that the high frequency EMI has been significantly attenuated. ",
"Another way of looking at this is as the high frequency energy passes from terminal 1 to terminal 2 (FIGS. ",
"3 and 4), it is diverted through the feedthrough capacitor 110 to the ground terminal which is also known as the third terminal or terminal 3. ",
"The feedthrough capacitor 110 also performs two other important functions: a) its internal electrodes 102 and 104 act as a continuous part of the overall electromagnetic shield housing of the electronic device or module which physically blocks direct entry of high frequency RF energy through the hermetic seal 112 or equivalent opening for lead wire ingress and egress in the otherwise completely shielded housing (such RF energy, if it does penetrate inside the shielded housing can couple to and interfere with sensitive electronic circuitry), and; b) the feedthrough capacitor 110 very effectively shunts undesired high frequency EMI signals off of the lead wires to the overall shield housing where such energy is dissipated in eddy currents resulting in a very small temperature rise.",
"\nFIG. ",
"4 is a schematic diagram showing the discoidal feedthrough capacitor 110 previously described in connection with FIGS. ",
"2 and 3. ",
"As one can see, it is a three-terminal device consistent with terminals 1, 2 and 3 illustrated in FIG. ",
"3.",
"\nFIG. ",
"5 is a quadpolar prior art feedthrough capacitor 132 which is similar in construction to that previously described in FIG. ",
"2 except that it has four through holes.",
"\nThroughout this description, functionally equivalent elements will be given the same reference number, irrespective of the embodiment being shown.",
"\nFIG. ",
"6 is a cross-section showing the internal electrodes 102, 104 of the capacitor 132 of FIG. ",
"5.",
"\nFIG. ",
"7 is a schematic diagram showing the four discrete feedthrough capacitors comprising the quadpolar feedthrough capacitor 132 of FIGS. ",
"5 and 6.",
"\nFIG. ",
"8 is an exploded electrode view showing the inner and outer diameter electrodes of the unipolar feedthrough capacitor 110 of FIGS. ",
"2 and 3. ",
"One can see the active electrode plates set 102 and the ground electrode plate set 104. ",
"Cover layers 134 are put on the top and bottom for added electrical installation and mechanical strength.",
"\nFIG. ",
"9 is an exploded view of the interior electrodes of the prior art quadpolar feedthrough capacitor 132 previously illustrated in FIG. ",
"5. ",
"As shown in FIG. ",
"9, the active electrode plate sets are shown as 102 and the ground electrode plates are shown as 104. ",
"Cover layers 134 serve the same purpose as previously described in connection with FIG. ",
"8.",
"\nFIG. ",
"10 illustrates a prior art quadpolar feedthrough capacitor 132 mounted on top of a hermetic insulator 118 wherein a wire bond substrate 136 is attached to the top as shown. ",
"Wire bond pads 138, 138′, 138″, and 138′″ and 140 are shown for convenient connection to the internal circuitry of the AIMD. ",
"This is more thoroughly described in FIGS. ",
"75 and 76 of U.S. Pat. ",
"Nos. ",
"7,038,900 and 7,310,216, the contents of which are incorporated herein.",
"\nFIG. ",
"11 is a cross-section taken generally from section 11-11 from FIG. ",
"10. ",
"In FIG. ",
"11, the internal circuit traces T.sub.1 through T.sub.4 to the wire bond pads 138-138′″ are shown. ",
"Referring back to FIG. ",
"10, there is an additional wire bond pad 140 shown on the left side of the wire bond substrate 136. ",
"This is also shown in FIG. ",
"11. ",
"This is a ground connection to the outside diameter of the hermetic seal ferrule 120 and provides a convenient connection point for electronic circuits and the like that need a ground attachment point on the inside of the AIMD.",
"\nFIG. ",
"12 is a schematic diagram of the prior art wire bond pad quadpolar hermetic feedthrough 132 of FIG. ",
"10.",
"\nFIG. ",
"13 is a prior art monolithic ceramic capacitor (MLCC) 142. ",
"These are made by the hundreds of millions per day to service the consumer electronics and other markets. ",
"Virtually all cell phones and other types of electronic devices have many of these. ",
"In FIG. ",
"13, one can see that the MLCC 142 has a body 144 generally consisting of a high dielectric constant ceramic such as barium titanate. ",
"It also has solderable termination surfaces 146 and 148 at either end. ",
"These termination surfaces 146 and 148 provide a convenient way to make a connection to the internal electrode plates of the MLCC capacitor 142. ",
"FIG. ",
"13 can also take the shape and characteristics of a number of other types of capacitor technologies, including rectangular, cylindrical, round, tantalum, aluminum electrolytic, stacked film or any other type of capacitor technology.",
"\nFIG. ",
"14 is a sectional view taken from section 14-14 in FIG. ",
"13. ",
"The left hand electrode plate set is shown as 150 and the right hand electrode plate set is shown as 152. ",
"One can see that the left hand electrode plates 150 are electrically connected to the external metallization surface 146. ",
"The opposite electrode plate set (or right hand plate set) 152 is shown connected to the external metallization surface 148. ",
"One can see that prior art MLCC and equivalent chip capacitors are also known as two-terminal capacitors. ",
"That is, there are only two ways electrical energy can connect to the body of the capacitor. ",
"In FIGS. ",
"13 and 14, the first terminal “1” is on the left side and the second terminal “2” is on the right side.",
"\nFIG. ",
"15 is an ideal schematic diagram of the prior art MLCC capacitor 142 of FIG. ",
"13.",
"\nFIG. ",
"16 is a more realistic schematic diagram showing the fact that the MLCC 142 structure as illustrated in FIG. ",
"13 has series inductance L. This inductive property arises from the fact that it is a two-terminal device and does not act as a transmission line. ",
"That is, its lead wires and associated internal electrodes all tend to add series inductance to the capacitor. ",
"It is well known to electrical engineers that MLCC capacitors will self-resonate at a particular frequency. ",
"FIG. ",
"17 gives the formula for this resonant frequency. ",
"There is always a point at which the capacitive reactance as shown in FIG. ",
"16 is equal and opposite to the inductive reactance. ",
"It is this point that these two imaginary components cancel each other out. ",
"If it weren't for resistive losses, at the resonant frequency the impedance between 146,1 and 148,2 as shown in FIG. ",
"16 would go to zero. ",
"However, the resistive losses of the inductor L and the equivalent series resistance of the capacitor C prevent this from happening. ",
"This is better understood by referring to FIG. ",
"18.",
"\nShown in FIG. ",
"18 are three curves. ",
"An ideal capacitor curve is shown which is very similar to the response of a feedthrough capacitor, such as shown in FIG. ",
"3. ",
"One can see that the attenuation goes up fairly linearly with frequency all the way up to very high frequencies even above 10,000 megahertz (MHz). ",
"The MLCC curve is for the capacitor of FIG. ",
"13. ",
"At low frequencies, in this case below 100 MHz, the MLCC curve tracks very closely to an ideal or a feedthrough capacitor. ",
"However, as the MLCC nears its self-resonant frequency (SRF), its attenuation tends to go up dramatically. ",
"This is because when one refers back to FIG. ",
"16, the inductive and capacitive reactance elements are tending to cancel each other out. ",
"As previously mentioned, if it weren't for its resistive losses at resonance (SRF), the MLCC chip would look like a short circuit, in which ideal case its attenuation would be infinite. ",
"This means that if it weren't for these resistive losses, we would have infinite attenuation at the SRF. ",
"Instead what we have is a peak of approximately 60 dB as shown. ",
"Above resonance, the MLCC capacitor becomes increasingly inductive and the attenuation drops dramatically. ",
"This is an undesirable effect and this is why feedthrough capacitors have generally been the preferred choice for use in EMI broadband filters.",
"\nFIG. ",
"19 shows three different size MLCC capacitors C.sub.1-C.sub.3 connected around a unipolar feedthrough pin or lead wire 114. ",
"Self-resonant frequency is dependent upon the internal inductance of a capacitor. ",
"This was illustrated and described in connection with FIG. ",
"16. ",
"One can reduce the amount of inductance by using a physically smaller MLCC capacitor. ",
"For example, referring to FIG. ",
"19, one could have one each of what is known in the art as a size 0402, a 0603 and a 0805 MLCC capacitor. ",
"This is an EIA designation wherein, for example, 0805 would be 0.080 inches long and 0.050 inches wide. ",
"Accordingly, these three MLCC capacitors C.sub.1-C.sub.3 would have three different resonant frequencies. ",
"This is more thoroughly described in U.S. Pat. ",
"No. ",
"5,973,907 and U.S. Pat. ",
"No. ",
"5,959,336 the contents of which are incorporated herein by reference. ",
"FIG. ",
"20 is the schematic diagram for the three MLCC capacitors of FIG. ",
"19.",
"\nFIG. ",
"21 shows the attenuation response for the three chip capacitor unipolar hermetic terminal in FIG. ",
"19. ",
"These three capacitors C.sub.1-C.sub.3 are acting in parallel as shown in the schematic diagram of FIG. ",
"20. ",
"Referring to FIG. ",
"21, we can see that there are now three resonant peaks representing the self-resonant frequency of each of these individual MLCC capacitors acting together in parallel. ",
"Shown for reference is the ideal capacitor response curve previously shown in FIG. ",
"18. ",
"The SRF for C.sub.1, C.sub.2 and C.sub.3 are also shown. ",
"The physically largest capacitor C.sub.1 will have the lowest self-resonant frequency whereas the physically smaller capacitor (C.sub.3) will have the highest self-resonant frequency. ",
"This is because, in general, the smaller the MLCC capacitor, the lower its internal inductance. ",
"Secondary factors that determine the value of the undesirable equivalent series inductance (ESL) of an MLCC capacitor include the number and spacing of internal electrodes, geometry, form factor and circuit board mounting techniques.",
"\nReferring once again to FIG. ",
"19, the reason why this approach has never been commonly practiced in the AIMD market is the fact that this is a complicated design and is also costly. ",
"Because of the space limitations and reliability implications, packing this many components into such a small place becomes impractical.",
"\nFIG. ",
"22 shows a different method of mounting MLCC capacitors, for example, those previously shown in FIG. ",
"19. ",
"In the industry, this is known as the tombstone mounting position, which is a highly undesirable thing to do when the capacitor is to be used as an EMI filter or an RF decoupling device (bad mounting and bad form factor). ",
"This is because the capacitor's inductive loop area L.sub.1 tends to increase. ",
"The increased inductive loop area (integral of area bounded under the loop) has the effect of directly raising the inductance L as previously described in connection with FIG. ",
"16. ",
"The reason this is undesirable is this particular capacitor will tend to self-resonate at a much lower frequency (and thereby becomes a less effective high frequency device or EMI filter).",
"\nFIG. ",
"23 illustrates a more desirable way to mount the MLCC capacitor 142 of FIG. ",
"22. ",
"This is a conventional flat surface mount technique, which has a much lower inductive loop area L.sub.2 as shown (area bounded under the loop). ",
"Accordingly, even though the two capacitors are identical in size and capacitance value, the MLCC capacitor 142 as shown in FIG. ",
"23 will resonate at a much higher frequency before it starts to become undesirably inductive.",
"\nFIG. ",
"24 is known in the art as a reverse geometry MLCC capacitor 142′. For comparative purposes, the physical size of the MLCC capacitor illustrated in FIG. ",
"24 is exactly the same dimensions as the MLCC capacitors 142 previously shown in FIGS. ",
"22 and 23. ",
"The important thing is the location of the termination surfaces 146′ and 148′. The MLCC capacitor 142′ in FIG. ",
"24 has been terminated along its long sides. ",
"Accordingly, its inductive loop area or the area bounded underneath the loop L.sub.3 is the smallest of all the loop configurations. ",
"Thus, the capacitor 142′ of FIG. ",
"24 will self-resonate at a much higher frequency as compared to the MLCC capacitors 142 shown in FIGS. ",
"22 and 23. ",
"A good treatment of this is found in a technical paper entitled, A CAPACITOR'S INDUCTANCE, which was given at the Capacitor and Resistor Technology Symposium in Lisbon, Portugal, Oct. 19-22, 1999. ",
"This paper was co-authored by Robert Stevenson and Dr. Gary Ewell of Aerospace Corporation. ",
"A related paper was given entitled, A CAPACITOR'S INDUCTANCE: CRITICAL PROPERTY FOR CERTAIN APPLICATIONS and was given by the same authors at the 49.sup.th Electronic and Components Technology Conference of the Institute of Electrical and Electronic Engineers held Jun. 1-4, 1999 in San Diego, Calif.\nFIG. ",
"25 is the same electrical schematic diagram as previously illustrated in FIG. ",
"16, but additionally showing the equivalent circuit model for an MLCC. ",
"Added are resistors IR and ESR. ",
"IR is the insulation resistance of the capacitor C. For electronic circuit analysis reasons, this IR resistor can generally be ignored. ",
"The reason for this is that it is typical that the value of IR is in excess of 10 Gigaohms (10,000,000,000 ohms). ",
"This number is so high compared to the values of the other components of the capacitor circuit model that it can be safely ignored. ",
"Also added to the complete schematic model shown in FIG. ",
"25 is the capacitor series resistance (ESR). ",
"This is the total ESR including the dielectric loss tangent of the ceramic materials themselves and all ohmic losses and other electrical connections within and external to the capacitor itself. ",
"As previously stated, the presence of resistor ESR is why at the self-resonant frequency, the insertion loss does not go to infinity.",
"\nFIG. ",
"26 is a prior art chip transient suppression diode 154, such as a transorb or the like.",
"\nFIG. ",
"27 is a schematic diagram showing the diode chip 154 of FIG. ",
"26 connected between an active medical device lead wire 114 and circuit ground. ",
"The dashed line shown in FIG. ",
"27 illustrates the shielded housing of the AIMD. ",
"The reason for diode chip 154 (or multiple diode arrays) is to help protect the sensitive electronic circuits of the AIMD from external high voltage insults. ",
"These could be electrostatic discharges or the application to the patient of automatic (high voltage) external defibrillation (AED). ",
"AEDs are commonly now found in government buildings, airports, airplanes and the like. ",
"It is very important that a pacemaker not be burned out during the application of an AED external defibrillation event. ",
"The diode chip 154 shown in FIGS. ",
"26 and 27 basically is typically an avalanche type diode which is also known in the art as a zener diode. ",
"In other words, they do not forward bias or short out until a certain voltage threshold is reached. ",
"These are also known in the art as transorbs and also have other market names. ",
"Such diodes can be back to back and placed in parallel in order to suppress biphasic high voltage AED defibrillation pulses.",
"\nFIG. ",
"28 is a prior art inductor chip 156. ",
"There are many manufacturers of these. ",
"These can either have ferrite elements or be non-ferromagnetic. ",
"They come in a variety of sizes, inductance values and voltage ratings.",
"\nFIG. ",
"29 is a schematic diagram of the inductor chip 156 of FIG. ",
"28.",
"\nReferring to FIG. ",
"30, one can see that an inductor circuit trace 158 is printed or deposited right on top of a prior art MLCC capacitor 142 to form an MLCC-T 160. ",
"The advantage here is that low cost MLCC's which have been produced from very high volume commercial capacitor operations could be utilized and the inductor trace 158 could be printed on as a supplemental operation. ",
"This forms a parallel inductor (L)-capacitor (C) resonant L-C circuit which creates a very high impedance at its resonant frequency. ",
"This is effective for suppressing a single RF frequency, such as that from Magnetic Resonance Imaging (MRI) equipment, or the like. ",
"This is more thoroughly described in U.S. Patent Application Publication No. ",
"US 2007-0112398 A1, the contents of which are incorporated herein by reference.",
"\nFIG. ",
"31 shows yet another way to deposit an inductor shape 158 onto a separate substrate 162 to form a parallel L-C resonant circuit. ",
"For example, the substrate 162 could be of alumina ceramic or other suitable circuit board material. ",
"This could then be bonded with a thin adhesive layer 164 to a prior art MLCC capacitor 142. ",
"The composite MLCC-T structure 160′, including corresponding metallization surfaces 146 and 148 on opposite ends, is illustrated in the electrical schematic diagram of FIG. ",
"34 where it is evident that the structure forms a parallel L and C “tank” or bandstop circuit\nFIG. ",
"32 is an isometric view of a novel composite monolithic ceramic capacitor-parallel resonant tank (MLCC-T) 160″ which forms a bandstop or tank filter 166 in accordance with previously referenced U.S. patent application Ser. ",
"No. ",
"11/558,349. ",
"Viewed externally, one can see no difference between the MLCC-T 160″ of the present invention and prior art MLCC capacitor 142 as shown in FIG. ",
"13. ",
"However, the novel MLCC-T 160″ has an embedded inductor 162 which is connected in parallel across the capacitor between its opposite termination surfaces 146 and 148.",
"\nFIG. ",
"33 illustrates an exploded view of the various layers of the novel MLCC-T tank filter 160″ shown in FIG. ",
"32. ",
"The novel MLCC tank (MLCC-T) 160″ includes an embedded inductor 162. ",
"At low frequencies, the embedded inductor 162 shorts out the capacitor from one end to the other. ",
"However, at high frequency, this forms a parallel tank circuit 166 which is again better understood by referring to the schematic diagram in FIG. ",
"34. ",
"Referring once again to FIG. ",
"33, one can see that as the capacitor stacks up from the top, we have an area of blank cover sheets 168 followed by one or more embedded inductor layers 162. ",
"These inductor traces can have a variety of shapes as further illustrated in FIG. ",
"83 of U.S. Patent Application Publication No. ",
"US 2007-0112398 A1. ",
"It will be obvious to those skilled in the art that there are a variety of optional shapes that could also be used. ",
"Then there are a number of other blank interleafs 170 before one gets to the capacitor electrode plate sets, 150 and 152. ",
"One can see the capacitor electrode plate set 150 which connects to the left hand termination 146 and one can also see the capacitor electrode plate set 152 which connects to the right hand termination 148. ",
"In FIG. ",
"33, only single electrodes are shown as 150, 152. ",
"However, it will be obvious to those skilled in the art that any number of plates “n” could be stacked up to form the capacitance value that is desired. ",
"Then bottom blank cover sheets 168 are added to provide insulative and mechanical strength to the overall TANK filter MLCC-T 160″.\nAfter sintering the composite structure at high temperature, the last step, referring back to FIG. ",
"32, is the application of the solderable termination surfaces 146 and 148. ",
"These termination surfaces can be a thick film ink, such as palladium silver, glass frit, gold plating, or the like and applied in many processes that are known in the art. ",
"Once again, the overall MLCC-T 160″, which is illustrated in FIG. ",
"32, looks identical to a prior art MLCC 142 as shown in FIG. ",
"13. ",
"However, embedded within it is a novel parallel inductor structure 162 creating a novel parallel tank or bandstop filter 166 shown in the schematic diagram of FIG. ",
"34.",
"\nReferring to schematic drawing FIG. ",
"34, one can see that the inductor L has been placed in parallel with the capacitor C which is all conveniently located within the monolithic structure MLCC-T 160″ shown in FIG. ",
"32.",
"\nIn FIG. ",
"35 only one pole of a quadpolar feedthrough capacitor 132 is shown, which is better understood by referring to its schematic diagram shown in FIG. ",
"36. ",
"One can see that there is a feedthrough capacitor 132 which is also known as a broadband EMI filter shown as C1, C2, C3 and C4 in FIG. ",
"36. ",
"In line with each one of these circuits is a parallel resonant bandstop filter MLCC-T 160 to block MRI pulsed RF frequencies or frequencies from similar powerful emitters. ",
"The function of these bandstop filters is better understood by referring to the complete description in U.S. Pat. ",
"No. ",
"7,363,090, the contents of which are incorporated herein.",
"\nReferring once again to FIG. ",
"35, one can see that there is a metallic ferrule 120 which is attached to a hermetic insulator 118 by means of gold braze 124. ",
"There are also two lead wires 114 and 114′ as shown. ",
"Lead wire 114 is mechanically and hermetically attached to insulator 118 by means of gold braze material 122. ",
"The bandstop filter or tank filter MLCC-T 160 is held in place with an insulative spacer plate 172. ",
"The feedthrough capacitor 132 is mounted on top as shown. ",
"Lead wire 114′ is attached to the other end of the tank filter MLCC-T 160. ",
"A capacitor outside diameter metallization 108 connects to the capacitor's internal ground electrodes 104. ",
"Electrical connection 126 is made between the capacitor's outside diameter metallization 108 and both the metal of the ferrule 120 and gold braze material 124.",
"\nFIG. ",
"37 is a different type of prior art MLCC feedthrough capacitor 142 that is built into a special configuration. ",
"It is known in the art by some as a flat-through capacitor (it also has other trade names). ",
"It will be referred to herein as a flat-through capacitor 174. ",
"At low frequencies, the flat-through capacitor 174 exhibits ideal capacitance behavior versus frequency. ",
"That is, its attenuation curve versus frequency is nearly ideal. ",
"This is because it is truly a three-terminal device which acts as a transmission line in a manner similar to those of prior art discoidal feedthrough capacitors 110. ",
"This is better understood by referring to its internal electrode plate geometry as shown in FIG. ",
"38. ",
"Shown is a through or active electrode plate 175 that is sandwiched between two ground electrode plates 178 and 178′. The through or active electrode plate 175 is connected at both ends by termination surfaces 180 and 182. ",
"When the capacitor is mounted between circuit trace lands 184 and 186 as shown in FIG. ",
"37, this connects the circuit trace together between points 184 and 186. ",
"Referring to the active circuit trace 175 in FIG. ",
"38, one can see that there is a current i1 that enters. ",
"If this is a high frequency EMI current, it will be attenuated along its length by the capacitance of the flat-through capacitor and emerge as a much smaller in amplitude EMI signal at terminal 2 as i1. ",
"Similar to discoidal feedthrough capacitors, the flat-through capacitor 174 is also a three-terminal capacitor as illustrated in FIG. ",
"37. ",
"The point of current input i1 is terminal 1, the point of circuit current egress i1 is known as terminal 2 and ground is known as terminal 3. ",
"In other words, any RF currents that are flowing down the circuit trace must pass through the electrodes 175 of the capacitor 174. ",
"This means that any RF signals are exposed for the full length of the electrode plate 175 between the ground electrodes 178 and the capacitance that is formed between them. ",
"This has the effect of making a very novel shape for a three-terminal feedthrough capacitor. ",
"One negative to this type of capacitor 174 is that it is not conveniently mountable in such a way that it becomes an integral part of an overall shield. ",
"There is always a frequency at which undesirable RF coupling 188 across the device will occur. ",
"This usually does not happen until 100 MHz or above. ",
"At very high frequencies, such as above 1 GHz, this problem becomes quite serious. ",
"Another negative, as compared to prior art discoidal feedthrough capacitors 110 (where the circuit current passes through a robust lead in a feedthrough hole), is that the flat-through capacitor circuit currents must flow through the electrodes of the flat-through capacitor itself (in prior art discoidal/feedthrough capacitors, the only current that flows in the electrodes is high frequency EMI currents). ",
"Monolithic ceramic manufacturing limitations on electrode thickness and conductivity means that prior art flat-through capacitors 174 have relatively high series resistance and can only be rated to a few hundred milliamps or a few amps at best (however, an implantable defibrillator must deliver a high voltage pulse of over 20-amps). ",
"Prior art MLCC and flat-through electrodes must be kept relatively thin to promote ceramic grain growth through the electrodes in order to keep the capacitor layers from delaminating during manufacturing or worse yet, during subsequent mechanical or thermal shocks which can cause latent failures.",
"\nFIG. ",
"39 is the schematic diagram of the prior art flat-through capacitor 174 as illustrated in FIG. ",
"37. ",
"Note that its schematic diagram is the same as that for the feedthrough capacitor 110 shown in FIGS. ",
"2 and 3. ",
"The difference is that feedthrough capacitors are inherently configured to be mounted as an integral part of an overall shield which precludes the problem of RF coupling (see FIGS. ",
"5-7).",
"\nFIG. ",
"40 illustrates the attenuation versus frequency response curve which is shown generically for the flat-through capacitor of FIG. ",
"37. ",
"If it weren't for cross-coupling of RF energy, it would perform as an ideal or nearly perfect capacitor would. ",
"However, because of this cross-coupling, there is always going to be a certain frequency at which the attenuation starts to parasitically drop off as shown. ",
"This drop off is very undesirable in active implantable medical device (AIMD) applications in that there would be less protection against high frequency EMI emitters such as cellular phones and the like. ",
"This parasitic drop off in attenuation due to cross-coupling is even a worse problem in military and space applications where EMI filter attenuation requirements of up to 10 or even 18 GHz, is important (implantable medical applications don't generally require filtering much above 3 GHz due to the effective reflection and absorption of human skin of RF energy at frequencies above 3 GHz). ",
"Space and military circuits have to operate in the presence of extremely high frequency emitters, such as GHz radars and the like. ",
"Accordingly, there is a need for a flat-through type of capacitor that eliminates the problems associated with this parasitic attenuation degradation due to RF cross-coupling across (or outside of around) the capacitor. ",
"In addition, there is also a need for flat-through capacitors that can handle much higher circuits through their “through” electrodes. ",
"The present invention fulfills these needs and provides other related advantages."
] |
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[
"Q:\n\nGet data synchronously when cached or get it async when unavailable\n\nI have an AngularJS app that uses routing and views. ",
"When a particular view is loaded and controller instantiates I have to prepare some $scope model data. ",
"This data can be provided by a dependent service or when service doesn't have it, I make an async call to get it from the server.",
"\nWhen I finally do have this data I have to change it a bit and then put it on my $scope.",
"\nThis I think perfectly falls into deferred/promise API. ",
"Getting data from the service is done using $resource service instance and is a promise already. ",
"The only problem I'm having is converting my synchronous code to a deferred/promise pattern.",
"\nQuestion\nHow can I change my synchronous code processing to become async so my function that provides data always returns a promise which would be immediately resolved when using sync code and after a while when asynchronously calling my server?",
"\nSo process:\n\ntry getting data synchronously\nif sync failed, get it async\nsuccess/fail\n\ndata available => manipulate it\ndata unavailable (either way) => reset state\n\nWhat I tried\nvar getData = function() {\n var defer = $q.defer();\n\n defer.promise\n .then(function () {\n // return cached item\n return dataCacheService.get(\"dataKey\");\n })\n .then(function(data) {\n // cache returned data?",
"\n if (!",
"data)\n {\n // no? ",
"get it from server returning a promise\n return dataResource.get({\n set: \"models\",\n id: $routeParams.id\n });\n }\n })\n .then(function (data) {\n // server returned data?",
"\n if (!!",
"data) // <= PROBLEM!!! ",
"This is not null, but is a Resource with unresolved promise?",
"\n {\n // yes? ",
"fine. ",
"manipulate it\n delete data.details;\n delete data.type.description;\n\n $scope.lists.set(data.type);\n\n return data;\n }\n // no data. ",
"sorry...\n $scope.resetType();\n })\n // something went wrong\n .catch($scope.resetType);\n\n // initiate deferred execution\n defer.resolve();\n\n return defer.promise;\n}\n\n...\n\n$scope.model = {\n item: getData()\n};\n\nA:\n\nYou can make your service such that it always returns a promise, if the data is available it will return the promise immediately otherwise after a REST call. ",
"For example your service might look like:\nvar dataThatMayOrMayNotBeAvailable=null;\n\nvar getDataThatMayOrMayNotBeAvailable=function(){\n var deferred = $q.defer();\n if(dataThatMayOrMayNotBeAvailable){\n deferred.resolve(dataThatMayOrMayNotBeAvailable);\n }else{\n $http({...}).success(function(data){\n dataThatMayOrMayNotBeAvailable=data;\n deferred.resolve(data);\n });\n }\n\nreturn deferred.promise;\n\n}\n\nUsage:\ngetDataThatMayOrMayNotBeAvailable().then(function(data){\n console.log(data);\n})\n\n"
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"\n26 So.3d 505 (2008)\nAMY LEE MILES\nv.\nSTATE.",
"\nNo. ",
"CR-06-1318.",
"\nCourt of Criminal Appeals of Alabama.",
"\nJune 20, 2008.",
"\nDecision of the Alabama Court of Criminal Appeals Without Published Opinion Affirmed.",
"\n"
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"Line of succession to the former Albanian throne\n\nThe line of succession to the former Albanian throne is an ordered list of those eligible to succeed to the headship of the Royal House of Albania, grand mastership of the dynastic orders and ascend the throne of Albania in the event the monarchy is restored. ",
"The native monarchy of Albania was deposed in 1939. ",
"The current head of the royal house is Leka (II), Prince of the Albanians.",
"\n\nHouse of Wied\nThe first modern Albanian monarchy, the Principality of Albania was established on 21 February 1914. ",
"The German prince William of Wied was selected by the Great Powers to rule the newly independent country.",
"\n\nPrince William left Albania on 3 September 1914 due to serious unrest in the country. ",
"Prince William never renounced his claim to the throne and was succeeded upon his death in 1945 by his only son Carol Victor, Hereditary Prince of Albania. ",
"With the childless death of the Hereditary Prince in 1973 the Wied claim to the Albanian throne is unclear.",
"\n\nCurrent situation \n:\n\n Hermann, 4th Prince of Wied (1814-1864)\n Elisabeth of Wied, Queen of Romania (1843-1916)\n William, 5th Prince of Wied (1845–1907)\n William Frederick, 6th Prince of Wied (1872-1945)\n Hermann, Hereditary Prince of Wied (1899-1941)\n Friedrich Wilhelm, 7th Prince of Wied (1931-2000)\n Prince Alexander (b 1960), renounced rights, unmarried\n Carl, 8th Prince of Wied (1961-2015)\n Maximilian, 9th Prince of Wied (b 1999)\n Prince Friedrich Wilhelm (b 2001)\n Prince Wolff-Heinrich (b 1979)\n Prince Metfried Alexander (b 1935)\n Prince Friedrich Christian (b 1968)\n Prince Ferdinand Constantin (b 2003)\n Prince Friedrich Conrad (b 2006)\n Prince Friedrich Carl (b 2007)\n Prince Friedrich Christian (b 2010)\n Prince Magnus Alexander (b 1972)\n Prince Dietrich (1901-1976)\n Prince Maximilian (1929-2008)\n Prince Ulrich (1931-2010)\n Prince Ulrich (b 1970)\n Prince Wilhelm (b 2001)\n Prince Georg (b 2004)\n Prince Philipp (b 2010)\n Prince Wilhelm (1936-1937)\n Prince Ludwig-Eugen (1938-2001)\n Prince Edzard (b 1968)\n William, Prince of Albania as: Vidi I or Scanderbeg II (1876-1945)\n Carol Victor, Hereditary Prince of Albania (Skënder) (1913-1973)\n\nHouse of Zogu\n\nThe second Albanian monarchy was established on 1 September 1928 when President Ahmet Zogu was proclaimed King of the Albanians. ",
"He reigned until 1939 when he was forced to flee the country following an invasion by Mussolini's Italy.",
"\n\nWith the death in exile of King Zog in 1961 he was succeeded as claimant to the throne and head of the House of Zogu by his only son Leka, Crown Prince of Albania, who was proclaimed King of the Albanians by the Albanian National Assembly in exile. ",
"King Leka remained head of the house and claimant to the throne until his death in 2011 when he was succeeded by his only son, Leka II.",
"\n\nZogu law of succession\nThe following articles of the Albanian kingdom's constitution of 1928 set out the succession to the throne:\n\nArticle 51. ",
"The Heir to the Throne shall be the King's eldest son and the succession shall continue generation after generation in the direct male line.",
"\nArticle 52. ",
"Should the Heir die or lose his rights to the Throne, his eldest son shall succeed. ",
"Should the Heir to the Throne die or lose his rights and leave no son, the succession shall pass to the brother coming after him.",
"\nArticle 53. ",
"Should there be no Heir to the Throne under articles 51 and 52, the King shall select his successor from among the male members of his family, but the King's selection shall be with the consent of Parliament. ",
"Should the King not use his prerogative, and the succession remain vacant, Parliament shall then select a male member of the King's family as successor to the Throne. ",
"In case no heirs exist in the King's family, or such as may exist are held incapable by a special parliamentary decision taken by a two-thirds majority of the members of the House, Parliament shall select a successor from the line of the King's daughters or sisters, but such successor must be of Albanian origin. ",
"When there are no males in the families above mentioned, Parliament shall select a successor of Albanian origin. ",
"Should the Throne remain vacant, the Council of Ministers shall exercise the Royal powers until the question of the successor is settled.",
"\n\nUpon the establishment of the monarchy as King Zog had no son, in accordance with the constitution he appointed his nephew Tati Esad Murad Kryeziu as heir to the throne. ",
"Prince Tati was displaced in 1939 by the birth of Leka, Crown Prince of Albania, the only son of King Zog.",
"\n\nSituation \n\nCrown Prince Leka II, the only living descendant of King Zog I and the head of the royal house , has no sons. ",
"The current heir presumptive to Prince Leka is Skënder Zogu, his first-cousin once removed. ",
"After him the following currently living male members of the Zogu family could also become heirs:\n\n Xhemal Pasha Zogu (1860–1911)\n Prince Xhelal Bey Zogu (1881–1944)\n (1) Skënder Zogu (b. 1933)\n (2) Mirgin Zogu (b. 1937)\n (3) Alexandre Zogu (b. 1963)\n (4) Michel Zogu (b. 1966)\n King Zog I (1895–1961)\n King Leka I (1939–2011)\n Crown Prince Leka II (born 1982)\n\nReferences \n\nAlbanian\nCategory:Albanian royalty\nCategory:Monarchism in Albania"
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"Copies by Vincent van Gogh\n\nCopies by Vincent van Gogh form an important group of paintings executed by Vincent van Gogh between 1887 and early 1890. ",
"While at Saint-Paul asylum in Saint-Rémy-de-Provence, France, where Van Gogh admitted himself, he strived to have subjects during the cold winter months. ",
" Seeking to be reinvigorated artistically, Van Gogh did more than 30 copies of works by some of his favorite artists. ",
" About twenty-one of the works were copies after, or inspired by, Jean-François Millet. ",
" Rather than replicate, Van Gogh sought to translate the subjects and composition through his perspective, color, and technique. ",
" Spiritual meaning and emotional comfort were expressed through symbolism and color. ",
" His brother Theo van Gogh would call the pieces in the series some of his best work.",
"\n\nBackground\nDuring the winter months at Saint-Remy Van Gogh had a shortage of subjects for his work. ",
" Residing at Saint-Paul asylum, he did not have the freedom he enjoyed in the past, the weather was too cold to work outdoors and he did not have access to models for paintings. ",
"Van Gogh took up copying some of his favorite works of others, which became the primary source of his work during the winter months.",
"The Pietà (after Delacroix) marks the start of a series of paintings that Van Gogh made after artists such as Jean-François Millet, Honoré Daumier and Rembrandt. ",
"Millet's work, who greatly influenced Van Gogh, figures prominently in this series. ",
" He wrote to Theo about these copies: \"I started making them inadvertently and now find that I can learn from them and that they give me a kind of comfort. ",
"My brush then moves through my fingers like a bow over the strings of a violin – completely for my pleasure.\"",
"\n\nSeveral religious works, such as The Pietà, were included in the series, notable exceptions in his oeuvre. ",
"Saint-Paul asylum, housed in an old monastery, may have provided some of the inspiration for the specific subject. ",
" The nuns devoutness sometimes annoyed him, but he did find solace in religion. ",
" He wrote: \"I am not indifferent, and pious thoughts often console me in my suffering.\"",
"\n\nVan Gogh Museum asserts that Van Gogh may have identified with Christ \"who had also suffered and been misunderstood.\" ",
"They also offer the conjecture of some scholars of a resemblance between the Van Gogh and the red-bearded Christ in The Pietà and Lazarus in the copy after Rembrandt. ",
"However it is unknown whether or not this was Van Gogh's intention.",
"\n\nCopy after Émile Bernard\nÉmile Bernard, an artist and Catholic mystic, was a close personal friend to Van Gogh. ",
"Bernard influenced Van Gogh artistically several ways. ",
"Bernard outlined figures in black, replicating the look of religious woodcut images of the Middle Ages. ",
" This resulted in a flattened, more primitive work. ",
"Van Gogh's Crows over the Wheatfield is one example of how Bernard's simplified form influenced his work. ",
"Bernard also taught Van Gogh about how to manipulate perspective in his work. ",
" Just as Van Gogh used color to express emotion, he used distortion of perspective as a means of artistic expression and a vehicle to \"modernize\" his work.",
"\n\nAs a demonstration of the sharing of artistic viewpoints, Van Gogh painted a copy in watercolor of a sketch made by Bernard of Breton woman. ",
"Van Gogh wrote to Bernard of a utopian ideal where artists worked cooperatively, focused on a common idea, to reach heights artistically \"beyond the power of the isolated individual.\" ",
"As a means of clarification, he stated that did not mean that several painters would work on the same picture, but they will each create a work that \"nonetheless belong together and complement each other.\" ",
" The Breton Women is one of many examples of how Van Gogh and one of his friend's brought their unique temperaments and skills to a single idea.",
"\n\nVan Gogh wrote to Bernard his trade of the Breton Women to Paul Gauguin: \"Let me make it perfectly clear that I was looking forward to seeing the sort of things that are in that painting of yours which Gauguin has, those Breton women walking in a meadow so beautifully composed, the colour with such naive distinction.\" ",
" Gauguin made a work, Breton Women at a Pardon which was may have been inspired by Bernard's work of Breton women.",
"\n\nCopy after Virginie Demont Breton\nVan Gogh painted a work of the engraving Man at Sea made by Virginie Demont-Breton, daughter of Jules Breton. ",
" Her engraving was exhibited at the Salon of 1889. ",
"The picture depicts, almost entirely in shades of violet, a peaceful scene of a mother sitting by a fire with her baby on her lap.",
"\n\nCopy after Honoré Daumier\nIn 1882 Van Gogh had remarked that he found Honoré Daumier's The Four Ages of a Drinker both beautiful and soulful.",
"\n\nVan Gogh wrote to his brother Theo of Daumier's artistic perspective and humanity: \"What impressed me so much at the time was something so stout and manly in Daumier's conception, something that made me think It must be good to think and to feel like that and to overlook or ignore a multitude of things and to concentrate on what makes us sit up and think and what touches us as human beings more directly and personally than meadows or clouds.\" ",
"Daumier's artistic talents included painting, sculpting and creating lithographs. ",
" He was well known for his social and political commentary.",
"\n\nVan Gogh made Men Drinking after Daumier's work in Saint-Remy about February 1890.",
"\n\nCopies after Eugène Delacroix\n\nBackground\nVan Gogh, motivated by the book The Imitation of Christ which included depiction of Christ as a suffering servant, worked on reprises of Eugène Delacroix's Pieta and Good Samaritan. ",
"Rather than representing \"a triumphant Christ in glory,\" he depicted Christ in his most perilous and painful period, his crucifixion and death. ",
"Of capturing the scenes of his religious work from long ago, Van Gogh described Delacroix's perspective of how to paint the historical religious figures: \"Eug. ",
"Delacroix, when he did a Gethsemane, had been beforehand to see what an olive grove was like on the spot, and the same for the sea whipped up by a strong mistral, and because he must have said to himself, these people we know from history, doges of Venice, crusaders, apostles, holy women, were of the same type as, and lived in a similar way to, their present-day descendants.\"",
"\n\nDelacroix's influence helped Van Gogh develop artistically and gain knowledge of color theory. ",
"To his brother Theo, he wrote: \"What I admire so much about Delacroix... is that he makes us feel the life of things, and the expression of movement, that he absolutely dominates his colours.\"",
"\n\nTable of paintings\n\nCopy after Gustave Doré\nPrisoners' Round (after Gustave Doré) was made by Van Gogh at Saint-Paul asylum in Saint-Rémy. ",
" This work like the reprises of Eugène Delacroix and Rembrandt's works, evokes Van Gogh's sense of isolation, like an imprisoned or dying man. ",
" Although sad, there is a sense of comfort offered. ",
" In a letter to his brother, Theo, Van Gogh mentioned that he found making it and Men Drinking (after Daumier) quite difficult.",
"\n\nFollowing Van Gogh's funeral, Émile Bernard wrote of the studies around his coffin: \"On the walls of the room where his body was laid out all his last canvases were hung making a sort of halo for him and the brilliance of the genius that radiated from them made this death even more painful for us artists who were there.\" ",
" Of the Doré reprise, he said, \"Convicts walking in a circle surrounded by high prison walls, a canvas inspired by Doré of a terrifying ferocity and which is also symbolic of his end. ",
"Wasn't life like that for him, a high prison like this with such high walls - so high…and these people walking endlessly round this pit, weren't they the poor artists, the poor damned souls walking past under the whip of Destiny?\"",
"\n\nCopy after Keisai Eisen\nWhile living in Antwerp Van Gogh become acquainted with Japanese wood block prints. ",
"In Paris, Keisai Eisen's print appeared on the May 1886 cover of Paris Illustré magazine which inspired Van Gogh to make The Courtesan. ",
"The magazine issue was entirely devoted to Japan. ",
" Japanese author, Tadamasa Hayashi, who lived in Paris, acquainted Parisians with information about Japan. ",
" In addition to providing information about its history, climate and visual arts, Hayashi explained what it was like to live in Japan, such as its customs, religion, education, religion, and the nature of its people.",
"\n\nVan Gogh copied and enlarged the image. ",
" He created a bright yellow background and colorful kimono. ",
" Influenced by other Japanese prints, he added a \"watery landscape\" of bamboo and water lilies. ",
" Frogs and cranes, terms used in 19th century France for prostitutes, with a distance boat adorn the border.",
"\n\nCopies after Utagawa Hiroshige\nIn the mid-19th century Japan opened itself to trade, making Japanese art available to the west. ",
"The works of Japanese print makers, Hiroshige and Hokusai greatly influenced Van Gogh, both for the beautiful subject matter and the style of flat patterns of colors, without shadow. ",
" Van Gogh collected hundreds of Japanese prints and likened the works of the great Japanese artists, like Hiroshige, to those of Rembrandt, Hals, and Vermeer. ",
"Van Gogh explored the various influences, molding them into a style that was uniquely his own. ",
" The Japanese paintings represent Van Gogh's search for serenity, which he describes in a letter to his sister during this period, \"Having as much of this serenity as possible, even though one knows little – nothing – for certain, is perhaps a better remedy for all diseases than all the things that are sold at the chemist's shop.\"",
"\n\nHiroshige, one of the last great masters of Ukiyo-e, was well known for series of prints of famous Japanese landmarks.",
"\n\nJaponaiserie: Flowering Plum Tree (after Hiroshige)\nThe Flowering Plum Tree is believed to be the first of three oil paintings made by Van Gogh of Utagawa Hiroshige's Japanese woodblock prints. ",
" He used color to emulate the effect of the printer's ink, such as the red and greens in the background and the tint of green on the white blossoms. ",
" After he moved to Arles, Van Gogh wrote to his sister that he no longer needed to dream of going to Japan, \"because I am always telling myself that here I am in Japan.\"",
"\n\nJaponaiserie: Bridge in the Rain (after Hiroshige)\nUtagawa Hiroshige's Evening Shower at Atake and the Great Bridge woodcut, which he had in his collection, inspired Van Gogh for its simplicity. ",
" The cloudburst, for instance, is conveyed by parallel lines. ",
"Such techniques were revered, but also difficult to execute when creating the wood block stamp for printing. ",
" By making a painting, Van Gogh's brushstrokes \"softened the boldness of the Japanese woodcut.\" ",
" Calligraphic figures, borrowed from other Japanese prints, fill the border around the image. ",
" Rather than following the color patterns of the original woodcut print, he used bright colors or contrasting colors.",
"\n\nCopy after Jacob Jordaens\nVan Gogh used Jordaen's subject and composition for his rendition of Cows. ",
"A later artist, Edward Hopper, also used Jordaen's Cows as a source of inspiration for his work. ",
"The painting is located at the Musée des Beaux-Arts de Lille in France. ",
"Jan Hulsker notes that the painting is a color study of an etching Dr. Gachet made of Jordaen's painting.",
"\n\nCopies after Jean-François Millet\n\nBackground\nThe \"peasant genre\" that greatly influenced Van Gogh began in the 1840s with the works of Jean-François Millet, Jules Breton, and others. ",
"In 1885 Van Gogh described the painting of peasants as the most essential contribution to modern art. ",
"He described the works of Millet and Breton of religious significance, \"something on high.\" ",
" A common denominator in his favored authors and artists was sentimental treatment of the destitute and downtrodden. ",
" He held laborers up to a high standard of how dedicatedly he should approach painting, \"One must undertake with confidence, with a certain assurance that one is doing a reasonable thing, like the farmer who drives his plow... (one who) drags the harrow behind himself. ",
" If one hasn't a horse, one is one's own horse.\" ",
" Referring to painting of peasants Van Gogh wrote to his brother Theo: \"How shall I ever manage to paint what I love so much?\"",
"\n\nVan Gogh Museum says of Millet's influence on Van Gogh: \"Millet's paintings, with their unprecedented depictions of peasants and their labors, mark a turning point in 19th-century art. ",
"Before Millet, peasant figures were just one of many elements in picturesque or nostalgic scenes. ",
"In Millet's work, individual men and women became heroic and real. ",
"Millet was the only major artist of the Barbizon School who was not interested in 'pure' landscape painting.\"",
"\n\nVan Gogh made twenty-one paintings in Saint-Rémy that were \"translations\" of the work of Jean-François Millet. ",
" Van Gogh did not intend for his works to be literal copies of the originals. ",
"Speaking specifically of the works after Millet, he explained, \"it's not copying pure and simple that one would be doing. ",
"It is rather translating into another language, the one of colors, the impressions of chiaroscuro and white and black.\" ",
"He made a copy of The Gleaners (Des glaneuses) by Millet. ",
"\n\nTheo wrote Van Gogh: \"The copies after Millet are perhaps the best things you have done yet, and induce me to believe that on the day you turn to painting compositions of figures, we may look forward to great surprises.\"",
"\n\nTable of paintings\n\nCopies after Rembrandt\nFrom Rembrandt, Van Gogh learned how to paint light into darkness. ",
" Rembrandt’s influence seemed present one evening in 1877 when Van Gogh walked through Amsterdam. ",
" He wrote: \"the ground was dark, the sky still lit by the glow of the sun, already gone down, the row of houses and towers standing out above, the lights in the windows everywhere, everything reflected in the water.\" ",
"Van Gogh found Rembrandt particularly adept at his observation of nature and expressing emotion with great tenderness.",
"\n\nIt's not clear if Van Gogh was copying after particular Rembrandt works for his copies or the spirit of the figures he portrayed. ",
" Examples of Rembrandt's angels and Lazarus are here for illustrative purposes.",
"\n\nIn Van Gogh's version of The Raising of Lazarus (after Rembrandt), Christ is depicted symbolically through the sun to evoke the healing powers of faith. ",
" Christ is further referenced in two ways by the setting and circumstance. ",
" First, miraculously, he brought Lazarus back to life again. ",
" It also foretold Christ's own death and resurrection. ",
"\nThe painting includes the dead Lazarus and his two sisters. ",
"White, yellow and violet were used for Lazarus and the cave. ",
" One of the women is in a vibrant green dress and orange hair. ",
" The other wears a striped green and pink gown and has black hair. ",
" Behind them is the countryside of blue and a bright yellow sun.",
"\n\nIn The Raising of Lazarus (after Rembrandt), van Gogh drastically trimmed the composition of Rembrandt's etching and eliminated the figure of Christ, thus focusing on Lazarus and his sisters. ",
"It is speculated that in their countenances may be detected the likenesses of the artist and his friends Augustine Rouline and Marie Ginoux. ",
"Van Gogh had just recovered from a lengthy episode of illness, and he may have identified with the miracle of the biblical resurrection, whose \"personalities are the characters of my dreams.\"",
"\n\nReferences\n\nBibliography\n Hulsker, Jan The Complete Van Gogh. ",
"Oxford: Phaidon, 1980. ",
"\n\nCategory:1889 paintings\nCategory:1890 paintings\nCategory:Paintings by Vincent van Gogh\nCategory:Vincent van Gogh paintings of Saint-Rémy\nCategory:Vincent van Gogh paintings of Paris\nCategory:Series of Vincent van Gogh paintings"
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"Contact form\n\nDo you have a question regarding your order, a question about one of our products or do you want some more information? ",
"Please fill in our contact form. ",
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"Weblectronics offers you to return products if they are undamaged, unused and in the original packing, within 14 days. ",
"Shipping costs are not refunded by Weblectronics. ",
"Is your product dead on arrival or broken during your warranty period? ",
"Please fill out our return form (Dutch). ",
"After completing the form, you receive a RMA Number from one of our employees. ",
"The shipment costs, in case of a broken article, will be refunded to an amount of € 6.95. ",
"Please always attatch a copy of your invoice with RMA number written on it.",
"\nYour return shipment has to be sent to:"
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"You heard about the Holocaust in which 6 million Jews were killed in Nazi Death Camps.",
"\n\nDid you hear about the \"threatened holocaust\" of 6 million Jews about 20 years earlier?",
"\n\nProbably not, even though a former Governor of New York wrote about it in 1919, because that early holocaust never became a best-seller.",
"\n\nPublished inThe American HebrewOctober 31, 1919by Martin Glynn\n\nIn Glynn's article, we find that World War I ended \"for everybody, but the Jew.\"",
"\n\nGlynn encourages the League of Nations to bring peace to the world, and he wants to \"give justice to the Jew and other oppressed peoples\".",
"\n\nHowever, this threatened Holocaust of 6 million Jews never became popular with the American or European public. ",
"Perhaps this is why the Zionists staged a new and improved version of the 6 million Holocaust during World War II. ",
"In this revised Holocaust, they made sure that some of the 6 million Jews were killed. ",
"This turned out to be the key to making the Holocaust a phenomenal success.",
"\n\nThe contents of the article are below. ",
"It serves as a lesson in how not to market a Holocaust.",
"\n\n1919, the crucifixion of (6 million) Jews Must Stop!",
"\n\nby Former Governor of NY State\n\nThe Crucifixion of Jews Must Stop!",
"\n\nBy Martin H. Glynn\n\n(Former Governor of the State of N.Y.)\n\nFrom across the sea six million men and women call to us for help, and eight hundred thousand little children cry for bread.",
"\n\nThese children, these men and women are our fellow-members of the human family, with the same claim on life as we, the same susceptibility to the winter's cold, the same propensity to death before the fangs of hunger. ",
"Within them reside the illimitable possibilities for the advancement of the human race as naturally would reside in six million human beings. ",
"We may not be their keepers but we ought to be their helpers.",
"\n\nIn the face of death, in the throes of starvation there is no place for mental distinctions of creed, no place for physical differentiations of race. ",
"In this catastrophe, when six million human beings are being whirled toward the grave by a cruel and relentless fate, only the most idealistic promptings of human nature should sway the heart and move the hand.",
"\n\nSix million men and women are dying from lack of the necessaries of life; eight hundred thousand children cry for bread. ",
"And this fate is upon them through no fault of their own, through no transgression of the laws of God or man; but through the awful tyranny of war and a bigoted lust for Jewish blood.",
"\n\nIn this threatened holocaust of human life, forgotten are the niceties of philosophical distinction, forgotten are the differences of historical interpretation; and the determination to help the helpless, to shelter the homeless, to clothe the naked and to feed the hungry becomes a religion at whose altar men of every race can worship and women of every creed can kneel. ",
"In this calamity the temporalities of man's fashionings fall away before the eternal verities of life, and we awaken to the fact that from the hands of one God we all come and before the tribunal of one God we all must stand on the day of final reckoning. ",
"And when that reckoning comes mere profession of lips will not weigh a pennyweight; but deeds, mere intangible deeds, deeds that dry the tear of sorrow and allay the pain of anguish, deeds that with the spirit of the Good Samaritan pour oil and wine in wounds and find sustenance and shelter for the suffering and the stricken, will outweigh all the stars in the heavens, all the waters in the seas, all the rocks and metals in all the celestian globes that revolve in the firmament around us.",
"\n\nRace is a matter of accident; creed, partly a matter of inheritance, partly a matter of environment, partly one's method of ratiocination; but our physical wants and corporeal needs are implanted in all of us by the hand of God, and the man or woman who can, and will not, hear the cry of the starving; who can, and will not, take heed of the wail of the dying; who can, and will not, stretch forth a helping hand to those who sink beneath the waves of adversity is an assassin of nature's finest instincts, a traitor to the cause of the human family and an abjurer of the natural law written upon the tablets of every human heart by the finger of God himself.",
"\n\nAnd so in the spirit that turned the poor widow's votive offering of copper into silver, and the silver into gold when placed upon God's altar, the people of this country are called upon to sanctify their money by giving $35,000,000 in the name of the humanity of Moses to six million famished men and women.",
"\n\nSix million men and women are dying -- eight hundred thousand little children are crying for bread.",
"\n\nAnd why?",
"\n\nBecause of a war to lay Autocracy in the dust and give Democracy the sceptre of the Just.",
"\n\nAnd in that war for democracy 200,000 Jewish lads from the United States fought beneath the Stars and Stripes. ",
"In the 77th Division alone there were 14,000 of them, and in Argonne Forest this division captured 54 German guns.",
"This shows that at Argonne the Jewish boys from the United States fought for democracy as Joshua fought against the Amalekites on the plains of Abraham. ",
"In an address on the so-called \"Lost Battalion,\" led by Colonel Whittlesey of Pittsfield, Major-General Alexander shows the fighting stuff these Jewish boys were made of. ",
"In some way or another Whittlesey's command was surrounded. ",
"They were short of rations. ",
"They tried to get word back to the rear telling of their plight. ",
"They tried and they tried, but their men never got through. ",
"Paralysis and stupefaction and despair were in the air. ",
"And when the hour was darkest and all seemed lost, a soldier lad stepped forward, and said to Col. ",
"Whittlesey: \"I will try to get through.\" ",
"He tried, he was wounded, he had to creep and crawl, but he got through.",
"To-day he wears the Distinguished Service Cross and his name is\n\nAbraham Krotoshansky.",
"\n\nBecause of this war for Democracy six million Jewsh men and women are starving across the seas; eight hundred thousand Jewish babies are crying for bread.",
"\n\n(Continued from page 582)\n\nIn the name of Abraham Krotoshinsky who saved the \"Lost Battalion,\" in the name of the one hundred and ninety-nine thousand and nine hundred and ninety-nine other Jewish boys who fought for Democracy beneath the Stars and Stripes won't you give copper, or silver, or gold, to keep life in the heart of these men and these women; to keep blood in the bodies of these babies?",
"\n\nThe Jew Has Helped Everybody But The Jew.",
"\n\nIn the world war the Jew has helped everybody but the Jew. \"",
"Over there\" he helped in camp, in council and in conflict. \"",
"Over here\" he helped the Red Cross, the Y.M.C.A., the Knights of Columbus, the Masons, the Salvation Army and everybody else. ",
"So now is the time for everybody to help the Jew, and God knows now is the time he needs it.",
"\n\nFrom out of the gloom of this war every other race, save one or two, has snatched a ray of sunshine. ",
"But amid the encircling gloom there is no light for the Jew \"to lead thou me on.\" ",
"The war is over for everyone, but the Jew. ",
"The knife is still at his throat and an unreasoning and unreasonable century-old lust for Jewish blood opens his veins. ",
"The Jew in Roumania, Poland and Ukrainia is being made the scapegoat of the war. ",
"Since the armistice has been signed thousands of Jews in Ukrainia have been offered up as living sacrifices to diabolical greed and fanatical passion -- their throats cut, their bodies rended limb from limb by assassin bands and rabid soldiery. ",
"In the city of Proskunoff one day a few weeks ago the dawn saw the door of every house wherein lived a Jew marked as a shambles for slaughter. ",
"For four days, from sunrise to sunset, fanatics plied the dagger like demons from hell, stopping only to eat with hands adrip with the blood of Jewishvictims. ",
"They killed the men; they were less merciful to women. ",
"These they violated, and then they killed. ",
"From a purpose to a fury, from a fury to a habit ran this killing of the Jews, until within four days the streets of Proskunoff ran red with blood like gutters of a slaughter house, until its homes became a morgue for thousands of slaughtered human beings whose gaping wounds cried out for vengeance and whose eyes had turned to stone at the horrors they had seen. ",
"As Hon. ",
"Simon W. Rosendale, aptly paraphrasing Bobby Burns' thought, in his speech not long ago, said it is the age-old story of \"man's inhumanity to man that makes countless thousands mourn.\" ",
"For as it has been at Proskunoff, so has it been in a hundred other places.",
"The bloody tale hath repetition ad nauseum. ",
"It is the same tear-stained story -- the same old stain upon the escutcheon of humanity. ",
"Verily, Byron was right when he wrote:\n\nTribes of the wandering feet and weary breastWhither shall ye flee to be at rest?The wild dove hath her nest, the fox his cave,Mankind their countries, Israel but the grave.",
"\n\nBut Israel is entitled to a place in the sun, and the crucifixion of Jews must stop. ",
"We repeat the war is over for everybody, but the Jew. ",
"Like Isaac the knife is at his throat, but unlike Isaac no power seems able to stop the steel from thirsting for his blood. ",
"But some power the world must raise up to prevent this decimation of a deserving race. ",
"For the peace of the world a League of Nations let us have by all means; but for the Humanity of the World, to give justice to the Jew and other oppressed peoples on earth, let us have a Truce of God! -- ",
"Albany Times Union.",
"\n\nArchived for Educational Purposes only Under U.S.C. Title 17 Section 107by Jew Watch Library at www.jewwatch.com\n\n*COPYRIGHT NOTICE**\n\nIn accordance with Title 17 U.S.C. Section 107, any copyrighted work in the JewWatch Library is archived here under fair use without profit or payment to thosewho have expressed a prior interest in reviewing the included information forpersonal use, non-profit research and educational purposes only.",
"Ref. ",
"http://www.law.cornell.edu/uscode/17/107.shtml\n\nIf you have additions or suggestions\n\nEmail Jew Watch [email protected]\n\nPhotocopy of 1919 TranscriptEntitled The Crucifiction of Jews Must Stop it refers to six million Jews sacrificed and is dated 1919!",
"\n\nThe New York Public Library holds a microfilm of the above manuscript. ",
"A researcher printed out the images from that microfilm and subequently converted them to jpg format.",
"\n\nComment\n\nOf course, the above document does not mean that the Holocaust never took place. ",
"Arch historical revisionist David Irving himself admits that there were \"death camps\". ",
"What is at issue here is the exact numbers involved, how they died and who actually benefitted from and promoted the \"Holocaust\". ",
"Was it in fact the Zionists who used the \"Holocaust\" to pave the way for the foundation of Israel?",
"\n\nTo answer this question, note the opening sentence of the final paragraph: \"But Israel is entitled to a place in the sun, and the crucifixion of Jews must stop\". ",
"This was first published nearly thirty years before the founding of modern Israel yet it anticipates it and opens many more questions that need to be answered."
] |
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[
"Dvorsky\n\nDvorsky is a surname. ",
"Notable people with the surname include:\n\n Bohumír Dvorský (1902–1976), Czech painter\n George Dvorsky (born 1970), Canadian bioethicist, transhumanist, and futurist\n Jakub Dvorský (born 1978), Czech video game designer\n Miroslav Dvorský (born 1960), Slovak operatic tenor\n Pavlo Dvorsky (born 1953), Ukrainian singer and composer\n Peter Dvorský (born 1951), Slovak operatic tenor\n Robert Dvorsky (born 1948), American politician\n Rudolf Antonín Dvorský (1899–1966), Czechoslovak dancer\n\nSee also \n 16241 Dvorsky, main-belt asteroid"
] |
{
"pile_set_name": "Wikipedia (en)"
}
|
[
0,
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[
"r\"\"\"TELNET client class.",
"\n\nBased on RFC 854: TELNET Protocol Specification, by J. Postel and\nJ. Reynolds\n\nExample:\n\n>>> from telnetlib import Telnet\n>>> tn = Telnet('www.python.org', 79) # connect to finger port\n>>> tn.write(b'guido\\r\\n')\n>>> print(tn.read_all())\nLogin Name TTY Idle When Where\nguido Guido van Rossum pts/2 <Dec 2 11:10> snag.cnri.reston..\n\n>>>\n\nNote that read_all() won't read until eof -- it just reads some data\n-- but it guarantees to read at least one byte unless EOF is hit.",
"\n\nIt is possible to pass a Telnet object to a selector in order to wait until\nmore data is available. ",
" Note that in this case, read_eager() may return b''\neven if there was data on the socket, because the protocol negotiation may have\neaten the data. ",
" This is why EOFError is needed in some cases to distinguish\nbetween \"no data\" and \"connection closed\" (since the socket also appears ready\nfor reading when it is closed).",
"\n\nTo do:\n- option negotiation\n- timeout should be intrinsic to the connection object instead of an\n option on one of the read calls only\n\n\"\"\"\n\n\n# Imported modules\nimport sys\nimport socket\nimport selectors\nfrom time import monotonic as _time\n\n__all__ = [\"Telnet\"]\n\n# Tunable parameters\nDEBUGLEVEL = 0\n\n# Telnet protocol defaults\nTELNET_PORT = 23\n\n# Telnet protocol characters (don't change)\nIAC = bytes([255]) # \"Interpret As Command\"\nDONT = bytes([254])\nDO = bytes([253])\nWONT = bytes([252])\nWILL = bytes([251])\ntheNULL = bytes([0])\n\nSE = bytes([240]) # Subnegotiation End\nNOP = bytes([241]) # No Operation\nDM = bytes([242]) # Data Mark\nBRK = bytes([243]) # Break\nIP = bytes([244]) # Interrupt process\nAO = bytes([245]) # Abort output\nAYT = bytes([246]) # Are You There\nEC = bytes([247]) # Erase Character\nEL = bytes([248]) # Erase Line\nGA = bytes([249]) # Go Ahead\nSB = bytes([250]) # Subnegotiation Begin\n\n\n# Telnet protocol options code (don't change)\n# These ones all come from arpa/telnet.h\nBINARY = bytes([0]) # 8-bit data path\nECHO = bytes([1]) # echo\nRCP = bytes([2]) # prepare to reconnect\nSGA = bytes([3]) # suppress go ahead\nNAMS = bytes([4]) # approximate message size\nSTATUS = bytes([5]) # give status\nTM = bytes([6]) # timing mark\nRCTE = bytes([7]) # remote controlled transmission and echo\nNAOL = bytes([8]) # negotiate about output line width\nNAOP = bytes([9]) # negotiate about output page size\nNAOCRD = bytes([10]) # negotiate about CR disposition\nNAOHTS = bytes([11]) # negotiate about horizontal tabstops\nNAOHTD = bytes([12]) # negotiate about horizontal tab disposition\nNAOFFD = bytes([13]) # negotiate about formfeed disposition\nNAOVTS = bytes([14]) # negotiate about vertical tab stops\nNAOVTD = bytes([15]) # negotiate about vertical tab disposition\nNAOLFD = bytes([16]) # negotiate about output LF disposition\nXASCII = bytes([17]) # extended ascii character set\nLOGOUT = bytes([18]) # force logout\nBM = bytes([19]) # byte macro\nDET = bytes([20]) # data entry terminal\nSUPDUP = bytes([21]) # supdup protocol\nSUPDUPOUTPUT = bytes([22]) # supdup output\nSNDLOC = bytes([23]) # send location\nTTYPE = bytes([24]) # terminal type\nEOR = bytes([25]) # end or record\nTUID = bytes([26]) # TACACS user identification\nOUTMRK = bytes([27]) # output marking\nTTYLOC = bytes([28]) # terminal location number\nVT3270REGIME = bytes([29]) # 3270 regime\nX3PAD = bytes([30]) # X.3 PAD\nNAWS = bytes([31]) # window size\nTSPEED = bytes([32]) # terminal speed\nLFLOW = bytes([33]) # remote flow control\nLINEMODE = bytes([34]) # Linemode option\nXDISPLOC = bytes([35]) # X Display Location\nOLD_ENVIRON = bytes([36]) # Old - Environment variables\nAUTHENTICATION = bytes([37]) # Authenticate\nENCRYPT = bytes([38]) # Encryption option\nNEW_ENVIRON = bytes([39]) # New - Environment variables\n# the following ones come from\n# http://www.iana.org/assignments/telnet-options\n# Unfortunately, that document does not assign identifiers\n# to all of them, so we are making them up\nTN3270E = bytes([40]) # TN3270E\nXAUTH = bytes([41]) # XAUTH\nCHARSET = bytes([42]) # CHARSET\nRSP = bytes([43]) # Telnet Remote Serial Port\nCOM_PORT_OPTION = bytes([44]) # Com Port Control Option\nSUPPRESS_LOCAL_ECHO = bytes([45]) # Telnet Suppress Local Echo\nTLS = bytes([46]) # Telnet Start TLS\nKERMIT = bytes([47]) # KERMIT\nSEND_URL = bytes([48]) # SEND-URL\nFORWARD_X = bytes([49]) # FORWARD_X\nPRAGMA_LOGON = bytes([138]) # TELOPT PRAGMA LOGON\nSSPI_LOGON = bytes([139]) # TELOPT SSPI LOGON\nPRAGMA_HEARTBEAT = bytes([140]) # TELOPT PRAGMA HEARTBEAT\nEXOPL = bytes([255]) # Extended-Options-List\nNOOPT = bytes([0])\n\n\n# poll/select have the advantage of not requiring any extra file descriptor,\n# contrarily to epoll/kqueue (also, they require a single syscall).",
"\nif hasattr(selectors, 'PollSelector'):\n _TelnetSelector = selectors.",
"PollSelector\nelse:\n _TelnetSelector = selectors.",
"SelectSelector\n\n\nclass Telnet:\n\n \"\"\"Telnet interface class.",
"\n\n An instance of this class represents a connection to a telnet\n server. ",
" The instance is initially not connected; the open()\n method must be used to establish a connection. ",
" Alternatively, the\n host name and optional port number can be passed to the\n constructor, too.",
"\n\n Don't try to reopen an already connected instance.",
"\n\n This class has many read_*() methods. ",
" Note that some of them\n raise EOFError when the end of the connection is read, because\n they can return an empty string for other reasons. ",
" See the\n individual doc strings.",
"\n\n read_until(expected, [timeout])\n Read until the expected string has been seen, or a timeout is\n hit (default is no timeout); may block.",
"\n\n read_all()\n Read all data until EOF; may block.",
"\n\n read_some()\n Read at least one byte or EOF; may block.",
"\n\n read_very_eager()\n Read all data available already queued or on the socket,\n without blocking.",
"\n\n read_eager()\n Read either data already queued or some data available on the\n socket, without blocking.",
"\n\n read_lazy()\n Read all data in the raw queue (processing it first), without\n doing any socket I/O.\n\n read_very_lazy()\n Reads all data in the cooked queue, without doing any socket\n I/O.\n\n read_sb_data()\n Reads available data between SB ... SE sequence. ",
"Don't block.",
"\n\n set_option_negotiation_callback(callback)\n Each time a telnet option is read on the input flow, this callback\n (if set) is called with the following parameters :\n callback(telnet socket, command, option)\n option will be chr(0) when there is no option.",
"\n No other action is done afterwards by telnetlib.",
"\n\n \"\"\"\n\n def __init__(self, host=None, port=0,\n timeout=socket._GLOBAL_DEFAULT_TIMEOUT):\n \"\"\"Constructor.",
"\n\n When called without arguments, create an unconnected instance.",
"\n With a hostname argument, it connects the instance; port number\n and timeout are optional.",
"\n \"\"\"\n self.debuglevel = DEBUGLEVEL\n self.host = host\n self.port = port\n self.timeout = timeout\n self.sock = None\n self.rawq = b''\n self.irawq = 0\n self.cookedq = b''\n self.eof = 0\n self.iacseq = b'' # Buffer for IAC sequence.",
"\n self.sb = 0 # flag for SB and SE sequence.",
"\n self.sbdataq = b''\n self.option_callback = None\n if host is not None:\n self.open(host, port, timeout)\n\n def open(self, host, port=0, timeout=socket._GLOBAL_DEFAULT_TIMEOUT):\n \"\"\"Connect to a host.",
"\n\n The optional second argument is the port number, which\n defaults to the standard telnet port (23).",
"\n\n Don't try to reopen an already connected instance.",
"\n \"\"\"\n self.eof = 0\n if not port:\n port = TELNET_PORT\n self.host = host\n self.port = port\n self.timeout = timeout\n sys.audit(\"telnetlib.",
"Telnet.open\", self, host, port)\n self.sock = socket.create_connection((host, port), timeout)\n\n def __del__(self):\n \"\"\"Destructor -- close the connection.\"\"\"",
"\n self.close()\n\n def msg(self, msg, *args):\n \"\"\"Print a debug message, when the debug level is > 0.",
"\n\n If extra arguments are present, they are substituted in the\n message using the standard string formatting operator.",
"\n\n \"\"\"\n if self.debuglevel > 0:\n print('Telnet(%s,%s):' % (self.host, self.port), end=' ')\n if args:\n print(msg % args)\n else:\n print(msg)\n\n def set_debuglevel(self, debuglevel):\n \"\"\"Set the debug level.",
"\n\n The higher it is, the more debug output you get (on sys.stdout).",
"\n\n \"\"\"\n self.debuglevel = debuglevel\n\n def close(self):\n \"\"\"Close the connection.\"\"\"",
"\n sock = self.sock\n self.sock = None\n self.eof = True\n self.iacseq = b''\n self.sb = 0\n if sock:\n sock.close()\n\n def get_socket(self):\n \"\"\"Return the socket object used internally.\"\"\"",
"\n return self.sock\n\n def fileno(self):\n \"\"\"Return the fileno() of the socket object used internally.\"\"\"",
"\n return self.sock.fileno()\n\n def write(self, buffer):\n \"\"\"Write a string to the socket, doubling any IAC characters.",
"\n\n Can block if the connection is blocked. ",
" May raise\n OSError if the connection is closed.",
"\n\n \"\"\"\n if IAC in buffer:\n buffer = buffer.replace(IAC, IAC+IAC)\n sys.audit(\"telnetlib.",
"Telnet.write\", self, buffer)\n self.msg(\"send %r\", buffer)\n self.sock.sendall(buffer)\n\n def read_until(self, match, timeout=None):\n \"\"\"Read until a given string is encountered or until timeout.",
"\n\n When no match is found, return whatever is available instead,\n possibly the empty string. ",
" Raise EOFError if the connection\n is closed and no cooked data is available.",
"\n\n \"\"\"\n n = len(match)\n self.process_rawq()\n i = self.cookedq.find(match)\n if i >= 0:\n i = i+n\n buf = self.cookedq[:i]\n self.cookedq = self.cookedq[i:]\n return buf\n if timeout is not None:\n deadline = _time() + timeout\n with _TelnetSelector() as selector:\n selector.register(self, selectors.",
"EVENT_READ)\n while not self.eof:\n if selector.select(timeout):\n i = max(0, len(self.cookedq)-n)\n self.fill_rawq()\n self.process_rawq()\n i = self.cookedq.find(match, i)\n if i >= 0:\n i = i+n\n buf = self.cookedq[:i]\n self.cookedq = self.cookedq[i:]\n return buf\n if timeout is not None:\n timeout = deadline - _time()\n if timeout < 0:\n break\n return self.read_very_lazy()\n\n def read_all(self):\n \"\"\"Read all data until EOF; block until connection closed.\"\"\"",
"\n self.process_rawq()\n while not self.eof:\n self.fill_rawq()\n self.process_rawq()\n buf = self.cookedq\n self.cookedq = b''\n return buf\n\n def read_some(self):\n \"\"\"Read at least one byte of cooked data unless EOF is hit.",
"\n\n Return b'' if EOF is hit. ",
" Block if no data is immediately\n available.",
"\n\n \"\"\"\n self.process_rawq()\n while not self.cookedq and not self.eof:\n self.fill_rawq()\n self.process_rawq()\n buf = self.cookedq\n self.cookedq = b''\n return buf\n\n def read_very_eager(self):\n \"\"\"Read everything that's possible without blocking in I/O (eager).",
"\n\n Raise EOFError if connection closed and no cooked data\n available. ",
" Return b'' if no cooked data available otherwise.",
"\n Don't block unless in the midst of an IAC sequence.",
"\n\n \"\"\"\n self.process_rawq()\n while not self.eof and self.sock_avail():\n self.fill_rawq()\n self.process_rawq()\n return self.read_very_lazy()\n\n def read_eager(self):\n \"\"\"Read readily available data.",
"\n\n Raise EOFError if connection closed and no cooked data\n available. ",
" Return b'' if no cooked data available otherwise.",
"\n Don't block unless in the midst of an IAC sequence.",
"\n\n \"\"\"\n self.process_rawq()\n while not self.cookedq and not self.eof and self.sock_avail():\n self.fill_rawq()\n self.process_rawq()\n return self.read_very_lazy()\n\n def read_lazy(self):\n \"\"\"Process and return data that's already in the queues (lazy).",
"\n\n Raise EOFError if connection closed and no data available.",
"\n Return b'' if no cooked data available otherwise. ",
" Don't block\n unless in the midst of an IAC sequence.",
"\n\n \"\"\"\n self.process_rawq()\n return self.read_very_lazy()\n\n def read_very_lazy(self):\n \"\"\"Return any data available in the cooked queue (very lazy).",
"\n\n Raise EOFError if connection closed and no data available.",
"\n Return b'' if no cooked data available otherwise. ",
" Don't block.",
"\n\n \"\"\"\n buf = self.cookedq\n self.cookedq = b''\n if not buf and self.eof and not self.rawq:\n raise EOFError('telnet connection closed')\n return buf\n\n def read_sb_data(self):\n \"\"\"Return any data available in the SB ... SE queue.",
"\n\n Return b'' if no SB ... SE available. ",
"Should only be called\n after seeing a SB or SE command. ",
"When a new SB command is\n found, old unread SB data will be discarded. ",
"Don't block.",
"\n\n \"\"\"\n buf = self.sbdataq\n self.sbdataq = b''\n return buf\n\n def set_option_negotiation_callback(self, callback):\n \"\"\"Provide a callback function called after each receipt of a telnet option.\"\"\"",
"\n self.option_callback = callback\n\n def process_rawq(self):\n \"\"\"Transfer from raw queue to cooked queue.",
"\n\n Set self.eof when connection is closed. ",
" Don't block unless in\n the midst of an IAC sequence.",
"\n\n \"\"\"\n buf = [b'', b'']\n try:\n while self.rawq:\n c = self.rawq_getchar()\n if not self.iacseq:\n if c == theNULL:\n continue\n if c == b\"\\021\":\n continue\n if c !",
"= IAC:\n buf[self.sb] = buf[self.sb] + c\n continue\n else:\n self.iacseq += c\n elif len(self.iacseq) == 1:\n # 'IAC: IAC CMD [OPTION only for WILL/WONT/DO/DONT]'\n if c in (DO, DONT, WILL, WONT):\n self.iacseq += c\n continue\n\n self.iacseq = b''\n if c == IAC:\n buf[self.sb] = buf[self.sb] + c\n else:\n if c == SB: # SB ... SE start.",
"\n self.sb = 1\n self.sbdataq = b''\n elif c == SE:\n self.sb = 0\n self.sbdataq = self.sbdataq + buf[1]\n buf[1] = b''\n if self.option_callback:\n # Callback is supposed to look into\n # the sbdataq\n self.option_callback(self.sock, c, NOOPT)\n else:\n # We can't offer automatic processing of\n # suboptions. ",
"Alas, we should not get any\n # unless we did a WILL/DO before.",
"\n self.msg('IAC %d not recognized' % ord(c))\n elif len(self.iacseq) == 2:\n cmd = self.iacseq[1:2]\n self.iacseq = b''\n opt = c\n if cmd in (DO, DONT):\n self.msg('IAC %s %d',\n cmd == DO and 'DO' or 'DONT', ord(opt))\n if self.option_callback:\n self.option_callback(self.sock, cmd, opt)\n else:\n self.sock.sendall(IAC + WONT + opt)\n elif cmd in (WILL, WONT):\n self.msg('IAC %s %d',\n cmd == WILL and 'WILL' or 'WONT', ord(opt))\n if self.option_callback:\n self.option_callback(self.sock, cmd, opt)\n else:\n self.sock.sendall(IAC + DONT + opt)\n except EOFError: # raised by self.rawq_getchar()\n self.iacseq = b'' # Reset on EOF\n self.sb = 0\n pass\n self.cookedq = self.cookedq + buf[0]\n self.sbdataq = self.sbdataq + buf[1]\n\n def rawq_getchar(self):\n \"\"\"Get next char from raw queue.",
"\n\n Block if no data is immediately available. ",
" Raise EOFError\n when connection is closed.",
"\n\n \"\"\"\n if not self.rawq:\n self.fill_rawq()\n if self.eof:\n raise EOFError\n c = self.rawq[self.irawq:self.irawq+1]\n self.irawq = self.irawq + 1\n if self.irawq >= len(self.rawq):\n self.rawq = b''\n self.irawq = 0\n return c\n\n def fill_rawq(self):\n \"\"\"Fill raw queue from exactly one recv() system call.",
"\n\n Block if no data is immediately available. ",
" Set self.eof when\n connection is closed.",
"\n\n \"\"\"\n if self.irawq >= len(self.rawq):\n self.rawq = b''\n self.irawq = 0\n # The buffer size should be fairly small so as to avoid quadratic\n # behavior in process_rawq() above\n buf = self.sock.recv(50)\n self.msg(\"recv %r\", buf)\n self.eof = (not buf)\n self.rawq = self.rawq + buf\n\n def sock_avail(self):\n \"\"\"Test whether data is available on the socket.\"\"\"",
"\n with _TelnetSelector() as selector:\n selector.register(self, selectors.",
"EVENT_READ)\n return bool(selector.select(0))\n\n def interact(self):\n \"\"\"Interaction function, emulates a very dumb telnet client.\"\"\"",
"\n if sys.platform == \"win32\":\n self.mt_interact()\n return\n with _TelnetSelector() as selector:\n selector.register(self, selectors.",
"EVENT_READ)\n selector.register(sys.stdin, selectors.",
"EVENT_READ)\n\n while True:\n for key, events in selector.select():\n if key.fileobj is self:\n try:\n text = self.read_eager()\n except EOFError:\n print('*** Connection closed by remote host ***')\n return\n if text:\n sys.stdout.write(text.decode('ascii'))\n sys.stdout.flush()\n elif key.fileobj is sys.stdin:\n line = sys.stdin.readline().encode('ascii')\n if not line:\n return\n self.write(line)\n\n def mt_interact(self):\n \"\"\"Multithreaded version of interact().\"\"\"",
"\n import _thread\n _thread.start_new_thread(self.listener, ())\n while 1:\n line = sys.stdin.readline()\n if not line:\n break\n self.write(line.encode('ascii'))\n\n def listener(self):\n \"\"\"Helper for mt_interact() -- this executes in the other thread.\"\"\"",
"\n while 1:\n try:\n data = self.read_eager()\n except EOFError:\n print('*** Connection closed by remote host ***')\n return\n if data:\n sys.stdout.write(data.decode('ascii'))\n else:\n sys.stdout.flush()\n\n def expect(self, list, timeout=None):\n \"\"\"Read until one from a list of a regular expressions matches.",
"\n\n The first argument is a list of regular expressions, either\n compiled (re.",
"Pattern instances) or uncompiled (strings).",
"\n The optional second argument is a timeout, in seconds; default\n is no timeout.",
"\n\n Return a tuple of three items: the index in the list of the\n first regular expression that matches; the re.",
"Match object\n returned; and the text read up till and including the match.",
"\n\n If EOF is read and no text was read, raise EOFError.",
"\n Otherwise, when nothing matches, return (-1, None, text) where\n text is the text received so far (may be the empty string if a\n timeout happened).",
"\n\n If a regular expression ends with a greedy match (e.g. '.*')",
"\n or if more than one expression can match the same input, the\n results are undeterministic, and may depend on the I/O timing.",
"\n\n \"\"\"\n re = None\n list = list[:]\n indices = range(len(list))\n for i in indices:\n if not hasattr(list[i], \"search\"):\n if not re: import re\n list[i] = re.compile(list[i])\n if timeout is not None:\n deadline = _time() + timeout\n with _TelnetSelector() as selector:\n selector.register(self, selectors.",
"EVENT_READ)\n while not self.eof:\n self.process_rawq()\n for i in indices:\n m = list[i].search(self.cookedq)\n if m:\n e = m.end()\n text = self.cookedq[:e]\n self.cookedq = self.cookedq[e:]\n return (i, m, text)\n if timeout is not None:\n ready = selector.select(timeout)\n timeout = deadline - _time()\n if not ready:\n if timeout < 0:\n break\n else:\n continue\n self.fill_rawq()\n text = self.read_very_lazy()\n if not text and self.eof:\n raise EOFError\n return (-1, None, text)\n\n def __enter__(self):\n return self\n\n def __exit__(self, type, value, traceback):\n self.close()\n\n\ndef test():\n \"\"\"Test program for telnetlib.",
"\n\n Usage: python telnetlib.py [-d] ... [host [port]]\n\n Default host is localhost; default port is 23.",
"\n\n \"\"\"\n debuglevel = 0\n while sys.argv[1:] and sys.argv[1] == '-d':\n debuglevel = debuglevel+1\n del sys.argv[1]\n host = 'localhost'\n if sys.argv[1:]:\n host = sys.argv[1]\n port = 0\n if sys.argv[2:]:\n portstr = sys.argv[2]\n try:\n port = int(portstr)\n except ValueError:\n port = socket.getservbyname(portstr, 'tcp')\n with Telnet() as tn:\n tn.set_debuglevel(debuglevel)\n tn.open(host, port, timeout=0.5)\n tn.interact()\n\nif __name__ == '__main__':\n test()\n"
] |
{
"pile_set_name": "Github"
}
|
[
0.041666666666666664,
0.013358778625954198,
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0.005847953216374269,
0.0026702269692923898,
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0.016666666666666666,
0.014925373134328358,
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0.0034602076124567475,
0.017543859649122806,
0.014925373134328358,
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0.006600660066006601,
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0.004166666666666667,
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0.008620689655172414,
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0.004081632653061225,
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0.007462686567164179,
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0.008403361344537815,
0.004629629629629629,
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0.0049261083743842365,
0.005284015852047556,
0.01056338028169014,
0.027777777777777776,
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0.0030120481927710845,
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0,
0.016666666666666666,
0.00390625,
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0.016666666666666666,
0.003246753246753247,
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0.016666666666666666,
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0.0070921985815602835,
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0,
0.01282051282051282,
0,
0,
0,
0.02,
0.016666666666666666,
0,
0.011400651465798045,
0.004702194357366771,
0,
0.007069913589945012,
0,
0,
0.004889975550122249,
0,
0,
0,
0.01098901098901099,
0,
0.005649717514124294,
0,
0.007246376811594203,
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0.006864988558352402,
0,
0,
0,
0,
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0.016129032258064516,
0.011834319526627219,
0,
0,
0.004889975550122249,
0.005876591576885406,
0,
0.0017761989342806395
] | 0.004028
| 5
|
[
"Taco Bell\n\nEngaged to head up the global giant’s highly-anticipated launch into the Australian market, Aruga delivered a high-impact, headline-grabbing hype campaign that not only secured a line around the block on official opening day, but left Taco Bell fans Australia-wide with serious FOMO. ",
"Aruga’s creative campaign extended beyond traditional media outreach, capitalising on the international brand’s reputation for trailblazing creativity and personality.",
"\n\nFollowing a record-breaking response from Aussie fans, the megabrand has continued to engage Aruga by way of an ongoing retainer, encompassing the launch of a further three new restaurants and seriously craveable menu additions. ",
"With 50+ new restaurants confirmed to open by 2021, Aruga will ensure there is oh so much to taco’bout.",
"\n\nResults\n\nUnprecedented launch-day hype at first restaurant opening in Annerley, attracting thousands of customers opening weekend and a sustained line out the door for the following six weeks\n\nA social community of 20,000+ pre-launch\n\nLaunched three further restaurants at Cleveland, North Lakes & Robina\n\nEngaged parkour twins Brodie and Dylan Pawson of Australian Ninja Warrior fame to unveil the ultimate #dudefood: the Double Crunchwrap"
] |
{
"pile_set_name": "Pile-CC"
}
|
[
0.010169491525423728,
0.005988023952095809,
0.008658008658008658,
0.009708737864077669,
0.006787330316742082
] | 0.008262
| 5
|
[
"\n\nDo you have any regrets about not going or going to college for programming? - ",
"CodeJustin\nhttp://codejustin.com/do-you-have-any-regrets-about-not-going-or-going-to-college/\n\n======\nphugoid\nI have reached an enlightenment recently.",
"\n\nPretty much all the technology around me is an instance of a gadget, that\nhas-a microprocessor, and has-a bunch of I/O ports to connect to some breakout\ncircuitry. ",
"In my 10 years of work since school, nothing I have touched did not\nfit that description.",
"\n\nSo if I could go back, I would probably major in Electrical (instead of\nMechanical) Engineering to have more fundamentals about hardware and software.",
"\nNot complaining though - my work has been interesting for the most part.",
"\n\n------\nCodeJustin\nI'm really hoping to get a lot of feedback and personal experiences from\nprogrammers about college.",
"\n\n"
] |
{
"pile_set_name": "HackerNews"
}
|
[
0,
0.013245033112582781,
0,
0,
0,
0,
0,
0
] | 0.001656
| 5
|
[
"Typically, students want to avoid evidence of disciplinary measures on their school records. ",
"While getting suspended for, say, drinking beer at a school football game might not automatically disqualify a student from most colleges, admissions officers do take those matters seriously and expect an applicant to express remorse and show growth, explained Diane Anci, a dean of admissions at Kenyon College, a small liberal-arts college in Ohio.",
"\n\nResponding to these concerns from students, many college-admissions offices began issuing statements on social media and on their websites last week promising seniors and future applicants that they would not be penalized for participating in nonviolent protests. ",
"The admissions office of Georgetown University, for example, tweeted: “We provide all applicants an opportunity to elaborate on any disciplinary infraction and carefully consider all context they provide. ",
"Participation in a peaceful protest will not negatively impact admission to Georgetown.”",
"\n\nTeens have been involved in other social movements over the past couple of years, such as Black Lives Matter and the Women’s March. ",
"But the post-Parkland movement is the first to elicit a widespread response from colleges. ",
"Drew Riley, the associate dean of admissions at Colgate, noted that his college has seen an uptick in political activism among their applicants in recent years, but that the coordinated, nation-wide activism around this issue is “unprecedented.” ",
"Colleges’ quick response could also be due to the fact that this movement is focused on high-school students—and includes national school walk-outs as one of its core actions. ",
"This makes concerns over school discipline more common than they may have been in previous movements.",
"\n\nBut while the #NeverAgain movement stands out for provoking a wave of public support, most of the schools’ statements didn’t particularly focus on the movement or on gun control—instead, the statements emphasized support for students’ free expression and engagement in activism more generally. ",
"The official account of UC Berkeley, for example, tweeted: “Dear prospective students: We fully support your right to peacefully protest, and would never refuse your admittance for doing so. ",
"Signed, the home of free speech.” ",
"Most schools emphasized that political participation of any kind fits in with the core mission of their school. ",
"A message from Duke read: “Duke has always valued active and responsible engagement in civic life among its students and applicants. ",
"We will always consider all applicants fully and individually … An applicant’s participation in peaceful protests has never been a reason for us to deny or rescind an offer of admission.”",
"\n\nThe administrators I spoke with emphasized that their support would extend to peaceful protest of any political leaning. ",
"Jon Boeckenstedt, a vice president for enrollment at DePaul University, A Catholic university in Illinois, said that DePaul would support students participating in any form of civic action, including a March for Life. ",
"He added, though, that this support does not give students carte blanche; his university was not endorsing “senioritis” or violent protests."
] |
{
"pile_set_name": "OpenWebText2"
}
|
[
0,
0.005714285714285714,
0,
0.004878048780487805,
0.011363636363636364,
0,
0,
0.008130081300813009,
0,
0,
0,
0.005235602094240838,
0,
0,
0.007518796992481203,
0,
0,
0.013761467889908258,
0.007142857142857143
] | 0.003355
| 5
|
[
"Relationship of soil terrestrial radionuclide concentrations and the excess of lifetime cancer risk in western Mazandaran Province, Iran.",
"\nThe main goal of this study is to lay out the map of the soil radionuclide activity concentrations and the terrestrial outdoor gamma dose rates in the western Mazandaran Province of Iran, and to present an evaluation scheme. ",
"Mazandaran Province was selected due to its special geographical characteristics, high population density and the long terrestrial and aquatic borders with the neighbouring countries possessing nuclear facilities. ",
"A total of 54 topsoil samples were collected, ranging from the Nour to Ramsar regions, and were based on geological conditions, vegetation coverage and the sampling standards outlined by the International Atomic Energy Agency. ",
"The excess lifetime cancer risks (ELCRs) were evaluated and the coordinates of sampling locations were determined by the global positioning system. ",
"The average terrestrial outdoor gamma dose rate was 612.38 ± 3707.93 nGy h(-1), at 1 m above the ground. ",
"The annual effective gamma dose at the western part of Mazandaran Province was 750 μSv, and the ELCR was 0.26 × 10(-2). ",
"Soil samples were analysed by gamma spectrometry with a high-purity germanium detector. ",
"The average (226)Ra, (232)Th, (40)K and (137)Cs activities were 1188.50 ± 7838.40, 64.92 ± 162.26, 545.10 ± 139.42 and 10.41 ± 7.86 Bq kg(-1), respectively. ",
"The average soil radionuclide concentrations at the western part of Mazandaran Province were higher than the worldwide range. ",
"The excess lifetime risks of cancer and the annual effective gamma doses were also higher than the global average."
] |
{
"pile_set_name": "PubMed Abstracts"
}
|
[
0,
0,
0,
0.004405286343612335,
0,
0,
0.008333333333333333,
0,
0,
0,
0
] | 0.001158
| 5
|
[
"[Atrial defibrillators or implantable atrioverters. ",
"Initial results].",
"\nThe atrial defibrillator is a new non-pharmacological treatment of atrial fibrillation (AF) for restoration of sinus rhythm. ",
"This device has two programmable modes: automatic or activated by the physician or patient. ",
"In the automatic mode, the device delivers a shock synchronous with the R wave to restore sinus rhythm when AF is detected. ",
"Two patients with paroxysmal AF resistant to pharmacological therapy were included in a study to assess the efficacy and safety of the atrial defibrillator in the mode activated by the physician. ",
"The device implanted in the pectoral region is connected to 3 electrodes, two for atrial defibrillation and sensing positioned in the coronary sinus and right atrium respectively and a sensing and pacing electrode in the right ventricle. ",
"The right ventricle is paced if a post-shock pause is detected. ",
"It is possible to interrogate the device with a programmer using its Holter function and so determine the number of episodes of AF sensed and treated. ",
"The number, intensity and energy of the shocks and the parameters of ventricular stimulation are programmable. ",
"In these two patients, the atrial defibrillator effectively reduced prolonged episodes of AF with a follow-up of 12 and 7 months. ",
"No pro-arrhythmic effects were observed. ",
"Further clinical evaluation is under way to assess this new mode of treatment, including the mode activated by the patient, safety and tolerance of the shocks. ",
"In our two patients, the treatment of prolonged episodes of AF was followed by reduction of many short or asymptomatic episodes."
] |
{
"pile_set_name": "PubMed Abstracts"
}
|
[
0.019230769230769232,
0,
0.007936507936507936,
0,
0.008064516129032258,
0,
0,
0,
0,
0,
0,
0,
0,
0
] | 0.002517
| 5
|
[
"420 F.2d 347\nAnthony G. SAVILLE, Petitioner, Appellant,v.Daniel A. O'BRIEN, Superintendent of Massachusetts Correctional Institution at Warwick, Massachusetts, Respondent, Appellee.",
"\nNo. ",
"7372.",
"\nUnited States Court of Appeals First Circuit.",
"\nDecember 17, 1969.",
"\nRehearing Denied January 13, 1970.",
"\n\nJohn G. S. Flym, Boston, Mass., for appellant.",
"\nLawrence P. Cohen, Asst. ",
"Atty. ",
"Gen., with whom Robert H. Quinn, Atty. ",
"Gen., John Wall, Asst. ",
"Atty. ",
"Gen., Chief, Criminal Division, Edward W. Hanley III, Asst. ",
"Atty. ",
"Gen., Matthew J. Ryan, Jr., Dist. ",
"Atty., ",
"Western District, and Leonard E. Gibbons, Asst. ",
"Dist. ",
"Atty., ",
"were on brief, for appellee.",
"\nBefore ALDRICH, Chief Judge, WOODBURY,* Senior Circuit Judge, and McENTEE, Circuit Judge.",
"\nMcENTEE, Circuit Judge.",
"\n\n\n1\nPetitioner, Anthony G. Saville, a state prisoner, was convicted in the Superior Court of Massachusetts on two indictments charging him with possession of counterfeit bank bills and possession of counterfeiting equipment in violation of M.G.L. (Ter. ",
"ed.) ",
"ch. ",
"267, §§ 9, 13. ",
"On appeal, the Supreme Judicial Court upheld the convictions, affirming the trial court's denial of petitioner's motion to suppress evidence obtained by a search made under a warrant allegedly issued without probable cause.1 Petitioner then sought a writ of habeas corpus. ",
"After an evidentiary hearing, the district court denied the writ. ",
"On Saville's request for a certificate of probable cause we agreed to hear his appeal but only on the question of whether there was probable cause for the issuance of the search warrant.",
"\n\n\n2\nThe warrant in question, issued on July 4, 1966, by one Collins, clerk of the Springfield district court, was based on the affidavit of Sergeant Desrosiers of the West Springfield Police. ",
"The affidavit, which was typed by Collins from what Desrosiers told him, reads as follows:\n\n\n3\n\"I have information based upon * * * statements made to me by Detective Richard Hurley of the Connecticut State Police that John J. Parisi has stated that Anthony Saville of 38 Burford Avenue West Springfield gave said Parisi 150 counterfeir (sic) ten dollar bills, this occurring at the print shop of said Saville located at 212 Bosworth Street in West Springfield yesterday afternoon.\" ",
"Two other affidavits, submitted by Desrosiers to the same court clerk earlier the same day in support of applications for warrants to search Parisi's home and place of employment, revealed that he had been arrested in Connecticut the previous day on charges of uttering counterfeit money and that when arrested he had in his possession forty bogus ten dollar bills.2\n\n\n4\nOn the basis of the information contained in the three affidavits,3 the clerk issued a warrant to search petitioner's print shop and evidence obtained in the search was introduced against him at trial.4\n\n\n5\nIn Jones v. United States, 362 U.S. 257, 269, 80 S.Ct. ",
"725, 729, 4 L.Ed.2d 697 (1960), the Supreme Court held that hearsay may be the basis for the issuance of a search warrant \"so long as [there is] a substantial basis for crediting the hearsay.\" ",
"This holding was amplified in Aguilar v. Texas, 378 U.S. 108, 84 S.Ct. ",
"1509, 12 L.Ed.2d 723 (1964). ",
"There the Court stated that where an affidavit is based on hearsay, the magistrate must be informed of some of the underlying circumstances from which the officer concluded that the informant was credible and his information reliable. ",
"The rule is the same whether the identity of the informant is disclosed or not. ",
"The sound policy behind this rule is to insure that a neutral officer is afforded the opportunity to exercise his independent judgment as to whether certain information in the hands of the police is sufficient to justify an invasion of privacy.",
"\n\n\n6\nThe affdavit in this case fails to satisfy the requirements of Aguilar.5 It said only that Detective Hurley had told Desrosiers that Parisi \"had stated\" that Saville gave him the counterfeit money at his print shop. ",
"Thus, Hurley may have received a call from someone who claimed to have overheard the remark at the neighborhood bar, see Spinelli v. United States, 393 U.S. 410, 417, 89 S.Ct. ",
"584, 21 L.Ed.2d 637 (1969); a cellmate of Parisi's could have furnished the information to the police; or the hearsay chain could have comprised only police officers. ",
"The affidavit simply did not reveal when or to whom the statement had been made.",
"\n\n\n7\nAs we have indicated, a basic policy of the Fourth Amendment is that the judgment of an independent magistrate should be interposed between the police and a suspect before an invasion of privacy is countenanced. ",
"See, e. g., Johnson v. United States, 333 U.S. 10, 14, 68 S.Ct. ",
"367, 92 L.Ed. ",
"436 (1948). ",
"The affidavit in the case at bar prevents the making of such a judgment by providing insufficient information for the purpose. ",
"Accordingly, we hold that the affidavit was insufficient on its face.",
"\n\n\n8\nThe danger presented by such a document is not hypothetical. ",
"Although we base this decision solely on the insufficiency of the warrant, we note that the evidentiary hearing below revealed that Detective Hurley had come by his information not from Parisi, but from an undisclosed third party, and that Desrosiers had obtained his information at least in part from the same unidentified informant. ",
"Moreover, since Desrosiers did not know to whom Parisi had spoken, nor through how many persons his information had passed before reaching Hurley, even Desrosiers could not have known whether the information was reliable or the informant credible.",
"\n\n\n9\nThis decision is consistent with Spinelli. ",
"There the Supreme Court was faced with an affidavit which stated, among other things, that the F.B.I. had been informed by a confidential, reliable informant that Spinelli was accepting wagers. ",
"In rejecting this statement as insufficient under Aguilar's dual standard, the Court observed that there was no indication how the informant came by this information. ",
"The affidavit did not say that he had personal knowledge nor, assuming that he had obtained the information indirectly, why his source was reliable. \"",
"It is clear,\" the Court concluded, \"that a Commissioner could not credit it without abdicating his constitutional function.\" ",
"Spinelli, supra at 416, 89 S.Ct. ",
"at 589.",
"\n\n\n10\nNor is it significant that one of the informants in the hearsay chain is named in the affidavit:\n\n\n11\n\"Irrespective of the informant's reliablity, he in turn may have received his information from someone wholly unreliable. ",
"Consequently, the fact that the agent vouched for the credibility or reliability of the informant cannot reach the crucial question posed by the hearsay on hearsay situation present in this case. ",
"For the reliability of both the anonymous hearsay source and the information he imparted to the informant is totally lacking.\" ",
"United States v. Roth, 391 F.2d 507, 510-511 (7th Cir. ",
"1967).",
"\n\n\n12\nInformant Hurley's source was in fact totally unreliable, because it was totally unknown.",
"\n\n\n13\nUnited States v. Ventresca, 380 U.S. 102, 85 S.Ct. ",
"741, 13 L.Ed.2d 684 (1965), does not require a different result. ",
"In that case the Court defined the standard by which a reviewing court should interpret affidavits which are made in support of warrants. ",
"It held that,\n\n\n14\n\"where [the] circumstances are detailed, where reason for crediting the source of the information is given, and when a magistrate has found probable cause, the courts should not invalidate the warrant by interpreting the affidavit in a hypertechnical, rather than a commonsense, manner.\" ",
"Ventresca, supra at 109, 85 S.Ct. ",
"at 746.",
"\n\n\n15\nIn that case a search warrant was obtained based on the affiant's belief that an illegal distillery was being operated in defendant's home. ",
"His information came both from personal observations and \"information received from other Investigators * * * assigned to this investigation.\" ",
"In upholding the validity of the affidavit, the Court held that it could not conclude that the whole warrant was based on hearsay because the affiant swore to at least partial personal observation. ",
"As to the information not based on personal observation, the Court observed that, read as a whole, the detailed observations recounted in the affidavit could not be fairly regarded as having come from other than official sources, and that observations made by fellow officers engaged in a common investigation are reliable.",
"\n\n\n16\nThe affidavit in the instant case is readily distinguishable for there is no claim that the affiant had personal knowledge and there is no indication that the information he imparted to the clerk came from official, viz., ",
"reliable, sources. ",
"Although Parisi, the imputed source of the information, was known, for reasons already stated the authenticity of the statement attributed to him could not be verified. ",
"To read this affidavit as anything but an open ended document giving no clue to the actual source of Detective Hurley's information, would go far beyond a \"commonsense interpretation.\" ",
"As we said in Rosencranz v. United States, 356 F.2d 310, 317 (1st Cir. ",
"1966):\n\n\n17\n\"It is one thing to expect the magistrate to give a commonsense reading to facts set forth and to draw inferences from them. ",
"It is quite another thing to expect the magistrate to reach for external facts and to build inference upon inference in order to create a reasonable basis for his belief that a crime is presently being committed.\"",
"\n\n\n18\nWe next consider the question of whether the error was harmless. ",
"Chapman v. California, 386 U.S. 18, 87 S.Ct. ",
"824, 17 L.Ed.2d 705 (1967). ",
"The standard that must be applied is whether it was harmless beyond a reasonable doubt. ",
"Chapman, supra at 24, 87 S.Ct. ",
"824. ",
"With regard to the search there was extensive testimony by two policemen and two experts. ",
"A state trooper described how he, in the company of three other policemen, searched the Saville premises and found a photographic negative of a ten dollar bill in a rubbish barrel behind the print shop. ",
"Desrosiers testified as to how he assisted in finding the negative, and also described in detail all the equipment that had been removed from the print shop in execution of the warrant. ",
"One expert witness testified that a lithograph machine produced by his company and owned by petitioner was capable of producing counterfeit money. ",
"He also gave his opinion regarding the photographic process that would have to be used to produce counterfeit money, stated that a vacuum frame could be used to make a counterfeit plate, and identified one of the Commonwealth's exhibits as a vacuum frame. ",
"The other expert was a special agent of the United States Secret Service who testified concerning the photographic negative seized at the shop, and stated that the bills in evidence, seized from Parisi, were counterfeit. ",
"By the Chapman standard, it cannot be gainsaid that the error complained of did contribute to petitioner's conviction on the charge of possessing counterfeiting equipment.",
"\n\n\n19\nBut petitioner was also convicted on the more serious charge of \"unlawful possession of bank bills with intent to utter.\" ",
"If his conviction on this count was not infected by the constitutional error, petitioner has not been prejudiced and cannot gain his freedom. ",
"Applying the Chapman test, however, we think that petitioner's conviction on this charge cannot stand either. ",
"The state's case against him rested on Parisi's testimony. ",
"But we are not willing to speculate that the accumulated testimony describing the search, and the evidence seized in its wake, did not influence the jury's determination of guilt on this charge also. ",
"Our decision, of course, does not prevent the state from retrying the petitioner, within a reasonable time, without relying on the tainted evidence.",
"\n\n\n20\nJudgment will be entered vacating the judgment of the district court and remanding the case to that court for further proceedings consistent with this opinion.",
"\n\n\n\nNotes:\n\n\n*\n By designation\n\n\n1\n Commonwealth v. Saville, 353 Mass. 458, 233 N.E.2d 9 (1968)\n\n\n2\n These two affidavits read, in part, as follows: \"I have information based upon * * * statements made to me by Detective Richard Hurley of the Connecticut State Police, Westbrook Barracks, that on July 3, 1966 one John P. Parisi of 38 Burford Avenue, West Springfield, was arrested in Old Lyme, Connecticut, on ten counts of uttering counterfeit ten dollar bills and that at the time of his arrest the said Parisi had in his possession forty counterfeit ten dollar bills all bearing serial # A-13705685-D. The said Parisi has a prior record for uttering forged checks in this Commonwealth.\"",
"\n\n\n3\n During oral argument counsel for petitioner conceded that the court could consider all three affidavits on the theory that they added nothing to the Commonwealth's case\n\n\n4\n Among the articles seized were a photostat copying machine; sheets of stock paper; a negative of the reverse side of a $10 bill; two pieces of cloth with printer's ink on them; three pieces of burnt paper stock, and other articles containing printer's ink. ",
"No counterfeit money was found\n\n\n5\n Where a magistrate has only the affidavits before him, the warrant must be judged on their contents. ",
"Aguilar v. Texas,supra at 109 n. 1, 84 S.Ct. ",
"1509.",
"\n\n\nON PETITION FOR REHEARING\n\n21\nPER CURIAM.",
"\n\n\n22\nAppellee's petition for rehearing, in addition to taking the inexcusable liberty of stating, three times, that we decided the case on a ground that we specifically said we did not, exhibits a misconception that we think calls for a substantive reply. ",
"Appellee concedes that there was a \"possibility\" that the essential affidavit was based on hearsay, but says that the magistrate was warranted in concluding otherwise, and that it was \"hypertechnical\" and \"speculative\" for us to say he could not. ",
"What appellee forgets is that the issuance of a warrant requires a showing of probable cause. ",
"This means that the moving party has a burden of proof. ",
"If an affidavit is blind as to whether it is based on hearsay or not, that burden is not met. ",
"Any other rule would permit the party seeking a warrant, and having only hearsay, to leave the affidavit blind, and hope for the best. ",
"It is not to be forgotten that if the information is reliable, or based upon other than hearsay, it is very easy for the party who is seeking the warrant, and who has complete control over what he chooses to produce, to say so.",
"\n\n\n23\nThe petition for rehearing is denied.",
"\n\n"
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"QUnit.test('AddPoint animation param (#5665)', function (assert) {\n\n var clock = TestUtilities.lolexInstall();\n var interval,\n done = assert.async(),\n chart = new Highcharts.",
"Chart({\n chart: {\n renderTo: 'container',\n width: 600,\n animation: {\n duration: 1000\n },\n type: 'spline',\n events: {\n load: function () {\n interval = setInterval(function () {\n this.series[0].addPoint(Math.random(), true, true, false);\n }.bind(this), 400);\n }\n }\n },\n series: [{\n data: [10, 10, 10, 10]\n }]\n });\n\n setTimeout(function () {\n clearInterval(interval);\n assert.strictEqual(\n chart.renderer.globalAnimation,\n false,\n 'Animation correctly set'\n );\n done();\n }, 1000);\n\n TestUtilities.lolexRunAndUninstall(clock);\n});\n"
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[
"1. ",
"Technical Field\nThe present invention relates to a discharge valve apparatus, a flush water tank apparatus including this discharge valve apparatus, and a flush toilet including this flush water tank apparatus; in particular, it relates to a discharge valve apparatus attached to a discharge port on a flush water tank for storing flush water used to flush a toilet, a flush water tank including this discharge valve apparatus, and a flush toilet including this flush water tank apparatus.",
"\n2. ",
"Description of Related Art\nAs shown in Patent Document 1 (Japanese Patent Unexamined Publication No. ",
"2013-104271), what are known as direct drive discharge valve apparatuses have been known for some time, in which an operating member extending from a manual operating apparatus is attached to a primary shaft member of a valve body disposed inside a discharge valve apparatus casing, and the valve body and valve body primary shaft member are pulled up from a valve port through a lifting action by the operating member moving in tandem with the manual operation.",
"\nIn such discharge valve apparatuses, an operating member extending from a manual operating device is attached to the primary shaft member of a valve body inside a casing when manufactured at a factory or the like, and the exterior casing of the discharge valve apparatus is assembled so as not to be easily removable and disassembled."
] |
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"pile_set_name": "USPTO Backgrounds"
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[
"Q:\n\nShould bugs be estimated in story points?",
"\n\nShould bugs be estimated in story points according to the Scrum methodology?",
"\nIn particular, what if a bug appears to be a quite complicated task, which in fact is a some missed functionality which has to be added, but it is formally still a bug from the client's point of view?",
"\n\nA:\n\nsome missed functionality which has to be added\n\nIt is not a bug; it is additional functionality.",
"\nIf the client still wants to classify it as a bug, that's fine. ",
" For the team doing the work it is a new effort. ",
" Therefore it should be treated as such.",
"\nEDIT\nAs a framework, Scrum does not specify specifics of process. ",
" There are no requirements to use user stories, story points, or even bugs. ",
" There are some common \"best practices\" out there. ",
" The team must determine what and how to use metrics, processes, etc. ",
"to the benefit of the product.",
"\n\nA:\n\nI believe this largely depends on the source of the bug. ",
"In my experience bugs are picked up in one of two ways:\n\nBugs in the work which is currently being developed\nA bug which escaped the in initial QA net and has been either found in a regression test, some exploratory testing, or reported by a customer.",
"\n\nIf the bugs you're talking about fall into the first category then they should already be covered in the User Story estimate - how long a piece of work will take to complete includes its estimation of complexity.",
"\nHowever, if we're talking about bugs which have been detected outside the current sprint then there are a couple of different ways of doing this. ",
"If they're P1 issues then they're likely to interrupt the current sprint and any estimation is most likely an overhead you don't need (and will be to be looked at immediately regardless of whether they're 1SP or 10SPs). ",
"However bugs which can be added to the backlog should be treated as any other backlog item (priorised and estimated alongside any other items). ",
"It's also worth mentioning that not all issues raised by customers are bugs, some are scripts/data fixes which should be treated in the same way.",
"\nUltimately any bug will take time time out of your sprint, but a low priority bug which will take a long time to fix will have a much lower business value than an urgent User Story. ",
"Estimating the effort involved in fixing it makes this a lot clearer.",
"\nIn short, estimating bugs for active User Stories and P1 support issues gives little value but there are definite advantages of estimating anything which can be scheduled to be fixed in future sprints.",
"\n\n"
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[
"INTRODUCTION {#sec0005}\n============\n\nA perspective from amyloid chromatography {#sec0010}\n-----------------------------------------\n\nA key biomarker for Alzheimer's disease (AD) progression is a decline in the concentration of the 1--42 isoform of amyloid-beta (Aβ~42~) in patient cerebrospinal fluid (CSF), which is correlated with clinical progression of AD \\[[@ref001]\\]. ",
"The basis of this drop in Aβ~42~ in CSF is believed to be sequestration of Aβ~42~ into insoluble deposits within the brain tissue. ",
"This phenomenon, the decline in a soluble protein in its mobile phase resulting from aggregation, is reminiscent of a common occurrence encountered by protein biochemists when performing high performance liquid chromatography (HPLC) that uses stainless steel capillary connecting tubing.",
"\n\nOur research group used this HPLC connecting tubing in experiments that subjected solutions of a number of different aqueous protein solutions to liquid shear (defined below) by forcing these solutions through this very small inner diameter tubing \\[[@ref003]\\]. ",
"Under certain experimental conditions, we demonstrated unexpected behavior, including deposition of solid protein aggregates on the capillary wall. ",
"We suggested that this deposition resulted from shear-induced aggregation of proteins due to the very small diameter of the capillary tubing.",
"\n\nRecently, it has been reported to this author \\[private communication, David Teplow\\] that HPLC amyloid studies in numerous laboratories find that significant amounts of amyloid disappear from the HPLC mobile phase. ",
"This result is anticipated by this author because of the many reports of sensitivity of Aβ, especially the Aβ~42~ isoform, to shaking, stirring, and other shear-generating disturbances and especially because of the report in which Aβ solutions are deliberately subjected to shear in carefully controlled circumstances and in which shear initiates a classic amyloid chemical cascade producing amyloid fibrils \\[[@ref004]\\]. ",
"The author of this paper attributes these HPLC amyloid losses primarily to shear-induced amyloid wall deposition in HPLC capillary tubing \\[[@ref003]\\]. ",
"Why is this wall deposition in narrow metal capillaries critical to AD clinicians and researchers, and what is the suspected molecular explanation for this protein aggregation?",
"\n\nExperimental findings studying the aggregation behavior of Aβ suggest that molecular shear, such as that encountered by proteins passing through HPLC capillaries, may contribute to the process of Aβ aggregation. ",
"Dustan and coworkers \\[[@ref004]\\] have suggested that even gentle shear used in their experiments, where only one hydrogen bond per molecule is broken, can initiate an amyloid cascade producing Aβ solids. ",
"It is well established that Aβ aggregates form more readily in solutions undergoing shear-generating disturbances. ",
"The question raised in this paper is whether similar shear forces are present in the brain that lead to Aβ aggregation and other possible related detrimental health consequences involving Aβ.",
"\n\nRecent studies describing the bulk flow of CSF and interstitial fluid (ISF) along perivascular pathways (PVP) suggest to this author that Aβ in these solutions moving through tightly confined spaces are probably undergoing a similar type of shear stress to that seen in the shear experiments described above. ",
"The following discussion will suggest the influence that molecular shear may have on the aggregation of proteins like Aβ, detail how bulk flow through PVP and the wider brain extracellular compartment may initiate shear-induced chemical processes, especially in the presence of membranes, and propose a role for this process in the membrane adsorption and deposition of Aβ~42~ in extracellular plaques and Aβ~40~ in the walls of cerebral arteries in cerebral amyloid angiopathy (CAA).",
"\n\nWhat is liquid shear? {#",
"sec0015}\n---------------------\n\n[Figure 1](#jad-54-jad160027-g001){ref-type=\"fig\"} illustrates various types of shear. ",
"There are two important types of liquid shear \\[[@ref005]\\] that can occur in the brain, laminar and extensional. ",
"Laminar shear is found, for example, in liquids confined to flow within a narrow bore capillary tube ([Fig.",
" 1c](#jad-54-jad160027-g001){ref-type=\"fig\"}) where the laminar flow rate profile of the liquid is bullet-shaped, fastest in the center and zero at the capillary wall. ",
"Any water-based liquid moving parallel to a wetted capillary wall will incur a maximum liquid shear stress in that solid-liquid boundary capillary wall region, and the minimum shear is found in the very center of the capillary. ",
"Why is this so? ",
"We can consider a flowing liquid inside a capillary as a set of very thin, hollow, very long, telescoping concentric liquid cylinders of equal thickness. ",
"In laminar flow, each cylinder flows within the capillary at a different speed than its neighbor because the layer next to the wall is an aqueous solution that sticks to the wall and does not move. ",
"The largest speed difference between these thin neighboring cylinder layers is found at the wall and the smallest speed difference is found at the very center of the capillary. ",
"Liquid shear is defined as the speed difference between each layer and its neighbor. ",
"Therefore, the largest shear rate will be found at the wall where the flow rate of the wetting layer immediately next to the wall is zero. ",
"Thus the resulting maximum shear stress is found between the flowing liquid layer next to that solid wall liquid boundary. ",
"This is illustrated in [Fig.",
" 2](#jad-54-jad160027-g002){ref-type=\"fig\"}, where the flow rate differences, indicated by the differences between neighboring arrow lengths, is smallest in the center and largest next to the wall, where there is no arrow at the wall because the flow rate there is zero. [",
"Figure 2](#jad-54-jad160027-g002){ref-type=\"fig\"} also illustrates the differing shear distortion effects on coiled polymer molecules residing in different parts of the capillary stream, the highest molecular distortion occurring next to the wall and the lowest in the center of the capillary. ",
"The molecule scale is greatly exaggerated in comparison with the scale of the capillary.",
"\n\n*Extensional shear* is generated, as illustrated in [Fig.",
" 1d](#jad-54-jad160027-g001){ref-type=\"fig\"}, when liquid flows through a tube whose diameter decreases with distance down the flow direction of the tube. ",
"A macroscopic example of extensional shear is a stream with dangerous rapids, where the water is forced to flow between many large exposed rocks. ",
"As water approaches the gap between two large rocks, it accelerates and then slows down again after passing between them, with eddies behind the rocks on the downstream side. ",
"If a coil of rope is put in upstream from the rocks, it has a tendency to stretch out as it transits the passage between the rocks. ",
"This is because there are accelerating water flow rates on the upstream side as the rope approaches the rock gap and decelerating water flow rates on the downstream side of the narrow rock passage, relaxing the stretch. ",
"Thus, initially the front part of the rope can experience stronger acceleration than the lagging part of the rope. ",
"The narrower the passage between the rocks, the faster the maximum flow through the passage between the rocks and the larger the extensional shear, illustrated in [Fig.",
" 3](#jad-54-jad160027-g003){ref-type=\"fig\"}.",
"\n\nExtensional shear can stretch a flexible polymer molecule. ",
"This is especially true of a certain class of protein polymers designated as intrinsically disordered proteins (IDP) \\[[@ref006]\\] that have many different possible conformations at normal temperatures rather than one fixed conformation. ",
"This IDP class includes Aβ molecules, among other amyloids.",
"\n\nThis paper proposes that both laminar and extensional shear of Aβ-containing CSF and ISF can play important roles in both the parenchymal and vascular parts of the brain by providing enough energy in the form of shear to induce molecular conformational changes that open new chemical pathways to flexible Aβ and other IDP molecules. ",
"It is proposed that these very narrow, congested brain pathways can lead to both aggregation and interaction with membrane walls confining the CSF and ISF.",
"\n\nTHE PROPOSED ROLE OF SHEAR IN AMYLOID-BETA AGGREGATION {#sec0020}\n======================================================\n\nThere are two major natural isoforms of Aβ, Aβ1--40 (Aβ~40~), and Aβ1--42 (Aβ~42~), composed of chains of 40 and 42 linked amino acids, respectively. ",
"Each of these isoforms, under certain temperature, pH, and Aβ concentration, and solution preparation conditions, spontaneously undergoes an *in vitro* amyloid cascade aggregation, which involves non-covalent Aβ molecule bonding reactions that proceed through a low molecular mass oligomer stage, proceeding then to a protofibril, and then to a fibril state that is similar in molecular structure with that found in AD plaque \\[[@ref007]\\]. ",
"Shaking and stirring of Aβ solutions initiates Aβ aggregation under conditions where no cascade reaction occurs in the absence of shear.",
"\n\nStudies of Aβ fibril formation have demonstrated that both the kinetics of fibril formation \\[[@ref008]\\] and types of fibril conformations \\[[@ref007]\\] are qualitatively different in quiescent and agitated solutions, implying that shear associated with agitation--- or that associated with passage of restricted flow in narrow passages such as that which occurs in a narrow diameter capillary tube--- may exert a powerful influence on Aβ aggregation. ",
"Shear may therefore be a key variable in the formation of amyloid plaques if Aβ-containing fluids are subject to shear within the brain.",
"\n\nAβ~42~, being a more hydrophobic molecule \\[[@ref009]\\], is much more sensitive to agitation-induced aggregation shear than Aβ~40~. Experiments with Aβ utilizing carefully defined shear conditions where there is not enough shear energy to break more than one hydrogen bond per Aβ molecule, have demonstrated shear-induced formation of amyloid fibrils \\[[@ref004]\\], indicating that it is not necessary to unfold the Aβ molecule to initiate the Aβ cascade reaction.",
"\n\nGiven the above discussion, our capillary protein results, and the report of similar losses from Aβ solutions undergoing HPLC experiments, this author suggests that these experimental results have a common shear-induced aggregation explanation that may provide clues to plaque formation in the brain \\[[@ref010]\\]. ",
"For example, given the very high sensitivity of Aβ~42~ to shear in comparison with the Aβ~40~ isoform \\[[@ref008]\\], it might be expected that, in brain regions where brain fluids containing Aβ are exposed to mild shear, Aβ~42~ might be subject to aggregation, whereas Aβ~40~ would be more resistant to shear. ",
"Thus, the CSF or ISF monomer Aβ~42~/Aβ~40~ concentration ratio would drop in the brain region with low shear as the aggregated Aβ~42~ selectively dropped out of solution. ",
"This same drop in Aβ~42~/Aβ~40~ ratio in spinal tap CSF is currently used as one of a limited number of successful biomarkers for following the progression of AD.",
"\n\nThe fluid flow geometry used in nearly all published *in vitro* Aβ shear experiments is generally not appropriate for modeling brain processes because the Aβ fluids did not have the same degree of flow restrictions that lead to the types of shear, especially extensional shear, suspected to be present in the brain. ",
"The author suggests that our capillary experiments \\[[@ref003]\\], updated and appropriately modified, can be used as a more appropriate model for studying shear processes such as ISF passage through the very narrow passages in brain parenchyma and CSF in vascular regions.",
"\n\nRelatively little is known about the fluid flow rates in those locations of the brain in which fluid shear might exist. ",
"It was earlier thought that there was no fluid flow within the brain parenchyma \\[[@ref012]\\]. ",
"However, the work of Cserr and coworkers \\[[@ref013]\\] appears to demonstrate that interstitial bulk flow does indeed take place. ",
"Evidence from studies carried out in rodents, including mice and rats, shows that CSF moves relatively rapidly along PVP surrounding brain blood vessels leading into the brain while ISF is reportedly drained along different periarterial pathways leading out of the brain \\[[@ref014]\\]. ",
"It is claimed that both of these brain fluid flows take place through basement membranes, the ISF through muscle cell membranes and the CSF through pial-glial basement membranes \\[[@ref014]\\].",
"\n\nShear in the brain vascular system {#sec0025}\n----------------------------------\n\nBecause of uncertainties in the structures and flow rates of CSF in the PVP, it is currently not possible to pinpoint the exact PVP structures or vascular regions where shear might be important. ",
"However, it is clear that Aβ-containing CSF flows into the brain perivascular pathway close to the outer walls of the arterioles. [",
"Figure 4](#jad-54-jad160027-g004){ref-type=\"fig\"} illustrates the probable locations of these postulated PVP locations \\[[@ref014]\\].",
"\n\nIt was originally suggested that the flow of CSF through the PVP is powered only by cerebral arterial pulsation. ",
"However, reports of recent NMR investigations of CSF-containing human brain ventricles \\[[@ref017]\\] suggest that the prime powering force for CSF flow in brain ventricles is the breath inhalation-exhalation cycle, with superimposed minor higher frequency heart pulse cycle contributions. ",
"These studies deal with CSF flow through the ventricular and cisternal spaces, and do not address perivascular fluid movement. ",
"It is reasonable to presume that respiration plays an important role, since it is apparently a key driver of CSF flow, but this has not been tested to date.",
"\n\nBlood pressure and arterial blood flow rates are controlled mainly by arterioles, whose endothelial cells control by chemical and mechanical means about 80% of the flow rate through the arterioles and into the capillaries. ",
"The means by which this is accomplished are complex, but it is clear that such control involves continuous adjusting of large parts of the arteriolar wall \\[[@ref018]\\]. ",
"It is not known how these adjustments affect the coupled flow and shear rates of the CSF in the PVP. ",
"Tracing CSF flow through the artery PVP to the narrower arteriolar region, it would be expected that the arteriolar PVP would also narrow because of overall space restrictions. ",
"Such narrowing could be a source of extensional shear in addition to laminar shear on walls confining the flowing CSF. ",
"If this flow is through basement membranes \\[[@ref014]\\], then additional shear from membrane structures will be encountered, as discussed below.",
"\n\nThus, periarterial Aβ molecules are subject to shear forces that can promote conformational changes that store shear energy in shear-distorted Aβ\\* molecules. ",
"These unstable molecules now are prone to thermodynamic forces that drive them to preferentially diffuse to regions of lower shear \\[[@ref019]\\]. ",
"One such region is the overlapping endfoot processes (OEP) between astrocyte feet in the arteriolar PVP (see [Fig.",
" 4](#jad-54-jad160027-g004){ref-type=\"fig\"}). ",
"This preferential migration would tend to increase the Aβ concentration in OEP regions of the PVP. (",
"See [Supplementary Material A](#S1){ref-type=\"supplementary-material\"} for further discussion of this concept.)",
"\n\nISF efflux routes used to rid brain parenchyma of Aβ waste {#sec0030}\n----------------------------------------------------------\n\nAβ is generated from the enzyme degradation of amyloid-β protein precursor in the synapse membrane. ",
"However, Aβ becomes part of a toxic molecule when incorporated into non-covalently bonded Aβ aggregate oligomer products. ",
"Therefore, Aβ-containing ISF must be cleared from the brain parenchyma before oligomer formation. ",
"Based on tracer studies, Carare and Weller and their collaborators have suggested \\[[@ref014]\\] that the primary route for this Aβ waste clearance process is primarily along vascular basement membranes. ",
"This proposed Aβ ISF efflux clearance route starts at the capillary basement membrane connecting to the basement membranes of the smooth muscle cells of the arteriole and then to the basement membranes of the arteries leading out of the cortex and the meninges arteries in the SAS, ultimately flowing into the lymphatic system. ",
"The flow of Aβ-containing ISF along this very narrow, tortuous, and relatively tightly confined route offers many opportunities for detrimental laminar and extensional shear-induced Aβ aggregation reactions.",
"\n\n[Figure 5](#jad-54-jad160027-g005){ref-type=\"fig\"} summarizes the above discussion regarding the Aβ-containing CSF flow path that parallels the arterial blood flow and illustrates the periarterial return flow ISF suggested by Carare and coworkers \\[[@ref014]\\], originating in the brain parenchyma next to the parenchyma capillaries and that flows in the opposite direction from that of the arterial and capillary blood flow, shown in [Fig.",
" 5](#jad-54-jad160027-g005){ref-type=\"fig\"} by dashed lines.",
"\n\n[Figure 5](#jad-54-jad160027-g005){ref-type=\"fig\"} also includes the more recent introduction of another proposed ISF flow pattern, namely the \"glymphatic system\" introduced by Nedergaard and colleagues \\[[@ref021]\\]. ",
"This glymphatic Aβ waste disposal system relies on a proposed tortuous, shear-inducing passage through the extracellular spaces (ECS) in the tightly-packed brain parenchyma, exiting the brain through perivenous flow paths. ",
"This glymphatic system is indicated at the center bottom of [Fig.",
" 5](#jad-54-jad160027-g005){ref-type=\"fig\"}. ",
"The contact between the two [Fig.",
" 5](#jad-54-jad160027-g005){ref-type=\"fig\"} circular brain fluid pathways represents the interface between the vascular CSF and parenchyma extracellular space ISF through the astrocyte OEP openings to the parenchyma.",
"\n\nIn the above discussion, the search has been for those regions in the brain where Aβ shear processes might be present. ",
"Two main regions have been identified, the vascular basement membranes containing the PVP and the Cararare-Weller ISF exit path, and the brain parenchyma. ",
"The next question to be addressed is what happens to Aβ molecules in the latter brain shear region that might initiate an amyloid cascade or other chemical reaction leading to toxic consequences?",
"\n\nShear effects on amyloid molecules {#sec0035}\n----------------------------------\n\nLaminar shear ([Fig.",
" 2](#jad-54-jad160027-g002){ref-type=\"fig\"}) can originate in any liquids confined to flow between narrow confining walls in the brain vascular system and parenchyma. ",
"The conformation of Aβ molecules under shear stress can be distorted in such a way that interior hydrophobic regions of the molecule are exposed to the Aβ's hydrophilic exterior environment ([Fig.",
" 6a, b](#jad-54-jad160027-g006){ref-type=\"fig\"}). ",
"Because of the narrowing of the brain fluid passage as it penetrates into the very narrow PVP and ECS flow passages of the vascular system and the brain parenchyma, there is also a high probability of developing extensional CSF shear ([Fig.",
" 6b](#jad-54-jad160027-g006){ref-type=\"fig\"}). ",
"Thus the shearing of the Aβ molecule can cause it to be stretched into more linear, higher energy conformations, designated as Aβ\\*, the asterisk representing an unstable, shear-excited molecular state.",
"\n\nProtein conformations, wall adsorption, and shear {#sec0040}\n-------------------------------------------------\n\nWhen solutions of highly flexible IDP such as Aβ are confined and flow, possibly in a pulsed, oscillating manner, through the brain in narrow CSF or ISF flow passages, such as the very narrow biological confines found in PVP \\[[@ref023]\\] and brain parenchyma, they are probably subjected to significant liquid shear forces that result in reversible Aβ molecular conformation changes. ",
"Such shear forces are dependent on a number of factors. ",
"Among these are solution flow rate, flow path shape, objects restricting the flow passage around which the fluid must flow within the flow path, and, especially important, cross sectional dimensions that constrict the flow path. ",
"For example, liquid shear generated by flow through a capillary is inversely proportional to the cube of its radius under otherwise identical flow conditions! ",
"Thus, halving the inner diameter of a capillary increases the shear rate by a factor of eight, given the same flowrate.",
"\n\nIn our capillary experiments \\[[@ref003]\\], we observed in electron micrographs a significant protein coating on the capillary wall. ",
"There were also other indications of accelerated losses of proteins to the wall during repeated protein injections, suggesting that the initial wall coating promoted increased wall adsorption in a catalytic manner. ",
"In these experiments, there were indications of a dependence of the rate of this wall aggregation on initial dissolved protein concentration. ",
"There were also indications that metastable wall aggregates slowly dissolved back into the solvent following cessation of the mobile phase solvent flow through the capillary. ",
"This combination of reversibility and protein concentration dependence is highly reminiscent of previously proposed mechanisms for *in vitro* reversible amyloid fibril formation \\[[@ref008]\\] as well as of AD clinical studies showing correlations between increasing dementia with Aβ concentration in brain CSF \\[[@ref001]\\].",
"\n\nAs indicated on the left side of [Fig.",
" 6](#jad-54-jad160027-g006){ref-type=\"fig\"}, protein conformations in quiescent solutions are, on average, such that hydrophilic amino acid side chains are concentrated on the surface of the protein directly interfacing with the aqueous environment, whereas hydrophobic side chains are, on average, found near the interior of the protein. ",
"Stretching and distortion of the sheared protein forces inner hydrophobic sites closer to the hydrophilic fluid surface, producing a more surface-hydrophobic molecular conformation. ",
"In such a conformation, protein molecules under shear conditions are rendered much more vulnerable to aggregation with other nearby sheared protein molecules. ",
"Wall solute adsorption is likely on internal brain regions when membrane surface bonding forces correspond to those of shear-stressed solutes. ",
"Stressed proteins are apparently strongly attracted to a stainless steel capillary wall, probably because of polar and ionic attractions. ",
"When these stressed proteins adsorb on a surface, the resulting protein coating can change the surface characteristics in such a manner that alters the types of stressed proteins attracted to that surface. ",
"Repeated injections without column cleaning gave some indications of a catalytic effect of initial wall coatings. ",
"That is, losses to the wall per injection increased with successive injections of the same volume into the same column, in some cases with so much wall adsorbed solute that laminar flow was no longer observed.",
"\n\nIf shear is significant in fluid flow within the brain, and if the primary types of shear are laminar and extensional, then the parts of the brain that experience the maximum shear are at the confining flow path walls. ",
"That is, at the membrane surfaces confining and restricting ISF and CSF flow rates.",
"\n\nAβ is found in CSF entering the brain in PVP surrounding brain arteries. ",
"Studies indicate that Aβ-containing ISF enters the vascular walls through the capillary basement membranes \\[[@ref014]\\]. ",
"It is suggested that there are numerous opportunities in the vascular walls where shear could be responsible for the formation of CAA deposits formed within brain artery walls.",
"\n\nThe structure of the PVP is currently the subject of much research and uncertainty regarding the structure of this CSF flow pathway \\[[@ref014]\\]. ",
"Estimates of relative dimensions of the perivascular brain fluid flow path confinement spaces needed for shear rate estimates in the vascular and parenchymal brain regions indicate that parenchyma dimensions are many orders of magnitude smaller than those of the PVP \\[[@ref012]\\]. ",
"However, CSF flow rates are probably also many orders of magnitude larger in the PVP system than in the vascular system. ",
"Thus it is entirely possible that shear rates could be roughly comparable in the two brain fluid systems. ",
"Despite all these uncertainties, it is becoming increasingly clear that neither the Aβ present in the perivascular nor that in the parenchymal fluid system is in a totally quiescent situation, and therefore both are subject to fluid shear that could possibly initiate Aβ amyloid condensation and cascade reactions.",
"\n\nThe majority of *in vitro* experiments with Aβ and its toxic oligomers have been carried out in quiescent situations. ",
"A critical experiment on shear-induced Aβ aggregation has been carried out under carefully controlled shear conditions \\[[@ref004]\\]. ",
"However, the experimental conditions of this and all other shear experiments with Aβ do not tightly confine the liquid and generate the same types of shear that can be imagined within the brain, especially with respect to extensional shear.",
"\n\nProposed chemical effects of shear on Aβ in ISF and CSF {#sec0045}\n-------------------------------------------------------\n\nIt is suggested in this paper that CSF flow within certain sections of the PVP and tunica generated by a systole pulse may be sufficient to create a shear-stressed, conformation-altered Aβ molecule, Aβ\\*, near the adventitial, muscle cell, and astrocyte feet walls of the PVP. ",
"The shear-energy rich Aβ\\* then preferentially diffuses either toward or away from the walls, thermodynamically driven to diffuse to a lower shear region \\[[@ref019]\\]. ",
"Diffusion away from the wall lowers the shear rate and, depending on the inherent lifetime of the Aβ\\* molecule, it reverts to the original low energy state Aβ conformation, releasing its shear energy to the environment as heat.",
"\n\nAn Aβ\\* molecule found in a liquid next to a wall subjected to maximum shear stress can be forced into a high-energy, shear-distorted conformation, exposing to the aqueous surroundings new hydrophobic and hydrophilic and possibly ionic regions of the Aβ molecule. ",
"With increasingly high Aβ\\* concentration brain fluids present near the wall, such as those found in AD, collisions between two Aβ\\* molecules have an increasing probability of forming a more stable (Aβ)~2~ dimer near the wall because both entities have similar attractive hydrophobic and hydrophilic intermolecular forces attracting nearby Aβ\\* molecules to each other. ",
"This dimer is more stable because less hydrophobic region is exposed to water and would be expected to lower the excess stress energy and release it during the transition from (Aβ\\*)~2~ to (Aβ)~2~ as thermal energy to its surroundings. ",
"Formation of either one of these dimers could then initiate an amyloid cascade reaction by reacting with more Aβ or Aβ\\* molecules.",
"\n\nIt has been proposed that there is rapid fluid exchange at the capillary interface of ISF \\[[@ref015]\\], presumably through the astrocyte OEP. ",
"Because the width of this OEP opening is on the order of 20--50 nm \\[[@ref024]\\], there is a probability of shear-induced Aβ conformation change, especially for molecules located next to the OEP wall depending on the flow rate through the OEP. ",
"Thus, it is proposed here that this resistance to CSF flow from the PVP through the astrocyte OEP into the parenchyma as well as the resistance to the perivascular ISF return flow results in energetic conformation changes that depend on the ISF flow rates, the degree of flow restriction, and on the ambient Aβ concentration. ",
"It is proposed that the ultimate consequence of these restricted tortuous cardiovascular passages is the formation of shear-induced CAA solids within and around the vascular walls resulting from shear-induced Aβ\\* cascade reactions, one consequence being the possible filling or at least narrowing of the astrocyte OEP flow path.",
"\n\nFlow resistance and CAA deposits from basement membrane components {#sec0050}\n------------------------------------------------------------------\n\nPerivascular ISF return flow through the artery or arteriolar walls is reported to be through the basement membranes, primarily those of the muscle cells in the tunica media \\[[@ref014]\\]. ",
"Basement membranes are important not only because of this proposed perivascular ISF return flow and changes in arterial structure caused by AD \\[[@ref026]\\] but also because of their possible importance in potential brain parenchymal shear as discussed above and later in this paper.",
"\n\nThere are three major components of basement membranes: laminin, collagen IV, and heparan sulfate proteoglycans (HSPG). ",
"Laminin and collagen form the major structural elements of the basement membrane. ",
"All of these components will interfere with the flow of Aβ-containing brain fluids in both vascular and parenchymal regions. ",
"HSPGs, one of which is symbolically diagramed in [Fig.",
" 7](#jad-54-jad160027-g007){ref-type=\"fig\"} (laminin and collagen components are not shown), appear to be one of the most chemically active parts of the basement membrane. ",
"HSPG and other proteoglycans found in this membrane perform different biological functions. ",
"The co-localization of HSPG with several forms of amyloid plaque implies an involvement of this molecule in the mechanism of amyloid formation \\[[@ref026]\\]. ",
"Alterations of these membrane components take place during the progression of AD, in particular during the growth and thickening of the vascular wall. ",
"With respect to vascular processes in this paper, it is suggested that HSPG molecules may help catalyze the formation of CAA deposits. ",
"A postulated mechanism for this catalysis is described in [Supplementary Material B](#S1){ref-type=\"supplementary-material\"}. ",
"Further discussion of basement membrane processes is found below.",
"\n\nSHEAR WITHIN BRAIN PARENCHYMA {#sec0055}\n=============================\n\nFluid flow of ISF in parenchymal extracellular space {#sec0060}\n----------------------------------------------------\n\nRecent research has supported the idea that parenchymal ISF flow is slow, but not quiescent. ",
"One review \\[[@ref015]\\] challenges the traditional animal studies-based understanding of CSF physiology, citing more recent molecular and cellular biology and NMR neuroimaging reports of complex, poorly understood CSF flow reversals. ",
"In addition to a directed flow of CSF within the brain, according to this review, there is a \"pulsatile to and fro movement throughout the entire brain.\" ",
"There is, according to Brinker et al. ",
"\\[[@ref015]\\], \"a continuous bidirectional fluid exchange at the blood brain barrier \\[that\\] produces flow rates which exceed the choroidal CSF production rate by far.\" ",
"They conclude that \"CSF circulation is much more complex, a combination of directed bulk flow, pulsatile to and fro movement, and continuous bi-directional fluid exchanges at the blood brain barrier and the cell membranes at the borders between CSF and ISF spaces.\"",
"\n\nThus, in view of the above comments and if results of the mouse experiments of Xie et al. ",
"\\[[@ref027]\\] can be extrapolated to humans, there may be oscillatory ISF flow with little net ISF flow through the human brain parenchyma during wakeful periods. ",
"If the above is the case, what are the different possible fates of the two major Aβ isoforms following their release from the synapse? ",
"Are there possible shear-related hypotheses that can be constructed and tested in laboratory brain parenchyma models?",
"\n\nThe unique role of Aβ~42~ in brain parenchyma {#sec0065}\n---------------------------------------------\n\nHong et al. ",
"\\[[@ref028]\\] report that Aβ~42~ oligomers in mouse model AD experiments adsorb strongly to the ganglioside GM1 embedded in mouse hippocampal neuron membranes (see [Fig.",
" 7d](#jad-54-jad160027-g007){ref-type=\"fig\"}). ",
"Such neuron surface oligomer adsorption is suspected to cause interference with neuron functioning. ",
"This Aβ~42~ oligomer adsorption process is reported \\[[@ref028]\\] to account for a significant portion of the missing anticipated free Aβ~42~ in the parenchymal brain segment, in comparison with the amount estimated to be released from the synapse. ",
"Therefore, it is assumed that Aβ~40~, the only major soluble Aβ monomer conformer remaining, is flushed out of the parenchyma and is found in circulating brain CSF and thus predominates in the brain vascular amyloid deposits associated with CAA. ",
"Two important questions remain unanswered. ",
"Why isn't Aβ~40~ also involved in parenchymal processes? ",
"What is the origin of toxic Aβ~42~ oligomers in the parenchyma? ",
"Possible answers to these questions are discussed in detail in [Supplementary Material C](#S1){ref-type=\"supplementary-material\"}. ",
"A short summary covering the major points made in the Supplementary Material follows.",
"\n\nSuggested possible consequences of parenchymal shear {#sec0070}\n----------------------------------------------------\n\nIt is proposed that even very slow ISF parenchymal flow rates can cause shear-induced formation of Aβ~42~\\*, but generate insufficient shear energy to form Aβ~40~\\*~,~ in the very narrow ECS (extracellular spaces) of the parenchyma. ",
"Because the shear is highest next to the membrane surface, it is proposed that there is sufficient shear energy to form the Aβ~42~\\* molecules near the membrane that are shear-distorted sufficiently to expose sufficient new potential bonding sites so that they are attracted to corresponding bonding sites on the membrane surface.",
"\n\nIt is suggested that while adsorbed to the membrane, the Aβ~42~\\* loses its shear energy to the membrane, changes its conformation back to that of Aβ and ultimately leaves the membrane to again join the flowing ISF. ",
"If the local Aβ concentration is sufficiently low, this adsorption/de-excitation/desorption cycle allows both Aβ~40~ and Aβ~42~ to be eliminated from the parenchyma. ",
"This cycle merely lowers the steady state ISF concentration of Aβ~42~. However, as local Aβ concentration increases, there is increased probability that, while adsorbed on the membrane, an Aβ~42~\\* is able to encounter another Aβ~42~\\* adsorbed to the membrane surface and form an (Aβ~42~\\*)~2~ dimer, which loses its energy to the membrane to become a stable membrane-attached (Aβ~42~)~2~ dimer. ",
"This stable dimer can now react with successive Aβ~42~\\* molecules to ultimately form neurotoxic oligomers. ",
"Except for the initial adsorption of the Aβ~42~\\* from the ISF to the membrane, the remaining oligomer formation could take place on the membrane.",
"\n\nNot all the ISF Aβ molecules will be found on or will migrate to the membrane walls confining the flowing ISF. ",
"Those Aβ molecules that are just near enough to the membrane to be exposed to slightly less than maximum shear will encounter large molecules in the ECS, some of which jut out from but are anchored to the membrane and some of which are suspended in the ECS. ",
"These molecules, collectively designated as the perineuronal network (PNN) \\[[@ref029]\\], will act as ISF flow impediments and cause shear, especially if present at high densities, where this can cause extensional shear. ",
"Many of these macromolecular structures contain component proteins which have regions containing bonding sites that can attract passing Aβ molecules. ",
"It is proposed that, when the Aβ concentrations are low, shear-induced Aβ~42~\\* molecules are attracted and attach temporarily to these HSPG flow impediments before reversibly detaching after a short period. ",
"However, at higher Aβ concentrations, two Aβ~42~\\* molecules, one attached to an HSPG, can collide in the ISF stream and condense before the release of the adsorbed Aβ~42~\\*, and start building a condensation chain that ultimately becomes an Aβ fibril.",
"\n\nThus, there are postulated to be two separate shear-induced processes, one leading to toxic membrane-embedded oligomers, all shear-induced chemical action taking place on the membrane surface at high Aβ~42~ concentrations, and the other taking place near the membrane on HSPG molecules because of shear-induced chemical interactions taking place because of HSPG flow impediments. ",
"Each of these processes is separately highly sensitive to increasing Aβ concentration because of competition between adsorption/desorption and dimer-forming chemical reactions. ",
"Symbolic illustrations and more detailed justification for the above summary are found in [Supplementary Material C](#S1){ref-type=\"supplementary-material\"}.",
"\n\nThere would appear to be a shear-induced coupling between the vascular and parenchymal flow cycles illustrated in [Fig.",
" 10](#jad-54-jad160027-g010){ref-type=\"fig\"}. ",
"Both of these cycles are highly sensitive to increases in Aβ concentration. ",
"However, they involve different Aβ isoforms. ",
"Aβ~42~ is the key isoform involved in both the membrane and ESC/PNN region reactions involving the removal via membrane oligomer and fibril formation of most of the Aβ~42~ molecules from the parenchymal ISF. ",
"Therefore, any Aβ that is cleared from the parenchyma through the proposed perivascular ISF Carare-Weller return and glymphatic ISF Aβ clearance pathways involves primarily the Aβ~40~ isoform, which is that found predominantly in CAA deposits as seen in [Fig.",
" 10](#jad-54-jad160027-g010){ref-type=\"fig\"}. ",
"The dashed and dotted lines in [Fig.",
" 10](#jad-54-jad160027-g010){ref-type=\"fig\"} illustrate the main hypotheses contained in this paper.",
"\n\nSHEAR IN OTHER AMYLOID DISEASES {#sec0075}\n===============================\n\nThe above hypotheses regarding shear-induced Aβ conformation changes possibly involved in AD need not be limited to Aβ or to this disease. ",
"A similar case as that outlined above can be made for the importance of investigating the effects of shear on microtubule associated tau protein molecules, which are also in the IDP protein class and have neurotoxic oligomers \\[[@ref030]\\]. ",
"This author strongly suggests that fundamental *in vitro* research on the effects of shear on amyloids and tau molecules, especially the interactions among amyloids, tau, shear, and membranes, deserves a greatly increased AD researcheffort.",
"\n\nThese shear-based chemical mechanism suggestions could well be applicable to many other amyloid-synuclein related diseases. ",
"Prions are also intrinsically disordered proteins, have many different strains with the same overall molecular composition, each strain representing a different conformation \\[[@ref031]\\]. ",
"Two different strains of *α*-synuclein, another intrinsically disordered protein, with two different structural conformations have been reported to cause two different neurodegenerative disorders \\[[@ref032]\\], Parkinson's disease and multiple system atrophy. ",
"Could these and other disease-causing, amyloid strains arise from different degrees and types of shear in different parts of the brain or body?",
"\n\nSUMMARY {#sec0080}\n=======\n\nThis paper explores the potential regions of the brain where laminar and extensional liquid shear might be present. ",
"On the basis of published liquid shear literature involving Aβ and other protein solutions, the author proposes that liquid shear induces distorted-conformation excited molecular states Aβ\\* that have been previously identified as \"unfolded\" or \"misfolded\" proteins that initiate amyloid cascade reactions. ",
"It is proposed that these higher than thermal energy Aβ\\* states are produced in CSF flowing next to or very near the fluid-confining walls of the brain CSF perivascular system and in interstitial fluid flowing more slowly through the tightly confined extracellular parenchymal spaces. ",
"These various shear energy-excited states are suggested as possible initiating molecular agents for membrane toxic oligomers, plaque formation, and CAA in a complex shear-related interplay between vascular and parenchymal Aβ cycles that are both highly dependent on Aβ concentration in a non-linear manner. ",
"It is suggested that the current research focus on identifying and studying toxic soluble oligomers of Aβ present in quiescent solutions may be incomplete and possibly even misleading. ",
"Several papers in the literature \\[[@ref007]\\] imply amyloid cascade products might differ in quiescent and flow conditions in which Aβ is sheared. ",
"This paper suggests that the brain membrane may be necessary to form a critical type of neurotoxic oligomer formed in an amyloid cascade. ",
"If the hypotheses put forward in this paper are correct, it is suggested that researchers should also be focusing on eliminating or preventing the formation of Aβ~42~\\* and the Aβ~42~\\*-membrane complex, since these two entities are suggested as precursors to toxic membrane oligomers. ",
"The Aβ~40~\\* is proposed as the precursor to CAA vascular solids suggested as the cause of reduced clearance rates of parenchymal Aβ.",
"\n\nSuggested experimental tests of the hypotheses contained in this paper {#sec0085}\n----------------------------------------------------------------------\n\nThere are many unknowns regarding human brain fluid flow patterns and resulting shear rates. ",
"However, most of the shear hypotheses presented in this paper are testable in the laboratory. ",
"Many previous amyloid shear studies have been carried out using comparatively irreproducible methods such as stirring and shaking or are concerned with processes at the air-water surface, which are important industrially. ",
"The brain presumably does not host such surfaces. ",
"Those few purely liquid experimental amyloid studies carried out with reproducible liquid shear forces do not have confined space geometries or dimensions that are suitable models for the kind of shear processes that possibly occur within the brain, especially with respect to extensional shear.",
"\n\nInvestigations are proposed using a different approach to shear experiments. ",
"The author will be submitting another closely related paper to this one that proposes a new, but simple basic experimental technique involving capillary tubing and other flow restrictive geometries that generate laminar and/or extensional shear and that is designed for testing many of the amyloid shear hypotheses proposed in this paper. ",
"Numerous critical experiments using this novel technique will be suggested in that paper for testing these hypotheses. ",
"The technique is based upon that used in our early shear experiments, but involves new experimental innovations.",
"\n\nThis retired researcher urges others to explore this new, potentially groundbreaking and, it is believed, critically important research area.",
"\n\nSupplementary Material\n======================\n\n###### Supplementary Material\n\n###### \n\nClick here for additional data file.",
"\n\n###### Supplementary Figure 1\n\nCartoon illustrating protein shear next to and near the wall with a hill followed by an outlet illustrating the Metzner effect \\[13\\]. ",
"The latter is a tendency of a shear-stressed polymer to preferentially migrate to and concentrate in a lower shear zone. ",
"To the left of the hill and to the right of the outlet, there is a solid protein coating forming due to wall shear. ",
"Note that molecules in the outlet are unsheared and relaxed in this very low shear zone. ",
"There is no tendency to aggregate in this zone, but there is a higher local protein concentration. ",
"This situation could represent the narrow astrocyte OEP leading to the parenchyma. ",
"However, if there is a significant outlet liquid flow, there could be significant shear and protein aggregation within this outlet flow path.",
"\n\n###### \n\nClick here for additional data file.",
"\n\n###### Supplementary Figure 2\n\nProposed Aβ/Aβ\\*/membrane cycles with low (A) and high (B) Aβ concentrations. ",
"At low Aβ concentration, the sheared Aβ (A1) molecule forms Aβ\\* (A2) is attracted to and adsorbed by the membrane (A3), alters its conformation to a low energy state Aβ (A4) and is released from the membrane (A5) in (A6, reoriented to A1), keeping the steady state Aβ concentration low. ",
"At high Aβ concentrations (B), this A cycle is interrupted by the formation of an Aβ\\* dimer (B3, B4), which initiates the formation of stable oligomers within the membrane (B5). ",
"This process can be toxic, for example, by forming an open membrane flow path that allows free passage to ions such as Ca^2+^(B6). ",
"White segments of the Aβ\\* molecule are hydrophobic and gray segments are hydrophilic. ",
"The same scheme is applied to the membrane, hydrophobic tails of which attract corresponding Aβ segments, and similarly with hydrophilic segments.",
"\n\n###### \n\nClick here for additional data file.",
"\n\n###### Supplementary Figure 3\n\nFlow impediments reacting with Aβ\\*. (",
"a) Sheared Aβ\\* molecules that are attracted to one another to form an Aβ dimer (b) without interacting with the wall or flow impediments; (c) single Aβ\\* attracted to both the membrane and the proteoglycan; (d) Aβ\\* dimer that could either be released or form the nucleus for a higher order oligomer that remains attached to this location; (e) GM1, a ganglioside that has a hydrophilic bulky exterior group and a hydrophobic anchor and has immobilized a membrane-embedded Aβ dimer providing a nucleus for oligomer formation in this location; (f) a single Aβ\\* locked on one proteoglycan that might then convert to a hairpin conformation that is shown in (g) as a focal point for the formation of a protofibril. ",
"This latter process could be similar to that proposed by Metzner et al., ",
"for the downstream formation of fibrils in their experiments with commercial polymers (Fig. ",
"4 in ref. ",
"\\[13\\]). ",
"HSPG not to scale.",
"\n\n###### \n\nClick here for additional data file.",
"\n\nThe author gratefully acknowledges helpful discussions and communications with Jeffrey Iliff, Lila Gierasch, Richard Vachet, Herbert Blades, Roy O. Weller, David Teplow, Dave Dunstan, David Talaga, Lorna Alston, Robert Thorne, David Colby, Conrad Yocum, Maxwell Siegel, Richard Kline, Susan Trumbore, and Virginia Ahrens.",
"\n\nThe author's disclosure is available online (<http://j-alz.com/manuscript-disclosures/16-0027r3>).",
"\n\nThe supplementary information is available in the electronic version of this article: <http://dx.doi.org/10.3233/JAD-160027>.",
"\n\n{#jad-54-jad160027-g001}\n\n{#jad-54-jad160027-g002}\n\n{#jad-54-jad160027-g003}\n\n![",
"Composition of the brain vascular arterial and capillary system. ",
"More detailed discussion on arteriole wall composition can be found in Morris et al. ",
"\\[[@ref014]\\].](jad-54-jad160027-g004){#jad-54-jad160027-g004}\n\n{#jad-54-jad160027-g005}\n\n{#jad-54-jad160027-g006}\n\n{#jad-54-jad160027-g007}\n\n{#jad-54-jad160027-g008}\n\n{ref-type=\"fig\"} in ref. ",
"\\[[@ref019]\\]). ",
"HSPG not to scale.](jad-54-jad160027-g009){#jad-54-jad160027-g009}\n\n{#jad-54-jad160027-g010}\n"
] |
{
"pile_set_name": "PubMed Central"
}
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[
"To apply, please create an account by clicking the 'Login' tab above. ",
"Once you have created an account, click on 'submissions.' ",
"Under 'your submissions' click 'add new.'",
"\n\nExam highlights\n\nThe exam consists of 60 multiple choice questions. ",
"Participants are given 90 minutes to complete the exam. ",
"The exam covers the eight Cornerstones of Supply Chain Management.",
"\n\nSupply Chain Concepts\n\nDemand and Supply Integration\n\nSupply Management and Procurement\n\nManufacturing and Service Operations\n\nTransportation\n\nInventory Management\n\nWarehousing\n\nOrder Fulfillment and Customer Service\n\nNo retakes will be offered for this exam if it is not passed on the first attempt.",
"\n\nCancellation Policy:Cancellations received by 11:59pm CST will be refunded: 100% (by July 31, 2018) and 50% (August 1-30, 2018). ",
"No refunds will be accepted after September 1, 2018.All cancellations must be made by e-mail to [email protected].",
"\n\nOnce you have created an account you will be able to fill out an application of eligibility,click on 'submissions.' ",
"Under your submissions click 'add new.'",
"\n\nIssues logging in or creating an account?Please contact Alison Krentz at [email protected]."
] |
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[
"Metal Gear Solid V: The Phantom Pain Review\n\nMetal Gear Solid V is exactly what open world games should strive to be. ",
"Whether it is the dynamic open-world that provides a myriad of strategic options, the depth of content, with its deluge of base building mechanics and development systems, or the pitch perfect shooting and stealth gameplay, The Phantom Pain is a masterclass in game design. ",
"Leave it to Hideo Kojima, the mind behind the Metal Gear series all these years, to send fans off on what is easily the best playing game in the series.",
"\n\nMetal Gear Solid V has been hailed as the last Metal Gear game, take that as you will, but it is definitely the last game for Kojima Productions. ",
"With Hideo’s lengthy and widely reported battle with Konami and his ensuing departure, to the huge development costs, there has been a cloud of anticipation bordering on hysterics surrounding this game. ",
"Suffice to say, The Phantom Pain more than delivers on a gameplay front, but when it comes to the delivery of the bewildering, borderline nonsensical story that Metal Gear fans know and love, Metal Gear Solid V raises as many questions as it answers.",
"\n\nLeaving longtime series fans to fill in the gaps, The Phantom Pains story is the weakest element but not nearly the death knell that many believe it to be. ",
"In fact, The Phantom Pain contains some incredibly powerful moments in the late game, and contains a sense of tension, as if something truly awful was about to occur for the latter half of the game, permeating your actions with emotion and leading to a epic climax. ",
"The first major issue is how much time it takes to see the “true ending” and the work involved, forcing many to believe they had finished the game, missing the most important story moments. ",
"The second, is relegating much of the story to codec recordings of conversations between Snake and the supporting cast, making players spend much of their time listening to audio logs and sitting still, hoping not to miss a single word.",
"\n\nDavid Hayter’s classic Snake has been replaced with Kiefer Sutherland which ultimately fits the tone of The Phantom Pain, painting the darkest and most violent Metal Gear story yet, but it would be wrong to say that Hayter is not missed. ",
"Sutherland does a fine job as Snake, but one wishes he had more to say, with most of his recorded work held in the codec conversations. ",
"He makes for a great Big Boss but he is underutilized and, ultimately the change feels unnecessary. ",
"Keeping Hayter would have been the easier and safer option, making the final decision all the more confusing. ",
"The other major change is Troy Baker taking over as Ocelot, where he does what sounds like Troy Baker doing a poor Patric Zimmerman impersonation. ",
"This is another change that makes little sense, possibly trying to account for the change in tone, feeling that Hayter and Zimmerman may have been too over-the-top for the subject matter. ",
"Ultimately both voice actors have shown they are more than capable to hand dark subject matter with some subtlety, making the final choice all the more bewildering.",
"\n\nThe story follows Big Boss and his new mercenary army, The Diamond Dogs, rebuilding Mother Base and hunting down Skull Face and his soldiers after the events of Ground Zeroes. ",
"To jump into The Phantom Pain without playing that prologue would be a major mistake, with it serving as a good primer for the gameplay and story within Metal Gear Solid V in hindsight. ",
"Gone are the hour and a half cutscenes and absurdly long codec talks, in their place are the pre-recorded audio logs and much more succinct mission custscenes The Phantom Pain feels like a direct response by Kojima to the criticisms of Metal Gear Solid 4. ",
"Gameplay is the focus, and while the story is substantial and will provide plenty for fans to speculate over, it misses many key pieces that the Metal Gear faithful may have been looking for. ",
"This is not The Revenge Of The Sith to Star Wars’ A New Hope, there is no direct connection up to the very moment the original Metal Gear starts, but it lays enough of the groundwork and contains its own massive twist that only could be in a Kojima game. ",
"Ultimately there are some missing elements but The Phantom Pain provides an interesting story that caries a sense of looming dread into the final hours that I have not seen in a game since Red Dead Redemption.",
"\n\nWhere The Phantom Pain shines is in the moment to moment gameplay, where it is absolutely one of the greatest stealth games ever made. ",
"The shooting is satisfying and precise, the guns feel wonderful and the options available are staggering. ",
"Buddies mix up gameplay depending on how you want to approach a situation, from stealth with DDog to riding in on the back of DHorse, situations can be tackled any way you see fit. ",
"So diverse are the tools and problems presented, that The Phantom Pain may be the first true sandbox. ",
"Content is dynamically presented in the open world, and an alert status can be avoided by literally driving kilometers away from the enemy base or a horse can be commanded to poop on the head of a knocked out enemy. ",
"Non lethal or extremely lethal, every option is open and has consequences.",
"\n\nThe other major feature is your base, fultoned soldiers helps increase the size and capability of Mother Base and as it grows it shows in game, with the ability to visit your base frequently to watch it progress. ",
"Animals can be captured and placed in a personal conservatory on-base, which fills more and more with each new species taken in. ",
"With better soldiers comes better research, intel, support and other factors, each one changing gameplay. ",
"Better intel leads to on-the-fly reports on enemy locations in the field, while your combat unit can be sent on missions to accrue supplies and new soldiers.",
"The research division allows access to insane end game items, new weapons and armor and a myriad of other toys for players to use. ",
"Every action has a purpose and a direct impact on how you play, and with the amount of options provided and the idea of having the missions play out in the open world, The Phantom Pain allows for some of the most hilarious, fun and dynamic moments in games.",
"\n\nSide content and main missions take place in the world, and unlike most open-world games, can be ran into on accident, tackled from any angle or downright avoided. ",
"The mission design almost always allows for total control over your strategy, making each one a giant puzzle to tackle or battlefield to assault. ",
"The design of the environments lend so well to the mission and gameplay design, with content always taking place in interesting and varied areas, causing players to change tactics and gear based on the situation. ",
"The world is gorgeous, the animations are full of that Metal Gear personality and the game, despite the story, feels so polished and hand crafted, it is hard to play another stealth game after the fact. ",
"Listening to classic 80’s tracks on your cassette while infiltrating an enemy base is one of the best moments in gaming and it is not something scripted or designed to be forced on the player. ",
"It is something you can find for yourself. ",
"That is The Phantom Pains philosophy, while so many other games actively deter players from having fun the way they want, by funneling them down corridors or making them play as a specific character, Metal Gear Solid V just lets you have fun.",
"\n\nIn a year filled with great games, none provides that pure sense of joy like Metal Gear Solid V does. ",
"Tranquilizing a group of guards and tossing them all in a jeep, only to fulton them all at once is a blast every time, and The Phantom Pain is chock full of player driven moments that make each experience with it one of a kind. ",
"It is the best playing Metal Gear ever, and despite the story issues, it provides a thrill that is unseen in most games today. ",
"Metal Gear Solid V: The Phantom Pain is not just one of the best games of the year, it is one of the best stealth games ever made."
] |
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[
"Q:\n\nHow can I compare elements in 2 lists in the same index in their respective lists in Python?",
"\n\nSay I have 2 lists\na = [1, 2, 3, 4, 7, 1]\nb = [1, 2, 4, 5, 7, 1]\n\nI want it to make a third list with only the elements that are equal in the same index in each list, in this case\nc = [1, 2, 7, 1]\n\nIs there a simple way to do this?",
"\n\nA:\n\nsimplest method would probably just be doing a list comprehension:\nc = [x for x,y in zip(a,b) if x == y]\n\nfor the sake of a different approach and just out of interest..could also do it this way:\nfrom itertools import compress\nmask = [x==y for x,y in zip(a,b)]\nc = list(compress(a,mask))\n\nor if numpy is an option (good for larger lists):\nimport numpy as np\na,b = np.array(a), np.array(b)\nc = a[np.equal(a,b)].tolist()\n\nall ways give: \n[1, 2, 7, 1]\n\n"
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[
"Free Economy Shipping On Orders Over $35 Use Coupon Code: FRSHIP35 at checkout.",
"\n\nNot to be used in conjunction with other offers. ",
"We reserve the right to limit or exclude certain items from promotion at our sole discretion. ",
"Not valid on items within the Corporate store. ",
"We reserve the right to cancel this promotion at any time without notice. ",
"Offer valid for economy shipping within the contiguous United States only. ",
"Surcharges on some oversized items may still apply. ",
"Offer valid thru October 1, 2017.",
"\n\nOur Loving Hearts Holiday Personalized Frame\n\nWe skillfully engrave the I or We heart design with any name or title you choose. ",
"Then complete the personalization with first name(s) of each child, grandchild, etc. ",
"in our exclusive, unique repeat pattern throughout the entire frame face.",
"\n\nChoose either horizontal or vertical orientation.",
"\n\nFill the frame with a special holiday, vacation or celebration photo and enjoy the memories for a lifetime!"
] |
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[
"Hormone Keeps Men Away From Attractive Women\n\nYet another strange power of oxytocin has been revealed: when given to men who are in a relationship, it compels them to keep a greater distance from women they find attractive. ",
"It’s true. ",
"Oxytocin has long been known to be a kind love drug. ",
"It’s production soars during childbirth, and it plays a major role in sexual arousal. ",
"Now, it seems, it also keeps monogamous relationships monogamous. ",
"A news release from the Society for Neuroscience reports that researchers at the University of Bonn gave oxytocin or a placebo via a nasal spray to a group of healthy, heterosexual males. ",
"Forty-five minutes later, the men were introduced to a female experimenter whom they later described as “attractive.” ",
"As the experimenter moved toward or away from the study volunteers, the men were asked to indicate when the experimenter was at an “ideal distance” as well as when the experimenter moved to a distance that felt “slightly uncomfortable.” ",
"The researchers found oxytocin led the men in committed relationships, but not those who were single, to keep a greater distance (10-15 cm) between themselves and the woman. ",
"Wait, there’s more: In a separate experiment, the researchers found oxytocin had no effect on the distance men kept between themselves and a male experimenter. ",
"Read more from the Society of Neuroscience."
] |
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[
"The Frank Sinatra guide to running a small business\n\nThe local councillor who couldn’t help me might have been a local version of one of those politicians who think it is sufficient to reach high office and do not have a vision or a plan to do anything when they get there.",
"\n\nPerhaps I am being unkind, but I could list you three British Prime Ministers in office in the last fifty years who thought being Prime Minister was in itself sufficient for their egos, and another three who really thought they could change things for the better. ",
"I am not going to list these PMs because I do not wish for a political debate, but they are not all on the same side of the political fence. ",
"We have had some who just liked being PM, and others who tried to get on with what they believed they should be doing.",
"\n\nI have been working with small businesses in one way or another throughout what one might grandly call my career, and until the last recession it was probably only the seriously entrepreneurial types who started new businesses. ",
"There were others who inherited the family business of course.",
"\n\nGoing back a few years, I came across people who had built vast empires from nothing or from cheekily borrowing large amounts of money on a promise or on conviction which they had conveyed to the lender. ",
"So I knew people who started engineering businesses with almost no money, and aristocrats who had inherited money but really knew how to run a hands-on business themselves. ",
"There is a certain talent needed whatever your background, which is to think on your feet and to know about people. ",
"It is not easily taught, but can be learned.",
"\n\nPeople these days often try to start businesses because they cannot get a job and need some income, but it takes a bit more than that to make it work.",
"\n\nSo, going back to the Prime Ministers, it is not sufficient to be in charge of a business. ",
"Just having one is not enough, because unless it is actively managed, it will fail as the three PMs failed their country. ",
"To be in business is to do because if you don’t do, you won’t be in business. ",
"It’s the truth, and many who think it is enough to put up a sign (or a website) will fail."
] |
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"Salomonsen, Hilde(Master thesis, The University of Bergen, 2011-12-03)\n\nExcessive nasal resonance in speech (hypernasality) is a disorder which may have negative communicative and social consequences for the person who has this problem. ",
"Excessive nasal resonance is often associated with cleft ..."
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"top pdf download website. ",
"no matter how old and unique is a pdf you want, we have got it anyway. ",
"check it yourself. ",
"and if you cannot find your pdf on this site we will find it for you and send you download pdf link.",
"\n\nAmoebic and bacillary dysentery morbidity rates showed marked increases during the same period.",
"\n\nTerm Bank – dysenterie amibienne – French English Dictionary\n\nTo ensure the quality of comments, you need to be connected. ",
"See details and add a comment. ",
"With Reverso you can dysenterie amibienne the French translation, dysenterie amibienne or synonym for la dysenterie amibienne and thousands of other words.",
"\n\nIt’s dyssenterie and only dysenterie amibienne a few seconds: With regard to typhoid, cholera, amoebic dysentery and hepatitis A, which are transmitted through contaminated water and food, the incidence of these diseases rose at an abnormal rate from 0 to 1, cases incases in and cases in Web News Encyclopedia Images Dysenterie amibienne.",
"\n\nYou want to reject amibiene entry: Learn English, French and other languages Reverso Localize: After two weeks in this prison, the author became ill with a high fever and amoebic dysentery. ",
"Web News Encyclopedia Dysenterie amibienne Context.",
"\n\nLa dysenterie amibienne › Research Explorer\n\nVous n’avez pas la dysenterie amibienne! ",
"To add entries to your own vocabularybecome a member dysenterie amibienne Reverso amibienme or login if dysenterie amibienne are already a member. ",
"Dysenterie amibienne don’t have amoebic dysentery! ",
"To add entries to your own vocabularybecome a member of Reverso community or login if you are already a member.",
"\n\nThe number of reported cases of amoebic dysentery dysenterie amibienne from dysenterie amibienne, in amibifnne Dahuk and Erbil to 6, for all three governorates. ",
"You can complete the translation of dysenterie amibienne given by the French-English Collins dictionary with other dictionaries such as: Learn English, French and other languages Reverso Localize: You can complete the translation of la dysenterie amibienne given by the French-English Collins dictionary with other dictionaries such as: The incidence dsenterie both giardiasis and amoebic dysentery has dropped modestly, but other water-borne diseases, such as diarrhoea and typhoid fever, have increased.",
"\n\nSign up Login Login. ",
"Avoid swimming and paddling in fresh water; swimming pools which are chlorinated dysenterie amibienne well maintained are safe.",
"\n\n“dysenterie amibienne” in English\n\nTo ensure the quality of comments, you need to be connected. ",
"With regard to typhoid, cholera, amoebic dysentery and hepatitis A, which are transmitted through contaminated water and food, the incidence of these diseases rose at an abnormal rate from 0 to 1, cases incases in and cases in It’s easy and only takes a few seconds: The incidence dysenterie amibienne both giardiasis and amoebic dysentery has dropped modestly, but other dysenterie amibienne diseases, such as diarrhoea and typhoid fever, have dysenterie amibienne.",
"\n\nYou want to reject this entry: Sign up Login Login. ",
"Or sign up in the traditional way. ",
"With Reverso you can find the French translation, dysenterie amibienne or synonym for dysenterie amibienne and thousands of other words."
] |
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[
"Q:\n\npreg_replace issues with hyperlinks\n\nbefore I decided to post my first question on StackOverflow I turned completely crazy, so here it goes:\nI've got a website that uses Google Calendar API to fetch event entries. ",
"In the description section users can fill in some details about the event. ",
"Now i'd like them to be able to put in hyperlinks. ",
"This can happen in a couple of ways.",
"\nUser types:\n\nwww.test.com\nhttp(s)://test.com\nhttp(s)://www.test.com\n<a href=\"[one of above]\" target=\"_blank\">test.com</a>\n\nWhat I'm desperately looking for is a way to convert them all to the format <a href=\"[http:// OR https:// OR www.]test.com\" target=\"_blank\">test.com</a>\nI have already tried this syntax:\n$pattern = \"/(?i)\\b((!<?:https?:\\/\\/|www\\d{0,3}[.]|[a-z0-9.\\-]+[.][a-z]{2,4}\\/)(?:[^\\s()<>]+|\\(([^\\s()<>]+|(\\([^\\s()<>]+\\)))*\\))+(?:\\(([^\\s()<>]+|(\\([^\\s()<>]+\\)))*\\)|[^\\s`!()\\[\\]{};:'\\\".",
",<>?«»“”‘’]))/\";\n$description = preg_replace($pattern, \"<a href='http://$1'>$1</a>\", $description);\n\nIt does change all events in the format www.test.com in a correct hyperlink, it does not change events in the format http(s)://www.test.com and http(s)://test.com. ",
"Input in the format <a href=\"[one of above]\" target=\"_blank\">test.com</a> becomes a mess.",
"\nNow I'm sad and tired. ",
"If someone could help me out, you're an absolute genius!",
"\n\nA:\n\nFinally solved it with a condition in PHP: here's the code so others can use it as well. ",
"Does add the path after .domain/ now.",
"\nThanks a lot for your help!",
"\nif (!",
"stristr($description, '<a href')){\n $pattern = \"~(?:https?://)?((?:[\\\\p{L}\\\\p{N}-]+\\\\.)+[\\\\p{L}-]{2,5})((\\\\S)*)~m\";\n $description = preg_replace($pattern, \"<a href=\\\"$0\\\" target=\\\"_blank\\\">$0</a>\", $description);\n}\n\n"
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[
" 4*i**2 + 42*i + 1137. ",
"Let o(a) = -7*a**2 + 5*a + 28. ",
"Determine 5*g(p) - 8*o(p).",
"\np**2 - 14\nLet f(s) = 26*s**3 - 3*s + 3. ",
"Suppose 3 = 1455*r - 1456*r. ",
"Let g(t) = -910*t**3 + 104*t - 104. ",
"Give r*g(k) - 104*f(k).",
"\n26*k**3\nLet v(d) = 15757*d - 6. ",
"Let k(z) = 43079632*z - 16406. ",
"Give 3*k(p) - 8203*v(p).",
"\n-15775*p\nLet k be 2/2 + (2 - 1). ",
"Let p(u) = k*u - 3*u - 4*u + u**2. ",
"Let w(y) = -2*y + 240. ",
"Let f(t) = 20. ",
"Let g(z) = -12*f(z) + w(z). ",
"What is 4*g(x) - 2*p(x)?",
"\n-2*x**2 + 2*x\nLet v be (6/21 - (-430)/(-35)) + 3. ",
"Let m be 322/8 + v/36. ",
"Suppose m = -10*w - 0. ",
"Let d(s) = 2*s + 3. ",
"Let r(j) = -j - 1. ",
"Determine w*d(p) - 9*r(p).",
"\np - 3\nLet y(i) = -2*i - 3. ",
"Let k(q) = 2*q - 4. ",
"Let p be k(3). ",
"Let t(m) = 118*m - 7. ",
"Let n(c) = -189*c + 11. ",
"Let f(d) = -5*n(d) - 8*t(d). ",
"Give p*y(z) + 6*f(z).",
"\n2*z\nLet j(r) = -153634*r + 76. ",
"Let a(y) = 6145*y - 3. ",
"Determine -76*a(l) - 3*j(l).",
"\n-6118*l\nSuppose -4*f - 3*t = -35 + 16, -2*t = -2. ",
"Let m(q) = 0 - 13*q - f*q**2 + 12*q - 5*q + 5. ",
"Let c(d) = 5*d**2 + 7*d - 6. ",
"What is -5*c(p) - 6*m(p)?",
"\n-p**2 + p\nLet u(p) = -16*p + 5. ",
"Let m(a) = 2263 - 761 - 751 - a - 750. ",
"What is -3*m(g) + u(g)?",
"\n-13*g + 2\nLet x(f) = -2. ",
"Let o(c) = -3. ",
"Let j(u) = -3*o(u) + 5*x(u). ",
"Let i(l) = -17*l + 5. ",
"Let t(a) = -4*a. ",
"Let m(r) = -i(r) + 4*t(r). ",
"Determine -2*j(y) + m(y).",
"\ny - 3\nLet a(z) = 14*z**2 - 608*z - 220. ",
"Let x(c) = -5*c**2 + 215*c + 73. ",
"Calculate 6*a(u) + 17*x(u).",
"\n-u**2 + 7*u - 79\nLet y(m) = -99*m**2 - 22*m - 22. ",
"Let i(d) be the second derivative of 11*d**4/6 + 5*d**3/6 + 5*d**2/2 + 23*d - 12. ",
"What is 22*i(c) + 5*y(c)?",
"\n-11*c**2\nLet o(x) = -2014*x + 19. ",
"Let l(a) = -6041*a + 66. ",
"Determine -2*l(s) + 7*o(s).",
"\n-2016*s + 1\nLet j(w) = -3*w - 58. ",
"Let a(f) = 8*f + 156. ",
"Let h(x) = -10*x - 195. ",
"Let d(u) = 16*a(u) + 13*h(u). ",
"Determine 7*d(q) - 5*j(q).",
"\nq + 17\nLet j(h) = -39*h**3 + 4*h**2 + 11*h + 4. ",
"Let k(d) be the second derivative of -d**5 + d**4/6 + d**3 + d**2 + 1103*d. ",
"Calculate -6*j(r) + 11*k(r).",
"\n14*r**3 - 2*r**2 - 2\nLet k(q) = 10 - 5 + 2 - 6. ",
"Let p(t) = 3*t - 5. ",
"Calculate -3*k(d) - p(d).",
"\n-3*d + 2\nLet x(n) = -2*n**3. ",
"Let v(s) = 80704 - 161409 + 80705 - 5*s**3. ",
"Calculate -2*v(b) - 4*x(b).",
"\n18*b**3\nLet f(j) = -31*j**3 + 27*j**2 - 4*j - 2. ",
"Let x(n) = -62*n**3 + 45*n**2 - 8*n - 3. ",
"What is 5*f(m) - 3*x(m)?",
"\n31*m**3 + 4*m - 1\nLet p(r) be the third derivative of r**4/4 - 5*r**3/6 - 1504*r**2. ",
"Suppose 3 + 5 = -2*h. ",
"Let f(x) = x - 1. ",
"What is h*f(k) + p(k)?",
"\n2*k - 1\nLet n(q) = q**3 + q**2 + q. Let s be ((-936)/(-136) - -3) + (-2)/(-17). ",
"Suppose -37 = -9*c - s. Let m(o) = 3*o**2 + 6*o. ",
"What is c*n(b) - m(b)?",
"\n3*b**3 - 3*b\nLet m = -372 + 250. ",
"Let j = 102 + m. Let f(i) be the third derivative of -i**4/24 - i**3/6 - 2*i**2. ",
"Let k(z) = -2*z**3 + 10*z + 10. ",
"Calculate j*f(l) - 2*k(l).",
"\n4*l**3\nLet w(k) = -2*k**3 + 2*k**2 + 2*k. ",
"Let z = -8576 - -8579. ",
"Let b(l) = 5*l**3 - 3*l**2 - 5*l. ",
"Calculate z*b(i) + 7*w(i).",
"\ni**3 + 5*i**2 - i\nLet l be (-1 - -2) + ((-20)/(-6))/(374/561). ",
"Let g(i) = 0*i**2 - 6*i + 0*i**2 - 2*i**2. ",
"Let s(r) = -4*r**2 - 11*r. ",
"Calculate l*s(m) - 11*g(m).",
"\n-2*m**2\nLet c(t) = -t**3 + 4*t. ",
"Let m(d) = -d**3 - 6*d**2 - 2*d - 12. ",
"Let q(p) = p**3 + 10*p**2 + 5*p + 20. ",
"Let b(n) = 5*m(n) + 3*q(n). ",
"Determine 5*b(k) - 6*c(k).",
"\n-4*k**3 + k\nLet r(i) = 126*i**2 - 9*i + 30. ",
"Let y(h) = -31*h**2 + 2*h - 8. ",
"Give 2*r(b) + 9*y(b).",
"\n-27*b**2 - 12\nLet b(d) = 2*d**3 - 5*d**2 + 20*d - 3. ",
"Let j(z) = -2*z**3 + 5*z**2 - 20*z + 2. ",
"What is -2*b(u) - 3*j(u)?",
"\n2*u**3 - 5*u**2 + 20*u\nLet k(p) = 1 + 1658*p**2 - 4956*p**2 + 1652*p**2 + 1647*p**2 + p. Let q(g) = -3*g**3 - 9*g**2 - 9*g - 9. ",
"Determine -18*k(u) - 2*q(u).",
"\n6*u**3\nLet a(g) = -404*g + 12. ",
"Let r(j) = -6*j + 2. ",
"Give a(f) - 5*r(f).",
"\n-374*f + 2\nLet b(u) = 18148*u + 244998. ",
"Let i(c) = c + 27. ",
"What is 2*b(m) - 18148*i(m)?",
"\n18148*m\nLet y(c) = -2*c + 2. ",
"Let a be y(1). ",
"Suppose -4*x - 11 + 35 = a. Let h(z) = -8*z + 2. ",
"Let b(m) = 7*m - 2. ",
"Calculate x*b(j) + 5*h(j).",
"\n2*j - 2\nLet p(y) = y. Let w(d) be the third derivative of 188*d**2 + 0 + 1/2*d**4 - 1/6*d**3 + 0*d. ",
"Give 6*p(j) - w(j).",
"\n-6*j + 1\nLet x(i) = -15 + 4 - i - 8*i**2 - 4*i - 6*i + 2*i. ",
"Let t(w) = 4*w**2 + 5*w + 6. ",
"Calculate 7*t(g) + 4*x(g).",
"\n-4*g**2 - g - 2\nLet a(w) = w + 1. ",
"Let t(h) = h**2 - 3*h - 8. ",
"Let s = 6587 - 6591. ",
"Determine s*a(u) - t(u).",
"\n-u**2 - u + 4\nLet a(g) = -8317*g - 10. ",
"Let b(j) = 33306*j + 42. ",
"Give -21*a(v) - 5*b(v).",
"\n8127*v\nLet l(k) = 20*k**3 - k**2 + 336*k + 1. ",
"Let b(m) = 16*m**3 - m**2 + 335*m + 1. ",
"What is 4*b(t) - 3*l(t)?",
"\n4*t**3 - t**2 + 332*t + 1\nLet s(p) = -620*p - 322. ",
"Let a(g) = 581*g + 320. ",
"Determine 16*a(d) + 15*s(d).",
"\n-4*d + 290\nLet p(d) = 35168 + 4*d - 35169 - d - 2*d. ",
"Let u(t) be the third derivative of -7*t**6/120 + 35*t**4/24 - 35*t**3/6 + 4*t**2. ",
"Give -35*p(l) + u(l).",
"\n-7*l**3\nLet h(d) = 2*d**2 + 5*d - 424. ",
"Let c(b) = -6*b**2 - 11*b + 845. ",
"What is -2*c(z) - 5*h(z)?",
"\n2*z**2 - 3*z + 430\nLet l(k) = -k**2 + k - 1. ",
"Let q(g) be the third derivative of 0*g**5 - 59*g**2 + 0 + 1/12*g**4 + 0*g - 1/2*g**3 - 1/120*g**6. ",
"What is 4*l(d) - 2*q(d)?",
"\n2*d**3 - 4*d**2 + 2\nLet h(s) = 4*s**2 + 2. ",
"Let z(q) = -54*q**2 - 42*q - 15. ",
"Calculate 8*h(m) + z(m).",
"\n-22*m**2 - 42*m + 1\nLet l(c) = 141*c + 34. ",
"Let u(f) = 732*f + 171. ",
"Determine 11*l(d) - 2*u(d).",
"\n87*d + 32\nLet a(c) = -3*c**3 + 12*c**2 - 2*c + 5. ",
"Let j(k) = 2*k**3 - 7*k**2 + k - 6. ",
"What is 3*a(h) + 4*j(h)?",
"\n-h**3 + 8*h**2 - 2*h - 9\nLet j(q) = -3*q + 49. ",
"Let t(k) = -12*k - 4 + 53 - 2*k + 20*k - 8*k. ",
"Determine 3*j(y) - 4*t(y).",
"\n-y - 49\nLet v(o) = 2*o**3 - 5*o**2 + 2*o + 1. ",
"Let t(f) = -3*f**3 + 6*f**2 - 2*f - 1. ",
"Suppose -x - 86*b + 15 = -90*b, -x = b. Calculate x*t(j) + 4*v(j).",
"\n-j**3 - 2*j**2 + 2*j + 1\nLet a(y) = 369*y**2 + 21*y - 9. ",
"Let f(u) = -169*u**2 - 10*u + 4. ",
"Calculate -3*a(t) - 7*f(t).",
"\n76*t**2 + 7*t - 1\nLet b(c) = -c**2. ",
"Let n(d) = 7*d - 177. ",
"Let s be n(26). ",
"Suppose -15 + 5 = s*h. ",
"Let f(r) = -3*r**2. ",
"Give h*b(g) + f(g).",
"\n-g**2\nLet s(z) be the third derivative of -5*z**2 + 0*z + 0 + 0*z**5 - 1/30*z**6 + 0*z**3 + 0*z**4. ",
"Let m(u) = u**3. ",
"What is 4*m(c) + 2*s(c)?",
"\n-4*c**3\nLet r(p) = p - 1. ",
"Let l(h) = 75*h + 23. ",
"Let b(m) = -33*m - 11. ",
"Let a(q) = -9*b(q) - 4*l(q). ",
"Give a(x) + 4*r(x).",
"\nx + 3\nLet c be 1 - (3 - (3 + 71)). ",
"Let g(y) = -c*y + 1 + 1 + 70*y - 1. ",
"Let j(p) = p. What is -g(o) - 6*j(o)?",
"\n-4*o - 1\nLet z(c) = -7*c + 115. ",
"Let a(n) = 5*n - 115. ",
"Give 5*a(r) + 4*z(r).",
"\n-3*r - 115\nLet o(c) = -4*c**3 + 3*c**2 - 4*c + 3. ",
"Let d(w) = -11*w**3 + 9*w**2 - 11*w + 8. ",
"Let s be (-54 - -51)*(11/3 + -1). ",
"Determine s*o(v) + 3*d(v).",
"\n-v**3 + 3*v**2 - v\nLet u(w) = w**2 - 19*w + 2. ",
"Let g(o) = o**2 - 18*o + 2. ",
"Let k = -2860 - -2865. ",
"Determine k*u(l) - 6*g(l).",
"\n-l**2 + 13*l - 2\nLet u(m) = m**3 + 10. ",
"Let g(r) = 3*r**3 + 53. ",
"Let q(j) = -2*g(j) + 11*u(j). ",
"Let z(c) = 10*c**3 + 7. ",
"What is 7*q(o) - 4*z(o)?",
"\n-5*o**3\nLet b(g) = 7*g**2 - g + 1. ",
"Let a(f) be the third derivative of -f**5/4 + f**4/12 - f**3/2 - 3556*f**2. ",
"What is 6*a(u) + 13*b(u)?",
"\nu**2 - u - 5\nLet k(x) = -6*x**3 + 4*x**2 + 3. ",
"Let s = 230 + -200. ",
"Suppose 2*d + s = 8*d. ",
"Let c(z) = 11*z**3 - 7*z**2 - 5. ",
"What is d*k(j) + 3*c(j)?",
"\n3*j**3 - j**2\nLet j(l) = -10*l**3 + 47*l**2 + 6*l + 15. ",
"Let g(s) = 5*s**3 - 25*s**2 - 3*s - 7. ",
"Calculate 13*g(r) + 6*j(r).",
"\n5*r**3 - 43*r**2 - 3*r - 1\nLet p(t) = t**2. ",
"Let u(x) = 2640*x + 4*x**2 - 2640*x - 3*x**2. ",
"Determine 4*p(y) - 9*u(y).",
"\n-5*y**2\nLet q(b) = 202*b**2 + 158*b - 5. ",
"Let d(n) = -n**2 - 52*n + 2. ",
"Determine 3*d(w) + q(w).",
"\n199*w**2 + 2*w + 1\nLet i(l) be the first derivative of 7*l**2/2 - 3*l - 100. ",
"Let f(m) = 4*m - 2. ",
"Let h = 12 - 9. ",
"Let o(d) = d. Let g be o(h). ",
"Give g*i(a) - 5*f(a).",
"\na + 1\nLet z(o) = -26*o + 608. ",
"Let p(x) = 9*x. ",
"Calculate -3*p(c) - z(c).",
"\n-c - 608\nLet w(f) = -f + 4. ",
"Let m be (3 + (-7)/4)/((-45)/(-18)). ",
"Let k(b) be the third derivative of -12*b**2 + 0*b - m*b**3 + 0. ",
"Give 4*k(v) + 3*w(v).",
"\n-3*v\nSuppose -9*w + 45 = 4*n, -4*n + 2*w = 26 - 60. ",
"Let p(a) = -a**3 - a**2 - 4*a - 2. ",
"Let t(f) = -5*f**3 - 4*f**2 - 17*f - 9. ",
"Calculate n*p(h) - 2*t(h).",
"\nh**3 - h**2 - 2*h\nLet b(f) = -2*f + 16. ",
"Let p(w) = 3. ",
"Let c(m) = b(m) - 5*p(m). ",
"Let h be -9 - (7 - 5)/((-2)/4). ",
"Let r(y) = y. Determine h*r(x) - 2*c(x).",
"\n-x - 2\nLet v(h) = -11*h**2 - 3*h + 5. ",
"Suppose 72 = 21*z + 3*z. ",
"Let u(w) = 10*w**2 + 2*w - 4. ",
"Calculate z*u(n) + 2*v(n).",
"\n8*n**2 - 2\nSuppose 0 = 5*i - w + 30, 19*i - 5*w + 15 = 21*i. ",
"Let j(b) = b - 1. ",
"Let v be 1 + -4 - (-88)/22. ",
"Let a(x) = -3*x**2 + 2*x - 5. ",
"Give i*j(l) + v*a(l).",
"\n-3*l**2 - 3*l\nLet p"
] |
{
"pile_set_name": "DM Mathematics"
}
|
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0.016129032258064516,
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0.047619047619047616,
0
] | 0.002564
| 5
|
[
"Self-expandable transcatheter aortic valve replacement is associated with frequent periprocedural stroke detected by diffusion-weighted magnetic resonance imaging.",
"\nLittle evidence is available regarding the risk of peri-procedural stroke detected by diffusion-weighted magnetic resonance imaging (DW-MRI) after transcatheter aortic valve replacement (TAVR). ",
"Our purpose was to evaluate stroke risk after TAVR using DW-MRI by enrolling consecutive patients who underwent transfemoral TAVR and post-procedural DW-MRI. ",
"We prospectively enrolled 113 consecutive patients who underwent transfemoral TAVR and post-procedural DW-MRI. ",
"We used balloon-expandable valves as first-line therapy and selected self-expandable valves only for patients with narrow sinotubular junctions or annuli. ",
"We set the primary endpoint as the number of high intensity areas (HIA) detected by DW-MRI regardless of the size of the area. ",
"To evaluate the risks of the primary endpoint, we employed a multivariable linear regression model, setting the primary endpoint as an objective variable and patient and clinical backgrounds as explanatory variables. ",
"Median patient age was 84 years, and 36.3% were men. ",
"Ninety-three patients underwent balloon-expandable TAVR and 20 underwent self-expandable TAVR. ",
"Symptomatic stroke occurred in 6 (5.3%) whereas asymptomatic stroke occurred in 59 (52.2%) patients. ",
"The incidence of symptomatic and total stroke was higher in patients who underwent self-expandable TAVR than those who underwent balloon-expandable TAVR (30.0% vs. 0.0%, p<0.001 and 90.0% vs. 50.5%, p=0.001, respectively). ",
"A multivariable linear regression model demonstrated an increased primary endpoint when self-expandable TAVR was performed (p<0.001). ",
"The other covariates had no significant relationship to the primary endpoint. ",
"Akaike information criterion-based stepwise statistical model selection revealed that valve type was the only explanatory variable for the best predictive model. ",
"Self-expandable valves were associated with increased numbers of HIA on DW-MRI after TAVR in patients with severe aortic stenosis."
] |
{
"pile_set_name": "PubMed Abstracts"
}
|
[
0,
0.005128205128205128,
0.012658227848101266,
0.009009009009009009,
0,
0.007874015748031496,
0,
0,
0.021052631578947368,
0,
0.008968609865470852,
0.007462686567164179,
0,
0,
0.015384615384615385
] | 0.005836
| 5
|
[
"CHAOBORUS PREDATION AND LIFE-HISTORY EVOLUTION IN DAPHNIA PULEX: TEMPORAL PATTERN OF POPULATION DIVERSITY, FITNESS, AND MEAN LIFE HISTORY.",
"\nThe effect of predation by the aquatic dipteran larva Chaoborus americanus on genetic diversity and life-history evolution in the cladoceran Daphnia pulex was investigated in large replicate laboratory populations. ",
"Instantaneous daily loss rates of clonal diversity and genetic variance for fitness indicate that 93-99% of initial genetic diversity can be removed from populations during the 8-12 generations of clonal reproduction that occur each year in natural populations. ",
"In the absence of predation, the principal evolved changes in mean population life history were smaller immature body size and increased and earlier fecundity. ",
"In the presence of size-selective Chaoborus predation, populations evolved toward larger body size and increased and earlier reproduction. ",
"The difference between these two trajectories is an estimate of the direct additive effect of Chaoborus predation. ",
"This effect was manifested as evolution toward larger body size with a trend toward earlier and increased reproduction."
] |
{
"pile_set_name": "PubMed Abstracts"
}
|
[
0.007246376811594203,
0,
0,
0,
0,
0,
0
] | 0.001035
| 5
|
[
"go-strftime\n===========\n\ngo implementation of strftime\n\n## Example\n\n```\npackage main\n\nimport (\n\t\"fmt\"\n\t\"time\"\n\n\tstrftime \"github.com/jehiah/go-strftime\"\n)\n\nfunc main() {\n\tt := time.",
"Unix(1340244776, 0)\n\tutc, _ := time.",
"LoadLocation(\"UTC\")\n\tt = t.In(utc)\n\tfmt.",
"Println(strftime.",
"Format(\"%Y-%m-%d %H:%M:%S\", t))\n\t// Output:\n\t// 2012-06-21 02:12:56\n}\n```\n"
] |
{
"pile_set_name": "Github"
}
|
[
0,
0,
0.025,
0,
0
] | 0.005
| 5
|
[
"Black Rook in Rainy Weather\n\nBlack Rook in Rainy Weather\n\nOn the stiff twig up there\n\nHunches a wet black rook\n\nArranging and rearranging its feathers in the rain.",
"\n\nI do not expect a miracle\n\nOr an accident\n\nTo set the sight on fire\n\nIn my eye, not seek\n\nAny more in the desultory weather some design,\n\nBut let spotted leaves fall as they fall,\n\nWithout ceremony, or portent.",
"\n\nAlthough, I admit, I desire,\n\nOccasionally, some backtalk\n\nFrom the mute sky, I can't honestly complain:\n\nA certain minor light may still\n\nLeap incandescent\n\nOut of the kitchen table or chair\n\nAs if a celestial burning took\n\nPossession of the most obtuse objects now and then ---\n\nThus hallowing an interval\n\nOtherwise inconsequent\n\nBy bestowing largesse, honor,\n\nOne might say love. ",
"At any rate, I now walk\n\nWary (for it could happen\n\nEven in this dull, ruinous landscape); sceptical,\n\nYet politic; ignorant\n\nOf whatever angel may choose to flare\n\nSuddenly at my elbow. ",
"I only know that a rook\n\nOrdering its black feathers can so shine\n\nAs to seize my senses, haul\n\nMy eyelids up, and grant\n\nA brief respite from fear\n\nOf total neutrality. ",
"With luck,\n\nTrekking stubborn through this season\n\nOf fatigue, I shall\n\nPatch together a content\n\nOf sorts. ",
"Miracles occur,\n\nIf you care to call those spasmodic\n\nTricks of radiance miracles. ",
"The wait's begun again,\n\nThe long wait for the angel.",
"\n\nFor that rare, random descent."
] |
{
"pile_set_name": "OpenWebText2"
}
|
[
0.006134969325153374,
0,
0.0025906735751295338,
0,
0,
0,
0,
0,
0
] | 0.00097
| 5
|
[
"Elachista brachyplectra\n\nElachista brachyplectra is a moth in the family Elachistidae. ",
"It was described by Edward Meyrick in 1921. ",
"It is found on Java and in Sri Lanka and southern India.",
"\n\nThe wingspan is 5–6 mm. ",
"The forewings are dark fuscous, slightly speckled with whitish and there is a short rather oblique white streak from the middle of the costa and a subdorsal dot beneath it. ",
"There is a white dot on the tornus, and a dot or short oblique streak on the costa rather beyond it. ",
"The hindwings are grey.",
"\n\nReferences\n\nCategory:Moths described in 1921\nbrachyplectra\nCategory:Moths of Asia"
] |
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"Q:\n\nHaving trouble implementing JsonObjectRequest\n\nI am having trouble implementing JsonObjectRequest for getting on JsonObject from the web. ",
"\nI am trying to create a new JsonObjectRequest :\n JsonObjectRequest jsonObjectRequest = new JsonObjectRequest(Request.",
"Method.",
"GET, url, null,\n new Response.",
"Listener<JSONObject>() {\n @Override\n public void onResponse(JSONObject response) {\n try {\n\n JSONObject ratesJsonObj = response.getJSONObject(\"rates\");\n String RON = ratesJsonObj.getString(\"RON\");\n\n Log.v(\"Currency\", RON);\n\n } catch (JSONException e) {\n e.printStackTrace();\n }\n\n }\n }, new Response.",
"ErrorListener() {\n @Override\n public void onErrorResponse(VolleyError error) {\n\n }\n });\n\nBut everything it's all squiggly an under highlited with red by android studio and it says\nError:(41, 47) error: reference to JsonObjectRequest is ambiguous, both constructor \nJsonObjectRequest(int,String,String,Listener<JSONObject>,ErrorListener)\nin JsonObjectRequest and constructor \nJsonObjectRequest(int,String,JSONObject,Listener<JSONObject>,ErrorListener) \nin JsonObjectRequest match\n\nDoes anyone have any idea what's wrong?",
"\n\nA:\n\ntry this way:\nJsonObjectRequest jsonObjectRequest = new JsonObjectRequest(Request.",
"Method.",
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[
"Drone Warfare: Jus Ad Bellum?",
"\n\nLAST MAY, during his address to Congress on national security, President Obama was interrupted by a woman’s voice from the floor. ",
"As captured on camera, the words of this disruptive questioner were at first barely audible but gradually gained in strength and commanded the room. “",
"Can you tell the Muslims that their lives are as precious as our lives?” ",
"she asked as several men in dark suits, holding her by the arms, escorted her out. “",
"Can you take the drones out of the hands of the CIA? ",
"Can you stop the signature strikes that are killing people on the basis of suspicious activity? ",
"Will you compensate the families of innocent victims you have killed?” ",
"Finally, as she was pressed through the chamber’s exit, “I love my country. ",
"I love the rule of law. ",
"The drones are making us less safe.”",
"\n\nPresident Obama, at first somewhat ruffled by these outbursts, appeared to allow the questioning to continue for a time. ",
"When silence returned to the chamber, he paused to reflect, extemporaneously. “",
"The voice of that woman is worth paying attention to,” he said. “",
"Obviously I do not agree with much of what she said. ",
"And obviously she wasn’t listening to me and much of what I said. ",
"But these are tough issues, and the suggestion that we can gloss over them is wrong.”",
"\n\nThe president’s interrogator was Medea Benjamin, cofounder of CODEPINK, a prominent women’s antiwar organization, and recently the author of Drone Warfare: Killing by Remote Control. ",
"The event was captured on camera, of course, and can be viewed at any of a number of websites (including here).",
"\n\nHer book, Drone Warfare, is a fierce polemic against the use of drone technology in warfare. ",
"Benjamin has next to nothing good to say about drones. ",
"Without relent, she hammers on the bad and the ugly of this technology. (",
"The good, if any, she grudgingly acknowledges near the end of her book, perhaps for fighting fires or locating lost children.) ",
"Her rendition of the bad and the ugly is impressive: it is a cancerous multibillion-dollar growth industry for the military-industrial complex, she writes, a blind, thoughtless form of murder practiced by desensitized young men and women toying with the lethal equivalents of joysticks. ",
"It is fundamentally immoral, slaying innocent bystanders along with calculated targets (“collateral damage” in the parlance of the military). ",
"It makes enemies of America’s friends — not only because of the carnage of innocents but also for the unauthorized invasion of other nations’ sovereign territories.",
"\n\nAt the moment, the United States has a considerable lead on drone technology. ",
"What will happen, Benjamin asks, when the rest of the world catches up (as it inevitably will)? ",
"How will the United States react when China or Russia asserts a similar right to lob drone-launched missiles into foreign territory as an act of “self-defense?” ",
"Will the United States be comfortable with the legal positions it has staked out at time when only it commanded this technology?",
"\n\nPublished in the spring of this year, Benjamin’s Drone Warfare has proven prophetic in its insistence that the American policy of drone strikes may undermine relations with other nations. ",
"In his recent visit to Washington, Pakistani Prime Minister Nawaz Sharif urged President Obama to end drone strikes on Pakistani soil (this, despite evidence that previous Pakistani regimes had authorized or at least condoned such strikes). ",
"A similar complaint was voiced by Afghanistan’s President Hamid Karzai, who, in late November this year, threatened to hold up that country’s security agreement with the United States because of civilian deaths caused by NATO drone strikes. ",
"The CIA’s drone warfare program is classified, so the number of innocent bystanders slain is unknown, but Benjamin cites an estimate of between 3,600 and 3,400 Pakistanis killed between 2004 and 2012. ",
"If these numbers are correct, the carnage in Pakistan would be as great as or greater than America suffered in 9/11.",
"\n\nBenjamin devotes a chapter to the legality of drone warfare and concludes it violates due process and international law. “",
"American presidents now assert the right to be judge, juror and executioner, a de facto license to kill free from the irksome interference of checks and balances,” she writes. ",
"A 007 presidency, in effect. ",
"Chillingly, Benjamin describes “Terror Tuesdays” — weekly meetings when President Obama and his staff add suspects to the drone hit lists. ",
"Under Presidents Ford, Carter, and Reagan, American policy forbade targeted assassination, but post 9/11, President Bush lifted this ban, and President Obama has, so far, left Bush’s policy in effect, and indeed, at least until very recently, greatly expanded the number of assassinations by drone strikes.",
"\n\nThe legal support for the executive’s right to order executions by drone is the Authorization for the Use of Military Force Act of 2001 (the AUMF), which gives the president power to “use all necessary and appropriate force […] to pursue those responsible for the 9/11 attacks.” ",
"For Benjamin, this legal justification is unpersuasive — she and like-minded critics argue that whether drone strikes are “necessary and appropriate” is the question, not the answer. ",
"Since the AUMF is specifically tied to pursuit of the perpetrators of the 9/11 attacks, even a drone supporter such as American University’s Professor Kenneth Anderson acknowledges reliance on the AUMF to pursue today’s terrorists “looks increasingly threadbare,” and that at some point “the president will have to act either under his own constitutional authority or obtain a new congressional authorization.” ",
"On balance, to this reviewer, the AUMF statutory basis for the drone program seems tenuous.",
"\n\nAs far as international law is concerned, Benjamin acknowledges the right of nations to “self-defense,” but outside a combat zone, she contends (and without citation) that “the killing must be necessary to protect life and there must be no other means, such as capture, or nonlethal incapacitation, to prevent that threat to life.” ",
"One wonders if she overstates the case, since, judged by this standard, it’s hard to see how any drone strike could be justified. ",
"To explain the government’s position, Benjamin quotes Harold Koh, one of President Obama’s legal advisors, who has argued that, as the United States is at war with al-Qaeda and the Taliban, it “may use force consistent with its inherent right to self-defense” including “lethal operations conducting with the use of unmanned aerial vehicles.” ",
"Amnesty International and Human Rights Watch hew much closer to Benjamin, and they separately accused the United States of breaking international law by killing civilians in missile and drone strikes intended for militants in Pakistan and Yemen. ",
"There are indications the Obama administration may be listening. ",
"Several recent anti-terrorist missions have notably involved on-the-ground kill or capture instead of drone strikes.",
"\n\nBenjamin also raises the vexing issue of drone strikes directed at American citizens, such as the case of Anwar al-Awlaki, a US citizen, Muslim cleric, and propagandist for an al-Qaeda–styled terrorist group, who was killed in a drone strike in Yemen. ",
"President Obama’s right to order the assassination of an American citizen on foreign soil was upheld in court as an executive decision beyond judicial review (meaning, the court concluded it could not second guess the president’s decision without entering into foreign policy issues reserved to the executive). ",
"What has happened, Benjamin asks, to the presumption of innocence and due process? ",
"As an American citizen, she urges, al-Awlaki was entitled to a jury trial (even if in absentia) to determine his guilt or innocence, not execution by executive decree. ",
"She glosses over the government’s justification, articulated by no less than President Obama himself: “[W]hen a US citizen goes abroad to wage war against America — and is actively plotting to kill U.S. citizens; and when neither the United States, nor our partners are in a position to capture him before he carries out a plot — his citizenship should no more serve as a shield than a sniper shooting down on an innocent crowd should be protected from a swat team.” ",
"Surprisingly, Benjamin provides no discussion of the “unwilling and unable doctrine,” an established principle of international law that sanctions governments taking action in another country’s territory to protect itself when the other government is “unwilling or unable” to do so, and a doctrinal underpinning of the administration's justification of drone use.",
"\n\nBenjamin shows considerable knowledge of her subject but displays little interest in teasing out the subtleties of its thorny issues. ",
"More nuanced arguments would help — a good advocate knows to take account of the opponent’s views, give credit where due, then state the counterargument. ",
"But this is not Benjamin’s style. ",
"In the end, she is less convincing for the full gallop at which she races to her conclusions. ",
"Whether one admires or opposes her conclusions, the reductive path Benjamin pursues is not always satisfying. ",
"Sic semper the polemic.",
"\n\nQuestions about morality and legality in war have an oxymoronic quality — war by its nature involves the suspension of the most fundamental moral injunction, “Thou Shalt Not Kill.” ",
"But questions about the right to engage in war and the means to conduct it have concerned us throughout the ages. ",
"The early Romans worried over having just cause to wage war — casus belli was the Latin phrase. (",
"A war unjustly started, they argued, would lack favor with the gods, and thus be doomed to defeat.) ",
"Later, Scholastic philosophers concerned themselves with issues of jus ad bellum — whether the means employed to engage in war are just — and in modern times nations have sought to bind themselves by treaty to refrain from the use of certain weaponry (such as chemical gas, to take an example in recent headlines). ",
"Benjamin is against the wars in Iraq and Afghanistan, as her involvement with CODEPINK demonstrates, but her new book asks us not to judge the wisdom of our current international conflicts, but the justice of using silent killing machines to slay perceived opponents. ",
"Despite its strident tone and argumentative style, her book deserves to be given grave consideration. ",
"To quote our president, “these are tough issues, and the suggestion that we can gloss over them is wrong.”"
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" In The\n\n Court of Appeals\n Ninth District of Texas at Beaumont\n ________________\n NO. ",
"09-16-00141-CV\n ________________\n\n MARK DAVIS AND ANGELIA DAVIS, Appellants\n\n V.\n\n JACQUELYN GARRETT AND ALBERT GARRETT, Appellees\n__________________________________________________________________\n\n On Appeal from the 284th District Court\n Montgomery County, Texas\n Trial Cause No. ",
"14-09-09775-CV\n__________________________________________________________________\n\n MEMORANDUM OPINION\n\n Appellees Jacquelyn Garrett1 and Albert Garrett filed a petition to establish a\n\nprivate easement on property owned by appellants, Mark Davis and Angelia Davis.2\n\nAfter a bench trial, the trial court signed a judgment establishing a private easement,\n\n\n\n 1\n Before trial began, counsel for the Garretts represented that Jacquelyn had\ndied during the pendency of the case.",
"\n 2\n For clarity, when referring to the parties individually, we will use their first\nnames. ",
"We note that, in various parts of the record, Angelia’s first name is also\nspelled as Angela.",
"\n 1\n\fin which it found that an easement existed, based upon express acknowledgment, by\n\nnecessity, and by estoppel, and the trial court also determined that the easement’s\n\nwidth is “equal to the width of a standard county road.” ",
"In four appellate issues, the\n\nDavises argue that (1) the evidence was legally and factually insufficient to support\n\nthe trial court’s finding of easement by necessity and the trial court abused its\n\ndiscretion by granting a trial amendment for that cause of action; (2) the evidence\n\nwas legally and factually insufficient to support the trial court’s finding of an express\n\neasement and the evidence conclusively established that the parties never agreed that\n\nan easement existed on the land; (3) the trial court erred by finding an easement by\n\nestoppel because it was not supported by pleadings, was not requested in a trial\n\namendment, and was not supported by legally and factually sufficient evidence; and\n\n(4) the trial court erred by altering the width of the easement because the Garretts\n\ndid not request that relief and the evidence conclusively established that the parties\n\nagreed that the current road is fourteen feet wide. ",
"We affirm the trial court’s\n\njudgment.",
"\n\n PROCEDURAL BACKGROUND\n\n In their petition to establish a private easement, the Garretts pleaded that the\n\nDavises had blocked them from the use of their property by erecting a gate and\n\npublicly stating that the Garretts do not have an easement. ",
"According to the Garretts’\n\n 2\n\fpetition, prior to April 25, 1998, Sydney and Ruth Davis owned real property,\n\ncomprised of Tract A and Tract B. The Garretts alleged that while Sydney and Ruth\n\nDavis owned the two tracts, they used Tract A to further the use of tract B by driving\n\nvehicles on a road through Tract A to access Tract B, and that “[t]his use of Tract A\n\nwas necessary for the property owner to get the full use and enjoyment of Tract B.”\n\nAccording to the Garretts’ petition, Sydney and Ruth Davis sold Tract B to Mr. and\n\nMrs. Wilbur Houdek, and Mrs. Houdek then sold Tract B to the Garretts in 1997.",
"\n\n The Garretts pleaded that Sydney and Ruth Davis “failed to grant any\n\neasement for the continued use of Tract A for the [b]enefit of Tract B, despite the\n\nfact that the conveyance locked Tract B, leaving its owner no access to the public\n\nhighway other than by crossing Tract A.” (emphasis added) The Garretts’ petition\n\nalleged that after Mrs. Houdek represented that an easement would exist on Tract A,\n\nthe Garretts continued to use Tract A, and Mark and Angelia allowed the Garretts to\n\ndrive on Tract A to reach Tract B. In addition, the Garretts asserted that their use of\n\nthe easement had been open, notorious, and continuous for ten years or more before\n\nthe date the Garretts’ suit was filed. ",
"According to the Garretts’ petition, appellants\n\nbegan to affirmatively interfere with the Garretts’ use of the road in 2013, including\n\nerecting a gate that prevented the delivery of mail to the Garretts’ home, blocking\n\nthe road with vehicles, refusing to allow the fire department access to the property,\n\n 3\n\fand preventing the Garretts from repairing the road. ",
"The Garretts requested that the\n\ntrial court declare their easement valid, permanently enjoin appellants and their\n\nagents, servants, and employees from interfering with the Garretts’ use of the\n\neasement, and award the Garretts damages and costs of suit.",
"\n\n THE EVIDENCE\n\n Albert testified that he began renting this ten-acre property from an individual\n\nnamed Mrs. Houdek, and eventually purchased the property from her in 1997. ",
"The\n\ndeed was recorded in 1998. ",
"According to Albert, in 1997 and 1998, he accessed the\n\nproperty by exiting from Daw Collins onto Davis Road and driving through some\n\nproperty owned by a paper mill. ",
"Albert explained that “at that time[,] the road was\n\nthe same from Daw Collins all the way to my property. ",
"Same consistency, same\n\nsurface.” ",
"According to Albert, the road was “composite asphalt and gravel.” ",
"Albert\n\ntestified that after he purchased the property in 1998, county equipment arrived to\n\npave the road, and the county paved the road only halfway to his home and left the\n\nrest of the road as it was. ",
"Albert testified that he continued to use the road, just as he\n\nhad before.",
"\n\n According to Albert, if he does not have access to the subject road, he cannot\n\naccess his property because it is “completely surrounded by a paper company tree\n\nfarm[,]” and the paper company is unwilling to sell any property for a road. ",
"Albert\n\n 4\n\fexplained that the road at issue is “the quickest and only way” to reach a public road\n\nfrom his property. ",
"Albert testified that Mrs. Houdek purchased the property from\n\nMr. and Mrs. Sydney Davis in 1963,3 and Houdek used the same road to access the\n\nproperty. ",
"Albert testified that his wife, Jacquelyn, ran a dog and bird breeding\n\nbusiness from the property for about ten years.",
"\n\n Albert explained that since the case began, he transferred six acres to his son\n\nbecause his son’s family came to live with Albert. ",
"Albert testified that the road now\n\nserves both pieces of property. ",
"Albert explained, “I need legal access so I can get a\n\nhome improvement loan if I want one, so I can sell my property if I want. ",
"I tried to\n\nget a reverse mortgage and couldn’t because I didn’t have a defined legal access.”",
"\n\nAlbert testified that when he moved onto the property, he thought he had actual\n\naccess. ",
"Albert testified that his access to the road was blocked during the middle of\n\n2012, when a gate was erected. ",
"Albert testified that in a previous petition he filed in\n\nJustice of the Peace Court, he described the road as fourteen feet wide.",
"\n\n Albert explained that he is unaware of any written easement that gives him\n\nrights to the road, and that the deed to the property did not reference access to the\n\nroad. ",
"In addition, Albert explained that when he bought the property, he never spoke\n\nto Sydney Davis or Mrs. Houdek about the subject road. ",
"Albert testified that he\n\n\n 3\n The record indicates that Sydney Davis is appellant Mark Davis’s father.",
"\n 5\n\fwould not have purchased the property if he did not believe he had free and clear\n\naccess. ",
"Albert testified that the Davises did not object to his use of the road or deny\n\nhim access to the road until he put the property up for sale. ",
"Albert testified that when\n\nhe realized he needed legal access to be able to sell the property, county engineers\n\nsuggested to him that he get the Davises to sign an easement.",
"\n\n After Albert’s testimony, his counsel requested a trial amendment to add\n\ncauses of action for easement by prescription and easement by necessity. ",
"The\n\nDavises’ counsel objected to the addition of a cause of action for easement by\n\nnecessity because he believed the case was about easement by prescription. ",
"The trial\n\ncourt granted Albert’s counsel’s request for a trial amendment. ",
"Albert’s counsel\n\nrested after testifying regarding his attorney’s fees.",
"\n\n Mark testified that he has lived at the same location for thirty-two years, and\n\nhe is the owner of record of the property pursuant to a deed. ",
"Mark denied that any\n\nwritten easement existed. ",
"Mark also testified that Albert bought part of the property\n\nfrom Mrs. Houdek, and he testified that he met Albert during that time. ",
"According\n\nto Mark, Albert initially rented the property, and when Mark found out that he was\n\nbuying the property, Albert approached Mark and his father and asked if he could\n\nget an easement. ",
"Mark testified that he told Albert he would not sell or give him an\n\neasement, but that he could use the road to enter and exit the property. ",
"Mark\n\n 6\n\fexplained that the power company has an eight-foot easement to use the road, but he\n\ndeclined the power company’s request to widen the easement to fifteen feet. ",
"Mark\n\nfurther testified that the telephone company has a service line along the road.",
"\n\n Mark explained that he saw Albert using the road regularly, and he also saw\n\nU.S. mail trucks and other delivery service trucks using the road. ",
"According to Mark,\n\nin 2008 or 2009, many people who were using the road were being noisy and stirring\n\nup dust, and packs of five to ten motorcycles often used the road. ",
"Mark testified that\n\nthe gate was erected because things had been stolen from the property, including\n\nsome items belonging to Albert. ",
"Mark explained that he gave Albert a key to the\n\ngate. ",
"The parties stipulated that the road in question runs through Mark’s property\n\nand onto the Garretts’ property. ",
"Mark testified that the road is approximately\n\nfourteen feet wide, but that two cars could pass “[p]ossibly in a pinch[.]” ",
"The\n\nDavises rested at the conclusion of Mark’s testimony.",
"\n\n After a recess, the trial court declared that an express easement, an easement\n\nby necessity, and easement by estoppel exist as to the road in question. ",
"The trial\n\ncourt declared that the easement exists “in a width equal to the width of the portion\n\nof that easement maintained by the County, since I don’t have any evidence other\n\nthan approximately 14 feet.” ",
"The trial court also awarded attorney’s fees to the\n\nGarretts.",
"\n\n 7\n\f On February 3, 2016, the trial court signed a written judgment memorializing\n\nits findings. ",
"After both sides requested findings of fact and conclusions of law, the\n\ntrial court filed findings of fact and conclusions of law. ",
"In its findings of fact, the\n\ntrial court found, among other things, that the Garretts’ property is landlocked; the\n\nGarretts have no other way to access their property than to cross the Davises’\n\nproperty; the Garretts have used the road since purchasing the property in 1998; and\n\nan easement across the Davises’ property “is necessary because no public roads\n\ntouch the land owned by Albert and Jacquelyn Garrett.” ",
"In its conclusions of law,\n\nthe trial court listed the elements of proof regarding the various types of easements\n\nit had declared existed, but did not explicitly state that the Garretts had proven those\n\nelements. ",
"However, as stated above, the trial court did state on the record at the\n\nconclusion of the trial that an easement by necessity existed.",
"\n\n ISSUE ONE\n\n In their first issue, the Davises argue that the trial court erred by declaring that\n\nan easement by necessity existed because “the trial amendment to add that cause of\n\naction was an abuse of discretion” and the evidence was legally and factually\n\ninsufficient to prove the Garretts’ entitlement to an easement by necessity. ",
"We turn\n\nfirst to the Davises’ argument regarding the granting of a trial amendment. ",
"We\n\nreview a trial court’s decision to permit a trial amendment for abuse of discretion.",
"\n\n 8\n\fMiller v. Wal-Mart Stores, Inc., 918 S.W.2d 658, 666 (Tex. ",
"App.—Amarillo 1996,\n\nwrit denied). ",
"A trial court abuses its discretion when it acts without reference to any\n\nguiding rules or principles; that is, whether its decision was arbitrary or\n\nunreasonable. ",
"Downer v. Aquamarine Operators, Inc., 701 S.W.2d 238, 241-242\n\n(Tex. ",
"1985).",
"\n\n Rule 63 of the Texas Rules of Civil Procedure provides as follows, in pertinent\n\npart: “[A]ny pleadings . . . ",
"offered for filing within seven days of the date of trial or\n\nthereafter . . . ",
"shall be filed only after leave of the judge is obtained, which leave\n\nshall be granted by the judge unless there is a showing that such filing will operate\n\nas a surprise to the opposite party.” ",
"Tex. ",
"R. Civ. ",
"P. 63. “",
"A court may not refuse a\n\ntrial amendment unless (1) the opposing party presents evidence of surprise or\n\nprejudice, or (2) the amendment asserts a new cause of action or defense, and thus\n\nis prejudicial on its face.” ",
"State Bar of Tex. ",
"v. Kilpatrick, 874 S.W.2d 656, 658 (Tex.",
"\n\n1994).",
"\n\n As discussed above, the Garretts’ petition pleaded that their property was\n\nlandlocked, and that their only means of reaching a public road from the property\n\nwas by using the road across the Davises’ property. ",
"Although counsel objected to\n\nthe trial amendment on the grounds that he believed the trial was focused on the\n\nissue of an easement by prescription, we conclude that the Garretts’ pleading\n\n 9\n\fprovided adequate notice that easement by necessity could be at issue. ",
"Consequently,\n\nthe Davises failed to demonstrate that the trial amendment operated as a surprise to\n\nthem. ",
"See Tex. ",
"R. Civ. ",
"P. 63. ",
"In addition, the Davises did not demonstrate that the\n\namendment presented a new cause of action. ",
"See id.; see also Kilpatrick, 874 S.W.2d\n\nat 658. ",
"Accordingly, the trial court did not abuse its discretion by granting the\n\nGarretts’ request for a trial amendment to explicitly plead a cause of action for\n\neasement by necessity.",
"\n\n We now turn to the legal and factual sufficiency of the evidence regarding the\n\ntrial court’s finding that an easement by necessity existed. ",
"We review the trial court’s\n\nfindings for legal and factual sufficiency of the evidence using the same standards\n\napplied in reviewing the legal and factual sufficiency of the evidence supporting a\n\njury’s answer to a jury question. ",
"Anderson v. City of Seven Points, 806 S.W.2d 791,\n\n794 (Tex. ",
"1991). ",
"Findings of fact in a case tried to the court have the same force and\n\ndignity as a jury’s verdict. ",
"Id. at 794. ",
"When the appellate record contains a reporter’s\n\nrecord, the trial court’s findings are binding only if supported by the evidence. ",
"Aldine\n\nIndep. ",
"Sch. ",
"Dist. ",
"v. Ogg, 122 S.W.3d 257, 265 (Tex. ",
"App.—Houston [1st Dist.]",
"\n\n2003, no pet.).",
"\n\n In a legal sufficiency review, we credit favorable evidence if a reasonable\n\nfactfinder could, and disregard contrary evidence unless a reasonable factfinder\n\n 10\n\fcould not. ",
"City of Keller v. Wilson, 168 S.W.3d 802, 827 (Tex. ",
"2005). ",
"Evidence is\n\nlegally sufficient if it “would enable reasonable and fair-minded people to reach the\n\nverdict under review.” ",
"Id. The factfinder is the sole judge of the credibility of the\n\nwitnesses and is responsible for resolving any conflicts in the evidence, weighing\n\nthe evidence, and drawing reasonable inferences from basic facts to ultimate facts.",
"\n\nId. at 819-21; Sw. ",
"Bell Tel. ",
"Co. v. Garza, 164 S.W.3d 607, 625 (Tex. ",
"2004). ",
"In a\n\nfactual sufficiency review, we consider and weigh all of the evidence, and we will\n\nset aside the trial court’s finding only if the evidence is so weak or the finding is so\n\nagainst the great weight and preponderance of the evidence that it is clearly wrong\n\nand unjust. ",
"Dow Chem. ",
"Co. v. Francis, 46 S.W.3d 237, 242 (Tex. ",
"2001). ",
"As long as\n\nthe evidence falls within the zone of reasonable disagreement, we cannot substitute\n\nour judgment for that of the factfinder. ",
"City of Keller, 168 S.W.3d at 822.",
"\n\n “To successfully assert a necessity easement, the party claiming the easement\n\nmust demonstrate: (1) unity of ownership of the alleged dominant and servient\n\nestates prior to severance; (2) the claimed access is a necessity and not a mere\n\nconvenience; and (3) the necessity existed at the time the two estates were severed.”",
"\n\nHamrick v. Ward, 446 S.W.3d 377, 382 (Tex. ",
"2014). ",
"As discussed above, Albert\n\ntestified that without access to the road across the Davises’ property, he cannot\n\naccess his property. ",
"Albert explained that his property is completely surrounded by\n\n 11\n\fa paper company tree farm, which will not grant him an easement, and the road at\n\nissue is “the quickest and only way[]” to reach a public road from his property. ",
"The\n\ntrial court also had documents and discovery responses before it showing that the\n\ndominant and servient estates were unified prior to severance, and that the necessity\n\nexisted when the two estates were severed. ",
"Crediting favorable evidence if a\n\nreasonable factfinder could, and disregarding contrary evidence unless a reasonable\n\nfactfinder could not, we conclude that the evidence would enable reasonable and\n\nfair-minded people to conclude that an easement by necessity existed and, therefore,\n\nis legally sufficient. ",
"See City of Keller, 168 S.W.3d at 827. ",
"Furthermore, considering\n\nand weighing all of the evidence, we conclude that the evidence supporting the\n\nexistence of an easement by necessity is not so weak nor is the finding so against the\n\ngreat weight and preponderance of the evidence as to be clearly wrong and unjust.",
"\n\nSee Francis, 46 S.W.3d at 242. ",
"Therefore, the evidence is factually sufficient.",
"\n\nAccordingly, we overrule issue one. ",
"Having found that the trial court did not abuse\n\nits discretion by allowing the trial amendment and that the evidence is legally and\n\nfactually sufficient to support the trial court’s finding that an easement by necessity\n\nexisted, we need not address issues two and three. ",
"See Tex. ",
"R. App. ",
"P. 47.1.",
"\n\n\n\n\n 12\n\f ISSUE FOUR\n\n We turn now to issue four, in which the Davises argue that the trial court erred\n\nby “altering” the width of the easement because the Garretts did not request that\n\nrelief and the evidence conclusively established that the parties agreed that the road\n\nis fourteen feet wide. ",
"The Garretts’ petition did not specify the width of the easement\n\nthey were requesting the trial court to declare. ",
"As discussed above, Albert testified\n\nthat the county paved the road halfway to his home. ",
"In addition, Mark testified that\n\nthe power company has an easement to use the road, and that the telephone company\n\nhas installed a line along the road. ",
"Albert testified that he had previously asserted\n\nthat the road was fourteen feet wide, and Mark testified that the road is fourteen feet\n\nwide. ",
"As discussed above, in its judgment, the trial court determined that an\n\neasement with “the width being equal to the width of a standard county road[]”\n\nexisted.",
"\n\n Section 251.007 of the Texas Transportation Code sets forth the width\n\nrequirements for first-class, second-class, and third-class county roads. ",
"Tex. ",
"Transp.",
"\n\nCode Ann. § ",
"251.007(c), (d), (e) (West 2013). ",
"The statute requires that a first-class\n\ncounty road must be not less than forty feet wide or more than one hundred feet\n\nwide, and the causeway must be at least sixteen feet wide; a second-class county\n\nroad must meet the requirements applicable to a first-class road; and a third-class\n\n 13\n\fcounty road may be less than forty feet wide but not less than twenty feet wide, and\n\nthe causeway may be less than sixteen feet but not less than twelve feet wide. ",
"Id.\n\n The evidence did not establish the classification of the county’s portion of the\n\nsubject road. ",
"Although Albert testified that he had alleged in another proceeding that\n\nthe road is fourteen feet wide, and Mark testified that the road is currently fourteen\n\nfeet wide, the trial court could have discounted Albert’s testimony about the prior\n\nfiling in the Justice of the Peace Court and could have chosen to disbelieve Mark’s\n\ntestimony regarding the width of the road. ",
"See City of Keller, 168 S.W.3d at 819-21;\n\nSw. ",
"Bell Tel. ",
"Co., 164 S.W.3d at 625. ",
"In addition, the trial court could reasonably\n\nhave taken into account the testimony that the power company has an easement to\n\nuse the road, and that the telephone company has installed a line along the road.",
"\n\nBecause the trial court could have disbelieved the only testimony regarding the width\n\nof the road and the width and classification of the county-paved portion of the road\n\nwere not in evidence, this Court cannot say that the trial court increased the width of\n\nthe road or erred by determining that the easement is the width of a “standard county\n\nroad.” ",
"See Tex. ",
"Transp. ",
"Code Ann. § ",
"251.007(c), (d), (e). ",
"The easement that the trial\n\ncourt granted is not wider than that requested by Garretts’ pleadings, nor is it wider\n\nthan could be reasonably inferred from the evidence. ",
"We overrule issue four and\n\naffirm the trial court’s judgment.",
"\n\n 14\n\f AFFIRMED.",
"\n\n ______________________________\n STEVE McKEITHEN\n Chief Justice\n\n\nSubmitted on April 25, 2017\nOpinion Delivered August 3, 2017\n\nBefore McKeithen, C.J., Kreger and Johnson, JJ.",
"\n\n\n\n\n 15\n\f"
] |
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[
"Q:\n\nComo pegar e salvar muitas entradas de dados em python?",
"\n\nGalera estou começando a programar e ate agora as entradas de dados eram assim:\n dado_1 = str(input('Seu nome: '))\n dado_2 = int(input('Sua idade: '))\n dado_3 = str(input('Sexo: '))\n\nMas eu fiquei com uma duvida, como eu pego os mesmos dados acima e os armazeno de forma \"infinita\" podendo por exemplo salvar 30 nomes ou 100 nomes junto com as outras informações e requisitar depois.",
"\n\nA:\n\nVariáveis de mesmo tipo podem ser agregadas em uma lista (vou usar a terminologia do Python), por exemplo:\nanimais=['cachorro', 'gato', 'galinha']\nprint(animais)\n['cachorro', 'gato', 'galinha']\n\nEstes valores podem ser acessados através da sua posição na lista (índice), sendo o primeiro item começando em zero.",
"\nprint(animais[2])\n'galinha'\n\nE novos valores podem ser facilmente adicionados:\nanimais.append('porco')\nprint(animais[3])\n'porco'\n\nVocê também pode ter listas podem ter como índice um nome (chave), ao invés de um valor numérico. ",
"Em Python eles são chamados de dicionários:\npessoa = { 'nome': 'Giovanni', 'idade': 45, 'sexo': \"M\" }\nprint(pessoa)\n{'idade': 45, 'sexo': 'M', 'nome': 'Giovanni'}\n\nE cada valor acessado tal qual na lista:\nprint pessoa['idade']\n45\n\nNeste caso a ordem não é preservada já que você acessa os valores pela chave. ",
"E o interessante é que você pode armazenar qualquer par de chave/valor dentro dos dicionários.",
"\nAssim pode-se responder sua pergunta com um programa que é mais ou menos assim:\n#!",
"/usr/bin/python3\n\n# lista com as pessoas, vazia por enquanto.",
"\npessoas = []\n\n# coloquei apenas 5 para não ficar cansativo mas pode ser qualquer valor.",
"\nfor i in range(5):\n nome = input('Nome : ')\n idade = int(input('Idade : '))\n sexo = input('Sexo : ')\n\n # cria um dicionário com o que foi entrado e adiciona à lista.",
"\n pessoas.append({ 'nome': nome, 'idade':idade, 'sexo':sexo })\n\n# e para cada pessoa armazenada...\nfor pessoa in pessoas:\n # recupera de pessoa tanto 'chave' como 'valor'.",
"\n for chave, valor in pessoa.items():\n print(\"{} => {}\".format(chave, valor))\n print(\"----\")\n\nClaro, estes valores estarão na memória apenas enquanto o programa estiver em execução, sendo descartados assim que ele for terminado.",
"\nEsta é uma explicação bem básica e vale a pena uma leitura sobre estes dois tipos de dados para, entre outras coisas, conhecer os demais métodos e atributos que podem ser utilizados para trabalhar com o conteúdo deles.",
"\n\n"
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[
"OLE IMPORTS began in 1999 with just 3 wines. ",
"Our unique portfolio of Spanish wines has now grown to over 100 wines today. ",
"My dear friend and partner Alberto Orte and I have searched the Spanish peninsula for wines that share four fundamental elements: terroir, quality fruit, exceptional winemaking and last but not least, wines that present an exceptional value."
] |
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[
"Saturday, February 09, 2008\n\nSaint Valentine's Day; A short History\n\nHi all, Here is some brief history of St. Valentine's Day celebrations.",
"\n\nTaken from many sources. ",
"Interesting at the least??",
"\n\nSparkling\n\nBee\n\nLupercalia: A \"Feverish\" Festival We may owe our observance of Valentine's Day to the Roman celebration of Lupercalia, a festival of eroticism that honored Juno Februata, the goddess of \"feverish\" (febris) love. ",
"Annually, on the ides of February, love notes or \"billets\" would be drawn to partner men and women for feasting and sexual game playing.",
"\n\nFrom Sinful to Saintly? ",
"Early Christians, clearly a dour bunch, frowned on these lascivious goings-on. ",
"In an attempt to curb the erotic festivities, the Christian clergy encouraged celebrants to substitute the names of saints. ",
"Then, for the next twelve months, participants were to emulate the ideals represented by the particular saint they'd chosen. ",
"Not too surprisingly, this prudish version of Lupercalia proved unpopular, and died a quick death.",
"\n\nEasier to Do: Substitute Romance for Eroticism But the early Christians were anything but quitters, so it was on to Plan B: modulate the overtly sexual nature of Lupercalia by turning this \"feast of the flesh\" into a \"ritual for romance!\" ",
"This time, the Church selected a single saint to do battle the pagan goddess Juno -- St. Valentine (Valentinus). ",
"And since Valentinus had been martyred on February 14, the Church could also preempt the annual February 15 celebration of Lupercalia. ",
"The only fly in the ointment was Valentinus himself: he was a chaste man, unschooled in the art of love.",
"\n\nPutting the Right \"Spin\" on the Saint To make the chaste Saint more appealing to lovers, the Church may have \"embellished\" his life story a little bit. ",
"Since it happened so long ago, records no longer exist. ",
"But if it didn't happen this way, it certainly makes for a better story... According to one legend, Valentinus ignored a decree from Emperor Claudius II that forbade all marriages and betrothals. ",
"Caught in the act, Valentinus was imprisoned and sentenced to death for secretly conducting several wedding ceremonies. ",
"While imprisoned, the future Saint cured a girl (the jailer's daughter) of her blindness. ",
"The poor girl fell madly in love with Valentinus, but could not save him. ",
"On the eve of his execution, Valentinus managed to slip a parting message to the girl. ",
"The note, of course, was signed \"From your Valentine.\"",
"\n\nNo More Lottery Drawings Despite the efforts of the Church, Valentine's Day continued to echo Lupercalia in at least one respect - men and women, married or single, would draw lots to select a \"valentine.\" ",
"Once paired, the couple exchanged gifts and sometimes love tokens as well. ",
"The custom of lottery drawings to select Valentines persisted well into the eighteenth century. ",
"Gradually, however, a shift took place. ",
"No longer did both parties exchange gifts; instead, gift-giving became solely the responsibility of the man! ",
"This new twist helped to finally bring an end to the random drawing of names, since many men were unhappy about giving gifts (sometimes very costly) to women who were not of their choosing. ",
"And now that individuals were free to select their own Valentine, the celebration took on a new and much more serious meaning for couples!",
"\n\nValentine Cards Appear The first written valentine is usually attributed to the imprisoned Charles, Duke of Orleans. ",
"In 1415, Charles fought his lonely confinement by writing romantic verses for his wife. ",
"By the sixteenth century written valentines were so common that St. Francis de Sales, fearing for the souls of his English flock, sermonized against them. ",
"Manufactured cards, decorated with Cupids and hearts, appeared near the end of the eighteenth century. ",
"A purchased valentine became the most popular way to declare love during the early decades of the nineteenth century. ",
"Miniature works of art, the cards were usually hand painted and were often lavishly decorated with laces, silk or satin, flowers (made from the feathers of tropical birds), glass filigrees, gold-leaf or even perfumed sachets!",
"\n\nI Love You! (",
"But Postage is Due...) Did you know that the current popularity of St. Valentine's Day owes much to the modern postal service? ",
"Until the mid-1800's, the cost of sending mail was far beyond the means of the average person. ",
"Even worse, the postal service demanded payment from the recipient, not the sender, of the letter! ",
"Imagine receiving a Valentine card, paying the postage due, then reading that you were \"...valued beyond rubies\" by your Valentine. ",
"Even more ironic... discovering that your Valentine card was from an unwelcome suitor! ",
"So, until the advent of the penny post, most valentine cards were hand delivered by the prospective lover.",
"\n\nSt. Valentine's Day in the new Millennium... St. Valentine's Day greeting cards are still very popular (only more Christmas cards are sent), but red roses and chocolate candies now often accompany the card. ",
"And the card itself has changed quite a bit...recent developments include cards that play romantic music; let you record a romantic message; even \"scratch-and-sniff\" cards! ",
"New technologies offer even more ways for lovers to say \"be mine!\" ",
"Some of the new technologies... video-tape a steamy Valentine wish! ",
"Send a love letter via email! ",
"Send an animated eCard! ",
"All fun..and easy to do!"
] |
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[
"Warning message\n\nWelcome to the site! ",
"This content is old and may not reflect my current opinions. ",
"I keep it up mainly for reference and because I hope at least some of it is still good, but I encourage you to check out more recent posts as well as my Start Here page\n\nSubmitted by Melissa on Wed, 06/29/2011 - 18:18\n\nI finally finished The End of Overeating. ",
"It has some great sections, but overall I had trouble finishing it because of the dry writing style. ",
"A lot of the food in the book blamed for overeating is meat. ",
"But if you keep reading, it's not really meat so much as a flavorless factory-farmed protein matrix for sugar and soybean oil engineered to induce exccessive consumption. ",
"Now that I only eat homemade pastured meat (and occasionally meat at some very good restaurants that source responsibly), I never gorge on meat. ",
"But I confess that before I cleaned up my diet, I did have trouble restraining myself with things like General Tso's Chicken and fried Buffalo Wings. ",
"When I see a study that shows meat causes weight gain, I kind of want to know \"what meat?\". ",
"If you mean this kind of garbage, that's not meat or food at all, that's an industrial product:\n\nIn China, dishes like orange-flavored chicken and sweet-and-sour chicken are widely available, but again, all the sugar is an American contribution. ",
"The dish we call \"General Tso's Chicken\" is loaded with sugar, much to the consternation of the Taiwanese chef who created it. \"",
"The dish can't be sweet,\" he insisted. \"",
"The taste of Hunan cuisine is not sweet.\"",
"\n\nThe Orange Chicken is described on the menu as \"tender, juicy chicken pieces lightly battered and fried, sauteed in a sweet and mildly spicy chili sauce with scallions.\" ",
"Preparation of the dish begins in the factory, where the meat is processed, battered, fried, and frozen. ",
"Like many processed meats, the dark chicken chunks contain as much as 19 percent of a water-based solution; oil and salt are added as well.",
"\n\nBoxes containing eight four-pound bags of ginger-citrus sauce, each with a refrigerated shelf life of about four months, are shipped to Chili's restaurants to accompany the chicken. ",
"The ingredients in the sauce sound relatively benign: sugar, hoisin sauce, vinegar, soy sauce, garlic, chili paste, modified food starch, and orange juice concentrate. ",
"But sugar is the dominant nutrient, and salt is listed three times.",
"\n\nAbout the Boneless Shanghai Wings, he said, \"Taking it off the bone is like taking the husk off the nut.\" ",
"That processing step reduces the need for chewing, making the food faster to consume. ",
"Those wings contain a solution of up to 25 percent water, hydrolyzed soy protein, salt, and sodium phosphate. ",
"The water is in there for several reasons. ",
"First, it bulks up the chicken-the industry calls this \"reducing shrinkage.\" ",
"Second, water is cheaper than chicken breast, so it's less costly to produce. ",
"And finally, water makes the food softer and chewing easier. ",
"Before the chicken is shipped from the manufacturing plant, it's battered, breaded, predusted, and frozen. ",
"This creates a salty coating that becomes crispy when fried in fat. \"",
"All this stuff absorbs fat, dries out this batter and breading, and replaces water with oil. ",
"So now you've got batter and breading that is probably 40 percent fat,\" according to the food consultant. ",
"The crispy coating, which also contains corn-syrup solids, dried yeast, and soybean oil, may represent up to half the volume of the nuggets on the plate.",
"\n\nRecommended Books\n\nAn anthropological study of an arctic tribe written in narrative form, this is a beautiful book that fleshes out aspects of life that are often ignored even by those who follow primal diets. ",
"Food is more than just survival, it has important spritual aspects that tie it to us and the places we live."
] |
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"The Saudi public prosecution concluded investigating citizens accused of spying for Iran and will transfer them to the relevant judicial authorities, the Saudi daily Okaz reported on Monday.",
"\n\n\n\nSaudi security forces had detained a number of citizens after learning that they communicated with Iranian intelligence apparatuses to carry out acts of espionage. ",
"The prosecution investigated the accused several times and recently finished and is now working on transferring the case to the relevant judicial authorities.",
"\n\n\n\nThis is the second case of its kind in the Saudi Arabia as in 2013 cooperation between the interior ministry and the intelligence led to the arrest of 32 people, 30 Saudis, an Iranian and an Afghani, who had formed a cell to spy for Iran. ",
"After looking into their case, 30 were convicted while two others, a Saudi and the Afghani, were exonerated.",
"\n\nThe preliminary ruling stipulated executing 15 of those found guilty while the 15 others, 14 Saudis and the Iranian, received prison sentences which ranged between 6 months and 25 years.",
"\n\nLast Update: Wednesday, 20 May 2020 KSA 09:49 - GMT 06:49"
] |
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[
"Circle, the $3 billion global crypto finance company backed by Goldman Sachs, is changing the world of crypto as we know it. ",
"In a blog post published today by co-founders, Sean Neville, and Jeremy Allaire, Circle will introduce a USD-Backed Cryptocurrency. ",
"USDC, as it’s called, is a cryptocurrency “stablecoin” tied to the value of the U.S. dollar and backed by physical dollars stored in bank accounts.",
"\n\nAs Circle’s website states, the technology allows users to “invest in crypto even if you’ve never invested in crypto.” ",
"Circle was launched in 2013 by Allaire and Neville in Boston, MA and has been on a \"mission to change the global economy\" ever since.",
"\n\n“When we founded Circle five years ago, we and many in the crypto community envisioned fiat money and financial contracts executing on top of distributed public network infrastructure, building on open standards that would allow us all to share value as instantly and easily as we can access content in web browsers and exchange messages in email and messaging apps. ",
"Just as HTTPS, SMTP, and SIP-enabled free borderless information sharing and communications, crypto assets, and blockchain technology will enable us to exchange value and transact with one another in a similar way: instantly, globally, securely and at low cost,” Neville and Allaire explained in the announcement.",
"\n\nThe stablecoin was developed in collaboration with Circle’s CENTRE affiliate consortium and allows individuals and institutions to “deposit US dollars from bank accounts, convert those dollars into tokens usable everywhere the internet reaches (subject to the token’s compliance controls), and redeem USDC tokens and cash out to bank accounts.”",
"\n\n30 essential partners across the industry including DigiFinex, CoinEx, Poloniex, KuCoin, OKCoin, Ledger, Coinplug, BitPay, and many other platforms, exchanges, applications, protocols, and wallets have announced their support for USDC. ",
"These partnerships will allow retail companies and investors around the world to use a price-stable cryptocurrency to trade against all digital assets.",
"\n\nAllaire said in an interview back in May, “there's a need for a \"compliant alternative\" to Tether.” ",
"Poloniex, Circle’s cryptocurrency exchange, appears to be that alternative, as it aims to replace the controversial Tether (USDT) with USDC, though he did not give a timetable for this transition."
] |
{
"pile_set_name": "OpenWebText2"
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|
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0.008,
0.015151515151515152,
0.006802721088435374,
0.008264462809917356,
0.014925373134328358,
0.0027100271002710027,
0.009584664536741214,
0.005780346820809248,
0.012605042016806723,
0,
0.00980392156862745,
0.015306122448979591
] | 0.009078
| 5
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[
"Nitrogen isotopic fractionation as a biomarker for nitrogen use efficiency in ruminants: a meta-analysis.",
"\nAnimal proteins are naturally 15N enriched relative to the diet and the extent of this difference (Δ15Nanimal-diet or N isotopic fractionation) has been correlated to N use efficiency (NUE; N gain or milk N yield/N intake) in some recent ruminant studies. ",
"The present study used meta-analysis to investigate whether Δ15Nanimal-diet can be used as a predictor of NUE across a range of dietary conditions, particularly at the level of between-animal variation. ",
"An additional objective was to identify variables related to N partitioning explaining the link between NUE and Δ15Nanimal-diet. ",
"Individual values from eight publications reporting both NUE and Δ15Nanimal-diet for domestic ruminants were used to create a database comprising 11 experimental studies, 41 treatments and individual animal values for NUE (n=226) and Δ15Nanimal-diet (n=291). ",
"Data were analyzed by mixed-effect regression analysis taking into account experimental factors as random effects on both the intercept and slope of the model. ",
"Diets were characterized according to the INRA feeding system in terms of N utilization at the rumen, digestive and metabolic levels. ",
"These variables were used in a partial least squares regression analysis to predict separately NUE and Δ15Nanimal-diet variation, with the objective of identifying common variables linking NUE and Δ15Nanimal-diet. ",
"For individuals reared under similar conditions (within-study) and at the same time (within-period), the variance of NUE and Δ15Nanimal-diet not explained by dietary treatments (i.e. between-animal variation plus experimental error) was 35% and 55%, respectively. ",
"Mixed-effect regression analysis conducted with treatment means showed that Δ15Nanimal-diet was significantly and negatively correlated to NUE variation across diets (NUE=0.415 -0.055×Δ15Nanimal-diet). ",
"When using individual values and taking into account the random effects of study, period and diet, the relationship was also significant (NUE=0.358 -0.035×Δ15Nanimal-diet). ",
"However, there may be a biased prediction for animals close to zero, or in negative, N balance. ",
"When using a novel statistical approach, attempting to regress between-animal variation in NUE on between-animal variation in Δ15Nanimal-diet (without the influence of experimental factors), the negative relationship was still significant, highlighting the ability of Δ15Nanimal-diet to capture individual variability. ",
"Among the studied variables related to N utilization, those concerning N efficiency use at the metabolic level contributed most to predict both Δ15Nanimal-diet and NUE variation, with rumen fermentation and digestion contributing to a lesser extent. ",
"This study confirmed that on average Δ15Nanimal-diet can predict NUE variation across diets and across individuals reared under similar conditions."
] |
{
"pile_set_name": "PubMed Abstracts"
}
|
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0.009523809523809525,
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0.0049261083743842365,
0.007751937984496124,
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0.007462686567164179,
0.009345794392523364,
0.003787878787878788,
0.0049504950495049506,
0.005780346820809248,
0,
0.003134796238244514,
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0.006802721088435374
] | 0.005531
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[
"// Copyright 2019 The Prometheus Authors\n// Licensed under the Apache License, Version 2.0 (the \"License\");\n// you may not use this file except in compliance with the License.",
"\n// You may obtain a copy of the License at\n//\n// http://www.apache.org/licenses/LICENSE-2.0\n//\n// Unless required by applicable law or agreed to in writing, software\n// distributed under the License is distributed on an \"AS IS\" BASIS,\n// WITHOUT WARRANTIES OR CONDITIONS OF ANY KIND, either express or implied.",
"\n// See the License for the specific language governing permissions and\n// limitations under the License.",
"\n\npackage procfs\n\nimport (\n\t\"io/ioutil\"\n\t\"os\"\n\t\"strings\"\n)\n\n// Environ reads process environments from /proc/<pid>/environ\nfunc (p Proc) Environ() ([]string, error) {\n\tenvironments := make([]string, 0)\n\n\tf, err := os.",
"Open(p.path(\"environ\"))\n\tif err !",
"= nil {\n\t\treturn environments, err\n\t}\n\tdefer f.Close()\n\n\tdata, err := ioutil.",
"ReadAll(f)\n\tif err !",
"= nil {\n\t\treturn environments, err\n\t}\n\n\tenvironments = strings.",
"Split(string(data), \"\\000\")\n\tif len(environments) > 0 {\n\t\tenvironments = environments[:len(environments)-1]\n\t}\n\n\treturn environments, nil\n}\n"
] |
{
"pile_set_name": "Github"
}
|
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0.011428571428571429,
0.00964630225080386,
0.009523809523809525,
0.013824884792626729,
0.030303030303030304,
0.012987012987012988,
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0,
0
] | 0.009746
| 5
|
[
"Ionizing radiation induces structural and functional damage on the molecules of rat brain homogenate membranes: a Fourier transform infrared (FT-IR) spectroscopic study.",
"\nHumans can be exposed to ionizing radiation, due to various reasons, whose structural effects on biological membranes are not well defined. ",
"The current study aims to understand the ionizing radiation-induced structural and functional alterations in biomolecules of brain membranes using Fourier transform infrared (FT-IR) spectroscopy using rat animal models. ",
"For this purpose, 1000 cGy of ionizing radiation was specifically directed to the head of Sprague Dawley rats. ",
"The rats were decapitated after 24 h. The results revealed that the lipid-to-protein ratio decreased and that irradiation caused lipid peroxidation and increases in the amounts of olefinic =CH, carbonyl, and methylene groups of lipids. ",
"In addition, ionizing radiation induced a decrease in membrane fluidity, disordering of membrane lipids, strengthening of the hydrogen bonding of the phosphate groups of lipid head-groups, and weakening in the hydrogen bonding of the interfacial carbonyl groups of lipids. ",
"Radiation further caused significant decrements in the α-helix and turns, and significant increments in the β-sheet and random coil contents in the protein structure. ",
"Hierarchical cluster analyses, performed in the whole region (3030-1000 cm(-1)), lipid (3030-2800 cm(-1)), and protein (1700-1600 cm(-1)) regions separately, successfully differentiated the control and irradiated groups of rat brain membranes and showed that proteins in the membranes are affected more than lipids from the damages induced with ionizing radiation. ",
"As a result, the current study showed that FT-IR spectroscopy can be used successfully as a novel method to monitor radiation-induced alterations on biological membranes."
] |
{
"pile_set_name": "PubMed Abstracts"
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[
"Metabolism and disposition of inorganic arsenic in laboratory animals and humans.",
"\nThe carcinogenicity of inorganic arsenic in humans, particularly in the lung and skin, has been reasonably well established through epidemiological investigations. ",
"However, there is no substantial experimental evidence for carcinogenicity in animals to support the human studies. ",
"Studies of metabolism and disposition of inorganic arsenic in various animal species are particularly relevant to determining the factors that might account for the lack of an animal model. ",
"Numerous studies of this type have been reported, but there do not appear to be clear qualitative or quantitative differences in the overall fate and disposition of inorganic arsenic in most animalsversus humans, although little is known at the cellular and subcellular level.",
"Sulphur chemistry, especially thiol status, is emerging as an important regulating factor in the overall fate and distribution of inorganic arsenic in the body, playing a role in the initial reduction of arsenate to arsenite and subsequent methylation, and possibly in determining tissue affinity and distribution properties. ",
"The metabolism of inorganic arsenic can be viewed as a redox cycle in which thiol compounds such as glutathione (GSH) possibly function as reducing agents and methyl donors as oxidising agents. ",
"One explanation for the possible sensitivity of certain malnourished human populations to the carcinogenic effects of inorganic arsenic may be related to the reduced availability of nonprotein sulphhydryl compounds such as GSH needed to drive the redox cycle and facilitate arsenic detoxification. ",
"Future carcinogenicity studies of inorganic arsenic in animals could be designed to address directly this aspect of the problem."
] |
{
"pile_set_name": "PubMed Abstracts"
}
|
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0,
0,
0,
0,
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0.003067484662576687,
0.005154639175257732,
0.003355704697986577,
0
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| 5
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[
"\n698 S.E.2d 556 (2010)\nSTATE\nv.\nWILLIAMS.",
"\nNo. ",
"COA09-1052.",
"\nCourt of Appeals of North Carolina.",
"\nFiled August 3, 2010.",
"\nCertification Date August 23, 2010.",
"\nCase Reported Without Published Opinion Reversed and ordered new trial in part and no error in part.",
"\n"
] |
{
"pile_set_name": "FreeLaw"
}
|
[
0,
0,
0.09090909090909091,
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0,
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| 5
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[
"Q:\n\nWhat's wrong with my insertion sort?",
"\n\nI'm trying to sort a large datafile using an Insertion-based sorting algorithm, the code runs fine but the output is incorrect. ",
"I've studied it over and over to absolutely no avail, can anyone see where I've gone wrong?",
"\npublic void sort(Comparable[] items) {\n for (int i = 1; i < items.length; i++) {\n Comparable temp = items[i];\n int j = i - 1;\n while (j >= 0 && items[j].compareTo(items[j]) > 0) {\n items[j + 1] = items[j];\n j = j - 1;\n }\n items[j] = temp;\n }\n}\n\nAn example datafile I have produced is...\n2\n1\n3\n5\n9\n6\n7\n4\n8\n\nAnd obviously the output should be 1,2,3,4... - but instead I get 1\n3\n5\n9\n6\n7\n4\n8\n8\n\nA:\n\nitems[j].compareTo(items[j]) should be items[j].compareTo(temp), otherwise you're just comparing the item against itself - you need to be comparing it against the object you want to insert.",
"\nThen items[j] = temp; will also cause an ArrayIndexOutOfBoundsException because, at the end of the loop, items[j] is smaller than temp, or j == -1, so we need to insert at the position after that - the simplest fix is just changing that to items[j+1] = temp;.",
"\n\n"
] |
{
"pile_set_name": "StackExchange"
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0,
0.007692307692307693,
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0.0015432098765432098,
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[
"This invention relates to an electronic musical instrument capable of producing musically rich performance tones by imparting random characteristics or casualness to the pitch, color and volume envelope to the musical tones generated by the musical instrument.",
"\nIn an electronic musical instrument, the pitch of the generated musical tone and the generation of the tone are generally controlled by key informations which are generated in accordance with the depressed keys of a keyboard. ",
"The pitch variation, the tone color and the volume envelope of the generated musical tone are set and controlled by various operating means, for example a pitch adjusting lever, a tone adjusting lever, etc, which are mounted on a panel of the musical instrument. ",
"However, since these operating levers are mounted on the panel of the musical instrument the player can not operate them freely during performance, and usually the player must operate them before the performance. ",
"Accordingly, during the performance the musical tones are generated always under the same conditions, (that is the same pitch variation, the same tone color and the same volume envelope) with the result that the generated musical tones lack variety, thus producing extremely monotoneous tones."
] |
{
"pile_set_name": "USPTO Backgrounds"
}
|
[
0,
0,
0,
0,
0
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[
"~ Government spending on education is 2.4% of Togo's GDP (down from 6% in early 1990s)\n\n~ Education funding is 13% of total Togo government expenditures (was 27% in 1990)\n\n~ Dropout rates in rural secondary schools are 3 times higher than in urban ones.",
"\n\n~ Of all 12-18 year olds:\n\n14% of girls nationwide attend secondary school\n\n9% of girls in rural areas attend secondary school\n\n46% of boys nationwide attend secondary school\n\n16% of boys in rural areas attend secondary school\n\nAlaffia's Education Projects\nfunded by sales of Alaffia products\n\n~Donated school supplies to over 11,700 students since 2004\n\n~Metal school roof donations in 4 schools in central Togo\n\n~1,250 benches built for numerous schools since 2004\n\nEducation Crisis in West Africa\n\nIn most of West Africa, there is a drop out rate of 70% before students reach 6th grade. ",
"While there are many complicated reasons for the failure of the educational system, lack of funding is one major factor. ",
"After structural adjustment programs were forced on African governments in the 1990s, funding to schools dropped considerably. ",
"Mismanagement and misallocation combined with inadequate funding contribute to the educational crisis in Africa and result in insufficient infrastructure and support. ",
"General poverty makes formal education an expensive choice for parents, and even more so when governments are unable to provide books, buildings or even teacher's pay.",
"\n\nEducational statistics show the results of funding and infrastructure insufficiency, and are especially evident in rural areas and for secondary education. ",
"In Togo, the government will provide a primary school teacher if the community provides the school. ",
"This means, that most villages have a primary school, and provided the teacher is paid by the government, most children have access to primary educations. ",
"The drop out rates are still high, but the majority of girls and boys do complete primary school (55% and 77% respectively). ",
"However, the situation gets much worse for secondary education.",
"\n\nRecipient of Alaffia school supplies with friends.",
"\n\nSchool benches are often too\nexpensive for village schools to furnish.",
"\nAlaffia has built 1,250 benches to date.",
"\n\nThe secondary school situation in Togo is due to several factors. ",
"Secondary schools only exist in relatively large towns. ",
"This means that students in surrounding villages must walk or find other transportation for up to 25 miles each way. ",
"Competition for seating or place in class is also high, and, as in primary school, students must pay a tuition fee each year. ",
"Students must pay for their own books, uniforms and supplies, which is a daunting expense for poor families. ",
"Secondary school requires a greater number of books and supplies, and many children spend their entire summer break working to save money to purchase these. ",
"Finally, students must pass an annual exam each year, or they lose their place in school. ",
"Poorer students, especially girls, have disproportionately more chores and household responsibilities and often have difficulty finding time to study for these exams. ",
"Farm and home responsibilities often take priority for these students, and they choose to abandon their formal educations.",
"\n\nFuture Consequences of Today's Educational Crisis\n\nToday, around half of adults in Africa are illiterate, and the majority of these are women. ",
"While reading and writing are not necessary for a fulfilling and productive life, illiteracy is a handicap in a world where information exchange is based on the written word. ",
"As global trade increases, illiteracy can put people at a disadvantage: it keeps them from realizing the full value of their products. ",
"And, perhaps even more disturbingly, the vast majority of students who do make it through the education system leaves or wants to leave Africa to find work elsewhere. ",
"This is causing a major loss of human capital that is very detrimental to the future of the continent.",
"\n\nAlaffia donated school supplies to families\naffected by floods in 2007.",
"\n\nOlowo-n'djo with school supply recipient.",
"\n\nAlaffia's Response to the Education Crisis\n\nEven though the current education system has many problems beyond the lack of funding (curricula issues, lack of traditional educational models, etc...), we still believe all children should have access to the economic opportunities that education can present. ",
"For this reason, we have supported education in our central Togo communities since 2004 through several projects.",
"\n\nOur very first project, which continues to this day, is providing school supplies - such as notebooks, pencils, pen, chalk, and so forth - and uniform fabric to 200 disadvantaged students each year. ",
"This project is also one in which our customers and supporters can particpate. ",
"Many of our retail locations provide school supply donation boxes each year. ",
"Look for them at your local store.",
"\n\nIn addition, we also carry out several school repair and furniture donation projects each year. ",
"Often, villages are able to build a school using local materials and labor, but cannot afford metal roofs and desks to complete the school. ",
"In 2011, The Wedge Co-Op and Whole Foods Florida partnered with Alaffia to donate school benches to schools in rural Togo.",
"\n\nFinally, since 2006 we have collected and distributed used bicycles to secondary school students to help them get to and from school. ",
"Read more about this project on our Bicycles for Education page."
] |
{
"pile_set_name": "Pile-CC"
}
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0.007905138339920948,
0.0033783783783783786,
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0.024390243902439025,
0.014705882352941176,
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0.008849557522123894,
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0.02459016393442623,
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0
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[
"WILKES-BARRE TOWNSHIP, Pa. — The Wilkes-Barre/Scranton Penguins hockey team has been a staple of the local sports scene for two decades, but the team̵...\n\nWILKES-BARRE TOWNSHIP, Pa. -- The Wilkes-Barre/Scranton Penguins hockey team has been a staple of the local sports scene for two decades, but the team's 10-year lease at the Mohegan Sun Arena expires in June.",
"\n\nThe Mohegan Sun Arena hosts 38 Penguins hockey games every season, not including pre-season and playoff games.",
"\n\nThe arena wants a hockey team to call the place home, and the Penguins need a place to play, but despite eight months of negotiations, there is no deal in place to keep the team here.",
"\n\nJason Gaylord of Exeter worries the Wilkes-Barre/Scranton Penguins could soon pull out of Luzerne County. ",
"Such a move would bother his 10-year-old son who skates for the Bantam League Penguins and follows the team.",
"\n\n\"I'm concerned because I feel like he's going to start to lose some interest and lose touch with some of the players. ",
"He looks forward to seeing when we come right up the road,\" Gaylord said.",
"\n\nLast season, the Penguins ranked 14th in the 30-team American Hockey League in attendance, drawing an average of more than 5,500 fans per game.",
"\n\nThe Wilkes-Barre/Scranton Penguins first hit the ice at the arena in Luzerne County 20 years ago. ",
"The team's early days at Mohegan Sun Arena near Wilkes-Barre saw sellouts. ",
"Sellouts at the arena are largely a thing of the past now.",
"\n\nAttendance peaked in the 2001-2002 season and was third in the league, averaging 8,300 fans a game. ",
"Now, 17 years later, attendance is down 33 percent.",
"\n\nThe Luzerne County Convention Center Authority wants the Penguins to renew the team's 10-year lease.",
"\n\nThe authority is a public board, but members tell Newswatch 16 they signed a confidentiality agreement with the team preventing them from discussing the lease negotiations going on with the Penguins organization.",
"\n\nThe CEO of the Wilkes-Barre/Scranton Penguins emailed Newswatch 16 that the two sides are working on, \"a long-term deal that is mutually beneficial\" and \"both sides are making good faith efforts to structure a deal that reflects today's challenges and changing market.\"",
"\n\n\"I never want them to leave,\" laughed Jen Smith.",
"\n\nSmith, of Wilkes-Barre, says she and her son would the miss the Penguins. ",
"The players interact with kids skating at the team's practice rink, the Toyota Sportsplex in Wilkes-Barre.",
"\n\n\"For these kids who look up to these athletes and to see that they're regular people and that they're nice and they're kind and they're giving back to the community is huge.\"",
"\n\nIf talks fall through, Mohegan Sun Arena could try to bring in another minor league hockey team, but fans want the team they've followed for the past 20 years.",
"\n\n\"It would just be devastating to lose them,\" Smith said."
] |
{
"pile_set_name": "OpenWebText2"
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0.01,
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0.00980392156862745,
0.004672897196261682,
0.0036900369003690036,
0.02,
0.02631578947368421,
0.009433962264150943,
0,
0.006211180124223602,
0
] | 0.00712
| 5
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[
"Artocarpus gomezianus aided green synthesis of ZnO nanoparticles: luminescence, photocatalytic and antioxidant properties.",
"\nWe report green synthesis of multifunctional ZnO nanoparticles (NPs) using Artocarpus gomezianus (AG) extract as fuel by solution combustion synthesis. ",
"The formation of NPs was confirmed by powder XRD, SEM, TEM and UV-Visible studies. ",
"The NPs were subjected for photoluminescence, photodegradative and antioxidant studies. ",
"XRD data reveals that the ZnO NPs possess wurtzite structure. ",
"UV-Visible spectrum shows absorbance maximum at 370 nm which corresponds to the energy band gap of 3.3 eV. Morphology studies indicate the highly porous nature of the NPs. ",
"PL spectra of NPs found to display very interesting blue, green and red emissions upon excitation at 325 nm. ",
"The NPs exhibit potential photocatalytic activity towards the degradation of methylene blue (MB) dye upon exposure to sun light and UV light. ",
"ZnO NPs found to have considerable antioxidant activity against DPPH (2,2-diphenyl-1-picrylhydrazyl) free radicals. ",
"The study successfully demonstrates a simple and eco-friendly method for the synthesis of efficient multifunctional ZnO nanoparticles using green synthetic approach."
] |
{
"pile_set_name": "PubMed Abstracts"
}
|
[
0.01639344262295082,
0.013071895424836602,
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0.016129032258064516,
0.005813953488372093,
0.009174311926605505,
0,
0,
0.006060606060606061
] | 0.010279
| 5
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[
"Moyea FLV Editor Ultimate\n\nMoyea FLV Editor Ultimate is one of the most useful FLV editors in the world. ",
"It imports MP3, F4V and FLV encoded with H.264, H.263, Flash 8, Flash 8 with alpha, Sorenson Spark, or Nellymoser.",
"\nYou can take it as an FLV/F4V/MP3 editor, FLV/F4V/MP3 splitter, FLV/F4V/MP3 joiner, FLV/F4V/MP3 cutter, MP3 to lossless FLV converter, etc. ",
"You can not only export FLV files but also SWF and HTML files for uploading on website or blog. ",
"Besides, you are also able to save project files for future editing. ",
"No matter what you have done to the FLV/MP3, there will be no loss to quality.",
"\nWhile using, you will be greatly attracted by its timeline and real-time preview function which greatly simplify the editing process. ",
"What you see is what you get.",
"\nWith the functions of trim, split, and merging, you are able to get whatever length of the FLV/F4V/MP3 files; split the file into several clips; rearrange the order; insert other clips, and merge into one. ",
"Video or audio extracting is also available. ",
"Users can even replace the original audio with a desired one. ",
"This version is the first release on CNET Download.com\n\nThank You\n\nBy registering you become a member of the CBS Interactive family of sites and you have read and agree to the Terms of Use, Privacy Policy and Video Services Policy. ",
"You agree to receive updates, alerts and promotions from CBS and that CBS may share information about you with our marketing partners so that they may contact you by email or otherwise about their products or services.",
"\nYou will also receive a complimentary subscription to the ZDNet's Tech Update Today and ZDNet Announcement newsletters. ",
"You may unsubscribe from these newsletters at any time."
] |
{
"pile_set_name": "Pile-CC"
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[
0.01904761904761905,
0.05263157894736842,
0.03546099290780142,
0.020833333333333332,
0,
0.01282051282051282,
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0,
0,
0.01293103448275862,
0.009174311926605505,
0.024793388429752067,
0
] | 0.012835
| 5
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[
"package test.listeners.github551;\n\nimport java.io.",
"IOException;\n\nimport org.testng.",
"Assert;\nimport org.testng.",
"TestNG;\nimport org.testng.annotations.",
"Test;\n\nimport test.",
"SimpleBaseTest;\n\npublic class Test551 extends SimpleBaseTest {\n\n @Test\n public void testExecutionTimeOfFailedConfig() throws IOException {\n ConfigListener listener = new ConfigListener();\n\n TestNG testNG = create(TestWithFailingConfig.class);\n testNG.addListener(listener);\n testNG.run();\n Assert.assertTrue(listener.executionTime >= TestWithFailingConfig.",
"EXEC_TIME);\n }\n}\n"
] |
{
"pile_set_name": "Github"
}
|
[
0,
0.0625,
0.07692307692307693,
0.02631578947368421,
0,
0.007556675062972292,
0
] | 0.024757
| 5
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[
"Bayern Munich are the latest major European club to express an interest in signing Dele Alli. ",
"The German champions are considering making a bid for the Tottenham Hotspur midfielder in the summer, but are aware that they will struggle to prise the 20-year-old away from White Hart Lane in the short term and are viewing him as a long-term project.",
"\n\nAlli has five years left on his contract at Tottenham, which he signed in September, and the club have made it clear that none of their leading players will be sold until they have spent at least one season at their new stadium, which is due to open in 18 months’ time. ",
"Daniel Levy, the chairman, is believed to value Alli at more than the"
] |
{
"pile_set_name": "OpenWebText2"
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0.02127659574468085,
0.003968253968253968,
0.007352941176470588,
0.028985507246376812
] | 0.015396
| 5
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[
" 2 + 3*v**3 + 2*v**2 - 393*v + 199*v - 5*v**3 to b*v + p*v**4 + t*v**2 + o*v**3 + u and give b.\n-4\nRearrange 10310*j - 3*j**2 - 5152*j - 5170*j + 7 to q*j + l*j**2 + b and give b.\n7\nExpress 40333*z - 40331*z + 1959*z**2 + 4460*z**2 in the form b + j*z + w*z**2 and give w.\n6419\nExpress 26312*k**3 - 2*k + k - 26537*k**3 in the form y + m*k + o*k**3 + h*k**2 and give m.\n-1\nRearrange -8*b**2 - 6*b**2 - 4114*b**3 + 6*b**2 + 7*b**2 to o + j*b + y*b**2 + m*b**3 and give j.\n0\nRearrange 2*o**3 - 41 + 79 - 10*o**2 + 9 + 24 + 32 to the form m*o**2 + z + i*o**3 + a*o and give i.\n2\nRearrange 486*j + 6*j**2 + 17*j**2 - 10*j**2 - 14*j**2 to the form h*j**2 + i + d*j and give h.\n-1\nRearrange -2 + 266*n**2 - 678*n**2 - 528*n - 306*n**2 + 528*n to r*n**2 + q + g*n and give q.\n-2\nRearrange -705*s**2 - 2*s**3 + 27830*s - 27816*s + 464*s**2 to t + u*s**2 + n*s + l*s**3 and give l.\n-2\nRearrange (72*m + 68*m - 151*m)*((-20 + 69 + 20)*(-3*m - 4*m + 5*m) + (m + 0*m - 2*m)*(0 - 1 + 0)) to q*m**2 + v + y*m and give q.\n1507\nExpress 35*l**3 + 6*l**2 + 332*l + 2*l**3 - 330*l as o*l + y + s*l**3 + f*l**2 and give f.\n6\nExpress -4*d**3 + 4*d**3 - 3*d**3 + (0*d**3 - 3*d**3 + d**3)*(5 + 32 + 34) + 49*d - 23*d**3 - 49*d in the form v*d + y + l*d**2 + a*d**3 and give a.\n-168\nRearrange 1597*w**4 - 2248*w + 4493*w - 2246*w + 1 to the form l*w**2 + i*w**4 + v + n*w**3 + t*w and give v.\n1\nRearrange 4 + 3*o + 48487*o**4 - 48486*o**4 + 5*o**3 + 0*o**3 - 4*o**2 to c + z*o**2 + a*o**4 + b*o + q*o**3 and give q.\n5\nRearrange (265*a - 152*a + 159*a)*(-5 + 4 + 3)*(-2 + 2 - 2) + (2*a + 0*a - 4*a)*(6 - 4 - 1) + a + 4*a + 2*a to the form x + c*a and give c.\n-1083\nExpress (24 + 18 + 9 - 5 + 0 + 4 + (1 + 1 - 1)*(1 - 1 + 1) - 5 + 2 + 2 - 1 + 3 + 0 - 2 + 3 - 3)*(-388*s**2 - 599*s + 599*s) as h*s + r*s**2 + q and give r.\n-19400\nExpress (2*l - 4*l + 3*l)*(-3*l + 4*l - 11*l)*(-5*l + l - l + (4 - 4 - 2)*(-l - 2*l + l) - 371 + 371 - 27*l) as g*l**3 + i*l + j + c*l**2 and give g.\n280\nRearrange 2197*z + 60*z + 819*z + 551*z - 203*z to q + d*z and give d.\n3424\nExpress -3294*o - 282*o - 4226*o + 828*o in the form m + l*o and give l.\n-6974\nRearrange -13 - 61*r**3 + 95*r**3 + 2*r**2 - r**2 - r**4 - 32*r**3 + 6*r to the form n + z*r**4 + s*r**2 + q*r + k*r**3 and give s.\n1\nExpress 927 - 5*m**3 - 10*m**3 + 3*m - 8*m - 930 - 3*m**2 in the form a*m**2 + s*m + j*m**3 + o and give j.\n-15\nRearrange 30*j**3 + 15*j**2 + 32*j**3 + 17*j**2 - 18*j - 64*j**3 + 8*j**2 to k*j + w*j**3 + n + z*j**2 and give k.\n-18\nExpress (4*y**2 + 5*y**2 - 6*y**2)*(-4*y + 29 - 29)*(-18 + 36 - 19) in the form b*y**3 + d + z*y**2 + u*y and give b.\n12\nExpress -13*b**3 - 495*b**2 - 49 - 14*b**3 + 496*b**2 + 4*b**3 in the form o*b + j + f*b**3 + h*b**2 and give f.\n-23\nRearrange (-3*t - 2*t - 2*t)*(-149*t**3 + 7221*t - 7221*t) to q*t**3 + g*t**2 + a*t**4 + i*t + r and give a.\n1043\nExpress (4*k**2 + 3*k**2 - 6*k**2)*(7*k - 3*k - 3*k + (-6 - 44 + 12)*(14 - 14 + 2*k) - 2 + 2 - 2*k) as l*k**2 + d*k + u + n*k**3 and give n.\n-77\nRearrange -63 + 377 - 252275*s + 252309*s + 55 to r*s + o and give r.\n34\nRearrange (-i**2 + i**2 + 2*i**2)*(2 + 2 - 2) + 3*i**2 - i**2 - 3*i**2 + (59*i + 59*i**2 - 30*i - 30*i)*(-3 + 4 - 3) to the form d*i**2 + h*i + s and give h.\n2\nRearrange (34*s**3 + 118 - 118)*(1 + 5 + 19)*(58 - 5 - 15) to the form m*s**3 + u*s**2 + n*s + h and give m.\n32300\nRearrange -932 + 4639*k + 932 - k**2 + 3163*k - 1 + 1 + 2*k**2 + (2*k**2 - k**2 + k**2)*(3 - 5 + 3) - 2*k**2 + k**2 + 3*k**2 to z*k + w + l*k**2 and give l.\n5\nExpress 26*b**4 - 5*b**3 - 3 - b**3 - 23*b**4 + 195*b**2 + b**3 - 4*b - 192*b**2 as c*b**4 + q + n*b + d*b**2 + s*b**3 and give n.\n-4\nRearrange -5*z + 60 - 642 + 593 + 831 + 920 to the form x*z + f and give f.\n1762\nRearrange 2 - v - 40*v**3 + v - 84*v**4 + 35*v**3 + 117*v**2 - 116*v**2 to the form m*v + r*v**2 + f*v**4 + u*v**3 + q and give r.\n1\nExpress -19 + 38 - 2*h**4 - 6*h**2 + 5*h**2 + 52 + 4 - 2*h**3 + h in the form m*h + w + x*h**2 + y*h**3 + i*h**4 and give m.\n1\nExpress 2003 + 2021 + 13124*l - 4024 + 2060*l as b + d*l and give b.\n0\nExpress (0*j + 3*j - 5*j)*(2 - 2 - 2*j) - 24*j**2 + 0*j + 5*j - 5*j - 4*j**2 + 103*j**2 - 16*j**2 as r*j + z*j**2 + w and give z.\n63\nExpress -99*v - 62 + 100*v - 1167*v**3 + 62 as f*v**3 + u*v + b*v**2 + t and give b.\n0\nRearrange -8 - 3*x**2 - 14 + 2*x**3 - 35*x - 13*x + 47*x + x**4 to t + w*x**4 + b*x**2 + h*x**3 + z*x and give z.\n-1\nRearrange 12*g + 6 + 30 - 34*g - 28*g - 11*g to z*g + u and give z.\n-61\nRearrange 148*u - 5*u**2 + 143*u - 454*u + 9 - 2*u**2 + 161*u to the form p + t*u**2 + z*u and give p.\n9\nRearrange -10*o + 5*o**4 + 1067 - 5*o**4 + o**2 - 531 - 538 + 2*o**4 + 4*o**3 to the form u*o**3 + i*o**4 + y*o + p*o**2 + f and give f.\n-2\nRearrange -852 - 23 - 535 - 6*o**2 - 184 to m*o + c + s*o**2 and give c.\n-1594\nExpress -3*s**2 - 1 + 1 + (-s**2 - s**2 + s**2)*(108 - 979 - 2253) as p + f*s + x*s**2 and give x.\n3121\nExpress (0*m + m + 0*m)*(-747*m**3 + 29278 - 1142*m**3 - 29278) in the form v*m**4 + l*m**3 + i*m + b + t*m**2 and give v.\n-1889\nExpress -10 + 10 + 4269*a - 1237*a + 805*a in the form h + t*a and give t.\n3837\nExpress -71 + 1022*f - 19 - 65 - 1014*f - 21 as x + v*f and give x.\n-176\nRearrange 41*c**2 + c + 367 + 79 - 84*c**2 - 107 + 44*c**2 to the form p*c**2 + h*c + y and give h.\n1\nExpress (2 - 1 + 0)*(0*y**3 - 2*y**3 + 3*y**3) - 2808*y**2 + 2808*y**2 - 264*y**3 as g*y**2 + a + r*y**3 + q*y and give r.\n-263\nRearrange 847906*c + 2 + 2*c**4 - 1 + 6508*c**3 - 847906*c to the form g*c + i*c**2 + o*c**4 + l*c**3 + s and give o.\n2\nRearrange -16*m**3 - 2*m**4 + 103 - 130 + 10*m**3 + 70*m + 4*m**3 to i*m**3 + w + r*m**4 + g*m**2 + d*m and give i.\n-2\nRearrange l - l + 2*l**3 + (-20*l**3 + 2*l**3 - 137*l**3)*(2 - 3 - 1) + (-4*l + 4*l - l**2)*(9 + 2*l - 9) to o*l**2 + c + w*l + z*l**3 and give z.\n310\nRearrange -3 - 4 + 248*k + k**3 + k**4 - 4*k**4 - 489*k + 242*k to the form o + b*k**4 + y*k + l*k**2 + w*k**3 and give o.\n-7\nRearrange 11*g - 21*g - 3*g**2 + 14 + 9*g - 1 - 7*g - 3*g**3 to the form j*g**2 + o*g + u + n*g**3 and give n.\n-3\nExpress (-3*f - 9*f + 5*f)*(-288 + 167 + 436) - f + 4*f - 2*f in the form d*f + g and give d.\n-2204\nExpress (c + 0 + 0)*(0 - 4 + 2) - 6*c + 0*c + 1 + c - c + 5*c + c + 6 in the form g*c + x and give g.\n-2\nExpress -572767 - 1376*x + 572767 as a + j*x and give j.\n-1376\nExpress (-158*z**2 - 38*z**2 + 39*z**2)*(-14*z + 23*z + 18*z)*(0 + 1 + 1) in the form h*z + g + x*z**3 + m*z**2 and give x.\n-8478\nExpress k**3 + 18655 - 19467 + 2*k + 0*k**3 in the form p*k + r + h*k**2 + a*k**3 and give a.\n1\nExpress 12*f**3 + 7277 + 2*f**3 - 14546 + 7271 + 128*f as d*f**3 + v + t*f**2 + h*f and give v.\n2\nExpress (d - 5*d + 2*d)*(-8646 - 9301 - 3715 - 8932)*(4*d**3 + 0*d + 0*d) as o*d + i*d**3 + w*d**2 + q + m*d**4 and give m.\n244752\nExpress -794*z**2 - 669*z**2 + 23*z**2 + 143*z**2 - 330*z**2 as h*z + u*z**2 + a and give u.\n-1627\nRearrange (2*a**2 + 4 - 4)*(4*a**2 + 4*a**2 - 5*a**2) - 1270*a**4 - 238*a**4 - 2725*a**4 - 1101*a**4 to h*a**4 + n + l*a**2 + b*a**3 + c*a and give h.\n-5328\nExpress -106*y + 47*y + 64*y - 32 + 2*y**3 - 2*y**2 as l + s*y + i*y**3 + a*y**2 and give l.\n-32\nExpress ((-3 + 6 + 0)*(3*f - 5*f + f) + (94 + 32 + 167)*(3*f - f + 0*f))*(2*f**3 - 4*f**3 - 7*f**3) as m*f**3 + i*f**2 + x*f + s*f**4 + o and give s.\n-5247\nExpress 331197 - 3*v - 332137 + 4*v as t*v + o and give o.\n-940\nExpress -58967*m - 133672*m - 53060*m - 164592*m + 60131*m - 38966*m + (m + 1 - 1)*(-2 + 1 + 3) in the form w + k*m and give k.\n-389124\nExpress (3*h - 2*h + 9*h)*(45 - 8 + 102) as k + r*h and give r.\n1390\nRearrange u**3 - 2*u + 20404*u**2 + 46 - 20404*u**2 - 16 to s*u**2 + j + k*u**3 + i*u and give i.\n-2\nExpress -g**2 - 3*g + 3*g + (9 - 21 - 25 + (-3 + 2 + 3)*(3 + 4 - 6))*(24*g**2 + 5*g**2 + 14*g**2) in the form n + x*g**2 + j*g and give x.\n-1506\nRearrange ((-3 + 3 + 1)*(-182 + 171 + 139) - 3 - 3 + 7)*(0*m - 11*m + 3*m) to the form y*m + n and give y.\n-1032\nExpress (0*t**4 - 2*t**4 + 0*t**4 + (2*t + 0*t - 4*t)*(-t**3 - 3*t**3 + 2*t**3))*(-2389 + 125 - 382) in the form x*t**4 + k + q*t**2 + r*t**3 + b*t and give x.\n-5292\nExpress 82*i**2 + i**4 + 65*i**2 + 66*i**2 - 306*i**2 - i**3 + 68*i**2 + 1 + i in the form n*i**3 + u*i + k*i**2 + o + p*i**4 and give k.\n-25\nExpress 3 - 660*q - "
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[
0.002684891383939468
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[
0.02631578947368421,
0.004310344827586207
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[
"Patients Screening Positive for Body Dysmorphic Disorder Show No Significant Health-Related Quality of Life Gain after Functional Septorhinoplasty at a Tertiary Referral Center.",
"\nBody dysmorphic disorder (BDD) is a psychiatric disorder defined by an excessive concern about one's physical appearance, especially regarding slight or imagined abnormities of the body. ",
"This study was conducted to compare postoperative quality of life (QOL) changes after primary septorhinoplasty among patients screening positive and those screening negative for BDD. ",
"Two common instruments for the screening of BDD were used namely the Dysmorphic Concern Questionnaire (DCQ) and the BDD Concern Questionnaire (BDDQ). ",
"For the determination of QOL changes, three validated screening instruments were used. ",
"The Functional Rhinoplasty Outcome Inventory (FROI-17) and the Rhinoplasty Outcomes Evaluation (ROE) were used as disease-specific instruments and the Short Form 36 Health Survey (SF-36) was used as a general instrument. ",
"All patients completed the FROI-17, the ROE, and the SF-36 preoperatively and 60 months postoperatively. ",
"The BDD questionnaires were singularly obtained 60 months after surgery. ",
"The authors identified 9.8% of our patients with a possible BDD diagnosis. ",
"The patients screening positive for BDD showed significantly lower ROE scores postoperatively, compared with those screening negative for BDD. ",
"QOL gains detected by the disease-specific instruments (ROE and FROI-17) were only significant in the non-BDD group. ",
"No significant QOL gains were detectable with the FROI-17, the ROE, and the SF-36 in the BDD group. ",
"In patients screening negative for BDD, QOL, as measured with the SF-36, improved significantly in five categories: physical functioning, role-functioning physical, bodily pain, general health, and social functioning. ",
"Patients screening positive for BDD did not improve in any categories of the general SF-36 questionnaire. ",
"Instead, their score in the \"mental health\" category was significantly lower 5 years after their surgery compared with preoperatively. ",
"Patients retrospectively screening positive for BDD in our cohort did not improve in QOL postoperatively. ",
"Alternative nonsurgical treatments such as cognitive behavioral treatment and/or selective serotonin reuptake inhibitors have been reported to be effective and should be considered as the treatment of choice. ",
"Some studies suggest that a smaller subgroup of BDD patients may benefit from functional rhinoplasty. ",
"Further research and larger long-term prospective outcome studies are needed to understand the influence of BDD symptoms on postoperative satisfaction and QOL changes after septorhinoplasty."
] |
{
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0.01092896174863388,
0.006666666666666667,
0.011494252873563218,
0.00904977375565611,
0.009523809523809525,
0.0136986301369863,
0.013333333333333334,
0.02097902097902098,
0.017094017094017096,
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0.009174311926605505,
0.009433962264150943,
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0.010526315789473684
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[
"Small-cell lung cancer (SCLC) accounts for 15--20% of all lung cancers and has an extremely aggressive nature with a poor prognosis ([@bib9]). ",
"Without treatment, the median survival time is 2--4 months ([@bib21]).",
"\n\nSeveral clinical markers are related to prognosis in patients with SCLC. ",
"Stage is the most important predictor of survival in SCLC ([@bib37]; [@bib36]; [@bib9]). ",
"The initial lactate dehydrogenase (LDH) level can indicate a high tumour burden and poor prognosis ([@bib19]; [@bib9]). ",
"Concurrent chemoradiotherapy (CCRT) in limited disease (LD) and prophylactic cranial irradiation (PCI) after complete response have improved the survival time of SCLC patients ([@bib32]; [@bib4]). ",
"Performance status (PS) has been used traditionally to predict the outcome of patients with SCLC ([@bib8]; [@bib9]). ",
"Gender, age, and body weight loss are also prognostic factors ([@bib39]; [@bib34]; [@bib8]). ",
"In addition to these clinical markers, many investigators have suggested that laboratory markers, such as neuron-specific enolase, carcinoembryonic antigen, cytokeratin fragment 19 (CYFRA 21-1), haemoglobin, albumin, alkaline phosphatase, and white blood cell count could be of prognostic value ([@bib3]; [@bib19]; [@bib36]; [@bib8]). ",
"However, the optimum prognostic factor for SCLC remains controversial.",
"\n\nThe systemic inflammatory response was shown to be associated with a poor prognosis in various solid tumours. ",
"Several inflammatory markers, such as C-reactive protein (CRP), Glasgow Prognostic Score, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) have been evaluated in various types of cancer ([@bib14]; [@bib25]; [@bib26]; [@bib38]; [@bib11]; [@bib30]; [@bib42]). ",
"Recently, tumour-associated neutrophils (TANs), which are distinct from naive neutrophils, were shown to be involved in tumour biology. ",
"Tumour cells themselves can recruit neutrophils into the tumour using specific chemokines ([@bib5]; [@bib15]; [@bib24]) and T cells ([@bib40]). ",
"TANs exert pro-tumourigenic effects ([@bib17]), including tumour initiation by genotoxic reactive oxygen species ([@bib20]), anti-apoptosis and angiogenesis by matrix metalloproteinase-9 ([@bib1]; [@bib27]), tumour growth, invasion and metastasis via neutrophil elastase ([@bib43]; [@bib23]) and suppression of the adaptive immune system ([@bib17]). ",
"Therefore, NLR might be considered a surrogate marker for TANs, and is readily available and cost-effective. ",
"Several reports have suggested the prognostic value of NLR in colorectal cancer, gastric cancer, non-small-cell lung cancer, soft-tissue sarcoma, and pancreatic cancer ([@bib25]; [@bib26]; [@bib38]; [@bib10]; [@bib29]; [@bib41]; [@bib44]). ",
"Because platelet activation is stimulated by proinflammatory cytokines and participates in neutrophil recruitment ([@bib18]), PLR has also been evaluated as an inflammatory marker; high PLR has been reported to be a risk factor for poor survival in pancreatic and colorectal cancers ([@bib38]; [@bib28]). ",
"Although high CRP was reportedly related to poor survival in a retrospective study ([@bib22]), the prognostic value of inflammatory markers, including NLR and PLR, is not well understood in SCLC.",
"\n\nWe hypothesised that inflammation is associated with the SCLC prognosis and that NLR or PLR may be good indicators of the inflammatory process. ",
"Therefore, in this retrospective study, we evaluated the association of NLR and PLR with the prognosis in SCLC patients who underwent the standard treatment.",
"\n\nMaterials and methods\n=====================\n\nStudy population\n----------------\n\nWe retrospectively reviewed all patients diagnosed with SCLC between July 2006 and October 2013 in Gyeongsang National University Hospital Regional Cancer Center and Changwon Samsung Hospital. ",
"Histologically confirmed cases were included in the study. ",
"All patients received combination chemotherapy based on platinum agents such as cisplatin or carboplatin as first-line treatment for at least one cycle. ",
"Patients who received non-platinum-based chemotherapy only or who did not receive chemotherapy were excluded from the study. ",
"This study was approved by the Institutional Review Board of each participating hospital.",
"\n\nClinical data collection\n------------------------\n\nBaseline characteristics including demographics, smoking, PS, and medical history were collected using an electronic medical record system. ",
"Complete blood cell counts at diagnosis, after the first cycle of chemotherapy (immediately before the second cycle of chemotherapy), and at the time of progression were obtained. ",
"At diagnosis, LDH was also evaluated. ",
"Mean and peak standardised uptake values (SUVs) of initial positron-emission tomography and computed tomography (PET-CT) were obtained if possible. ",
"Both NLR and PLR were recorded at diagnosis, after the first cycle of chemotherapy, and at the time of disease progression.",
"\n\nStatistical analysis\n--------------------\n\nThe optimal cutoff values for NLR and PLR were determined using time-dependent receiver operating curve (ROC) analysis. ",
"Time-dependent ROC analysis was performed using R software, version 3.03 (The R foundation for statistical computing, Vienna, Austria. ",
"<http://www.r-project.org>) and the 'timeROC\\' package ([@bib2]; [@bib7]). ",
"The NLR was calculated from the differential counts by dividing the neutrophil number by the lymphocyte number. ",
"The NLR values were categorised into two groups: \\<4 and ⩾4. ",
"The PLR was calculated by dividing the platelet count by the lymphocyte count; a PLR ⩾160 was considered to be elevated.",
"\n\nStatistical analyses were performed using SPSS 21.0 for Windows software (SPSS Inc., Chicago, IL, USA). ",
"Continuous variables were expressed as means with standard deviation (s.d.) ",
"and range, and compared between the low- and high-NLR groups using the Mann--Whitney *U*-test or Wilcoxon signed-rank test. ",
"The categorical variables were presented as the numbers of patients and percentages and compared using the *χ*^2^- or Fisher\\'s exact test.",
"\n\nThe overall survival (OS) was calculated from the time of diagnosis to the time of death. ",
"The progression-free survival (PFS) was defined as the period from the time of therapy initiation to the time of disease progression or death. ",
"Survival analyses were performed using the Kaplan--Meier method. ",
"Significant differences between groups were identified using the log-rank test. ",
"Multivariate analysis of survival was performed using the Cox proportional hazards model, and the associated 95% confidence interval was calculated. ",
"All tests were two-sided, and *P*\\<0.05 was considered to indicate statistical significance.",
"\n\nResults\n=======\n\nPatient characteristics\n-----------------------\n\nIn total, 187 patients were enrolled in this study between July 2006 and October 2013. ",
"The median follow-up time was 40.28 months (range, 2.60--89.26 months). ",
"The baseline characteristics of the patients are shown in [Table 1](#tbl1){ref-type=\"table\"}. ",
"The median age was 68 years (range, 43--84 years) and 162 patients (86.6%) were male and 25 (13.4%) were female. ",
"The majority of patients were current or ex-smokers (*n*=172, 92%). ",
"performance status was generally good, 163 patients (87.2%) were Eastern Cooperative Oncology Group (ECOG) PS 0 or 1. ",
"Only 67 patients (35.8%) were LD and 120 (64.2%) were ED at the time of diagnosis.",
"\n\nThe most often used chemotherapeutic regimen was etoposide-based combination chemotherapy (*n*=155, 82.9%). ",
"Irinotecan (*n*=32, 17.1%) was also used as a first-line combination agent in place of etoposide. ",
"Clinical response was evaluated after two or three cycles of chemotherapy. ",
"Among the 187 patients, 153 (81.8%) obtained at least partial response; the disease control rate was 86.1%. ",
"Of the 125 patients with disease progression, 75 (60.0%) received second-line chemotherapy. ",
"In LD, 62 of 67 patients (92.5%) were treated with thoracic radiotherapy (RT). ",
"Forty-seven of 187 patients (25.1%) received PCI after the first-line chemotherapy.",
"\n\nNLR and PLR according to disease and treatment status\n-----------------------------------------------------\n\nMean NLR and PLR values were compared according to disease and treatment status ([Table 2](#tbl2){ref-type=\"table\"}). ",
"Mean±s.d. ",
"NLR was 3.78±3.13 at diagnosis, and decreased significantly to 2.63±2.80 after one cycle of chemotherapy (*P*\\<0.001). ",
"Compared with after one cycle of chemotherapy, mean±s.d. ",
"NLR increased significantly to 4.50±6.37 at disease progression (*P*\\<0.001). ",
"Mean±s.d. ",
"PLR after one cycle of chemotherapy also decreased significantly from 183.16±98.21 at diagnosis to 173.16±119.93 (*P*=0.01). ",
"However, there was no significant difference in mean±s.d. ",
"PLR at disease progression (*vs* after one cycle of chemotherapy, *P*=0.518).",
"\n\nFactors associated with NLR\n---------------------------\n\nClinical and laboratory factors according to NLR group are shown in [Table 3](#tbl3){ref-type=\"table\"}. ",
"Age, gender, smoking status, first-line chemotherapy regimen, mean or peak SUV at initial PET-CT, and LDH were similar between the groups. ",
"However, PS was significantly worse (ECOG PS 2--3 in low *vs* high, 7.0% *vs* 25.4%, respectively, *P*\\<0.001) and clinical stage was relatively more advanced (ED in low *vs* high, 56.3% *vs* 81.4%, respectively, *P*=0.001) in the high-NLR group compared with the low-NLR group. ",
"Additionally, more patients received thoracic RT (low *vs* high, 42.2% *vs* 13.6%, respectively, *P*\\<0.001) and PCI (low *vs* high, 31.2% *vs* 11.9%, respectively, *P*=0.004) in the low-NLR group. ",
"Although platelet count did not show a significant difference (*P*=0.484), the mean PLR at diagnosis was higher in the high-NLR group (low *vs* high, 150.19 *vs* 254.69, respectively, *P*\\<0.001).",
"\n\nAdditionally, the rate of objective response (complete and partial response) to first-line chemotherapy was significantly lower in the high-NLR group than in the low-NLR group (low *vs* high, 85.2% *vs* 74.6%, respectively, *P*=0.037).",
"\n\nAssociation of NLR and PLR with survival\n----------------------------------------\n\nIn total, median OS was 10.84 months and median PFS was 6.67 months. ",
"NLR and PLR levels at diagnosis had different impacts on survival ([Figure 1](#fig1){ref-type=\"fig\"}). ",
"High NLR at diagnosis was associated with worse OS (NLR\\<4 *vs* NLR⩾4, median OS 11.17 *vs* 9.20 months, respectively, *P*=0.019) and PFS (NLR\\<4 *vs* NLR⩾4, median PFS 6.90 *vs* 5.49 months, respectively, *P*=0.005). ",
"In contrast, PLR at diagnosis was not associated with OS (PLR\\<160 *vs* PLR⩾160, median OS 10.42 *vs* 11.17 months, respectively, *P*=0.467) and PFS (PLR\\<160 *vs* PLR⩾160, median PFS 6.67 *vs* 6.31 months, respectively, *P*=0.205).",
"\n\nPatients with a high NLR at both diagnosis and after one cycle of chemotherapy showed worse OS and PFS than patients with low or high NLR at diagnosis and low NLR after one cycle of chemotherapy ([Figure 2A](#fig2){ref-type=\"fig\"}, *P*\\<0.001 and *P*=0.007, respectively). ",
"In addition, patients with a high NLR at disease progression and a low NLR at diagnosis had a worse OS than patients with low NLR both at diagnosis and disease progression (*P*=0.033, [Figure 2B](#fig2){ref-type=\"fig\"}). ",
"Similarly, PFS was worse in patients with a high NLR both at diagnosis and after one cycle of chemotherapy compared with those with low NLR after one cycle of chemotherapy (*P*\\<0.001 *vs* an initial low NLR, and *P*=0.004 *vs* initially high NLR; [Figure 2C](#fig2){ref-type=\"fig\"}). ",
"However, there was no significant difference in the PFS between changes in NLR according to progression time ([Figure 2D](#fig2){ref-type=\"fig\"}).",
"\n\nAccording to clinical stage and disease course, NLR had a slightly different impact on survival. ",
"At the time of diagnosis, the ED survival curve showed significant differences according to the NLR (*P*=0.018) compared with LD, which consisted of only 11 high-NLR patients (*P*=0.946; [Figure 3A and B](#fig3){ref-type=\"fig\"}). ",
"This survival curve pattern was statistically more significant in ED patients after one cycle of chemotherapy (*P*=0.001), whereas no significant differences according to NLR status were observed in LD patients after one cycle of chemotherapy (*P*=0.601; [Figure 3C and D](#fig3){ref-type=\"fig\"}). ",
"At the time of disease progression, LD patients showed a significant difference in survival according to the NLR (*P*=0.008). ",
"However, no statistical significance was found in ED patients according to the NLR (*P*=0.085; [Figure 3E and F](#fig3){ref-type=\"fig\"}).",
"\n\nIn subgroup analysis of PLR according to clinical stage and disease course, PLR and OS were not correlated, except when survival of LD patients was compared using the PLR level at disease progression (PLR\\<160 *vs* PLR⩾160, median OS 24.87 *vs* 13.73 months, respectively, *P*=0.022).",
"\n\nUnivariate analysis was performed for clinical and laboratory factors. ",
"Factors associated with poor OS were ED, elevated LDH, and high NLR at any time. ",
"Factors related to poor PFS were ED, elevated LDH, irinotecan-based first-line regimen, and high NLR at diagnosis. ",
"Stage, LDH, NLR, and PLR at diagnosis were included in the multivariate analysis ([Table 4](#tbl4){ref-type=\"table\"}). ",
"ED, elevated LDH, and high NLR, but not high PLR, at diagnosis were independent prognostic factors for OS and PFS.",
"\n\nDiscussion\n==========\n\nIn this study we reviewed the prognostic significance of NLR and PLR with other clinical factors in SCLC patients. ",
"PLR had little influence on survival; however, ED, elevated LDH, and high NLR at diagnosis were associated with poor OS and PFS in SCLC patients who underwent first-line chemotherapy.",
"\n\nThe high-NLR group included significantly more ED patients than the low-NLR group in this study. ",
"Therefore, worse survival in the high-NLR group might be explained in part by selection bias, because the low-NLR group included more LD patients, who had a better prognosis than ED patients and who received additional curative treatments such as CCRT and PCI. ",
"However, several findings suggest that NLR was an independent prognostic marker regardless of stage. ",
"For OS and PFS, NLR was demonstrated as a prognostic factor via multivariate analysis including stage and LDH. ",
"In addition, subgroup analysis according to stage showed that OS in the high-NLR group was significantly shorter than in the low-NLR group in ED patients. ",
"Although no significant difference in OS in LD patients was found, the numbers of LD patients with a high NLR at diagnosis (*n*=11) and after one cycle of chemotherapy (*n*=5) were too small for statistically significant evaluation, and the high-NLR group at disease progression showed significantly decreased OS in LD patients (*n*=17). ",
"Furthermore, the high-NLR group had worse PS at diagnosis than the low-NLR group. ",
"For these reasons, we suggest that NLR is an independent prognostic factor for survival in SCLC patients.",
"\n\nAs shown in [Tables 2](#tbl2){ref-type=\"table\"} and [3](#tbl3){ref-type=\"table\"}, the NLR level changed with the disease and treatment course, and the response rate was lower in patients with high NLR at diagnosis. ",
"The NLR level decreased significantly even after only one cycle of chemotherapy. ",
"Given that the treatment response was over 80% in this study, a decrease in the tumour burden may be achieved in most patients after one cycle of chemotherapy. ",
"At disease progression, the NLR level increased significantly compared with after one cycle of chemotherapy. ",
"These results imply that the NLR may reflect tumour burden and help in assessing the treatment response and monitoring recurrence or progression of SCLC. ",
"The clinical importance of the NLR is supported by our findings that the subgroup of patients who failed to achieve a low NLR after one cycle of chemotherapy and patients with a high NLR at disease progression showed poor survival.",
"\n\nA high NLR indicates an increased neutrophil count and/or a decreased lymphocyte count, as well as relative lymphopaenia. ",
"Lymphocytes have a crucial role in tumour defence by inducing cytotoxic cell death and inhibiting tumour cell proliferation and migration ([@bib13]; [@bib31]). ",
"In contrast, large numbers of neutrophils affect the cytolytic activity of lymphocytes or natural killer cells and could negatively affect tumour growth ([@bib35]). ",
"In addition to the TANs described above, neutrophil extracellular traps (NETs), which are fibres composed of chromatin and neutrophil proteins ([@bib6]), are known to be associated with cancer. ",
"TANs are more prone to NETs than their normal counterparts ([@bib6]; [@bib16]). ",
"An experimental study demonstrated that widespread deposition of NETs induced by sepsis sequesters circulating tumour cells and promotes metastasis ([@bib12]). ",
"NETs may protect circulating tumour cells by adhering to them and recruiting platelets ([@bib16]). ",
"These theoretical considerations support the role of NLR, reflecting the extent of neutrophilia in malignancy.",
"\n\nNLR is an easily measurable and repeatable parameter and thus clinically useful. ",
"However, several problems exist. ",
"NLR may occasionally not be a tumour-specific marker because other inflammatory conditions and steroid treatments could be confounding factors. ",
"Some authors have suggested that NLR should be assessed together with other inflammatory markers such as CRP ([@bib33]; [@bib45]). ",
"In addition, numerous articles have reported on NLR using different cutoff levels that require validation. ",
"In a study that showed a significant correlation between the NLR and survival in patients with stage IV gastric cancer, the authors used a NLR level of 2.5 and median survival was significantly longer in the group with a low-NLR level ([@bib46]). ",
"Other studies reported a correlation between NLR and survival, using various cutoff values ([@bib46]; [@bib26]; [@bib11]; [@bib41]).",
"\n\nThis study had several limitations. ",
"First, the sample size was relatively small, which limits generalising our findings. ",
"Second, as with all retrospective studies, there are several limitations inherent to its design, including the retrospective data collection. ",
"Nevertheless, to our knowledge, this is the first study to suggest the usefulness of NLR and investigate the prognostic role of NLR in SCLC patients.",
"\n\nIn conclusion, NLR at the time of diagnosis is a readily available and effective measurement that reflects the prognosis in SCLC patients. ",
"NLR determination during treatment and monitoring may help in assessing the treatment response and predicting recurrence. ",
"Further prospective studies are needed to evaluate cutoff values and confirm our results.",
"\n\nThis work is published under the standard license to publish agreement. ",
"After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License.",
"\n\n{#fig1}\n\n{#fig2}\n\n{#fig3}\n\n###### Baseline characteristics\n\n **Number of patients (%)** ***n=*****187**\n ------------------------------------------------- --------------------------------------------\n Age, years (*n=*187) 68 (range 43--84)\n **Sex (*n=*187)** \n Male 162 (86.6)\n Female 25 (13.4)\n **Smoking at diagnosis (*n=*187)** \n Never smoker 15 (8.0)\n Current or ex-smoker 172 (92.0)\n **ECOG PS at diagnosis (*n=*187)** \n 0--1 163 (87.2)\n 2--3 24 (12.8)\n **Stage (*n=*187)** \n Limited disease 67 (35.8)\n Extensive disease 120 (64.2)\n **LDH at initial diagnosis (*n=*187)** \n Normal range 72 (38.5)\n Abnormally elevated 115 (61.5)\n **Chemotherapy regimen (*n=*187)** \n Etoposide-based 155 (82.9)\n Irinotecan-based 32 (17.1)\n **Response for initial chemotherapy (*n=*187)** \n Complete response 14 (7.5)\n Partial response 139 (74.3)\n Stable disease 8 (4.3)\n Progressive disease 7 (3.7)\n Not evaluable 19 (10.2)\n **Second-line chemotherapy (*n=*125)** \n Yes 75 (60.0)\n No 50 (40.0)\n **Thoracic radiotherapy (*n=*187)** \n Yes 62 (33.2)\n No 125 (66.8)\n **Prophylactic cranial irradiation (*n=*187)** \n Yes 47 (25.1)\n No 140 (74.9)\n\nAbbreviations: ECOG=Eastern Cooperative Oncology Group; LDH=lactate dehydrogenase; PS=performance status.",
"\n\n###### Change of NLR and PLR at diagnosis, after one cycle chemotherapy, and at progression\n\n **Value** **At diagnosis** **After one cycle of chemotherapy** ***P*** **After 1 cycle of chemotherapy** **At progression** ***P***\n ---------------- ------------------ ------------------------------------- --------- ----------------------------------- -------------------- ---------\n NLR, mean±s.d. ",
" 3.78±3.13 2.63±2.80 \\<0.001 2.63±2.80 4.50±6.37 \\<0.001\n PLR, mean±s.d. ",
" 183.16±98.21 173.16±119.93 0.01 173.16±119.93 181.69±143.11 0.518\n\nAbbreviations: NLR=neutrophil-lymphocyte ratio; PLR=platelet-lymphocyte ratio; s.d.=standard deviation.",
"\n\n###### Clinical manifestations and laboratory parameters according to NLR at diagnosis\n\n **NLR \\<4** **Number of patients (%)** ***n*****=128** **NLR ⩾4** **Number of patients (%)** ***n*****=59** ***P***\n ------------------------------------------------------ -------------------------------------------------------- ------------------------------------------------------ ---------\n **Age, years (*n=*187)** 68 (range 43--84) 68 (range 43--82) 0.976\n Sex (*n=*187) 0.383\n Male 109 (85.2) 53 (89.8) \n Female 19 (14.8) 6 (10.2) \n Smoking at diagnosis (*n=*187) 0.671\n Never smoker 11 (8.6) 4 (6.8) \n Current or ex-smoker 117 (91.4) 55 (93.2) \n ECOG PS at diagnosis (*n=*187) \\<0.001\n 0--1 119 (93.0) 44 (74.6) \n 2--3 9 (7.0) 15 (25.4) \n Stage (*n=*187) 0.001\n Limited disease 56 (43.8) 11 (18.6) \n Extensive disease 72 (56.3) 48 (81.4) \n **Platelet, × 10^9^/l, mean±s.d. (*",
"n=*187)** 267±109 324±400 0.484\n **PLR at diagnosis, mean±s.d. (*",
"n=*187)** 150.19±78.13 254.69±99.79 \\<0.001\n LDH at diagnosis (*n=*187) 0.579\n Normal range 51 (39.8) 21 (33.6) \n Abnormally elevated 77 (60.2) 38 (64.4) \n Chemotherapy regimen (*n=*187) 0.225\n Etoposide-based 109 (85.2) 46 (78.0) \n Irinotecan-based 19 (14.8) 13 (22.0) \n Response for initial chemotherapy (*n=*187) 0.037\n Complete response 11 (8.6) 3 (5.1) \n Partial response 98 (76.6) 41 (69.5) \n Stable disease 6 (4.7) 2 (3.4) \n Progressive disease 6 (4.7) 1 (1.7) \n Not evaluable 7 (5.5) 12 (20.3) \n **Mean SUV at initial PET-CT, mean±s.d. (*",
"n=* 164)** 7.15±2.43 7.10±3.07 0.341\n **Peak SUV at initial PET-CT, mean±s.d. (*",
"n=* 164)** 9.71±3.14 10.29±6.38 0.188\n Second-line chemotherapy (*n=*125) 0.379\n Yes 55 (62.5) 20 (54.1) \n No 33 (37.5) 17 (45.9) \n Thoracic radiotherapy (*n=*187) \\<0.001\n Yes 54 (42.2) 8 (13.6) \n No 74 (57.8) 51 (86.4) \n Prophylactic cranial irradiation (*n=*187) 0.005\n Yes 40 (31.2) 7 (11.9) \n No 88 (68.8) 52 (88.1) \n\nAbbreviations: ECOG=Eastern Cooperative Oncology Group; LDH=lactate dehydrogenase; NLR=neutrophil-lymphocyte ratio; PET-CT=positron-emission tomography and computed tomography; PLR=platelet-lymphocyte ratio; PS=performance status; s.d.=standard deviation; SUV=standardised uptake value.",
"\n\n###### Multivarate analysis for overall survival and progression-free survival\n\n **Overall survival** **Progression-free survival** \n ---------------------- ---------------------- ------------------------------- ------- ----------- -------------- -------\n **Stage** \n LD Reference Reference \n ED 1.546 1.072--2.230 0.020 1.700 1.193--2.422 0.003\n **LDH** \n Normal Reference Reference \n Elevated 1.507 1.078--2.107 0.016 1.658 1.199--2.294 0.002\n **NLR at diagnosis** \n \\<4 Reference Reference \n ⩾4 1.465 1.012--2.119 0.043 1.474 1.033--2.105 0.032\n **PLR at diagnosis** \n \\<160 Reference Reference \n ⩾160 0.896 0.628--1.280 0.547 0.961 0.685--1.347 0.816\n\nAbbreviations: CI=confidence interval; ED=extensive disease; HR=hazard ratio; LDH=lactate dehydrogenase; NLR=neutrophil-lymphocyte ratio; PLR=platelet-lymphocyte ratio.",
"\n\n[^1]: These authors contributed equally to this work.",
"\n"
] |
{
"pile_set_name": "PubMed Central"
}
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| 5
|
[
"Q:\n\nOut of memory error in loading multiple models in Forge Viewer\n\nI am working on a project that has 14 Navisworks (NWC) models. ",
"I am able to load the composite model into the viewer (which takes some time but works).",
"\nHowever, when I am loading models one by one into Viewer, I get out of memory error before all 14 are loaded. ",
"Total file size is about 500MB.",
"\nI observed that viewer is very responsive right until browser crashes (while model loading was taking place in the background).",
"\nI suspect this to be an issue of total number of polygons & geometry. ",
"I tied to use NOP_VIEWER.initDebugTools() extension but it doesn't seem to show total count from all models. ",
"It seems to show the details of only first model.",
"\n\nIs there a way to stop Viewer creating more geometry before it runs out of memory?",
"\nIs there a way to find statistics of all models with DebugTools extension?",
"\nIs there another way to count polygons of loaded models?",
"\n\nThanks\nBandu\n\nA:\n\nIs there a way to stop Viewer creating more geometry before it runs out of memory?",
"\n\nTry and limit the memory consumption in your load options:\nvar config3d = {\n memory: {\n limit: 1024 // in MB\n }\n};\nvar viewer = new Autodesk.",
"Viewing.",
"Viewer3D(container, config3d);\n\nBTW the default limits are:\nDesktop 600 MB\nMobile 195 MB\n\nIs there a way to find statistics of all models with DebugTools extension?",
"\n\nUnfortunately the built-in DebugTools does not work with multiple models.",
"\nBut that shouldn't stop you from querying stats on a per model basis:\nlet modelArray = viewer.impl.modelQueue().getModels();\nlet targetModel = modelArray[index];\ntargetModel.getGeometryList() // retrieves geometry info about a specific model\n\nYou can even bake an extension of your own to suit multiple models.",
"\n\nIs there another way to count polygons of loaded models?",
"\n\nmodel.getGeometryList().geomPolyCount\n\n"
] |
{
"pile_set_name": "StackExchange"
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0.022900763358778626,
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| 5
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[
"\"Smoking and drinking are injurious to health.\" \"\"",
"Warrior of Dharma...\" \"Warrior of Dharma...\"\" \"\"Warrior of Dharma\" (KARMAYODHA) India is the country, which conducted war to save the dignity of lady.\" \"",
"In the same land, there is a society which carved the dignity of lady.\" \"",
"Even though a lady is the meaning of patience.\" \"",
"She treated pain as a responsibility.\" \"",
"She lives as daughter, sister, wife and at the end as mom she leaving some memories.\" \"",
"That is only a fact.\" \"",
"Today a lady who wants to end her life as a mother, is safe in the society?\" \"",
"No.\" \"",
"When the girls grown up to a woman...\" \"Even the parents tried to reach in high position of their life.... ...may sometimes forget about their safety.\" \"",
"Forthem it is only a remembrance.\" \"\"",
"Everyone having eye blindness\"\" \"\"ln which us, everyone having eye blindness\"\" \"\"The mind is feeling bad by the show of the fade vision\"\" \"\"Need the spectacles..\"\" \"\"Need the spectacles..\"\" \"\"The fifty peoples buy a kid for twenty silver coins\"\" \"\"And can see the teasing her by tucking from clothes at the waste\"\" \"\"ln the way can see the hopeless face and can see the begging hands\"\" \"\"ln the beside of that can see an air conditioned car\"\" \"\"ln which can see the licking of the glorious breast as a dog\"\" \"\"The mind is feeling bad by the show of the fade vision\"\" \"\"Need the spectacles..\"\" \"\"Need the spectacles..\"\" \"\"Can see the damaged wedding chain\"\" \"\"The undamaged bottle of the drinks can see\"\" \"\"When the poverty steps in to home\"\" \"\"Can see a tied in the backend of the mango tree\"\" \"\"And can see the searching of the ant in the blood on the ground\"\" \"\"The mind is feeling bad by the show of the fade vision\"\" \"\"Need the spectacles..\"\" \"\"Need the spectacles..\"\" \"\"Need the spectacles..\"\" \"\"Need the spectacles..\"\" \"Movie Channel\" \"1000 times told you..\" \"He should be killed.\" \"",
"You are missing the opportunities.\" \"",
"Don't come in front of me as losers.\" \"",
"Understand?\" \"",
"Movie Channel\" \"Move aside...\" \"Move...\" \"'Warrior of Dharma'!\" \"'",
"Warrior of Dharma'!\" \"'",
"Warrior of Dharma'!\" \"",
"You rascal!\" \"",
"Mad Mady sir!\" \"",
"Hello sir!\" \" ",
"Now you looks smart.\" \"",
"Good morning sir!\" \" ",
"Morning!\" \"",
"Mady sir...\" \" Morning!\" \"",
"Dear Sir!\" \"",
"Where were you for the last two days?\" \"",
"Just relaxing.\" \"",
"Stop joking and come to the point sir.\" \"",
"Commissioner is much tensed.\" \"",
"Your phone is engaged.\" \"",
"Engaged!\" \"",
"Anyway, a nice treat is waiting for...\" \"For whom?\" \"",
"Commissioner\" \"And, Yusuf Patel and his men are shot dead.\" \"",
"Tell the truth sir, isn't that you?\" \"",
"Hmmm...\" \"Don't tell to anybody.\" \"",
"Why don't you add me to your team?\" \"",
"I have many things to learn.\" \"",
"These are lessons which we have to study ourselves.\" \"",
"You can't do something with your muscles.\" \"",
"Call the weapon in charge!\" \"",
"Hey!\" \"",
"Call the weapon in charge now.\" \"",
"May I come in sir?\" \" ",
"You are already in.\" \"",
"So there is no need of a formality.\" \"",
"Good morning sir!\" \"",
"Where the hell!\" \"",
"Where were you forthe last 24 hours?\" \"",
"Not 24 hours sir!\" \"",
"Exactly, its 37 hours sir.\" \"",
"I tried you in your set and there was no response!\" \"",
"And your mobile was always engaged.\" \"",
"There was some urgent works.\" \"",
"If you try now it will ring!\" \"",
"See, the budget session is going on.\" \"",
"Before going for the lunch, ...a detailed report about Dharavi firing should be on chief minister's table.\" \"",
"What to say Maddy?\" \" ",
"Sir, one second.\" \"",
"Dear, take this gun and clean it well.\" \" ",
"Ok sir.\" \"",
"Barrel cleaning sir\" \"So you did it.\" \"",
"You know who is Yusuf Patel?\" \"",
"Who cares?\" \"",
"He is nothing to me.\" \"",
"An anti social element who works against our nation.\" \"",
"That's all I know.\" \"",
"So...\" \" So?\" \"",
"So what?\" \"",
"So Yusuf Patel, whom you were looking for is shot at Dharavi.\" \"",
"I was after him for two days and I didn't even have a shave.\" \"",
"It's before two years when you had a last shave.\" \"",
"I shot him with two pellets dipped in poison to give him a royal death.\" \"",
"And there will be no proof.\" \"",
"Ok sir, I'm leaving. ",
"I must have a bath before a sleep.\" \"",
"You can call me at any time.\" \"",
"I'm at your service, sir!\" \"",
"Dears... I'm very much glad to congratulate Miss.\" \"Shalini Nair for this people.\" \"",
"Our honorable central minister Mr. P V Thomas is arriving today evening for the second schedule inauguration of the Kovalam bypass.\" \"",
"As I must participate in that function...\" \"Brother...\" \"Brother will come.\" \"",
"You don't worry.\" \"",
"I'm concluding my words with my best wishes to Salini Nair, the pride of this school.\" \"",
"Thank you.\" \"",
"I'm inviting Miss.\" \"Shalini Nair to receive the honorfrom the district collector Mohamed Riyas.\" \"",
"Come on dear, go...\" \"Movie Channel\" \"Thank you sir!\" \"",
"Movie Channel\" \"I think the foreigners are suffering from financial crisis.\" \"",
"Why?\" \"",
"No need of much.\" \"",
"But there is not even 10 rupees.\" \"",
"So that's it!\" \"",
"Shame to them!\" \"",
"It's only because of them Indians are giving something to us.\" \"",
"Make it fast. ",
"lt's getting late.\" \"",
"I must leave.\" \"",
"How is today's collection?\" \"",
"Around 2000 rupees!\" \"",
"You do one thing.\" \"",
"Give her 500 rupees from that.\" \"",
"Let's have the calculations later.\" \"",
"Take this..\" \"You rascals!\" \"",
"What nonsense are you doing?\" \"",
"Sorry!\" \"",
"She got wet.\" \" ",
"Move I said!\" \"",
"She will get cold.\" \"",
"Come on dear, I will help you to change your dress.\" \"",
"Move back you dog.\" \"",
"No Manu.\" \"",
"Leave them.\" \"",
"No..\" \"Lave me...\" \"Lave me...\" \"Manu... manu.. no...\" \"Run...\" \"Run man...\" \"Come on.\" \"",
"Police!\" \"",
"Escape!\" \"",
"Get inside the vehicle.\" \"",
"No sir.\" \"",
"We have our vehicle.\" \"",
"I said get inside.\" \"",
"What happened?\" \"",
"I thought that they are trying to live.\" \"",
"But they are becoming social nuisances.\" \"",
"It's only because of you I am not doing anything.\" \"",
"It's not us.\" \"",
"They started first.\" \"",
"They misbehaved to Lena.\" \"",
"It's enough.\" \"",
"All of you go inside.\" \"",
"is there something serious?\" \"",
"Nothing!\" \"",
"Just a shock to them.\" \"",
"Leave it.\" \"",
"Where is Shalu?\" \" ",
"She is with her studies inside.\" \"",
"Ok then. ",
"I'm leaving.\" \" ",
"Ok.\" \"",
"Muscles are paining.\" \"",
"Mother, do you think we will do something wrong?\" \"",
"Not till now.\" \"",
"But now...\" \"Leave it mother.\" \"",
"Balachandran uncle was just showing the real behavior of an Sl.\" \"",
"Where is our sister?\" \"",
"When sister is being honored brothers are fighting outside!\" \"",
"It's better not to show you this!\" \"",
"So this is it!\" \"",
"It will cost for maximum 4 dollars.\" \"",
"But look here what I have brought for you!\" \"",
"Wow!\" \"",
"Mobile!\" \"",
"Thank you so much!\" \"",
"So you cheated this from them between the fight!\" \"",
"What is the need of a mobile phone for a school going girl?\" \"",
"Yes.\" \"",
"This is enough to distract her from studies.\" \"",
"I know to buy her a mobile phone if she wants.\" \"",
"When did she become sister to you only?\" \"",
"I forgot that I am an unfortunate.\" \"",
"Again he started his sentiments.\" \"",
"Hey, it's getting late.\" \"",
"There is a fish carrier to be taken by us from Nagarkovil.\" \"",
"Let's go.\" \"",
"We are leaving mother.\" \" ",
"Ok.\" \"",
"It's a beautiful phone.\" \"",
"Let me see!\" \"",
"Stop shouting.\" \"",
"Let me see.\" \"",
"Hey, Shalini is there with a phone.\" \"",
"Come fast.\" \"",
"What is this?\" \"",
"Mobile phone.\" \"",
"Your brother Manu gave you?\" \" ",
"lt's impossible.\" \"",
"You are lucky.\" \"",
"I can't even dream of a mobile phone as my grandfather is there.\" \"",
"Same situation is in my home too.\" \"",
"Danny is coming.\" \"",
"Better hide the phone.\" \"",
"It's a new phone?\" \"",
"If so?\" \" ",
"Not to you.\" \"",
"Why did you give him the phone?\" \"",
"Give it back.\" \"",
"I don't need these cheap phones.\" \"",
"I have Black Berry with me.\" \"",
"Black berry!\" \"",
"Nonsense.\" \"",
"Come on man.\" \"",
"Let's go.\" \"",
"Christy, now you can note down a girl's phone number.\" \"",
"9495358955.\" \"",
"She is studying with me in 10th standard.\" \"",
"You gave me Black berry last time.\" \"",
"But this time I want money.\" \"",
"Now you can start calling her!\" \"",
"Movie Channel\" \"Hello!\" \"",
"Mamma, What's the time now!\" \"",
"I'm waiting for a long time here.\" \"",
"Sorry dear.\" \" ",
"This is too much!\" \"",
"Mamma is on the way.\" \"",
"Hardly 10 minutes.\" \"",
"Sorry.\" \"",
"Saji, I'm busy right now as I want to pick my daughter from the school.\" \"",
"I will call you back.\" \"",
"Sorry.\" \"",
"This is too much.\" \" ",
"What?\" \"",
"What happened?\" \"",
"I can't do this last minute assignments.\" \"",
"I want to leave on 5 o'clock itself.\" \"",
"Listen Arathi.\" \"",
"This is not a government office.\" \"",
"Here customers are the king.\" \"",
"Ok, leave it.\" \"",
"You sit down.\" \"",
"What's your problem man!\" \"",
"You looks so cute!\" \"",
"Yes, I know.\" \"",
"If you feel this so called sympathy to your wife?\" \"",
"That's Arathi. ",
"I like this boldness!\" \"",
"Pathetic!\" \"",
"I'm going.\" \"",
"Hello!\" \"",
"Mamma is coming dear.\" \"",
"I must ask you one thing.\" \"",
"Are you not ashamed of as I told you these words?\" \"",
"No. ",
"never.\" \"",
"I can't imagine an office without you.\" \"",
"I will wait for you.\" \"",
"Ugly!\" \"",
"Diya!\" \" ",
"Yes!\" \"",
"Get inside the car soon!\" \"",
"Your mother met with an accident on her way.\" \"",
"I just spoke to her!\" \"",
"No need to be tensed. ",
"I will take you.\" \"",
"Come on dear.\" \"",
"Get inside fast.\" \"",
"Get in.\" \"",
"Dear, I'm nearing the gate.\" \"",
"Give the phone to me.\" \"",
"Hey, leave it..\" \"Leave me.\" \"",
"Give the phone to me.\" \"",
"Leave me.\" \"'",
"Dear, what happened?\" \"' ",
"Mamma!\" \"",
"Dear daughter!\" \"",
"13 years old girl was kidnapped from Mumbai city.\" \"",
"This is the third incident reporting this week.\" \"",
"Hurry up!\" \"",
"Move fast.\" \"",
"Hey stop.\" \"",
"Have you seen this girl any where?\" \" ",
"No sir.\" \"",
"Where is this girl?\" \" ",
"l don't know sir.\" \"",
"Tell me.\" \"",
"Sir!\" \"",
"Sir...\" \"You can ask anything you want to know.\" \"",
"Look at this carefully.\" \"",
"Have you seen this girl anywhere?\" \"",
"Say... I don't know her.\" \"",
"Movie Channel\" \"Escape.\" \"",
"Run!\" \"",
"Stop there you!\" \"",
"Where is Chandraji?\" \"",
"Don't you say?\" \"",
"No Chachaji.\" \"",
"No!\" \"",
"No Chachaji.\" \"",
"No!\" \"",
"Come on.\" \"",
"Come on baby!\" \" ",
"No Chachaji.\" \"",
"Let's play hide and seek!\" \"",
"No Chachaji.\" \"",
"No!\" \" ",
"Come here girl.\" \"",
"Ok, I will leave you.\" \"",
"But only after a play!\" \"",
"Don't do me anything Chachaji.\" \"",
"Please leave me!\" \"",
"It's very hot. ",
"lsn't it?\" \"",
"No.\" \"",
"No Chachaji.\" \"",
"At first uncle will get you.\" \"",
"After that you can close your eyes and I will hide!\" \"",
"Come on girl.\" \"",
"Where are you going dear?\" \"",
"Where can you go?\" \"",
"Come on dear!\" \"",
"I got you!\" \"",
"Hello Maddy sir!\" \"",
"Come.\" \"",
"Do you know this girl?\" \"",
"I don't know.\" \"",
"Don't know?\" \" ",
"No.\" \"",
"This is not that old Chandraji who was ready to answerto the cheap police officers.\" \"",
"I don't know.\" \"",
"And if I do, I'm not going to say.\" \"",
"You will.\" \"",
"You will say.\" \"",
"Hey, take him in to the vehicle.\" \"",
"Come on.\" \"",
"Move.\" \" ",
"Leave me.\" \"",
"Chandraji!\" \"",
"I have informed Khayas bhai.\" \"",
"Khayas!\" \"",
"Khayas Khanna!\" \"",
"A new name.\" \"",
"Tony, check it out.\" \" ",
"Sir.\" \"",
"I need the full details.\" \" ",
"Ok sir.\" \"",
"Relax Maddy sir.\" \"",
"The girl you are looking for must be on her way to Khayas Bhai.\" \"",
"Shut up!\" \"",
"Attend the phone sir.\" \"",
"Just speak Maddy sir!\" \"",
"Close your eyes dear.\" \"",
"This uncle is going to play hide and seek.\" \"",
"Bastard!\" \"",
"You are finished.\" \"",
"Movie Channel\" \"Do you know Salu?\" \"",
"In the disco club.\" \"",
"Sir, he is the man.\" \"",
"He?\" \"",
"That dancing guy also was there.\" \"",
"Ok.\" \"",
"Come.\" \"",
"Speak out!\" \"",
"Speak out you!\" \"",
"I'm only a driver.\" \"",
"Don't lie.\" \"",
"Tony, I'm here.\" \"",
"Tell the name.\" \" ",
"Salu.\" \"",
"You bastard!\" \"",
"I will...\" \"You nasty!\" \"",
"I will kill you.\" \"",
"Do you know who I am?\" \"",
"Do you know who I am?\" \"",
"No.\" \"",
"Do you know Mad Maddy?\" \"",
"The police!\" \"",
"That's me. ",
"I kill people.\" \"",
"Do you know this girl?\" \"",
"You know this girl?\" \"",
"I kill people.\" \"",
"You know this girl?\" \" ",
"Mother!\" \"",
"Hey!\" \"",
"You are a Keralite, a Malayali.\" \" ",
"Yes.\" \"",
"Tell me where is this girl?\" \"",
"You know this girl.\" \" ",
"No.\" \"",
"Say the truth...\" \" l don't know.\" \"",
"Or I will kill you.\" \"",
"Come on, tell me.\" \"",
"You know this girl.\" \"",
"You...\" \"Toilet is closed.\" \" ",
"Why?\" \"",
"Sir is on duty inside.\" \"",
"You may go. ",
"I said go.\" \"",
"What happened to her?\" \"",
"What happened to her?\" \" ",
"l will tell.\" \"",
"Ok, tell me.\" \" ",
"l will tell.\" \"",
"For the last one month this girl was marked by us.\" \" ",
"Ok.\" \"",
"Today we handed over her to Sack.\" \"",
"Sack.\" \"",
"Who is he?\" \"",
"Come on...please.\" \"",
"He is the right hand to Khayas Khanna.\" \"",
"Khayas Khanna!\" \"",
"Who is he?\" \"",
"I have never seen him.\" \"",
"Now where is that girl?\" \"",
"Please!\" \"",
"Please!\" \"",
"She might be taken in to somewhere in south.\" \"",
"South!\" \" ",
"Yes.\" \"",
"To where?\" \" ",
"Kerala.\" \"",
"Kerala?\" \"",
"Ok, where in Kerala?\" \"",
"How is the transportation?\" \"",
"Container.\" \"",
"Container?\" \"",
"How?\" \"",
"The girls are transported in sophisticated containers.\" \"",
"Sophisticated containers?\" \"",
"I don't know any thing else.\" \"",
"Please leave me.\" \"",
"Tony, I get smell a long journey.\" \"",
"I need a good car.\" \"",
"Buy, borrow or steal. ",
"I don't care.\" \"",
"I'm going now.\" \"",
"If you were lying, vouch me.\" \"",
"I will come back and I will kill you.\" \"",
"Warrior of Dharma!\" \"",
"Warrior of Dharma!\" \"",
"Warrior of Dharma!\" \"",
"Warrior of Dharma!\" \"",
"Warrior of Dharma!\" \"",
"Warrior of Dharma!\" \"",
"Warrior of Dharma!\" \"",
"Warrior of Dharma!\" \"",
"Warrior of Dharma!\" \"",
"Are you sitting here watching TV?\" \"",
"It's time to light the lamp.\" \"",
"Go and do it.\" \"",
"How many times I have told you not to wearthis short skirt?\" \"",
"But grandpa, this is inside the house!\" \"",
"Girls should be careful in these things.\" \"(",
"Chanting!\" \")\" \"",
"Oh God!\" \"",
"Save us from all troubles.\" \"",
"Oh God!\" \"(",
"Singing the prayer)\" \"Can't you sing a little more loudly?\" \"(",
"Singing the prayer)\" \"Hello!\" \"",
"Shalu!\" \"",
"What's up?\" \"",
"He is disturbing me again.\" \"",
"You relax.\" \"",
"We will find him.\" \"",
"I'm afraid!\" \"",
"I don't know how he got my number.\" \"",
"That's him.\" \"",
"Danny.\" \"",
"Isn't that over?\" \"",
"Grandpa is calling.\" \"",
"See you later.\" \"",
"Good night.\" \"",
"Either TV or phone. ",
"lsn't there anything to study?\" \"",
"What is the problem between grandpa and grand daughter?\" \"",
"I'm a good fellow if I support her.\" \"",
"Otherwise I'm a disturbance.\" \"",
"No.\" \"",
"They loves you very much.\" \"",
"Am I correct?\" \"",
"Yes.\" \"",
"We, the old generation people are like a liability to the new generation.\" \"",
"That's not true.\" \"",
"Most often we say no to their decisions. ",
"lt's fortheir safety.\" \"",
"Every one knows it.\" \"",
"Come, I will massage your body.\" \"",
"You please go and study something.\" \"",
"Oh God!\" \"",
"Movie Channel I'm afraid!\" \"",
"Why did you give him your number?\" \"",
"I didn't.\" \"",
"Look, he is calling.\" \"",
"Pick it.\" \" ",
"No Shalu.\" \"",
"Attend the call.\" \"",
"We just want to know who he is.\" \"",
"Hello!\" \"",
"What do you want?\" \"",
"Switch on the loud speaker.\" \"",
"My name is Varun. ",
"I'm coming to the point straightly.\" \"",
"I love Shalu very much.\" \"",
"Stupid!\" \"",
"If you repeat this I will inform my brother.\" \"",
"Ok.\" \"",
"No need of that.\" \"",
"I will never call you.\" \"",
"What did he say?\" \"",
"Don't you hear?\" \"",
"He loves me!\" \"",
"I was watching you there.\" \"",
"What's going on here?\" \"",
"Nothing sir.\" \"",
"Go to your class room.\" \"",
"Hurry up.\" \" ",
"Come.\" \"",
"Let's go.\" \"",
"You can say like that.\" \"",
"But I'm a mother.\" \"",
"I don't want any one's sympathy.\" \"",
"I want my daughter back.\" \"",
"Movie Channel\" \"Why don't you inform earlier about your visit?\" \"",
"An official visit.\" \"",
"Where is mother?\" \"",
"Doctor is examining her.\" \"",
"What happened?\" \" ",
"Nothing special.\" \"",
"Usual check up.\" \"",
"After examining her, a strong coffee is his routine.\" \"",
"After that a 500 rupees too is a must.\" \"",
"Hello Madhavan!\" \"",
"It's been a long time since I last met you.\" \"",
"How's mother?\" \".\" \" ",
"Every thing normal.\" \"",
"Then some traumatic complaints.\" \"",
"She is getting aged.\" \"",
"Yes.\" \"",
"Don't leave her alone for a long time.\" \"",
"I know you are a busy man.\" \"",
"But you know, she is developing a kind of depression.\" \"",
"A kind of loneliness.\" \"",
"My dear son!\" \"",
"When did you arrive my lovely boy!\" \"",
"Look at you, what is your condition!\" \"",
"I was telling to him.\" \"",
"Doctor!\" \"",
"Don't you examine me?\" \" ",
"Yes.\" \"",
"Don't you have your coffee?\" \" ",
"Yes.\" \"",
"Then you may leave now.\" \"",
"Now I'm an outsider.\" \"",
"Ok, see you.\" \" ",
"Ok.\" \"",
"Come dear!\" \"",
"Don't worry about me.\" \"",
"Why are you here now?\" \"",
"I'm on an investigation.\" \"",
"How are the children at home?\" \"",
"All are fine.\" \"",
"One minute mother!\" \"",
"Hello cyber cell!\" \"",
"I'm DCP Madhavamenon from Mumbai police.\" \"",
"Please inform ACP Nandakumar that I have arrived at Kerala.\" \"",
"Give it to me.\" \"",
"First you take a bath and have yourfood.\" \"",
"Ok, give the phone.\" \"",
"What to do this boy!\" \"",
"Your uncle's behavior is like an exact police officer.\" \"",
"That is because he can identify the thieves very well.\" \"",
"That's true.\" \"",
"He likes us very much!\" \"",
"Why did she go inside as the phone rings?\" \"",
"It might be herfriends.\" \"",
"He is the reason for all these.\" \"",
"Then I don't want any thing.\" \"",
"Hey!\" \" ",
"Leave it\" \"After filling the stomach it's easy to avoid food!\" \"",
"Says that he is studying for B.Tech 3rd semester at Trivandrum Engineering College.\" \"",
"He wants to see me.\" \"",
"There is nothing wrong in seeing him.\" \"",
"He will do nothing.\" \"",
"You are mad.\" \"",
"Shalu, we are leaving.\" \"",
"Bye.\" \" ",
"Bye.\" \"",
"Bye bye.\" \" ",
"Bye!\" \"",
"I will call you later.\" \"",
"Who is the caller?\" \"",
"It's Anjali.\" \"",
"Anjali!\" \"",
"Go and study something.\" \"",
"What happened to you?\" \"",
"What are you thinking about since you came here?\" \"",
"Nothing mother.\" \"",
"Why are you working so hardly like this?\" \"",
"Why can't you look after our properties and live peacefully?\" \"",
"Dear!\" \"",
"Don't worry about that.\" \"",
"You may go and sleep.\" \"",
"Don't you have to go early at tomorrow morning?\" \" ",
"Yes.\" \"",
"Movie Channel I'm coming.\" \"",
"Shalu...\" \"Here is your Tiffin.\" \"",
"Why did you cut the call?\" \"",
"That's Anjali calling from bus stop.\" \"",
"Shall we go?\" \"",
"What happened to this girl?\" \"",
"Who ever it may be.\" \"",
"Now a day your phone calls are too much.\" \"",
"It will affect your examination results.\" \"",
"Don't worry brother!\" \"",
"Shalini!\" \"",
"Stop playing with your mobile.\" \" ",
"Ok.\" \"",
"What's up?\" \"",
"I'm fed up of him.\" \"",
"He told me that he will commit suicide.\" \"",
"Then we will be safe.\" \"",
"Anyway, you just meet him.\" \"",
"No.\" \"",
"No need of that.\" \"",
"You should.\" \"",
"You aren't brave.\" \" ",
"Yes.\" \"",
"is that him?\" \" ",
"Yes.\" \"",
"Pick the phone.\" \"",
"Ask him where to come.\" \"",
"Pick it and ask him.\" \"",
"Hello!\" \"",
"Shalini please!\" \"",
"Don't cut off the phone.\" \"",
"Today we should meet.\" \"",
"I just want to see you and talk to you.\" \"",
"That's all.\" \"",
"Don't tell me 'no'.\" \"",
"Please.\" \"",
"Ok.\" \"",
"Where should I come?\" \"",
"Hi Shalini!\" \"",
"What happened?\" \"",
"is that you who called me?\" \" ",
"Yes.\" \"",
"I will tell you one thing.\" \"",
"Tell me. ",
"I will obey whatever you tell me.\" \"",
"I have no time for a romance or to send SMS by phone.\" \"",
"So don't disturb me any more.\" \"",
"Then?\" \"",
"If you repeat this I will inform my brothers.\" \"",
"If they came to know this they will beat you.\" \"",
"I don't care that.\" \"",
"But they will take my phone back.\" \"",
"I liked your character.\" \"",
"I will never disturb you.\" \"",
"Because I love you.\" \"",
"But if you changed your mind at any time, ok?\" \"",
"Not ok. ",
"I'm leaving.\" \"",
"Thanks for coming.\" \"",
"One coffee!\" \"",
"No. ",
"I must go to school.\" \"",
"Ok, I will drop you.\" \"",
"No. ",
"I don't want to travel with you on your bike.\" \"",
"Not bike. ",
"it's a car with me.\" \"",
"You can sit on the back seat.\" \"",
"This is our last meeting.\" \"",
"I will never disturb you.\" \"",
"Please!\" \"",
"Ok.\" \"",
"But I will sit at the back.\" \"",
"Ok.\" \"",
"Come on!\" \"",
"Come!\" \"",
"As we said, I have sent her.\" \"",
"Movie Channel\" \"Come in!\" \"",
"Surab.\" \"",
"Surab, tell me.\" \"",
"Sir, as I told you I got that girl.\" \"",
"Age?\" \"",
"Around 13.\" \"",
"Thirteen?\" \"",
"Super Good.\" \"",
"Very Good!\" \"",
"Hand overthem to Selvam at Chathanpetti\" \"But I need that Mumbai girl here.\" \"",
"Don't forget to set her Photo and virginity certificate.\" \"",
"Ok sir.\" \"",
"Saip is waiting.\" \"",
"Hello!\" \"",
"Long time no seeing!\" \"",
"Long time!\" \"",
"I want to see the girl.\" \"",
"Ok baby!\" \"",
"How is she?\" \"",
"Nice.\" \"",
"Thank you.\" \"",
"Virginity certificate?\" \"",
"What happened to my daughter?\" \"",
"Nothing.\" \"",
"She will come.\" \"",
"Don't worry.\" \"",
"Aren't we here with you?\" \"",
"But my daughter!\" \"",
"I think its Manu.\" \"",
"Let me see.\" \"",
"Any information?\" \"",
"She didn't arrived at the school in the morning.\" \"",
"I got information as she went to the free zone at the high way to...\" \" meet somebody called Varun after I dropped her at the bus stop.\" \"",
"Then?\" \"",
"Many people come to an ice cream parlor.\" \"",
"So they didn't notice him.\" \"",
"Shalu informed Devi that she often got a call...\" \" in her phone from some one.\" \"",
"Then Anjali is right.\" \"",
"She went to tell him not to disturb her any more.\" \"",
"How could he get her number as she is not interested in him?\" \"",
"That's a classmate of her who gave her numberto Varun.\" \"",
"Who is that?\" \"",
"Danny.\" \"",
"Movie Channel I heard that the leopard has arrived.\" \"",
"But this is cheetah!\" \"",
"Get inside.\" \"",
"I'm lucky to get realized by you\" \"Maharashatra tigers and the political tycoons must be fed up of you\" \"That's why they send you o Kerala.\" \"",
"Didn't you get the male?\" \"",
"Yes.\" \"",
"Then?\" \"",
"According to the informations, one thing is sure.\" \"",
"As the survey lens is made more active by the defense and...\" \" central investigators, the flesh marketers traveled to south.\" \"",
"Kovalam, Dhanushkodi,Thoothukudi!\" \"",
"An interesting thing is the way how they are transporting these girls.\" \"",
"In specially built containers.\" \"",
"I got that lead from Mumbai itself.\" \"",
"Anything else?\" \"",
"Aryankavu check post is safer than Amaravila\" \" So they might go to thoothukkudi through Chenkotta.\" \"",
"There is a village named Chathanpetty near Thenkashi.\" \"",
"There is a Kalabhairava temple.\" \"",
"A temple where girls are transformed into Devadasi girls (sex workers).\" \"",
"According to the information I got, some groups are working for that.\" \"",
"No doubt in that.\" \"",
"Ok, thank you. ",
"I will call you.\" \"",
"You must!\" \"",
"Also you may meet that lG law and order.\" \"",
"Why?\" \"",
"Protocol?\" \"",
"What ever it may be!\" \"",
"Just meet him.\" \"",
"Ok.\" \"",
"Thank you.\" \"",
"Tell me, to whom are you giving these numbers?\" \"",
"Christopher.\" \"",
"What's your benefit?\" \"",
"Sometimes 500 rupees.\" \"",
"Sometimes 1000 rupees.\" \"",
"Where is this Christopher now?\" \"",
"I don't know sir.\" \"",
"Tell the truth.\" \"",
"No need of shouting.\" \"",
"This is police station.\" \"",
"We didn't know these things.\" \"",
"You should know.\" \"",
"Every parent who is running to make money after sending their...\" \" children to school should know this.\" \"",
"Otherwise you will be n police stations like this.\" \"",
"Now tell me.\" \"",
"Where is he?\" \"",
"I only have his phone number.\" \"",
"He will deposit the money into my account.\" \"",
"Then call him.\" \"",
"Don't you see his phone?\" \"",
"When your child uses costly phones you...\" \" should ask them about the source\" \"No response.\" \"",
"Then tell the number.\" \"",
"9961100221 .\" \"",
"Transporting girls from Mumbai to Kerala!\" \"",
"Who told you this rubbish ness?\" \"",
"After the terrorist attacks in Delhi, Mumbai and Kashmir..\" \" their government became more vigilant.\" \"",
"So they found that south is safer for them.\" \"",
"Except some news paper reports and intelligent alert,..\" \" there is no solid proof.\" \"",
"I'm sorry sir.\" \"",
"This is only a truth.\" \"",
"What would you like for your lunch?\" \"",
"Mutton or pork!\" \"",
"Look out for some fish.\" \"",
"Now tell me.\" \"",
"Sir if you search in your computer you can find that...\" \" in Kerala more than 600 women missing cases are reporting per year.\" \"",
"We should think about it seriously sir.\" \"",
"Otherwise it will be too late.\" \"",
"Yes.\" \"",
"How any times I've told you to send some one to...\" \" my home from AR camp?\" \"",
"I will send soon sir.\" \"",
"Make it fast!\" \"",
"What were you saying?\" \"",
"I didn't say anything.\" \"",
"You do your work. ",
"I will take care of mine.\" \"",
"But don't disturb me.\" \"",
"You!\" \"",
"Hey!\" \"",
"Hello!\" \"",
"Did you see him?\" \"",
"Who gave lPS to this ugly fellow?\" \"",
"What did he said?\" \"",
"My dialogues were waste.\" \"",
"It's because of you I met him. ",
"I know how to investigate my case.\" \"",
"I'm not an ordinary cheap encounter specialist.\" \"",
"I will give one bullet against 10 bullets.\" \"",
"That's Maddy's style.\" \"",
"That's why I'm called mad Maddy!\" \"",
"Cool down Maddy.\" \"",
"He is shameful to our department.\" \"",
"Anyway I'm sorry. ",
"I will be with you.\" \"",
"And today morning I noted news that a 13 years old girl is ...\" \" missing in the limits of Kovalam police station.\" \"",
"I think there are some similarities with your case.\" \"",
"Kovalam Principal Sl is one mister Balachandran.\" \"",
"He will help you.\" \"",
"Financial crisis have affected every where, Dollar is so cheaper now.\" \"",
"Financial crisis have affected every where, Dollar is so cheaper now.\" \"",
"Do you have Indian rupee.\" \"",
"Not that from Pakistan.\" \"",
"We need originals.\" \"",
"Hey!\" \"",
"Have you got any information about your sister?\" \".\" \"",
"No.\" \"",
"We got only a phone number.\" \"",
"This is him.\" \"",
"Christopher!\" \"",
"Look!\" \"",
"But no response.\" \"",
"is he a foreigner?\" \"",
"Stop joking. ",
"is here any one in that name?\" \"",
"There are so many people here.\" \"",
"How can I know there names?\" \"",
"We got his number.\" \"",
"Tell me.\" \"",
"9961100221\" \"This is him.\" \"",
"Christopher!\" \"",
"Look!\" \"",
"But no response.\" \"",
"Who is he?\" \"",
"That's him who quarreled with you in the beach.\" \"",
"Where can we find him now?\" \"",
"He stays nearthe light house.\" \"",
"Movie Channel\" \"Where is my sister?\" \"",
"Tell me, where is ny sister?\" \"",
"I don't know.\" \"",
"Manu!\" \"",
"Hey, move back.\" \"",
"Where is that girl?\" \"",
"I just collect their numbers and hands over.\" \"",
"I don't know anything else.\" \"",
"To whom are you giving these numbers/ Tell me\" \"Satan Sunny.\" \"",
"Shalini. ",
"I'm very close to that family.\" \"",
"Now the investigation reached a hard core...\" \" criminal called Satan Sunny\" \"He has just came out for a parole last week.\" \"",
"What was the offense?\" \"",
"Kidnapping, Rape and murder.\" \"",
"Just shoot him.\" \"",
"They should never get any countenance...\" \" from any law or religion.\" \"",
"Satan Sunny!\" \"",
"Where is he now?\" \"",
"Cotton hill colony is his place.\" \"",
"But it's not easy to catch him from there.\" \"",
"I know.\" \"",
"Nothing is easy.\" \"",
"Where is Sunni's house?\" \"",
"Which Sunny?\" \"",
"Some call him Satan.\" \"",
"Who are you?\" \"",
"I'm a friend if him.\" \"",
"Afterthat house.\" \"",
"That green house?\" \"",
"One with a beard. ",
"I smell some thing wrong.\" \"",
"Ok. ",
"I can see him. ",
"I will take care.\" \"",
"Which is Sunny's house?\" \"",
"That one.\" \"",
"One man is coming to you.\" \"",
"Who?\" \"",
"He said he is yourfriend.\" \"",
"Ok.\" \"",
"Who are you?\" \"",
"I'm John.\" \"",
"What do you need?\" \"",
"I need a help.\" \"",
"What help?\" \"",
"You should come with me.\" \"",
"No.\" \"",
"is this your son?\" \"",
"Movie Channel\" \"Balachandran, I'm taking him.\" \"",
"This is Kerala.\" \"",
"No problem. ",
"I will call you.\" \"",
"Movie Channel\" \"Kidnapping,Rape,Murder!\" \"",
"Tell me about this girl.\" \"",
"I don't know.\" \"",
"You don't know?\" \"",
"Tell me.\" \"",
"I don't know sir.\" \"",
"Yes.\" \"",
"You won't say?\" \"",
"I don't know.\" \"",
"Don't know?\" \"",
"So Satan Sunny doesn't know anything.\" \"",
"No sir.\" \"",
"Leave me.\" \"",
"You don't know this girl?\" \"",
"No. ",
"I was dealing with one another case.\" \"",
"Aren't you Mr. Sunny?\" \"",
"Four girls were trapped to Dubai, in the name of nursing I was there to pick them from railway station.\" \"",
"Where we are going?\" \"",
"The office of travel mate is near by.\" \"",
"Where are you going through this way?\" \"",
"Maintenance works are going on at the office.\" \"",
"We are going to the guest house.\" \"",
"For what?\" \"",
"Your stay is arranged here.\" \"",
"But we are not staying there.\" \"",
"We are going to Dubai as you said earlier.\" \"",
"Details will be given to you from there.\" \"",
"From where?\" \"",
"You stop the vehicle.\" \"",
"Stop the vehicle I said.\" \"",
"Stop the vehicle.\" \"",
"Catch them.\" \"",
"Don't let her go.\" \"",
"Sunny, get her.\" \"",
"Come on.\" \"",
"I don't know anything more sir.\" \"",
"No?\" \"",
"No.\" \"",
"These are done by them directly.\" \"",
"Who are they?\" \"",
"Surab and Anoop.\" \"",
"Where are hey now?\" \"",
"I don't know sir.\" \"",
"Are you sure?\" \"",
"Virgins are packed to foreign countries ...\" \" and others will be sold in Indian markets.\" \"",
"This girl?\" \"",
"I don't know sir.\" \"",
"Don't know?\" \"",
"No sir. ",
"I have already told you what all I knew.\" \"",
"I dropped Sorab and Anoop in a go down near Veli railway station.\" \"",
"That's all I know.\" \"",
"Please leave me sir.\" \"",
"I'm leaving you Satan!\" \".\" \"",
"I'm going to make you free.\" \"",
"Cutting fingers, questioning by hanging him upside down!\" \"",
"Maddy are you really mad?\" \"",
"This is Kerala.\" \"",
"Here the court will take the final decision.\" \"",
"Now you please stop it.\" \"",
"Law is the same every where.\" \"",
"Maddy, this is my area.\" \"",
"Please stop it.\" \"",
"Sir, I will never repeat this.\" \"",
"Sure?\" \"",
"Sure.\" \"",
"Please sir.\" \"",
"I know that.\" \"",
"You will not.\" \"",
"You will not.\" \"",
"No...no.\" \"",
"Please.\" \"",
"Please. ",
"I will never even look up on girls in my life.\" \"",
"What are you doing?\" \"",
"Please!\" \"",
"I promise in the name of my child.\" \"",
"Maddy!\" \"",
"No. ",
"I will not allow this\" \"Such a cruel investigation for a missing girl of some where?\" \"",
"Not a missing girl from some where.\" \"",
"She is my daughter.\" \"",
"What?\" \"",
"She is my daughter.\" \"",
"Movie Channel\" \"No.\" \"",
"Please.\" \"",
"No.\" \"",
"No...\" \"Sir!\" \"",
"Maddy!\" \"",
"Where are you?\" \"",
"Sir I will call you later sir.\" \"",
"No.\" \"",
"Now you talk to your wife.\" \"",
"Arathy.\" \"",
"Maddy on line.\" \"",
"Madhavetta!\" \"",
"Arathy!\" \"",
"Our daughter!\" \"",
"You relax.\" \"",
"Trust me.\" \"",
"I will be there with our daughter.\" \"",
"Are you angry with me?\" \"",
"Come on.\" \"",
"Why should I?\" \"",
"Are you angry with me?\" \"",
"You relax.\" \"",
"I will call you later.\" \"",
"I will call you back.\" \"",
"Ok?\" \"",
"Movie Channel\" \"Leave!\" \"",
"Leave.\" \"",
"Leave her.\" \"",
"Stop there.\" \"",
"Stop there.\" \"",
"Stop.\" \"",
"Leave me!\" \"",
"Leave me!\" \"",
"Brother!\" \"",
"Brother!\" \"",
"Brother!\" \" ",
"Dear!\" \"",
"Hello!\" \"",
"Leave her.\" \"",
"Leave her I said!\" \"",
"Try to be truthful in yourjob.\" \"",
"Just send them to the correct place.\" \"",
"That's all is our duty.\" \"",
"Move back you nasty\" \"Come here.\" \"",
"Move.\" \" ",
"Leave me.\" \"",
"Hello!\" \"",
"Brother!\" \"",
"Shalu...dear!\" \"",
"Hello!\" \"",
"Why are you not answering?\" \"",
"Hello!\" \"",
"Where are you?\" \"",
"Shalu!\" \"",
"Hello!\" \"",
"Shalu!\" \"",
"Where are you?\" \"",
"Hello!\" \"",
"Hello!\" \"",
"Shalu!\" \"",
"Hello!\" \"",
"Where are you?\" \"",
"Hello!\" \"",
"Anoop!\" \"",
"Take them in to the vehicle.\" \"",
"Come.\" \"",
"It's switched off.\" \"",
"How can it be possible?\" \"",
"She just called us!\" \"",
"Nonsense.\" \"",
"At the right time that flight took off.\" \"",
"What?\" \"",
"I heard a sound of a flight taking off.\" \"",
"Then it will be near some airport.\" \"",
"That's right!\" \"",
"I heard a sound of a train also.\" \"",
"You try to remember it correctly.\" \"",
"Where can we find these two?\" \"",
"Got it!\" \"",
"Kochuveli!\" \"",
"That closed godown.\" \"",
"Come fast.\" \"",
"Good morning sir!\" \"",
"Good morning sir!\" \"",
"James!\" \" ",
"Yes Sir!\" \"",
"What about your tracking and hacking?\" \" ",
"lt's going on sir.\" \"",
"I didn't get you?\" \"",
"Sir, about that K P murder case...\" \"Not that. ",
"I'm asking for some children.\" \"",
"Try to get it first.\" \"",
"Sir....that is...\" \" No need to explain.\" \"",
"Sir!\" \"",
"That numbers should be tracked between one hour.\" \"",
"Any help should be given to Mumbai DCP Madhavamenon within no time.\" \"",
"This is not a request. ",
"lt's an order.\" \"",
"Yes sir.\" \"",
"Come here.\" \"",
"Move.\" \"",
"Climb up fast.\" \"",
"Get in fast.\" \"",
"Be careful.\" \"",
"is nobody here?\" \"",
"Don't make noise.\" \"",
"Look!\" \"",
"A piece of dress.\" \"",
"Here is a mobile with its sim card!\" \"",
"Insert that sim in your mobile.\" \"",
"Fast.\" \"",
"Sound of a vehicle.\" \"",
"It may be them.\" \"",
"Come.\" \"",
"No one is here.\" \"",
"According to cyber cell BSNL tower 3 is near railway station.\" \"",
"There were signals from that before an hour.\" \"",
"I think its here.\" \"",
"No.\" \"",
"Be careful.\" \"",
"Movie Channel\" \"Don't do that.\" \"",
"Sit down.\" \"",
"Sit down.\" \"",
"Do you know this girl?\" \"",
"We are also in search of her.\" \" ",
"What?\" \"",
"She is his sister.\" \"",
"Shalini.\" \"",
"Really!\" \" ",
"Yes.\" \"",
"Sir No!\" \"",
"Manu!\" \"",
"Why are you here?\" \"",
"We got a call from Shalini.\" \"",
"Before getting the details the call cut off.\" \"",
"We came here with some hints.\" \"",
"Sir...\" \"Don't think that they are children.\" \"",
"They are expert truck drivers.\" \"",
"They are familiar with each and every road in Kerala and Tamil Nadu.\" \"",
"They will be useful for your type of investigation.\" \"",
"Fasal!\" \"",
"Manu's mother is alone at home.\" \"",
"You come with me.\" \"",
"Hey, Ok.\" \" ",
"Ok.\" \"",
"Stop.\" \"",
"Stop.\" \"",
"Come fast.\" \"",
"Get in.\" \"",
"Movie Channel\" \"What can I say?\" \"",
"Balettan is trying his best.\" \"",
"He says that a similar case has taken place in Mumbai too.\" \"",
"Mumbai deputy commissioner has come here to investigate it.\" \"",
"My daughter!\" \"",
"Nothing will happen to her.\" \"",
"Are you sad?\" \"",
"I always used to warn you against everything.\" \"",
"That was because I need you as safe as this forever.\" \"",
"Grandpa!\" \"",
"Parents often give their children whatever they like.\" \"",
"But they will become dangerous sometime.\" \"",
"Here a mobile is the villain!\" \"",
"Dear!\" \"",
"There was a generation without these facilities.\" \"",
"But at that time there was love and relations.\" \"",
"But now it's all about money.\" \"",
"If we the old people lay down on the verandah as a wooden block, ...it gives the house some kind of security.\" \"",
"But the new generation fails to realize that.\" \"",
"That's why we are send to charity homes.\" \"",
"I'm sorry grandpa!\" \"",
"Sometimes I felt angry with you.\" \"",
"Leave it dear!\" \"",
"Oh God.\" \"",
"Please take care of my children.\" \"",
"Movie Channel I did it for her happiness.\" \"",
"But now...\" \"You did nothing.\" \"",
"It was because of your love.\" \"",
"Nandan!\" \"",
"There is vital information.\" \"",
"Yes!\" \"",
"Among the two sim cards there are no signals from one of them.\" \"",
"That might be the one we found from the godown.\" \"",
"May be.\" \"",
"But to the second sim, signals from six towers at the MC road were found.\" \"",
"Means, they might be planning to go to Tamil Nadu.\" \"",
"Ok.\" \"",
"Around 100 kilometers from Thenkashi.\" \"",
"That means they can reach Thoothukudi by two three hours.\" \"",
"Thoothukudi!\" \"",
"From Thoothukudi port, ...its only around 20-25 notic mile to international water line.\" \"",
"They will enter into the international sea root through Indian ocean.\" \"",
"Then they will hand over these children.... ...to the ship which will be waiting in the international water.\" \"",
"After that we will never get them back.\" \"",
"So if you are planning something, ...you should do before they will get into the ship.\" \"",
"Yes.\" \"",
"You are right.\" \"",
"Good luck Maddy!\" \"",
"What about that Mumbai girl?\" \"",
"Deal is done for 5 lakh dollars.\" \"",
"That means 2 crore rupees.\" \"",
"Make it fast.\" \"",
"Yes.\" \"",
"But cool down!\" \"",
"It's the belief that one who can does sex with small girls can regain their youthfulness..... lt's this belief which feeds us.\" \"",
"So, before they change their mind we should do the business.\" \"",
"Ok?\" \"",
"Ok.\" \"",
"Where is Surab now?\" \"",
"At Kulathupuzha.\" \"",
"Mumbai girl should be packed from the Indian port as fast as possible.\" \"",
"Ok?\" \"",
"Ok.\" \"",
"All of you get out.\" \"",
"You can get the waterthere.\" \"",
"Get out.\" \"",
"Get out fast.\" \"",
"Stop there.\" \"",
"Get her!\" \"",
"Stop.\" \"",
"Stop there.\" \"",
"Come.\" \"",
"Move!\" \"",
"Get inside.\" \"",
"Get inside.\" \"",
"Leave I said.\" \"",
"Leave her.\" \"",
"Leave me.\" \"",
"Come.\" \"",
"Leave her.\" \"",
"You can come with me.\" \"",
"Come.\" \"",
"Come.\" \"",
"Come fast.\" \"",
"Come.\" \"",
"Come fast.\" \"",
"Anoop!\" \"",
"Where are you going?\" \"",
"Don't we need a private place?\" \"",
"Stop there.\" \"",
"So this is your braveness!\" \"",
"Our family.\" \"",
"Our parents who sells their house for us.\" \"",
"They don't sleep.\" \"",
"So?\" \"",
"It's near.\" \"",
"Come.\" \"",
"Come.\" \"",
"I was telling about those girls.\" \"",
"Come up!\" \"",
"Come.\" \"",
"Movie Channel\" \"Every girl has the fear in her mind that at any time they can be attacked by men like you.\" \"",
"Let them sleep without that fear at least for one night.\" \"",
"Come!\" \"",
"Come.\" \"",
"Come.\" \" ",
"Leave.\" \"",
"Leave me!\" \"",
"Give them tea!\" \"",
"Tea!\" \"",
"Any thing to Eat!\" \" ",
"No.\" \"\"",
"Did anybody sing in this summer?\"\" \"\"",
"Don't you hear the tune I sang for you?\"\" \"\"",
"You, singing rain don't fade from me\"\" \"\"Let it shower in your laugh\"\" \"\"lt wears the feathers of moonlight\"\" \"\"No one knows that, it was my mind\"\" \"\"Did anybody sing in this summer?\"\" \"",
"Movie Channel\" \"\"You are the love inside as thorn which pains\"\" \"\"You are he fruit with honey in it\"\" \"\"You are the hidden wind\"\" \"\"You, leaving us as the star in the sky\"\" \"\"You swim the small waves\"\" \"\"As a floating melody!\"\" \"",
"Movie Channel\" \"\"You are searching for fire as waves\"\" \"\"Tell me which is the lonely way?\"\" \"\"",
"Lamp is lightening in me, You are swinging in my heart\"\" \"\"Oh evening that disappears at distances\"\" \"\"Will the moon comes that way!\"\" \"\"",
"Did anybody sing in this summer?\"\" \"",
"Movie Channel\" \"I will come within seconds.\" \"",
"No.\" \"",
"I will not late.\" \"",
"What?\" \"",
"What happened?\" \"",
"Don't know.\" \"",
"Someone got suicide.\" \"",
"A..\" \"Man and woman.\" \"",
"I told here onward.\" \"",
"What are you doing?\" \"",
"Sir, Sorry sir.\" \"",
"Intelligence SP told about you.\" \"",
"Movie Channel\" \"Mercy...\" \"Thank you.\" \"",
"Balachandran, one girl is assassinated.\" \"",
"Mercy.\" \"",
"The missed one of them came from Thiruvalla and ready to go foreign.\" \"",
"Ya..\" \"I'm known.\" \"",
"She is a companion of the girl got that time's hit under case.\" \"",
"The bleeding from the body is not stopped right now.\" \"",
"That means she died within time.\" \"",
"One thing I'm sure.\" \"",
"Their traveling will be in this route.\" \"",
"Yes.\" \"",
"You are right.\" \"",
"None of the container wants to go Aryamkavu ..\" \" without proper checking.\" \"",
"Ya..\" \"I'm ready for any help.\" \"",
"Okay.\" \"",
"I will call you later.\" \"",
"We are going.\" \"",
"Where?\" \"",
"To Chathanpetty.\" \"",
"Chathanpetty?\" \"",
"For what?\" \"",
"That may be a girl missing case for you.\" \"",
"It is one of the cases that keep as a record.\" \"",
"But, for us..\" \"For us, it's our sister's life.\" \"",
"Sir,\" \"The person who doesn't miss anything couldn't understand that.\" \"",
"We are leaving.\" \"",
"For me doesn't miss anything is an investigation only.\" \"",
"Go.\" \"",
"Go and find out.\" \"",
"Don't come in front of me.\" \"",
"Go and find out.\" \"",
"Surab,\" \"Tell brother.\" \"",
"In the inner sea our ship is reached before two days.\" \"",
"If the settlement not done within tomorrow,\" \"They will go with their own way.\" \"",
"I know about a forest way.\" \"",
"That is safe.\" \"",
"In that way, we can reach outside of border.\" \"",
"Except Mumbai lady, everyone's deals should be done by Selvam.\" \"",
"I don't know.\" \"",
"There are unusual obstacles in my way.\" \"",
"Relax.\" \"",
"Surab.\" \"",
"Take it easy man.\" \"",
"Take it easy man.\" \"",
"More than it, we faced many thinks.\" \"",
"This I wish to see.\" \"",
"I will see.\" \"",
"Movie Channel I want to see my mom and brother.\" \"",
"Mady.\" \"",
"Nandhan.\" \"",
"Where are you?\" \"",
"Sreesailam.\" \"",
"I got an info regarding a person doing transporting.\" \"",
"Ok.\" \"",
"He had a yard his own.\" \"",
"For the transporting of kids, he caught by the police ...\" \" report of Thirunalvali.\" \"",
"Then?\" \"",
"That I mentioned Chathanpetty, there is he staying.\" \"",
"He is a powerfull guy.\" \"",
"I heard that police and politics will be under his control.\" \"",
"Then, The Thirunalvelli SP Panniel Selvam is my friend.\" \"",
"If you want..\" \"Not now.\" \"",
"If need, tell you.\" \"",
"I wish, I was with you.\" \"",
"Any way.. take care Mady.\" \"",
"Ok.\" \"",
"Thank you.\" \"",
"Thank you.\" \"",
"Walk.\" \"",
"I can't.\" \"",
"I can't any more.\" \"",
"Stand up and walk.\" \"",
"Get in.\" \"",
"Can we go?\" \"",
"Give one dose too.\" \"",
"Otherwise our work will increase.\" \"",
"Leave me.\" \"",
"Movie Channel\" \"Hay..\" \"Stop there.\" \"",
"I will kill you.\" \"",
"Take him.\" \"",
"Your inspectortold that your elder daughter's marriage is fixed.\" \"",
"Then why you make problems on these times?\" \"",
"If I told about you, I think that I will get promotion.\" \"",
"Selvam ....\" \"Selvam.\" \"",
"Thenkasi Selvam.\" \"",
"I will sale your mom, daughter and your sister.\" \"",
"Its my business.\" \"",
"Why don't you understand these all?\" \"",
"Dad, phone.\" \"",
"Do deal.\" \"",
"Dad, I couldn't.\" \"",
"Tell Galena Madam.\" \"",
"Surab will reach there.\" \"",
"Ok, madam.\" \"",
"You want to keep safely ] the ladies that he brings.\" \"",
"Understand?\" \"",
"Why you have thus a doubt?\" \"",
"Want to sale them, fast.\" \"",
"That Mumbai lady loading is on settled.\" \"",
"For Kerala ladies also ready.\" \"",
"Sale wants to do within time.\" \"",
"Ok, madam.\" \"",
"Where is that useless police?\" \"",
"Fast.\" \"",
"That girl wired check skirt.\" \"",
"That girl.\" \"",
"Leave me\" \"Take the vehicle.\" \"",
"Function is going on.\" \"",
"Small girl.\" \"",
"Super girl.\" \"",
"Fortoday, I will take.\" \"",
"Movie Channel\" \"Go, and look that.\" \"",
"Hero is come.\" \"",
"Attacked my brothers.\" \"",
"Now on we want to sit with a finger in mouth.\" \"",
"A person from other came from other place,\" \" Come into my place and attacking my people,Can go with his life?\" \"",
"look his walk.\" \"",
"What a style?\" \"",
"What are you looking?\" \"",
"Do you know this girl?\" \"",
"I don't know.\" \"",
"Please leave me sir, I will do anything foe you.\" \"",
"Do you know this girl?\" \"",
"No.\" \"",
"Ya..\" \"I know.\" \"",
"Where is the girl?\" \"",
"Galena madam.\" \"",
"She is in her hand.\" \"",
"Who is Galena?\" \"",
"Gayas Ganna will say.\" \"",
"Galena will do.\" \"",
"Gayas Ganna.\" \"",
"Call to Galena.\" \"",
"Tell Selvam.\" \"",
"The customer I told you is ready.\" \"",
"He is your friend from Bangalore.\" \"",
"He wants a small kid.\" \"",
"I show him that Trivandrum girl's photo.\" \"",
"Do you know that man well?\" \"",
"Ya..\" \"10 years, I know him.\" \"",
"Not 10-20 years.\" \"",
"For Galena money is important.\" \"",
"Did he have money?\" \"",
"10 lakh.\" \"",
"No bargaining.\" \"",
"Give the money and tell him to take her.\" \"",
"10 lakh.\" \"",
"Ok, madam.\" \"",
"Then...\" \"Sir, Money?\" \"",
"You will give.\" \"",
"I.\" \"For what?\" \"",
"You will give.\" \"",
"Kanna..\" \"Do fast.\" \"",
"Dad..\" \"What I want to do?\" \"",
"Keep mum.\" \"",
"In front of you is lion.\" \"",
"How is that?\" \"",
"For this place, dad is the lion.\" \"",
"Then, this lion?\" \"",
"That, I told you a false.\" \"",
"This is the original lion.\" \"",
"Where is the money?\" \"",
"Where is money?\" \"",
"There.\" \"",
"Then you can watch my moving through this mobile.\" \"",
"If Selvam did anything, kill those two.\" \"",
"No.\" \"",
"Sir,lt's not required.\" \"",
"We are not familiar with it.\" \"",
"It is not competition.\" \"",
"In some situation, any person will use anything.\" \"",
"Ok, sir, it's good to have a guard that is familiarthan non familiar.\" \"",
"I will kill you.\" \"",
"If I will leave you, don't stop anywhere.\" \"",
"You want to travel whole the time.\" \"",
"If you think that they made any mistake, fire them.\" \"",
"Sir, come.\" \"",
"By the look can't understand that you are from Bangalore.\" \"",
"For it, there is no definite language at all.\" \"",
"He is my friend.\" \"",
"Ok.\" \"",
"Ok.\" \"",
"Money?\" \"",
"Surab..\" \"I want to see that kid.\" \"",
"Hay..\" \"You gave the money.\" \"",
"Then Why confuse?\" \"",
"Go and see.\" \"",
"Movie Channel\" \"Hay, listen.\" \"",
"I'm not coming to misuse you.\" \"",
"I'm coming to escape you.\" \"",
"is it true?\" \"",
"Yes.\" \"",
"Your brother Manu and Karthik are with me.\" \"",
"Where is them?\" \"",
"One second.\" \"",
"Manu.. come here.\" \"",
"Manu brother....\" \"Daughter...\" \"Salu..\" \"Manu Brother...\" \"Daughter..\" \"I'm coming.\" \"",
"My mind is saying as something is wrong.\" \"",
"Go and check.\" \"",
"Madam..\" \"Madam..\" \"He is danger.\" \"",
"He is danger, madam.\" \"",
"Surab...\" \"Block him,\" \"Manu take her.\" \"",
"Come daughter.\" \"",
"Shoot him.\" \"",
"Come, and take her to hospital.\" \"",
"Do you know this girl?\" \"",
"Do you know this girl?\" \"",
"She is my daughter.\" \"",
"Do you know this girl?\" \"",
"Don't know?\" \"",
"Sure?\" \"",
"You don't know her?\" \".\" \"",
"Sure?\" \"",
"Where is the girl?\" \"",
"Where is the girl?\" \"",
"Where?\" \"",
"In port.\" \"",
"Where in port?\" \"",
"Warehouse no:5 What?\" \"",
"Warehouse no:5 Sure?\" \"",
"When I say good bye to people, I mean it.\" \"",
"Don't force me to come back.\" \"",
"Ok?\" \"",
"Movie Channel\" \"Mady....\" \"Mad Mady...\" \"Mady....\" \"Mad Mady...\" \"Mad...\" \"Mad Mady... I'm Gayas Ganna.\" \"",
"Gayas Ganna...\" \"Where is my daughter?\" \"",
"Where is my daughter?\" \"",
"Leave that.\" \"",
"Let us play a game?\" \"",
"Can we play a game?\" \"",
"is it?\" \"",
"I'm coming to take back my daughter.\" \"",
"Where is my daughter?\" \"",
"Came.\" \"",
"I know that you should come.\" \"",
"Look, fifty-fifty, 50-50.\" \"",
"You will come or not, will come or not.\" \"",
"Like me, I don't know that is I'm a women or men.\" \"",
"You did it.\" \"",
"You..\" \"Don't you remember anything?\" \"",
"I'm Gayas Ganna.\" \"",
"Do you remember Gayas Ganna?\" \"",
"At least remember?\" \"",
"Do you remember Gayas Ganna?\" \"",
"Yet?\" \"",
"A girl with 13 years old.\" \"",
"Remember?\" \".\" \"",
"Remember?\" \"",
"Don't cry.\" \"",
"Don't cry.\" \" ",
"Leave me.\" \"",
"Mad...mad... mad...\" \"Mady..\" \"At the time you removed my sex, I'm waiting for you.\" \"",
"In the past 8 years.\" \"",
"To become your daughter's 13 years.\" \"",
"No.\" \"",
"Yes.\" \"",
"From that time, I waited.\" \"",
"Look the power of a person who lost his gender.\" \"",
"When I saw the disappointment and pain in your face,\" \"A kind of cyclic pleasure..\" \"you damn.\" \"",
"Diya...\" \"Diya...\" \"Diya...\" \"Age 13.\" \"",
"Daughter of Madhava Menon.\" \"",
"Deputy Commissioner of Police.\" \"",
"The most encounter specialist.\" \"",
"Where is my daughter?\" \"",
"You..\" \"No Mady..\" \"You couldn't do anything to me.\" \"",
"I'm the only one person known about where is your daughter.\" \"",
"Thank you god.\" \"",
"Please.\" \"",
"Where is my daughter?\" \"",
"Your daughter..\" \"What a sweet child.\" \"",
"Because of I can't accept her, I sold her.\" \"",
"I sold her.\" \" ",
"No.\" \" ",
"Yes.\" \"",
"Please.\" \"",
"It's my last question.\" \"",
"Where is my daughter?\" \"",
"Where is my daughter?\" \"",
"Relax..\" \"Relax..\" \"Your daughter will feel the hotness and sigh of an old one.\" \"",
"Now on I will hit you, and you will tell.\" \"",
"Now on I will hit you, and you will tell.\" \"",
"Where is my daughter?\" \"",
"Tell.\" \"",
"I wouldn't tell.\" \"",
"Those who insult the small kids, it is a punishment that the society would like to give, to the sexual phonetic perverts as like you.\" \"",
"Movie Channel lt's not for my daughter.\" \"",
"It's for the criminals like you who do the injustice.\" \"",
"I'm doing the same duty as like each policeman want to save the society.\" \"",
"Where is my daughter?\" \"",
"Yes. ",
"I'm Mad Mady.\" \"",
"The brutal encounter specialist.\" \"",
"Tell me.\" \"",
"Where is my daughter?\" \"",
"No.\" \"",
"No. ",
"I wouldn't say.\" \"",
"Go and find out her.\" \"",
"I will kill you.\" \"",
"Where is my daughter?\" \"",
"How much you will do?\" \"",
"I will kill you.\" \"",
"Where is my daughter?\" \"",
"Where is my daughter?\" \"",
"Shoot me.\" \"",
"You find out your daughter.\" \"",
"Go.\" \"",
"Shoot me.\" \"",
"Don't you look the containers?\" \"",
"Go... and seek.\" \"",
"Go and find out her.\" \"",
"Do yourjustice.\" \"",
"Your daughter....\" \"is in sea or in sky or in land.\" \"...",
"Only I know.\" \"",
"Go and find out her.\" \"",
"It's a pleasure that more than the pain that you given to me.\" \"",
"The groaning of your daughter for pity in front of an old man, who is going to take her virginity.\" \"",
"That I want to hear.\" \"",
"Stop.\" \"",
"Get down.\" \"",
"Bring it down.\" \"",
"Movie Channel\" \"Daughter..\" \"Daughter..\" \"Diya..\" \"Daughter..\" \"Hey..\" \"Wakeup.\" \"",
"Daughter...\" \"Diya...\" \"Papa is here.\" \"",
"Papa is here.\" \"",
"I know that papa will come.\" \" ",
"Papa came.\" \"",
"I don't say anyone that papa is police.\" \"",
"You are a brave girl my sweet heart.\" \"",
"What is this?\" \"",
"What is this?\" \"",
"What is this?\" \"",
"They inject this for sleeping.\" \"",
"My God!\" \"",
"My God!\" \"",
"Movie Channel I got my daughter back.\" \"",
"I got my daughter back.\" \"",
"None of the parents having the pain like this.\" \"",
"Let it be an inspiration to any police officer's.\" \"",
"It shall be an inspiration to the police officer who likes to work with fairness.\" \"",
"And let this Mad Mady continue the verdict of a Karmayodha.\" \"",
"Movie Channel\" \"Warrior of Dharma...\" \"Warrior of Dharma...\" \"Warrior of Dharma...\" \"Warrior of Dharma...\" \"Warrior of Dharma...\" \"Warrior of Dharma...\" \"Warrior of Dharma...\" \"Warrior of Dharma...\""
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"# $NetBSD: Makefile,v 1.43 2017/02/12 06:25:43 ryoon Exp $\n\nDISTNAME=\tqalculate-units-0.9.4\nPKGREVISION=\t28\nCATEGORIES=\tmath\nMASTER_SITES=\t${MASTER_SITE_SOURCEFORGE:=qalculate/}\n\nMAINTAINER=\[email protected]\nHOMEPAGE=\thttp://qalculate.sourceforge.net/\nCOMMENT=\tUtility for conversion between units using Qalculate\n\nUSE_LANGUAGES=\t\tc c++\nUSE_LIBTOOL=\t\tyes\nUSE_PKGLOCALEDIR=\tyes\nUSE_TOOLS+=\t\tautoconf gmake intltool msgfmt pkg-config\nGNU_CONFIGURE=\t\tyes\n\npre-configure:\n\t${RUN} cd ${WRKSRC}; autoconf\n\n.include \"../../math/qalculate/buildlink3.mk\"\n.include \"../../x11/gtk2/buildlink3.mk\"\n.include \"../../sysutils/desktop-file-utils/desktopdb.mk\"\n.include \"../../mk/bsd.pkg.mk\"\n"
] |
{
"pile_set_name": "Github"
}
|
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0.00741839762611276
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| 5
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[
"/**\n * Convert array of 16 byte values to UUID string format of the form:\n * XXXXXXXX-XXXX-XXXX-XXXX-XXXXXXXXXXXX\n */\nvar byteToHex = [];\nfor (var i = 0; i < 256; ++i) {\n byteToHex[i] = (i + 0x100).toString(16).substr(1);\n}\n\nfunction bytesToUuid(buf, offset) {\n var i = offset || 0;\n var bth = byteToHex;\n return bth[buf[i++]] + bth[buf[i++]] +\n bth[buf[i++]] + bth[buf[i++]] + '-' +\n bth[buf[i++]] + bth[buf[i++]] + '-' +\n bth[buf[i++]] + bth[buf[i++]] + '-' +\n bth[buf[i++]] + bth[buf[i++]] + '-' +\n bth[buf[i++]] + bth[buf[i++]] +\n bth[buf[i++]] + bth[buf[i++]] +\n bth[buf[i++]] + bth[buf[i++]];\n}\n\nmodule.exports = bytesToUuid;\n"
] |
{
"pile_set_name": "Github"
}
|
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0.001430615164520744
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| 5
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[
"Kratom Capsules in {{lpg_city}} {{lpg_state}}\n\nKratom Capsules in {{lpg_city}} {{lpg_state}}\n\nWe offer our customers a variety of Kratom Capsules in {{lpg_city}} {{lpg_state}}. ",
"At low doses, Kratom can give you energy. ",
"At high doses, Kratom can make you sleepy and can reduce pain. ",
"Kratom products are known to provide relaxation, improve mood, improve energy, and relieve pain for customers. ",
"Many people use Kratom for anxiety relief.",
"\n\nAt NuWave Botanicals, we offer an abundance of blends such as white vein and red vein to our kratom users in {{lpg_city}} {{lpg_state}}. ",
"All of these blends can have a multitude of effects. ",
"The White Vein blend, for example, is known to last a little longer than other types of Kratom and can keep you focused. ",
"Red vein is used for peace and tranquility.",
"\n\nExamine our products below and pick out the right choice for you. ",
"If you have any questions, please contact us.",
"\n\nIf you use Kratom products, be aware that you may experience side effects such as nausea, constipation, dizziness, sweating, itching, dry mouth, seizures, muscle tremors, liver damage, and hallucinations. ",
"Please use the amounts of Kratom responsibly.",
"\n\nWhat is Kratom?",
"\n\nKratom is also known as Mitragyna Speciosa. ",
"Kratom is a tropical tree with a long history of conventional use in parts of Africa and Southeast Asia. ",
"Kratom is otherwise called Thom, Thang, and Biak. ",
"Its leaves and the teas prepared from them have for some time been utilized by individuals in that area to oversee pain and narcotic withdrawal and to fight off weakness. ",
"Kratom is really devoured all through the world for its energizer impacts and as a narcotic substitute (in type of tea, bit, smoked, or ingested in containers).The unique plant has been around this world for quite some time now. ",
"However, most people had never even heard of Kratom nor the origin of Kratom until as of recently, within the past couple years.",
"\n\nConsumers all over the world and in {{lpg_city}} {{lpg_state}} now desire and have a strong appetite for this plant, as its herbal remedies are quite obvious and well-documented to the public. ",
"However, there are effects and parts of this plant that are still unknown to the public. ",
"Til today, the plant doesn’t have much proper research conducted on it, so its efficacy is still not fully verified. ",
"However, scientists and curious people in {{lpg_city}} {{lpg_state}} alike are working to change that as some have found that the effects from this plant are very beneficial to the human body.",
"\n\nWhere did Kratom come from though? ",
"The origin of Kratom is not completely known. ",
"Only assumptions can be made from bits and pieces found within recorded history of this plant. ",
"We know so far that the Kratom plant originates from Southeast Asia. ",
"It has been used within that area by native cultures for a variety of purposes, for many centuries. ",
"For example, tribal societies had used it in the past as a mild stimulant by chewing on its leaves, as it was very similar to Khat or Coca in a functional sense.",
"\n\nOver the years, we now know of more side effects, such as nausea, constipation, dizziness, sweating, itching, dry mouth, seizures, muscle tremors, liver damage, and hallucinations. ",
"However, this may only occur if Kratom is used irresponsibly. ",
"This is why strive to remind people to always be careful with the amount of Kratom being consumed.",
"\n\nKratom Capsules in {{lpg_city}} {{lpg_state}} – Benefits\n\nA variety of benefits have been found from the use of kratom:\n\nThere is information that proposes kratom has both energizer and sedative impacts.",
"\n\nKratom has sedative like impacts and has been utilized as an energizer by indigenous in the tropical and subtropical areas of Asia as a substitute for sedative clients to battle withdrawal manifestations, to treat muscle throb, weakness, and different conditions notwithstanding be a pain relieving, a sedative substitute, an antihypertensive, an antidiabetic and against diarrheal, hostile to leukemic, and anorectic .",
"\n\nIt is said that at low portions, kratom produces an energizer impact while at higher dosages, it shows sedative like impact. ",
"The impact recommended that the concentrate of kratom restrains professional incendiary go between discharge and vascular penetrability in blend with invulnerability upgrade, incitement of tissue fix, and mending forms.",
"\n\nThere is a likelihood for kratom to be therapeutically utilized as an agony executioner and as a superior sedative substitute later on.",
"\n\nApparently kratom have upper movement by its huge decrease in corticosterone levels in mice presented to the constrained swim test and tail suspension test. ",
"Presentation to kratom remove for 7 days expanded the time spent in open arm of raised in addition to labyrinth, showing the plausibility of anxiolytic-like impacts of kratom separate.",
"\n\nThe antinociceptive impacts appear to be the most contemplated and kratom may have more pain relieving action than morphine in tail-flick and hot-plate tests. ",
"The impact of kratom may be inalienable to its ability to infiltrate the blood–mind obstruction.",
"\n\nThe horizontal nerve center direct restraint may chiefly clarify the anorectic impacts of kratom in rodents getting more fit because of decrease in water and nourishment admission other than influencing the degree of cholecystokinin, a peptide hormone of the gastrointestinal framework which is related with hunger concealment. ",
"Of note, the cholecystokinin level was not influenced by the methanolic concentrate of kratom, so the anorectic impact of the plant concentrate might be credited to different components.",
"\n\nIn an investigation, kratom is an intense antinociception without remuneration or revultion with lessened antinociceptive resistance, physical reliance, respiratory discouragement, or gastrointestinal travel hindrance in mouse models. ",
"The examination proposed that those properties, for example, inability to enlist an intracellular protein and delta enmity may both be fruitful in isolating antinociception from undesirable symptoms."
] |
{
"pile_set_name": "Pile-CC"
}
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| 5
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[
"Q:\n\nSQL combine SELECT statements into two columns\n\nTWO Tables SQL 2005 Tables\n Trend Table\n Enter Exit Number \n .01 .01 0\n .02 .02 1\n .03 .03 2\n .04 .04 3\n\n Orders Table\n Ticker Enter Exit\n EUR 0 1\n GBP 2 3\n\nRequirement: A single query to produce the Enter and Exit Values from Trend Table given only the Ticker Symbol from the Orders Table.",
"\nA Ticker Value will provide Enter and Exit Integers in the Orders Table that correspond to the Number Column in The Trend Table which points to the actual Decimal Enter and Exit values that the query should output.",
"\nEnter and Exit Values need to be in separate columns. ",
" The following query produces output with values in 1 column only (see output)\n SELECT T.Enter\n FROM Trend AS T INNER JOIN Orders AS O ON O.Enter = T.Number\n WHERE (O.Ticker = 'EUR')\n UNION\n SELECT D.Exit\n FROM Trend AS D INNER JOIN Orders AS F ON F.Exit= D.Number\n WHERE (F.Ticker = 'EUR')\n\n OUTPUT:\n Exit\n 0.01\n 0.02\n\nA:\n\nIs this what you are after?",
"\nSELECT Orders.",
"Ticker, T1.Enter, T2.Exit\nFROM Orders\nINNER JOIN Trend T1 ON Orders.",
"Enter = T1.Number\nINNER JOIN Trend T2 ON Orders.",
"Exit = T2.Number\n\n"
] |
{
"pile_set_name": "StackExchange"
}
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0.009302325581395349,
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0.0084985835694051,
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0.04411764705882353,
0.020833333333333332,
0
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| 5
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[
"Gallery\n\nListing Agent\n\nListed By\n\nRequest more information\n\nThank you for the email, we'll get back to you shortly\n\nName (required)Email Address (required)Questions/Comments\n\nDescription\n\nBeautiful new construction in up and coming Buena Vista area! ",
"Open floor plan with exceptional finishes! ",
"Close to downtown, Germantown, and within walking distance of the Farmer's market! ",
"House currently under construction. ",
"Completion date expected early July."
] |
{
"pile_set_name": "Pile-CC"
}
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0.00796812749003984,
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0.027777777777777776,
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[
"Herpes simplex virus type 2 serological testing and psychosocial harm: a systematic review.",
"\nSerological testing for herpes simplex virus (HSV) type 2 in persons without a history of genital herpes is not recommended, partly because of concerns that an HSV-2 diagnosis would lead to negative psychosocial sequelae. ",
"This review aimed to examine the evidence regarding the psychosocial effects of HSV-2 serological testing. ",
"Eight electronic databases were searched for empirical studies indexed before March 2010. ",
"Abstracts from relevant conferences were reviewed and senior authors contacted to find unpublished materials. ",
"Eligible studies examined participants without a history of genital herpes who underwent HSV-2 serological testing and reported data from at least one quantitative or qualitative psychosocial assessment conducted after receiving HSV results. ",
"Of nine studies that satisfied the inclusion criteria, seven reported that HSV-2 diagnosis by serological test did not have a persistent negative impact on 309 participants' mental health or sexual attitude and satisfaction. ",
"Two studies reported a negative impact of testing; one found that five HSV-2-seropositive college students had increased distress 3 months post-testing compared with HSV-2-negative individuals, and the other found self-reports of sexual undesirability up to 1 year after diagnosis in some people. ",
"The perceived severity of a genital herpes diagnosis was moderately severe for participants before testing; however, post-testing, the reported severity of a herpes diagnosis was lower among those testing HSV-2 positive. ",
"HSV-2 diagnosis by type-specific serological testing did not result in long-term psychosocial harm in most persons without an identified history of genital herpes. ",
"Concerns about sustained emotional impact should not deter clinicians from offering HSV-2 serological testing to appropriate patients."
] |
{
"pile_set_name": "PubMed Abstracts"
}
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[
"Reggie Torbor\n\nReggie Jermaine Torbor (born January 25, 1981) is a former American football linebacker. ",
"He was drafted by the New York Giants in the fourth round of the 2004 NFL Draft. ",
"He played college football at Auburn.",
"\n\nTorbor has also played for the Miami Dolphins and Buffalo Bills. ",
"He earned a Super Bowl ring with the Giants in Super Bowl XLII beating the New England Patriots.",
"\n\nEarly years\nTorbor attended and played high school football for Robert E. Lee High School in Baton Rouge, where he was a running back and linebacker. ",
"He rushed for 1,563 yards and 10 touchdowns as a junior while accumulating 1,241 yards and 14 touchdowns a senior on his way to an All-State selection. ",
"He finished his high school career with 18 sacks.",
"\n\nCollege career\nFollowing high school, Torbor attended Auburn University, where he was a four-year letterman in football. ",
"He appeared in all 13 games for the team as a senior, recording 38 tackles (15 for a loss), 10.5 sacks, four forced fumbles and a fumble recovery on his way to Second-team All-SEC honors. ",
"He finished his collegiate career with 46 games played (22 starts), 120 tackles, 32 tackles for a loss, 19.5 sacks, 10 passes defensed, five forced fumbles, three fumble recoveries and a blocked kick. ",
"His sack total ranked him fifth in school history at the time of his departure.",
"\n\nProfessional career\n\nPre-draft\n\nNew York Giants\nTorbor was drafted by the New York Giants in the fourth round (97th overall) of the 2004 NFL Draft. ",
"He wore No. ",
"58 with the team during his rookie season.",
"\n\nDuring his rookie season in 2004, Torbor appeared in all 16 games while starting one. ",
"His first NFL start came against the Washington Redskins on September 19. ",
"In a December 12 contest against the Baltimore Ravens, Torbor sacked quarterback Kyle Boller and forced a fumble that was recovered by defensive end Osi Umenyiora and returned 50 yards for a touchdown. ",
"In the season finale against the Dallas Cowboys he recorded half a sack and recovered a Vinny Testaverde fumble that lead to a Giants touchdown. ",
"Torbor finished the year with 21 tackles, three sacks (all in the final four games of the season), two forced fumbles and a fumble recovery.",
"\n\nPrior to the 2005 season, Torbor switched from No. ",
"58 to No. ",
"53. ",
"He was also inactive for the team's first-round playoff game against the Carolina Panthers after undergoing hernia surgery. ",
"He earned a starting job during the preseason, but was benched for ineffective play during the team's Week 3 contest. ",
"He went on to appear in 14 games, starting nine, while missing two. ",
"On the year, he recorded 34 tackles, an interception, three passes defensed, a forced fumble and a fumble recovery. ",
"His interception came off St. Louis Rams quarterback Marc Bulger while his fumble recovery came against Dallas Cowboys quarterback Drew Bledsoe.",
"\n\nIn 2006, Torbor appeared in all 16 regular season games for the Giants while starting one, despite it being was reported during the preseason he was a long shot to make the team. ",
"On defense, he recorded 16 tackles, a sack and a forced fumble. ",
"He also added 14 special teams tackles, which tied him with fellow linebacker Chase Blackburn for the team lead. ",
"His forced fumble, which was recovered by safety Gibril Wilson, came against running back Travis Henry and the Tennessee Titans on November 26.",
"\n\nA restricted free agent in the 2007 offseason, Torbor received a fourth-round tender from the Giants. ",
"This meant that any team that signed Torbor would have to give the Giants a fourth-round pick in the 2007 NFL Draft as compensation. ",
"He signed his tender on May 3.",
"\n\nThat season, Torbor went on to appear in all 16 games for the Giants for the second straight season, and started six of them. ",
"All six of his regular season starts, and his four subsequent starts, were in place of injured linebacker Mathias Kiwanuka. ",
"On the season, he recorded 29 tackles, a sack and a pass defensed on defense while adding seven tackles on special teams. ",
"During the playoffs, he sacked quarterback Tony Romo in the team's divisional win over the Dallas Cowboys. ",
"He finished the postseason with 10 tackles and a sack, including two tackles in the Giants' Super Bowl XLII victory over the New England Patriots.",
"\n\nMiami Dolphins\nAfter his contract expired with the Giants, Torbor became an unrestricted free agent in the 2008 offseason. ",
"On February 29, Torbor agreed to terms on a four-year, $14 million contract with the Miami Dolphins.",
"\n\nDuring the 2008 offseason, it was reported that Torbor was projected to start for the Dolphins at inside linebacker alongside Channing Crowder, but would face pressure from Akin Ayodele.",
"\n\nTorbor was released on May 27, 2010.",
"\n\nBuffalo Bills\nTorbor signed with the Buffalo Bills on June 5, 2010. ",
"He started 10 games in 2010, recording 41 tackles. ",
"In 2011, during training camp, he injured his shoulder and was later placed on injured reserve.",
"\n\nFamily\nTorbor and his wife Michelle have two sons, Reggie Jr. and Cameron\n\nReferences\n\nExternal links\nMiami Dolphins bio\nNew York Giants bio\n\nCategory:1981 births\nCategory:Living people\nCategory:Sportspeople from Baton Rouge, Louisiana\nCategory:Players of American football from Louisiana\nCategory:African-American players of American football\nCategory:American football defensive ends\nCategory:American football linebackers\nCategory:Auburn Tigers football players\nCategory:New York Giants players\nCategory:Miami Dolphins players\nCategory:Buffalo Bills players\nCategory:Super Bowl champions"
] |
{
"pile_set_name": "Wikipedia (en)"
}
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[
"It is well known that predatory journals do not follow standard polices proposed by the World Association of Medical Editors (WAME). ",
"Predatory journals are usually newly established journals that spread their \"call for papers\" worldwide and charge the publication in open access journals ([@r1]). ",
"It is clear that predatory journals are those who serve for their own financial profit ([@r2]).",
"\n\n*Biochemia Medica* is an open access journal that does not charge manuscript processing or publishing. ",
"All editorial staff are continuously educated and directed to follow the highest ethical and scholarly publishing standards in all steps of the manuscript processing. ",
"They are all laboratory medicine professionals, who apart from their regular jobs, are in charge of different phases in Journal processing as volunteers. ",
"The publisher of the Journal is scientific and professional association of laboratory medicine professionals, Croatian Society of Medical Biochemistry and Laboratory medicine (CSMBLM).",
"\n\nIn practice, each manuscript submitted to the Journal passes several phases during editorial, peer reviewing and publishing process. ",
"The steps between the first online submission and the first Editor-in-Chief's decision are schematically presented in [Figure 1](#f1){ref-type=\"fig\"}. ",
"Every publisher, editor, reviewer and author knows that these phases require respectable time and that that time depends on Journal's policy. ",
"The time that passes between online submission of the manuscript and the first Editor-in-Chief's decision that is made after checking for research integrity issues and peer-review is between 6 to 8 weeks. ",
"The rest of the period, prior to manuscript acceptance in the overall timeline depends on the authors. ",
"They should, in a timely manner, properly answer to reviewers' recommendations.",
"\n\n{#f1}\n\nResearch integrity checkup of the manuscript consists of text similarity analysis using Crosscheck plagiarism detection service provided by CrossRef ([@r3]). ",
"Apart from that, research integrity editors also analyze the manuscript for potential salami publication ([@r4]). ",
"Furthermore, each manuscript is evaluated regarding ethical aspects of conducted and presented work ([@r5]). ",
"The final report gives the recommendation whether to proceed with editorial process, to return to the author for smaller corrections and explanation or to reject the manuscript for some of the major breaches of research integrity.",
"\n\nEvery editor worldwide knows that the quality of the journal must be continuously improved to be in accordance with recommendations related to ethics, peer-review, online submission system, technical issues, journal web page demands and many others. ",
"Every year the editors of *Biochemia Medica* try to identify as many issues to be corrected or improved in order to maintain certain quality level.",
"\n\nIn October 2018, after two-year preparation, editorial-publishing office of the journal *Biochemia Medica* has launched new web page because the old one could not compete with modern demands. ",
"We have fully transferred all previous, old and recent issues to the new web page. ",
"Due to new web page requirements, we changed our server provider and registrar of the domain Biochemia-medica.com. ",
"The journal remained open access and free of charge, with copyright transferred to the CSMBLM and with the open-access license under the Creative Commons Attribution 4.0 International License. *",
"Biochemia Medica's* impact factor for 2017 was 3.653 and the journal was in the Q1 in the category of Medical Laboratory Technology according to Web of science Journal citation reports (JCR).",
"\n\nDuring November and December 2018, without knowledge of the editorial staff, unknown perpetrator(s) downloaded a respectable number of articles published in *Biochemia Medica* in portable document format (PDF) and launched an illegal web page under the same journal name with downloaded articles. ",
"They represented themselves as Journal published by CSMBLM and used the name of Editor-in-Chief to send \"call for paper\" e-mails with all other relevant information they gathered from our web page in order to get potential authors' interest. ",
"They stated that the journal covered wide area of natural science and biomedicine to attract wider range of authors from different areas. ",
"They promised fast peer-review and publication in just a few days from submission. ",
"The first suspicion was raised by Journal's Editor-in-Chief based on the e-mail received at the end of December during Christmas holidays ([Figure 2](#f2){ref-type=\"fig\"}). ",
"The day after, one of the Chinese authors who wanted to submit the manuscript to *Biochemia Medica* send an e-mail addressed to the correct e-mail address of the Editorial office with the question about the true domain of *Biochemia Medica*. ",
"He wanted to know which of the two, \"com\" or \"org\", was the correct Journal's web page. ",
"Furthermore, he sent us the e-mail received as invitation \"call for papers\" e-mail with listed contacts. ",
"It was obvious that the listed contacts were very similar but not identical to the true Editor-in-Chief's and Journal's contacts. ",
"As correct suffix was and still is \"com\", Senior Editor opened the web page with suffix \"org\" and revealed the existence of the web page that violated copyright of the *Biochemia Medica*.",
"\n\n{#f2}\n\nWe contacted immediately our server provider and web page designer who in short time identified the server that hosted the illegal web page and its location in Turkey. ",
"They also advised us to contact the Turkish server provider and to inform them about copyright violation by the web page they had hosted. ",
"We have kindly asked them to remove illegal web page immediately. ",
"In very short time, Turkish server provider did so. ",
"We have also contacted the Department for Cyber Criminal of the Ministry of the Interior of the Republic of Croatia and National Computer Emergency Response Team (CERT), an expert group that handles computer security incidents. ",
"Furthermore, we have contacted staff from Portal of Croatian Professional and Scientific Journals (HRČAK). ",
"All of them advised us how to collect and how to save \"original e-mail headers\" received from cyber criminals and from the authors who might collaborate with them. ",
"As one of the *Biochema Medica*'s Editorial Board member is a professor from one of the Turkish University, we have asked him to help us contact the Turkish Cyber police and Turkish national CERT. ",
"Previously listed activities resulted favorable for our Journal because the first server host and illegal web page were removed in two days. ",
"However, few hours after that we have noticed that the illegal web page became available again and was hosted by another server provider.",
"\n\nWe have contacted again Croatian National CERT, Croatian server provider, our Turkish collaborators and HRČAK. ",
"All of them agreed that it will not be enough to contact server providers because it seemed that cyber criminals have a strategy to move from one server provider to another and that we have to contact Registrar which was localized somewhere in India. ",
"HRČAK staff helped us to compose a report on our Journal's copyright violation for acquiring financial gain. ",
"In two weeks' time from the first notification about violation, Registrar blocked the illegal web page.",
"\n\nDuring this process and later, many potential authors found our original web page and contacts surfing the internet. ",
"Some of them were confused by existence of two different Journal web pages and later they were confused when the illegal one terminated but they submitted their manuscripts through contacts available on this web page. ",
"All those manuscripts were out of scope and not in compliance with *Biochemia Medica*'s Instructions for authors. ",
"Some of the authors sent more than one manuscript. ",
"Editor-in Chief answered to each e-mail and informed authors that unknown Cyber criminals deceived them. ",
"Some of the authors sent us e-mails received from Cyber criminals including \"e-mail headers\" as well as the acceptance decision and invoices ([Figure 3](#f3){ref-type=\"fig\"}). ",
"Prices were different with the opportunity to arrange a better price deal depending on the author.",
"\n\n{#f3}\n\nAlthough this was a very harmful experience, we have learned a lot from it and we would like to share this with scientific journals' community. ",
"Therefore, we present a short workflow on how to manage situations like this if it will be necessary in the future ([Table 1](#t1){ref-type=\"table\"} and [Table 2](#t2){ref-type=\"table\"}).",
"\n\n###### People, services and institutions that can help resolve issues regarding web page theft, cyber-criminal or scientific journal copyright violation\n\n 1\\. Your server provider and Registrar of the domain. ",
"Server providers are usually available 24 hours daily. ",
"Customer can report suspicious incident at any time. ",
"They have competences to help you locating server provides which host illegal web page and Registrars.",
"\n --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------\n 2\\. Web-designers could also be able to do the same as server providers.",
"\n 3\\. National CERT: they can give you advice how to download the headers of suspicious e-mails. ",
"Those headers might help CERT personal to identify IP addresses of the senders.",
"\n 4\\. Cybercriminal office of the Ministry of the interior; report the incident.",
"\n CERT - Computer Emergency Response Team. ",
"IP -- Internet Protocol.",
"\n\n###### What you should do to overcome and prevent the problem\n\n ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------\n 1\\. Save the \"headers\" of all suspicious e-mails and send them to the National CERT and Cybercriminal team of the Ministry of the interior\n ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------\n 2\\. Report the incident to the Registrar of the domain and server provider. ",
"They usually have a link available on their web page through which you can report suspicious activities. ",
"Inform yourself about business policy of the Registrar and the ways to prepare the report.",
"\n\n 3\\. Report all illegal e-mail addresses to the relevant e-mail service (Google, Yahoo, Microsoft, Apple, *etc*.)",
"\n\n 4\\. Report spams and phishing e-mails.",
"\n\n 5\\. To prevent similar situation register your web page with more different and overcurrent domains (for example com, org, net, and the one with national extension).",
"\n\n 6\\. Register with your e-mail address at the NormShield service. ",
"NormShield will inform you in case someone registers a domain that looks similar to your domain, but you should be aware that this service does not cover the internet space worldwide.\\\n NormShield is a cyber-risk rating service that monitors cyber-risk posture of individual or organization through combination of several types of assessment ([@r6]).",
"\n\n CERT - Computer Emergency Response Team.",
"\n ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------\n\nWe wish to thank all the people who helped us in this situation: our server provider and registrar of the domain, national CERT, HRČAK team, Cyber-criminal team, our Turkish friends, and Senior Editor Ana-Maria Simundic. ",
"In addition, we would like to thank each one who helped us with useful advices. ",
"Furthermore, we thank the authors who sent us all suspicious e-mails and information.",
"\n\n**Potential conflict of interest:** None declared.",
"\n"
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"Yoga classes\n\nAerial yoga classes\n\n200/300 hour yoga teacher training course\n\nYoga Village About Us\n\nYoga Village is mainly situated in Goa which is one of the most relaxed and beautiful places in India. ",
"Along with Goa, we have our branches in Dharamsala and Pune as well. ",
"We are certified meditation and yoga school approved by Government of India.",
"\n\nThe inspiration and motto behind starting Yoga Village in Goa was this place natural beauty. ",
"Come here and enjoy the splendid beauty, peace and relaxed atmosphere with Yoga Village. ",
"Get a blissful healthy with a touch of nature with us. ",
"We are situated in the Ambola beach of the Goa which is the perfect place to meditate and connect with the inner you. ",
"Feel the beautiful vibes of nature when you enjoy your yoga sessions at Yoga Village.",
"\n\nWe are having qualified international teachers which offers a variety of health improvement courses like 200 hour yoga training and courses, Aerial yoga course, kundalini meditation retreats, Reiki healing training,\n\nYoga Village® in Goa is your first step towards a initiative of living a healthy and natural life along with thanking to nature for giving us so much to enjoy our life peacefully with the power of Yoga.",
"\n\nJoin Rama for kundalini meditation retreat, therapy and get enlighten. ",
"In Bali, INDONESIA.",
"\n\n\n\nThis Teacher Training Course Program is a combination of theory and hands on practicing of the important yoga elements. ",
"We will help students learn to analyze how to teach and practice the techniques learned 200 hour yoga TTC\n\nOnly 1299 Euro Yoga hall available as small, medium and large size. ",
"you can venue hire. ",
"wooden Huts are available at reasonable rates. ",
"Beach Huts & venue hire Aerial Yoga is a dynamic deep opening practice that will also greatly enhance any sporting activities. ",
"Therefore the training is also good for personal growth, you don’t necessarily have to teach. ",
"Aerial Yoga\n\nOnly 949 Euro In our 10 day Kundalini Meditation Course we discover our mind through various meditation and breathing techniques as a tool to clarify the questions and relations between mind and body; between outside and inside. ",
"10-Day Private Bone Healing Therapy / Kundalini Meditation\n\nTags :"
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"Q:\n\nWordpress: Adding Widget Sidebar for specific template\n\nProblem: A third sidebar I've added is not appearing on the target page.",
"\nDescription: I wanted to see if anyone can see anything I'm missing in the steps to create and display a widget sidebar in a particular template. ",
"Using the situation described below the sidebar appears on the widgets admin page but when the template renders the sidebar is the default sidebar, which suggests that the dynamic sidebar is not being found by the template. ",
"This is the second sidebar I've added. ",
"if I replace the sidebar name in the template tag with the name of the first additional template the page renders with the first customized sidebar.",
"\nSteps to create additional widget sidebars and display them with selected templates\n1) Register the sidebar in the child theme in functions.php\n2) In the registration process assign a name and ID to the new sidebar\n3) Create an additional sidebar template based on the existing template. ",
"Copy the existing template and change the name of the dynamic template to match the newly registered sidebar\n4) Go to the template where you want the sidebar to display and insert the name of the sidebar into the get_sidebar() template tag.",
"\n5) Go to the admin panel and drag widgets onto the new sidebar book post\nSpecifically this might look like:\n\nRegister the sidebar:\nif ( function_exists ('register_sidebar'))\n register_sidebar( array(\n 'name' => __('bookpost'),\n 'id' => 'sidebar-bookpost',\n 'description' => 'Sidebar for showing ad and section list on the template single-book.php',\n 'before_widget' => '<div id=\"%1$s\" class=\"widget %2$s\">',\n 'after_widget' => '</div>',\n 'before_title' => '<h2 class=\"widgettitle\">',\n 'after_title' => '</h2>' ));\n\nAssign name bookpost and sidebar-bookpost\nCreate an additional sidebar template named sidebar-bookpost.php. ",
"Edit the line\n\nSo that it now reads\nget_sidebar('bookpost');\n\nand finally use the widgets admin page to assign widget.",
"\n\nA:\n\nAre you trying to get dynamic sidebar??",
"\nif so then use \n<?",
"php if ( is_active_sidebar( 'sidebar-bookpost' ) ) : ?",
">\n\n <?",
"php dynamic_sidebar( 'sidebar-bookpost' ); ?",
">\n\n<?",
"php endif; ?",
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"MEDIA DAY: RED CARPET FOR THE REDSTER COMMUNITY\n\nALPINE OCT 16, 2017\n\nMEDIA DAY: RED CARPET FOR THE REDSTER COMMUNITY\n\nALPINE OCT 16, 2017\n\nAlpine\n\nOCT 16, 2017\n\nWhen the most successful ski team in the world invites 120 international media experts to the Atomic base camp in Altenmarkt, before the green light for the new World Cup and Winter Olympics, then it’s media day. ",
"Great to see them on the red carpet of the Redster Community again: today’s ski superstars Mikaela Shiffrin and Marcel Hirscher along with 38 others from the Atomic power line up, who in the super 2016 / 2017 season celebrated 12 World Championship medals, 24 World Cup wins, 66 podium places and seven crystal globes. ",
"And if all goes according to plan, then the Redster Party can easily carry on in two weeks time…\n\nHungry for action and raring to race with just two weeks to go before the official opening of the World Cup in Sölden! ",
"Year after year the unofficial one is the Atomic Media Day here in Altenmarkt, where the inner circle of the Ski World Cup meets in the APC (Atomic Pro Center), and nowhere else can the fascination for ski racing and that racing stable feeling be felt as much as here.",
"\n\n“This unique racing spirit which we have in the team and in the company makes things possible, which are nearly impossible!”",
"\n\nChristian Höflehner, Atomic Race Manager\n\nRedster G9 I Image Clip01:04 mins\n\nLast winter every third race was won statistically by one of the Redster unit athletes, and by the end of the season together they had accumulated 7,000 World Cup points. ",
"Which made Atomic, with the launch of the G9 REDSTER generation with Servotech, not only the most successful brand on the global market but also in ski racing the by far most successful ski brand in the world. ",
"The bar has been set high and the omens are perhaps, due to Marcel Hirscher’s lack of training because of his injury, not as good as last year. ",
"But on the other hand it gives the six times Overall World Cup winner and outright Atomic athlete a start to the season without any pressure: “We’re not talking about free skiing or training, we’re talking about real racing and until my leg is ready for this, I need to be patient” the ski superstar said at the Media Day with great serenity from his historical wins. ",
"But Marcel wouldn’t be Marcel, if he didn’t give it everything to get back onto the race circuit as quickly as possible: “There are still ups and downs, but it’s getting better, even if my ankle still hurts.”",
"\n\nMIKAELA SHIFFRIN WANTS TO WIN THE WORLD CUP AND OLYMPIC GOLD\n\nMikaela Shiffrin doesn’t have any problems. ",
"In her career up until now, she’s achieved everything (she’s Olympic champion, World Cup champion, Overall World Cup winner) but there’s still a lot more to win. ",
"At Atomic the US superstar stated her aim for the coming season: “I want to win the World Cup and Gold at the Olympics”. ",
"Lots of experts also believe Mikaela can increase her trophy collection considerably this year too, especially as the expert in technical disciplines also has lots of potential for Super G and Alpine combined. ",
"In ladies ski racing she will remain the yardstick of all things to come and all insiders in the ski scene believe this will be the case too.",
"\n\nWITH A STRONG A-TEAM FOR THE OLYMPIC WINTER\n\nThe fact that the most successful ski brand in the world also has the strongest race team can still continue soon, even if Marcel Hirscher is still recovering from his injury. ",
"Downhill World Cup winner Peter Fill puts the secret of success in a nutshell: “All of us want to do better every year and especially this year, with the Winter Olympics.” ",
"What is true for the experienced old-hand, also applies to all the big names in the Redster Team. ",
"Sofia Goggia, Stephanie Venier, Mauro Caviezel, Manuel Feller, Marco Schwarz, Matthias Hargin, Travis Ganong, Marc Digruber. ",
"It can be an epic winter for all of them! ",
"Those making a comeback in the team: Mirjam Puchner, Michaela Kirchgasser, Nils Hintermann, all of them are also very happy with their fitness progress. ",
"And until the season’s climax in February, there’s still a lot of time left too."
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"Q:\n\nWhen child divs are floated, parent divs lose auto-height\n\nI have a parent div called main. ",
"It has a bunch of child divs in it, which I floated left or right.",
"\nWhen I finished floating the last one, the height of the main div completely vanished, throwing off the layout of my page. ",
"I gave it a height:100%; just for now, but it will be overly tall on most resolutions. ",
"How can I keep it at a fluid height, only as much as needed to contain the elements?",
"\n\nA:\n\nContain your floats.",
"\nOn the div called main add overflow:hidden;. ",
" That should contain it.",
"\n\n"
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"Q:\n\nPass variables to route with URL::to in Laravel\n\nHere is how I am calling it in a create.blade.php of the same controller as the route I am trying to call:\n{{ Form::open(['route' => 'myRoute']) }}\n <button type=\"submit\" href=\"{{ URL::to('myRoute') }}\" class=\"btn btn-danger btn-mini\">Delete</button>\n{{ Form::close() }}\n\nThe Route is: \nRoute::post('myRoute', ['as' => 'timeline.myRoute', 'uses' => 'TimelineController@myRoute']);\n\nI want to pass an integer to the the route. ",
"I know that ->with() doesn't work like in View::make(). ",
"What is an efficient way to pass a variable into myRoute? ",
"Any help is appreciated.",
"\n\nA:\n\nJeemusu was 90% correct but forgot to specify a variable when opening a form.",
"\nWhat ultimately ended up working was:\n{{ Form::open(array('route' => array('timeline.myRoute', $id))) }}\n <button type=\"submit\" href=\"{{ URL::route('timeline.myRoute', array($id)) }}\" class=\"btn btn-danger btn-mini\">Delete</button>\n{{ Form::close() }}\n\nWith the Route in Route.php:\nRoute::post('myRoute/{id}', ['as' => 'timeline.myRoute', 'uses' => 'TimelineController@myRoute']);\n\nAnd the function in my controller:\nclass TimelineController extends BaseController\n{\n public function myRoute($id) {\n return $id;\n }\n}\n\nHope this helps anyone who had my problem.",
"\n\n"
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"Pozuelo de Aragón\n\nPozuelo de Aragón is a municipality located in the province of Zaragoza, Aragon, Spain.",
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"What is IQ?",
"\n\nIQ stands for intelligence quotient and measures the ability to problem solve. ",
"The mean IQ is adjusted to be 100 every year, and the standard deviation is adjusted to be 15. ",
"In other words, about 68% of all people will lie in the range 85 to 115. ",
"The following ranges roughly mean the following:\n\nUnder 70: Feeble-Mindedness\n\n70-79: Borderline Deficiency\n\n80-89: Dullness\n\n90-109: Normal or Average Intelligence\n\n110-119: Superior Intelligence\n\n120-140: Very Superior Intelligence\n\nOver 140: Genius or near Genius\n\n\n\n\n\nThe Following ranges roughly describe what changes in IQ may look like\n\n0-5 Points: Very Little Difference\n\n6-15 Points: Noticeable Difference\n\n16-25 Points: Significant Difference\n\n26-50 Points: Large Personality and Mentality Shifts\n\nMore than 50 Points: Life Changing Difference"
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"Toward a model of microsaccade generation: the case of microsaccadic inhibition.",
"\nMicrosaccades are one component of the small eye movements that constitute fixation. ",
"Their implementation in the oculomotor system is unknown. ",
"To better understand the physiological and mechanistic processes underlying microsaccade generation, we studied microsaccadic inhibition, a transient drop of microsaccade rate, in response to irrelevant visual and auditory stimuli. ",
"Quantitative descriptions of the time course and strength of inhibition revealed a strong dependence of microsaccadic inhibition on stimulus characteristics. ",
"In Experiment 1, microsaccadic inhibition occurred sooner after auditory than after visual stimuli and after luminance-contrast than after color-contrast visual stimuli. ",
"Moreover, microsaccade amplitude strongly decreased during microsaccadic inhibition. ",
"In Experiment 2, the latency of microsaccadic inhibition increased with decreasing luminance contrast. ",
"We develop a conceptual model of microsaccade generation in which microsaccades result from fixation-related activity in a motor map coding for both fixation and saccades. ",
"In this map, fixation is represented at the central site. ",
"Saccades are generated by activity in the periphery, their amplitude increasing with eccentricity. ",
"The activity at the central, fixation-related site of the map predicts the rate of microsaccades as well as their amplitude and direction distributions. ",
"This model represents a framework for understanding the dynamics of microsaccade behavior in a broad range of tasks."
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"My Hexcellent Adventure – Be a Champ!",
"\n\nBy Chris VanMeter\n\nGreetings my fellow Shard lovers! ",
"In my last article I talked about the different draft archetypes and where I felt that they sat with the addition of Primal Dawn. ",
"This time on “My Hexcellent Adventure,” I want to dive a little deeper into the new champions added with Primal Dawn and the different decks that I have been able to draft with them.",
"\n\nAt the end of my last piece, I alluded to Uzzu the Bonewalker as being extremely powerful and allowing for multiple different archetypes. ",
"This is definitely true and leads to some of the more interesting decks that you can draft with Primal Dawn. ",
"Generally, when using an Uzzu deck we will be two or three shards and end up splashing a fourth or fifth. ",
"To do so, we will rely on Uzzu the Bonewalker’s champion ability, or cards like Hallowed Radiance, Hextricator, and Resource Optimizing Infusion Device.",
"\n\nThere are many different cards that you can play in your Uzzu decks. ",
"In fact, Uzzu’s flexibility lets you play anything, really. ",
"That said, there are a couple cards that I will generally look for in the early picks if I am going to end up playing an Uzzu multi-shard deck.",
"\n\nThese two cards are extremely powerful, and they greatly reward you for playing multiple shards. ",
"With Necrotic being available in Blood, Ruby, Sapphire, and Diamond shards, when we see an early Scion of Volosolov, or even a late one, I am generally keen to take the card and move in.",
"\n\nScion of Volosolov can be played in Yotul Mogak decks, but it fits very well in almost any Uzzu strategy.",
"\n\nLyrical Chanter is my pick for best uncommon in the set. ",
"As a 2/1 for two with only a single Wild threshold requirement, it is a decent body that can draw you a random Chant. ",
"But the Empower ability is really what puts it over the top. ",
"Most of the multi-shard Uzzu decks are Chant decks which are generally sparked by an early Lyrical Chanter.",
"\n\nTake this deck for example:\n\nThis deck was awesome, and I had a blast playing it. ",
"Lyrical Chanter is insane, especially when you have at least one Death Chant in your deck. ",
"Getting two random Chants when it comes into play and the being able to get it back with a Death Chant (or any other Chant once you have the Death Chant in play) is just so much value.",
"\n\nThe other card that really impressed me in this particular draft was Trufflehead. ",
"Death Chant doesn’t revert the card when it is returned to your hand, so any bonuses that it has will stay. ",
"Trufflehead will become a 6/6 when it goes to the crypt and will stay as such when you return it to your hand.",
"\n\nMidnight Convergence and Midnight Paladin were both pretty underrated at first, but they are seeing more and more play even in traditional two-shard decks. ",
"Be sure to grab them early if you are wanting to play multi-shard.",
"\n\nHere is another Uzzu the Bonewalker deck that I drafted.",
"\n\nThis deck was also very fun. ",
"We still had the double Lyrical Chanter, but we also got to fix our shards with a bunch of Hextricators. ",
"These constructs also made our Purge very powerful in the late game. ",
"Young Seer in particular is sweet in these decks, since hitting a Lyrical Chanter lets us play an Empowered Chanter for zero resources.",
"\n\nIn general, when drafting a Chant based Uzzu deck, I am base Wild/Ruby with cards of the rest of the shards. ",
"These decks are very powerful, and since Uzzu lets us gain any threshold that we need, they are generally going to be playable and can overpower most opponents. ",
"Just remember to prioritize removal. ",
"We aren’t going to have many ways to interact in the early game, and we need to get into the mid/late game for our Chant card advantage to take over.",
"\n\nImportant cards to keep in mind for Chant based Uzzu decks:\n\nLyrical Chanter\n\nMonk of the Six Strikes\n\nRecoiler\n\nYoung Seer\n\nMost Chants\n\nMost Removal\n\nNext I want to talk about the Diamond/Sapphire fliers deck headlined by the new champion Fiona Honeyfinch.",
"\n\nI liked trying this archetype when it was just Armies of Myth, primarily because I felt like Windspeaker was one of the super powerful, but underused uncommons in the set. ",
"Now that we have the support for this shard combination, I have been very successful when the decks come together.",
"\n\nThe headlining cards for this strategy are Spellstone Gargoyle, Chilltail Guide, and Windspeaker from Armies of Myth.",
"\n\nThese uncommons are extremely powerful and really just require that we play a bunch of troops with flight in our deck, or troops that can gain flight as we will see from my latest Fiona draft deck.",
"\n\nThe curve on this deck is beautiful, and I was able to take advantage of some generally underplayed cards by having a clear game plan in each of my matches. “",
"Race with flight’” was my mantra, and it worked out splendidly.",
"\n\nRuneweb Weaver and Quell are generally cards that you can get in the 14-17 pick range, and they work very well in this archetype. ",
"Almost all of our troops are going to have flight, and this will likely let us jump our Runeweb Weaver and make it so that the troop we gave defensive to won’t be able to block anyway since all of my attacking troops will have flight.",
"\n\nThere are some skyguard troops out there, so having access to Windspeaker, Spirit Eagle, and Chilltail Guide is very nice, as is something like Incubation Webs. ",
"Removal is at a premium in this strategy, but make sure you also have lots of threats.",
"\n\nCloudspeaker is an interesting card. ",
"There aren’t many two attack, two cost fliers, so utilizing a defensive two drop that can bolster our attacking troops is nice. ",
"It’s also great that Cloudspeaker also generally goes pretty late in the draft.",
"\n\nSpellstone Gargoyle and Chilltail Guide are easy first picks that can send you into this archetype, so be on the lookout for them late in the draft.",
"\n\nRaven Talon has been one of my favorite new champions. ",
"The Wild/Diamond health-gain style of deck has been very fun to play and can lead to some pretty silly board states. ",
"I also like that some of the deceptively powerful cards for this archetype, like Sylvan Bard, generally go late.",
"\n\nHere is a Raven Talon deck that I drafted.",
"\n\nThis deck was extremely fun and I got to do some very silly things. ",
"I was surprised to pick up three copies of Ghost Howler, as he is by far the premier card in this strategy. ",
"I have had quite a few multiple-Ghost Howler decks and they have all been insane. ",
"It doesn’t take all that many Young Seers and Sylvan Bards in play for a few Raven Talon and bard triggers with your Ghost Howler out to finish a game.",
"\n\nRemoval in this archetype is at a premium, so make sure you keep an eye out for Totem Trap, Pride’s Fall, Fearless Fray. ",
"Don’t forget pump actions to use as pseudo-removal cards.",
"\n\nThese decks generally have a lot of troops in them, so make sure that you are picking ones that are either the best stats at their cost (like Risen Lancer or Pious Paladin) or have lots of great synergy with the rest of the deck (like Sylvan Bard, Chlorosaur, or Cheery Songbird).",
"\n\nYou can generally tell that the Wild/Diamond deck is open when you are seeing Ghost Howlers get passed. ",
"If there is one that goes around, there will likely be more passed if they are opened.",
"\n\nOne of the strongest draft champions right now is Yotul Mogak, and that is mainly because of how insane his champion ability is when combined with the cards Cleave or Staggering Blast. ",
"Yotul’s power is further exacerbated by how awesome all of these cards and interactions are with the headline uncommon, Whirling Brutalizer.",
"\n\nHere is a Yotul deck that I drafted. ",
"It wasn’t perfect, but still did very well.",
"\n\nWe didn’t have any Whirling Brutalizer or Staggering Blast, but we still were able to take advantage of how amazing Yotul’s champion ability is with damage based cards. ",
"Bombwright hitting for two, being able to make our Highlands Blackbelt do extra damage, or getting insane value out of a Burning Tendrils was the name of the game for this draft.",
"\n\nGenerally, there are going to be a lot of removal cards at our disposal when we are Ruby/Blood, so making sure that we have great threats or some card advantage like Grave Offering when we play this archetype is generally pretty important.",
"\n\nOne card that I have been pretty impressed with is Vampython. ",
"There isn’t much that can kill it and it’s a huge body on defense that can let us climb back up in health once we start to take over the game with all of our removal.",
"\n\nYotul is great, and every time that I have an insane Ruby/Diamond deck I just get wrecked in the finals of the draft by Yotul + Cleave as a three-for-one.",
"\n\nMorgan McBombus is the newest champion that I have been the least impressed with. ",
"There have been some sweet decks that I’ve been able to snag with multiple Combat Trainings or Seeing Reds, but even still those types of effects are so vulnerable to removal that it can be rough to try and lean on them too hard.",
"\n\nMaking sure that we have a good number of actions to be Morgan McBombus is really where I have had issues. ",
"A lot of times, my Bombus decks end up as just Benvolio decks. ",
"Here is a sample Ruby/Sapphire deck that I have drafted.",
"\n\nThis deck did better than I expected it to, but I found out very quickly that Mackerel Mitts is poor in the main. ",
"Although it can be backbreaking in some situations out of the reserves, I would much rather have actual removal, bounce, or something like Soothsaying instead.",
"\n\nHaving a good curve with aggressive and/or evasive troops is the hallmark of a Ruby/Sapphire deck, and when we decide to go Morgan McBombus it’s important to ensure that you have some good three cost actions so you can make a Bumblebot on turn three.",
"\n\nI was pretty impressed with Shadestalker in this deck, though. ",
"When combined with troops that can get out of hand fairly quickly like Crazed Raider, Shadestalker can end the game in a hurry. ",
"Beguiling Temptress was another card that surprised me as being better than I had hoped.",
"\n\nAll in all though, I think that Morgan McBombus is a pretty weak champion choice. ",
"If I were to end up with an aggressive Ruby/Sapphire deck, I would rather just be Urgnock or Benvolio instead.",
"\n\nI have only drafted Kagulichu once, and that was in the first couple days of Primal Dawn before I was taking screen caps of my decks. ",
"I was unimpressed and wished that I had branched out into another shard and just played Uzzu the Bonewalker. ",
"All of the cards that we are going to want to play in a Kagulichu deck are also usable in a Uzzu the Bonewalker, three-or-more shard deck. ",
"I feel that going Uzzu will ultimately give you a more powerful deck. ",
"I don’t think that the self bury and “random” card draw from Kagulichu is worth not being able to play powerful cards from every shard. ",
"I would love to be proven wrong though!",
"\n\nIf I had to rate the new champions among themselves I would put it as follows:\n\n\n\nHow have you fared so far in Primal Dawn drafting? ",
"Winning all of the packs, or just barely getting by to your next draft? ",
"I would love to see some screen caps of the different decks that all of you out there have drafted with the new champions, so please feel free to share on the forums!",
"\n\nUntil next time, may Kismet smile on your top decks, and may all of your P1P1 be Legendary!",
"\n\nTwitter | Facebook | Twitch\n\nWith 20 years of TCG experience, Chris VanMeter brings a unique perspective to HEX. ",
"Favoring constructed decks that can either go under the competition or as far over it as possible, you can find Chris playing draft, sealed, and constructed on his Twitch channel and talking about his experiences endlessly via social media.",
"\n\nDiscuss this article in our forums!"
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[
"LONDON – The good news is that U.S. greenhouse gas emissions are continuing to decline. \"",
"Over the last four years, our emissions of the dangerous carbon pollution that threatens our planet have actually fallen,\" said President Obama in his State of the Union address last month.",
"\n\nThe bad news is the United States is exporting its polluting gases, particularly in the form of coal, like never before.",
"\n\nFigures released earlier this month by the U.S. Energy Information Administration show U.S. coal exports reached a record of more than 115 million tons in 2012, more than double the 2009 figure.",
"\n\nIn a report examining the legal implications of increased U.S. coal exports, the Columbia Law School notes that greenhouse gas emissions are not just a national issue.",
"\n\n\"Because the impacts of CO2 emissions are global in nature, it makes no difference from a climate change perspective whether coal mined in Wyoming is consumed in Chicago or Shanghai,\" it says.",
"\n\nHigher levels of CO2\n\nCoal is far more polluting in terms of greenhouse gases than either oil or gas, emitting higher levels of CO2 and also other toxic substances such as sulfur dioxide, nitrogen oxide and mercury.",
"\n\nThe drop in U.S. emissions – according to the EIA, total U.S. carbon emissions have now fallen by more than 8 percent since peaking in 2007 – is in part due to the economic slowdown, but more so to a move from coal-fired electricity generation to less carbon-intensive natural gas, particularly gas produced from hydraulic fracturing or \"fracking.\"",
"\n\nIn 2005 coal accounted for half of all electricity generation in the United States: now it generates 37 percent of the country's electricity, with forecasts that figure will drop to around 20 percent by 2030.",
"\n\nThe move to gas has been spurred both by tougher regulations on pollution and, with gas production booming, an overall drop in energy prices. ",
"There has also been strong growth in renewable energies, particularly in solar power.",
"\n\nUnfazed by domestic decline\n\nU.S. coal giants such as Arch Coal, Alpha Natural Resources and Peabody Energy have not let the decline in domestic demand faze them. ",
"Instead they've gone wholesale into export markets, particularly in Europe, with coal-exporting terminals on the U.S. East Coast operating at maximum capacity.",
"\n\nHigh gas prices within the European Union make U.S. coal extremely competitive as an energy source. ",
"Bad weather has contributed to an uptake in demand.",
"\n\nThe collapse in price on the EU's European Trading Scheme carbon market and a vast oversupply of so-called pollution permits is another reason for the surge in U.S. coal imports. ",
"Worries about energy security and an over-dependence on gas supplies from Russia and the countries of central Asia are additional factors driving the trade.",
"\n\nEIA figures show Europe is now by far the biggest customer for U.S. coal, importing more than all other markets combined. ",
"U.S. exports to the UK jumped by about 70 percent in 2012.",
"\n\nExports to Germany, which phased out nuclear power generation in response to the Fukushima accident in Japan, have also increased.",
"\n\nEurope's energy companies are taking advantage of relatively cheap coal imports while they can. ",
"EU regulations, particularly the Large Combustion Plants Directive, stipulate that older coal plants that do not meet stringent emissions targets must be shuttered.",
"\n\nWhile tighter regulations on pollution could result in a decline in U.S. coal exports to Europe in the years ahead, it's unlikely producers in Pennsylvania or Montana will be cutting back on their activities. ",
"Asia, by far the biggest coal-consuming region, where demand continues to grow, is the next target.",
"\n\nFourth-largest exporter\n\nThe United States is the world's fourth largest exporter of coal – after Australia, Indonesia and Russia. ",
"U.S. firms are now setting their sights on the big markets in Asia, particularly China and India.",
"\n\nCoal lobbyists are pushing for new coal terminals to be built on the U.S. West Coast to provide easier access to Asia. ",
"Exports to China – the world's biggest coal producer and consumer – have been growing rapidly. ",
"Last year one U.S. coal company signed a $7 billion export agreement with an Indian conglomerate. ",
"Other deals are in the pipeline.",
"\n\nA recent report from the UK's Tyndall Centre for Climate Change Research looked at the growth of the shale gas industry in the United States and questioned whether it had contributed to a global drop in CO2 emissions.",
"\n\nThe answer was no: Tyndall's calculations suggest that more than half of the emissions avoided in the U.S. power sector – through the switch from coal to gas – may have been exported as coal.",
"\n\n\"Without a meaningful cap on global carbon emissions, the exploitation of shale gas is likely to increase total emissions,\" said the report. \"",
"For this not to be the case, consumption of displaced fuels must be reduced globally and remain suppressed indefinitely.\"",
"\n\n\"In effect displaced coal must stay in the ground.\"",
"\n\nThis article originally appeared at The Daily Climate, the climate change news source published by Environmental Health Sciences, a nonprofit media company."
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"Article Tools\n\nCan you give me a biography of Caroline Hazard? — ",
"Arlene Kupchella\n\nBy Michael Redmon\n\nCaroline Hazard’s father was enchanted\nby Santa Barbara in the early 1880s, when he stayed at the\nluxurious Arlington Hotel. ",
"Soon after, he bought property up in\nMission Canyon and built the estate Mission Hill in 1885. ",
"This\nbegan daughter Caroline’s own love affair with Santa Barbara, where\nshe would spend all or part of the next 60 years.",
"\n\nCaroline Hazard was born in Peace Dale, Rhode Island, in 1856.",
"\nThe family was quite affluent and Caroline received her early\neducation at home at the hands of private tutors. ",
"She then attended\nan exclusive private school, the Mary A. Shaw School in Providence,\nRhode Island. ",
"After spending some time pursuing studies in Europe,\nshe returned to the States to earn a master’s degree in art from\nthe University of Michigan in 1899. ",
"She later received a doctorate\nin literature at Brown University and a doctorate in law from Tufts\nUniversity. ",
"Later in life, Mills College in Oakland would bestow\nupon her an honorary doctorate in literature. ",
"Painting and writing\nbecame two life-long passions.",
"\n\nIn 1899, Hazard was appointed president of Wellesley, a women’s\ncollege in Massachusetts, a post she would hold for 11 years.",
"\nDuring these years she was also a prolific author, penning two\nbiographies, books of poetry, and innumerable essays, reviews, and\nother works as well as acting as editor of a major work on women in education.",
"\n\nDuring her repeated visits to Santa Barbara, she became\ninterested in local history, with a focus on the Spanish era. ",
"She\noften would climb aboard a buggy and drive out to one of the nearby\nmissions to render it in watercolor. ",
"Some of these paintings, such\nas that of La Purísima, are important historical documents,\ncapturing these monuments of California’s past before serious\ndeterioration set in or alterations were made. ",
"For many years, her\npaintings were hung in the art gallery of the Santa Barbara public\nlibrary during Easter time.",
"\n\nHazard is perhaps best remembered locally for her early\ninvolvement with the Santa Barbara Museum of Natural History. ",
"Her\nbrother, Rowland, was an avid collector of bird eggs. ",
"In 1916, he\nhad built near Mission Hill the Tudor revival-style Dial House, so\nnamed for a sundial that his father had placed on an old stone\nwall. ",
"In 1917, he joined the board of the Museum of Comparative\nOology, founded by William Leon Dawson in order to display his own\nextensive egg collection. ",
"The museum got its modest beginning in\ntwo small buildings on Dawson’s Mission Canyon property.",
"\n\nRowland died of a heart attack in early 1918 and his sister\nreplaced him on the museum board. ",
"There was a growing disquiet over\nDawson’s narrow focus for the museum and some of his financial\npractices. ",
"Hazard sided with those who wanted to see the museum\nexpand, and in 1922 she donated part of the family land for a new\nmuseum dedicated in memory of her brother, whose widow donated the\nfunding for the new buildings.",
"\n\nDawson resigned in early 1923, and the museum was given a new\nname, the Santa Barbara Museum of Natural History, to reflect its\nexpanded horizons. ",
"In ensuing years, Hazard would continue to give\nland and funds to the fledgling institution. ",
"She also spearheaded a\ndrive in 1926 to purchase land south of the mission for a park.",
"\nToday that land is part of Mission Historical Park.",
"\n\nDuring World War II, Hazard leased Dial House for use as a\nwomen’s shelter. ",
"She also became honorary chair of a group to fund\na museum for the Santa Barbara Historical Society. ",
"Caroline Hazard\ndied in March 1945 at Mission Hill. ",
"The two Hazard family homes are\nnow part of a retreat for the Anglican Sisters of the Holy\nNativity, known as St. Mary’s Retreat House.",
"\n\nMichael Redmon, director of research at the Santa Barbara\nHistorical Society, will answer your questions about Santa\nBarbara’s history. ",
"Write him c/o The Independent, 122 West Figueroa\nSt., Santa Barbara, CA 93101."
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[
"[Nursing knowledge production: transposition and repercussions on the graduation teaching].",
"\nThe research aimed to analyze the production of knowledge in nursing at a public university, in order to evaluate the impact of that production during the Nursing Graduation. ",
"An exploratory and descriptive research has been done in two stages. ",
"The first one consisted of gathering the reports of researches executed by the teachers who coordinated them from 2000 to 2009. ",
"As a result of this stage, it was mapped the type of studies performed, the themes and the theoretical and methodological references most utilized. ",
"During the second stage we studied the current pedagogical project used in the Graduation course, and crossed the data with the previously, to create a dimension to some of the transpositions and applications of the knowledge produced by the researches to the Nursing Graduation course. ",
"We concluded that, in different ways, not only the application of the studies has been occurring but also the transposition of ideals that cross through the research groups to which they belong, being able to bring change to nursing education."
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"\n#ifndef DATETIME_PERIOD_PARSER_HPP___\n#define DATETIME_PERIOD_PARSER_HPP___\n\n/* Copyright (c) 2002-2004 CrystalClear Software, Inc.\n * Use, modification and distribution is subject to the \n * Boost Software License, Version 1.0. (",
"See accompanying\n * file LICENSE_1_0.txt or http://www.boost.org/LICENSE_1_0.txt)\n * Author: Jeff Garland, Bart Garst\n * $Date: 2008-11-13 15:10:23 -0500 (Thu, 13 Nov 2008) $\n */\n\n#include <boost/throw_exception.hpp>\n#include <boost/date_time/string_parse_tree.hpp>\n#include <boost/date_time/string_convert.hpp>\n\n\nnamespace boost { namespace date_time {\n\n\n //! ",
"Not a facet, but a class used to specify and control period parsing \n /*! ",
"Provides settings for the following:\n * - period_separator -- default '/'\n * - period_open_start_delimeter -- default '['\n * - period_open_range_end_delimeter -- default ')' \n * - period_closed_range_end_delimeter -- default ']' \n * - display_as_open_range, display_as_closed_range -- default closed_range\n *\n * For a typical date_period, the contents of the input stream would be\n *@code\n * [2004-Jan-04/2004-Feb-01]\n *@endcode\n * where the date format is controlled by the date facet\n */\n template<class date_type, typename CharT>\n class period_parser {\n public:\n typedef std::basic_string<CharT> string_type;\n typedef CharT char_type;\n //typedef typename std::basic_string<char_type>::const_iterator const_itr_type;\n typedef std::istreambuf_iterator<CharT> stream_itr_type;\n typedef string_parse_tree<CharT> parse_tree_type;\n typedef typename parse_tree_type::parse_match_result_type match_results;\n typedef std::vector<std::basic_string<CharT> > collection_type;\n\n static const char_type default_period_separator[2];\n static const char_type default_period_start_delimeter[2];\n static const char_type default_period_open_range_end_delimeter[2];\n static const char_type default_period_closed_range_end_delimeter[2];\n\n enum period_range_option { AS_OPEN_RANGE, AS_CLOSED_RANGE };\n\n //! ",
"Constructor that sets up period parser options\n period_parser(period_range_option range_opt = AS_CLOSED_RANGE,\n const char_type* const period_separator = default_period_separator,\n const char_type* const period_start_delimeter = default_period_start_delimeter,\n const char_type* const period_open_range_end_delimeter = default_period_open_range_end_delimeter,\n const char_type* const period_closed_range_end_delimeter = default_period_closed_range_end_delimeter)\n : m_range_option(range_opt)\n {\n delimiters.push_back(string_type(period_separator));\n delimiters.push_back(string_type(period_start_delimeter));\n delimiters.push_back(string_type(period_open_range_end_delimeter));\n delimiters.push_back(string_type(period_closed_range_end_delimeter));\n }\n\n period_parser(const period_parser<date_type,CharT>& p_parser)\n {\n this->delimiters = p_parser.delimiters;\n this->m_range_option = p_parser.m_range_option;\n }\n\n period_range_option range_option() const\n {\n return m_range_option;\n }\n void range_option(period_range_option option)\n {\n m_range_option = option;\n }\n collection_type delimiter_strings() const\n {\n return delimiters;\n }\n void delimiter_strings(const string_type& separator,\n const string_type& start_delim,\n const string_type& open_end_delim,\n const string_type& closed_end_delim)\n {\n delimiters.clear();\n delimiters.push_back(separator);\n delimiters.push_back(start_delim);\n delimiters.push_back(open_end_delim);\n delimiters.push_back(closed_end_delim);\n }\n\n //! ",
"Generic code to parse a period -- no matter the period type.",
"\n /*! ",
"This generic code will parse any period using a facet to\n * to get the 'elements'. ",
" For example, in the case of a date_period\n * the elements will be instances of a date which will be parsed\n * according the to setup in the passed facet parameter.",
"\n * \n * The steps for parsing a period are always the same:\n * - consume the start delimiter\n * - get start element\n * - consume the separator \n * - get either last or end element depending on range settings\n * - consume the end delimeter depending on range settings\n *\n * Thus for a typical date period the contents of the input stream\n * might look like this:\n *@code\n *\n * [March 01, 2004/June 07, 2004] <-- closed range\n * [March 01, 2004/June 08, 2004) <-- open range\n *\n *@endcode\n */\n template<class period_type, class duration_type, class facet_type>\n period_type get_period(stream_itr_type& sitr, \n stream_itr_type& stream_end,\n std::ios_base& a_ios, \n const period_type& /* p */,\n const duration_type& dur_unit,\n const facet_type& facet) const \n {\n // skip leading whitespace\n while(std::isspace(*sitr) && sitr !",
"= stream_end) { ++sitr; } \n\n typedef typename period_type::point_type point_type;\n point_type p1(not_a_date_time), p2(not_a_date_time);\n\n\n consume_delim(sitr, stream_end, delimiters[START]); // start delim\n facet.get(sitr, stream_end, a_ios, p1); // first point\n consume_delim(sitr, stream_end, delimiters[SEPARATOR]); // separator\n facet.get(sitr, stream_end, a_ios, p2); // second point\n\n // period construction parameters are always open range [begin, end)\n if (m_range_option == AS_CLOSED_RANGE) {\n consume_delim(sitr, stream_end, delimiters[CLOSED_END]);// end delim\n // add 1 duration unit to p2 to make range open\n p2 += dur_unit;\n }\n else {\n consume_delim(sitr, stream_end, delimiters[OPEN_END]); // end delim\n }\n\n return period_type(p1, p2);\n }\n\n private:\n collection_type delimiters; \n period_range_option m_range_option;\n\n enum delim_ids { SEPARATOR, START, OPEN_END, CLOSED_END };\n\n //! ",
"throws ios_base::failure if delimiter and parsed data do not match\n void consume_delim(stream_itr_type& sitr,\n stream_itr_type& stream_end,\n const string_type& delim) const\n {\n /* string_parse_tree will not parse a string of punctuation characters \n * without knowing exactly how many characters to process\n * Ex [2000. ",
"Will not parse out the '[' string without knowing \n * to process only one character. ",
"By using length of the delimiter \n * string we can safely iterate past it. */",
"\n string_type s;\n for(unsigned int i = 0; i < delim.length() && sitr !",
"= stream_end; ++i) {\n s += *sitr;\n ++sitr;\n }\n if(s !",
"= delim) {\n boost::throw_exception(std::ios_base::failure(\"Parse failed. ",
"Expected '\"\n + convert_string_type<char_type,char>(delim) + \"' but found '\" + convert_string_type<char_type,char>(s) + \"'\"));\n }\n }\n };\n\n template <class date_type, class char_type> \n const typename period_parser<date_type, char_type>::char_type \n period_parser<date_type, char_type>::default_period_separator[2] = {'/'};\n\n template <class date_type, class char_type> \n const typename period_parser<date_type, char_type>::char_type \n period_parser<date_type, char_type>::default_period_start_delimeter[2] = {'['};\n\n template <class date_type, class char_type> \n const typename period_parser<date_type, char_type>::char_type \n period_parser<date_type, char_type>::default_period_open_range_end_delimeter[2] = {')'};\n\n template <class date_type, class char_type> \n const typename period_parser<date_type, char_type>::char_type \n period_parser<date_type, char_type>::default_period_closed_range_end_delimeter[2] = {']'};\n\n } } //namespace boost::date_time\n\n#endif // DATETIME_PERIOD_PARSER_HPP___\n"
] |
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"pile_set_name": "Github"
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[
"Q:\n\nHow do I locate child element using protractor locators?",
"\n\nCan you suggest locator for <input> element in the following DOM? ",
"by.repeater only gets me till <td> element. ",
"Any subsequent protractor locator is not locating <input> element underneath. ",
"Thank you in advance!",
"\n<table class=\"table table-striped table-hover\">\n <thead>\n <tbody class=\"ng-scope\" ng-repeat=\"devices in collection track by $index\" >\n <tr class=\"ng-scope ng-isolate-scope\" st-select-row=\"devices\" st-select-mode=\"single\">\n <td>\n <chk-select class=\"ng-isolate-scope\" emitselectedrec=\"selectedRows\" chkmode=\"multiple\" rowobj=\"clusters\">\n <input type=\"checkbox\" ng-transclude=\"\" ng-click=\"pushToSelected(row)\" uid=\"1\">\n </chk-select>\n </td>\n </tr>\n </tbody>\n</table>\n\nA:\n\nWhat if you would rely on the chk-select element and it's rowobj attribute:\nelement(by.css(\"chk-select[rowobj=clusters] input[type=checkbox]\"));\n\n"
] |
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"pile_set_name": "StackExchange"
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[
"Christian movie makers opt for black cast after glut of whitewashed Bible films BY JONATHAN MERRITT Religion News ServiceAugust 14, 2015 A flood of faith films led many to dub 2014 \"The Year of the Bible,\" but it was also a year of the status quo in Hollywood. ",
"Read more here: http://www...\n\nAug 11 2015 : The Times of India (Chennai) Coca-Cola funding study to shift blame for obesity from bad diet?Anahad O'Connor NYT NEWS SERVICE Coca-Cola, the world's largest producer of sugary beverages, is backing a new “sciencebased“ solution to the obesity crisis: To maintain a healthy we...\n\nAug 11 2015 : The Times of India (Chennai) HIKING TRAGEDY - Parents die of thirst to let 9-yr-old son live Charles de Gaulle airport (France): A nine-year-old French boy who survived a desert hike in which his parents appear to have died of thirst, has been flown home from New Mexico, an airport o...\n\nJul 29 2015 : The Times of India (Chennai) 3 scientists probing warming may have been killed: UK profAlexandra Sims . ",
"THE INDEPENDENT A Cambridge professor has reportedly clai med three scientists investigating the effect of global warming upon melting Arctic ice may have been assassinate...\n\nJul 28 2015 : The Times of India (Chennai) Whitney Houston's daughter dies at 22 Los Angeles:PTI Bobbi Kristina Brown, the only daughter of singers Whitney Houston and Bobby Brown, died on Sunday , nearly six months after she was found unresponsive in a bathtub of her home, her family said. ",
"She w...\n\nJul 27 2015 : The Times of India (Chennai) Transact online: Govt may tell foreign-funded NGOsBharti Jain New Delhi: Move Will Eliminate Need To File Applications ManuallyForeign-funded non-governmental organizations (NGOs) will soon have to conduct all their transactions and dealings...\n\nJul 26 2015 : The Times of India (Chennai) SILICON SUPERSTITIONS Astrologers and fortune-tellers thrive in the Bay Area, serving an uncertain tech communityA long time ago, in England, there lived a blacksmith named Dunstan. ",
"In those days, one of the main jobs a blacksmith had was the creati...\n\npanish town is going to the dogs: Council grants pets same rights as humansPublished July 24, 2015Fox News LatinoObviously, the people of the tiny Spanish hamlet of Trigueros del Valle have not read George Orwell's seminal novella \"Animal Farm\" or they probably would have mulled this o...\n\nPolice say 'drifter' killed 2, injured 9 in Lafayette, La. movie theater shootingPublished July 24, 2015FoxNews.comFacebookTwitterlivefyreEmailPrint The man who opened fire in a Louisiana movie theater Thursday night, killing two patrons before turning the gun on himself when poli... \n\nMan makes bid to sell unborn baby for Rs 2 lakh TNN | Jul 25, 2015, 12.54 AM ISTCHENNAI: Police are searching for a man who locked up his pregnant girlfriend for a week while he struck a deal to sell their unborn child in Tiruvallur, 60km from Chennai.",
"Police said T John Victor, 27, a resident of Kondanch..."
] |
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"pile_set_name": "Pile-CC"
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0,
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0.004395604395604396,
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[
"David K. Dill\n\nDavid K. Dill (July 7, 1955 – August 8, 2015) was an American politician and member of the Minnesota House of Representatives. ",
"A member of the Minnesota Democratic–Farmer–Labor Party, he represented District 3A in northeastern Minnesota. ",
"He was also a consultant, a commercial pilot and an aircraft and power plant mechanic.",
"\n\nEarly life and career\nDill graduated from Southport High School in Indianapolis, Indiana, then attended Indiana University Bloomington. ",
"He served as city administrator for Orr, Minnesota for 11 years prior to being elected to the Minnesota House of Representatives.",
"\n\nMinnesota House of Representatives\nDill was first elected to the Minnesota House of Representatives in 2002 and re-elected every two years until his death in 2015. ",
"He served as chairman of the Iron Range Legislative Delegation during the 2005–2006 biennium.",
"\n\nPersonal life\nDuring the summer months, Dill spent time in northwestern Ontario tending to his business, Thunderhook Fly-Ins.",
"\n\nDill was diagnosed with Type 2 diabetes in his early 20s. ",
"He later acknowledged that he did not look after his health, allowing his weight to surpass 300 pounds. ",
"In 2008, Dill underwent gastric bypass surgery, losing more than 150 pounds. ",
"As a result of diabetic nephropathy, Dill eventually had only 15% renal function and needed to go on dialysis or have a kidney transplant. ",
"He was hoping for a transplant from his sister. ",
"Dill announced that he nevertheless intended to run for re-election. ",
"On October 12, 2010, he received a kidney transplant at Hennepin County Medical Center in Minneapolis. ",
"The transplant was successful. ",
"He later had a pacemaker installed to treat an irregular heartbeat.",
"\n\nDeath\nDill was hospitalized at the Mayo Clinic in mid-July 2015 to undergo chemotherapy. ",
"He died on August 8, 2015, of cancer at the age of 60 at Camp Thunderhook in Armstrong, Ontario.",
"\n\nA funeral service was held on August 15 at the Backus Community Center in International Falls, Minnesota.",
"\n\nReferences\n\nExternal links\n\n Rep. David Dill official Minnesota House of Representatives website\n Vote Smart – Rep. David Dill Profile\n\nCategory:1955 births\nCategory:2015 deaths\nCategory:Politicians from Indianapolis\nCategory:People from St. Louis County, Minnesota\nCategory:Indiana University Bloomington alumni\nCategory:Members of the Minnesota House of Representatives\nCategory:Minnesota Democrats\nCategory:Organ transplant recipients\nCategory:Deaths from cancer in Minnesota\nCategory:Deaths from kidney cancer\nCategory:21st-century American politicians\nCategory:Commercial aviators"
] |
{
"pile_set_name": "Wikipedia (en)"
}
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[
"Unlike Mercedes Benz and NSU, BMW never dabbled in rotary engines. ",
"That oversight is rectified by today's Nice Price or Crack Pipe 2002, but will its price have you saying a little dab'll do you?",
"\n\nIts color may have been polarizing, and its potential for catastrophic mechanical failure may have caused many a sphincter to clench, but spectacular looks and an apparently engaging price overcame those obstacles, leading yesterday's 1988 Lotus Esprit to a safe 66% Nice Price win. ",
"Y'all are a sucker for a pretty face, you know that, right?",
"\n\nLotus has fired their CEO and has cancelled the proposed 2014 Esprit. ",
"That needn't affect your …\nRead more Read more\n\nWith their 1962 arrival, BMW's Neue Klasse small sedans and coupes introduced a number of styling tropes which served for years as iconic representations of the brand. ",
"The D-pillar's Hoffmeister kink, forward-leaning shark's nose face, and of course the double kidney grille, alone or combined let you immediately know the car's origin.",
"\n\nToday's 1968 BMW 2002 maintains all those elements, but its BMW-ness no longer extends to its major mechanicals. ",
"There, the car has - as was once popularized in song by the Vapors - been turning Japanese. ",
"I really think so.",
"\n\nIn place of the original 1,990-cc M05 which put out a factory 100-bhp, this 2002 now sports a Mazda 1,146-cc 12A rotary which in RX-7 guise pumped out. . . ",
"100-bhp. ",
"Well, at least the Mazda hummer put out less torque (100 lb-ft vs. 157 for the M05) and maintains a reputation for drinking like Nick Cage in Leaving Las Vegas.",
"\n\nThe Wankel is backed up by an equally Mazdarrific 5-speed stick and is claimed to have but 100 miles on it since a rebuild. ",
"Ahh, I love the smell of fresh apex seals in the morning. . .",
"\n\nUnfortunately, the current owner has not been able to properly jet the Weber 44 IDA down draught, and hence the car apparently doesn't run all that well at the moment. ",
"The IDAs are pretty flexible and easy to tune carbs, so that might mean some other monkey business is going on - like that pair of needle nose Vise-Grips® clamping off a hose in the engine shot. ",
"What's that all about?",
"\n\nYou could ask the same thing regarding the car's aesthetic appearance as well. ",
"The seller claims this to be a '68, and that he added the ungainly aluminum bumpers because. . . ",
"well, I can't think of a reason to do so. ",
"Also, I'm pretty sure that the 2002 had round tail lights up until about '72 or '73, and this one has the rectangular units. ",
"Rounding out the exterior there's, some rocker extensions, fugly chrome wheels, and a \"New Black vinyl rag top with sun roof\" which is, um well, different.",
"\nInside, the stock low-backs have given way to a set of red and black high wing sport seats, while the arm rests and steering wheel continue the color theme. ",
"The doors are also shy a pair of speakers. ",
"That or the car suffers from mice something fierce.",
"\n\nI hope I haven't sold this Mazda-powered 2002 short, it is after all an interesting, and seemingly solid car. ",
"The changes made to it are not my cup of tea, but perhaps you will think differently.",
"\n\nShould you think that you, or anyone else, should part with their hard earned cash for this Bavarian-Mazda-Wankel then $4,800 will need to be sourced. ",
"That or OBO, but as we don't deal in grey areas here, you now need to vote on the dollar amount. ",
"What do you think, is $4,800 a deal for this BMW with a hummer? ",
"Or, is there just too much that needs to be done to make that price a done deal?"
] |
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"pile_set_name": "Pile-CC"
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[
"Introduction\n============\n\nConnexins (Cx) are a family of proteins with four transmembrane regions, which are encoded by 21 genes in humans and which form hexameric connexons (= hemichannels). ",
"These connexons can either function as transmembrane ion channels or assemble into gap junctions (GJ) by the docking of two hemichannels from adjacent cells and directly mediate signaling between cells by passing ions, metabolites and signaling molecules up to 1 kDa in mass. ",
"Both hemichannels and GJ channels formed by different connexins play important roles in tissue homeostasis and have therefore been proposed as potential new targets for the treatment of epilepsy, cardiac arrhythmia, cancer, stroke, essential tremor, and corneal wound healing (Nemani and Binder, [@B19]; Salameh and Dhein, [@B21]; Bodendiek and Raman, [@B4]; Kandouz and Batist, [@B11]).",
"\n\nSince the 1980s several endogenous as well as exogenous molecules that modulate GJ channels have been discovered. ",
"The peptidic GJ channel activator rotigaptide, which mainly activates Cx43, advanced into clinical trials for the treatment of atrial fibrillation (phase II, terminated in 2007) and endothelial dysfunction (Lang et al., [",
"@B12]), while GAP-134, an orally available di-peptidic analog of rotigaptide, recently completed phase I clinical trials for the treatment of atrial fibrillation (ClinicalTrials.",
"Gov). ",
"However, apart from these exceptions, the development of GJ channel modulators as pharmacological tools and potential therapeutics is still in its infancy. ",
"Most existing modulators are either of low potency and exhibit little selectivity either for connexin channels or among individual connexin subtypes. ",
"For example, one of the most commonly used GJ channel blockers, carbenoxolone, a more water soluble derivative of the pentacyclic triterpenoid glycyrrhetinic acid, reversibly inhibits GJ currents in human fibroblasts with an IC~50~ of 3 μM and reduces Cx26 and Cx38 hemichannel currents in *Xenopus* oocytes with IC~50~s of 21 and 34 μM, respectively. ",
"However, at similar concentrations carbenoxolone also inhibits several other targets such as the enzyme 11β-hydroxysteroid dehydrogenase (IC~50~ ∼5 μM; Monder et al., [",
"@B18]), voltage-gated Ca^2+^ currents (IC~50~ 48 μM; Vessey et al., [",
"@B28]), and the structurally similar pannexin channels (IC~50~ 2--5 μM; Locovei et al., [",
"@B13]). ",
"At even lower concentrations carbenoxolone inhibits P2x7 receptors (IC~50~ 175 nM; Suadicani et al., [",
"@B25]). ",
"Other commonly used connexin blockers like the long-chain alcohols heptanol and octanol, the diphenylborate 2-APB or flufenamic acid are similarly either of low potency or lack selectivity for connexin channels (for a recent review see: Bodendiek and Raman, [@B4]).",
"\n\nPotent connexin subtype selective modulators are urgently needed to further elucidate the physiological and pathophysiological roles of the different connexins and to perform proof-of-concept studies validating connexins as potential drug targets for various diseases for which they have been proposed as novel targets. ",
"We therefore screened a small library of compounds containing ion channel modulating pharmacophores for their effects on Cx50 GJ channels. ",
"Cx50 was used as an exemplary connexin because it is expressed robustly in expression systems. ",
"Cx50 is mainly expressed in the crystalline lens. ",
"In lens epithelial cells, it is co-expressed with Cx43 and plays an important role in postnatal lens growth (White et al., [",
"@B31]; Rong et al., [",
"@B20]). ",
"In fiber cells, where it is co-expressed with Cx46, it has been shown to be an important component of the lens microcirculation, essential for maintenance of lens transparency (Mathias et al., [",
"@B14], [@B15]). ",
"Genetic deletion of Cx50 causes mild cataracts and significantly decreases lens growth (White et al., [",
"@B31]; Rong et al., [",
"@B20]), while missense and frame shift mutations have been found in families with inherited cataracts (Berthoud and Beyer, [@B3]; Mathias et al., [",
"@B15]). ",
"To further study the role of Cx50 channels in the lens, a potent and selective blocker would be of great interest. ",
"Such an inhibitor is likely to be useful to dissect the contribution of the coupling provided by Cx50 to lens development and transparency. ",
"In this study, we describe the design of two Cx50 inhibitors with IC~50~s of 1.2 and 2.4 μM. Both compounds exhibit excellent selectivity for Cx50 over Cx43, and Cx46, which are also expressed in the lens (\\<18% inhibition at 10 μM), and strongly reduced junctional currents in primary lens epithelial cells isolated on postnatal day 6, a developmental time-point where Cx50 provides the majority of the coupling in the epithelium. ",
"These new pharmacological tool compounds will be useful to further explore the role of Cx50 in lens physiology and pathophysiology and for structure function studies of connexins.",
"\n\nMaterials and Methods {#s1}\n=====================\n\nChemicals and reagents\n----------------------\n\nClotrimazole (CAS No. ",
"23593-75-1), triphenylmethane (CAS No. ",
"519-73-3), triphenylmethyl chloride (CAS No. ",
"76-83-5), triphenylmethanol (CAS No. ",
"76-84-6), 3,3,3-triphenylpropionic acid (T51, CAS No. ",
"900-91-4), (*R*)-(+)-α,α-diphenyl-2-pyrrolidinemethanol (T52, CAS No. ",
"22348-32-9), (*S*)-(−)-α,α-diphenyl-2-pyrrolidinemethanol (T53, CAS No. ",
"112068-01-6), diphenyl-4-pyridylmethane (T160, CAS No. ",
"3678-72-6), and triphenylmethylamine (T162, CAS No. ",
"5824-40-8) were purchased from Sigma-Aldrich (St. Louis, MO). ",
"Tetraphenylmethane (T161, CAS No. ",
"630-76-2) was purchased from Alfa Aesar (Ward Hill, MA). ",
"2-Chlorotrityl chloride (T3-Cl, CAS No. ",
"42074-68-0) and diphenyl-4-pyridylmethanol (T50, CAS No. ",
"1620-30-0) were purchased from TCI America (Portland, OR). ",
"T1-T4, T9, T11, T13, T20, T34, T35, T39, T41, T43, T44, T54, T57, T61, T64, T66-T75, T78-T80, T85, and T97 were available in the Wulff laboratory compound library and had been previously synthesized and characterized (Wulff et al., [",
"@B33]). ",
"The remaining compounds were synthesized using Grignard, chlorination and alkylation reactions described as general methods A, B, and C (see also Figure [3](#F3){ref-type=\"fig\"}). ",
"New chemical entities (NCEs) were characterized by melting point (Melting Point B-540, Büchi), ^1^H-NMR (Avance 500, Bruker), mass spectrometry (MS: LCQ, Thermo Scientific; HRMS: LTQ-Orbitrap XL Thermo Scientific), and/or combustion analysis (2400 Series II combustion analyzer, Perkin Elmer). ",
"All MS and HRMS spectra were recorded with ESI as ionization mode if not stated otherwise. ",
"In cases where no sufficient analytical data for previously reported compounds (T109, T117, T129, T141, T143, T144, T154-OH, and T165) were available ^1^H-NMR, MS and/or combustion data in addition to melting points are also provided.",
"\n\nChemical synthesis\n------------------\n\n### General method A\n\nTriaryl methanols were synthesized through a Grignard reaction by stirring 25 mmol of magnesium turnings and 10--15 mmol of the required arylbromide in 50 mL of anhydrous diethyl ether. ",
"To initiate the reaction, catalytic amounts of iodine were added. ",
"The remaining 15--20 mmol of the required arylbromide were diluted with or dissolved in anhydrous diethyl ether (50 mL) and added slowly allowing gentle reflux. ",
"The reaction mixture was refluxed until all magnesium was consumed. ",
"Then, a solution of the required benzophenone (25 mmol) in anhydrous diethyl ether (50 mL) was added drop wise and the resulting mixture was heated under reflux for 12--24 h. After completion of the reaction the mixture was cooled to 0°C, poured into 100 mL of cold water and acidified with concentrated HCl. ",
"The organic phase was separated, and the aqueous phase was extracted three times with diethyl ether. ",
"The organic phases were combined, washed with NaHCO~3~ (10%) and dried over sodium sulfate. ",
"After evaporation of the solvent the crude triaryl methanols were obtained either as solid or as oily residues, which were recrystallized from petroleum ether (40--60°C) several times, if necessary.",
"\n\n### General method B\n\nThe triaryl methyl chlorides were obtained according to McNaughton-Smith et al. ([",
"@B16]) by adding a five-fold excess of acetyl chloride to a stirred solution of the respective triaryl methanol in dichloromethane. ",
"After stirring the reaction mixture at room temperature for 12--24 h the solvent was evaporated and toluene (2 × 50 mL) was added and again removed under vacuum to afford the crude triaryl chlorides.",
"\n\n### General method C\n\nTo a solution of the respective triaryl chloride (5 mmol) in anhydrous acetonitrile (100 mL) an excess of the respective amine (10--20 mmol) as hydrogen acceptor was added and the resulting mixture was refluxed for several hours. ",
"The progress of the reaction was monitored by TLC. ",
"Work up I: The mixture was poured into cold water (400 mL) and kept at 4°C for a few hours. ",
"The precipitate was filtered off, thoroughly washed with water to remove any remaining amine, and recrystallized from ethanol. ",
"Work up II: the solvent was evaporated and the crude residue was purified by column chromatography and/or recrystallization.",
"\n\n1-\\[(2-Chlorophenyl)(diphenyl)methyl\\]-4-methyl-2-phenyl-1*H*-imidazole (T89) was synthesized from T3-Cl (2.5 g, 7.98 mmol) and 4-methyl-2-phenylimidazole (1.26 g, 7.98 mmol), and triethylamine (1.11 ml, 7.98 mmol) as hydrogen acceptor in anhydrous acetonitrile (100 mL). ",
"After 24 h of refluxing the solvent was evaporated to afford a creamy residue, which was dissolved in dichloromethane (200 mL), washed with water (2 × 50 mL), and dried over Na~2~SO~4~. Evaporation of the solvent gave the crude product which was recrystallized from petroleum ether (40--60°C)/dichloromethane. ",
"T89 was obtained as a white powder (650 mg, 18.7%): Mp 226°C; ^1^H NMR (DMSO-*d*~6~) δ: 1.41 (s, 3H, −CH~3~), 6.92 (d, 1H, ^3^*J* = 6.9 Hz), 7.17--7.27 (m, 13H), 7.32 (dt, 1H, ^3^*J* = 7.3 Hz, ^4^*J* = 1.3 Hz), 7.39 (t, 2H, ^3^*J* = 7.7 Hz), 7.42 (d, 1H, ^3^*J* = 7.8 Hz), 7.83 (d, 2H, ^3^*J* = 7.5 Hz); MS (ESI) *m/z* calcd 435.2 \\[M + H\\]^+^; found 435.5 \\[M + H\\]^+^; Anal. ",
"calcd for C~29~H~23~ClN~2~: C, 80.08; H, 5.33; N, 6.44; found: C, 79.70; H, 5.09; N, 6.59.",
"\n\n1-\\[(2-Chlorophenyl)diphenylmethyl\\]-2,5-dihydro-1*H*-pyrrole-2,5-dione (T91) was synthesized from T3-Cl (1.6 g, 5 mmol) and maleimide (1.94 g, 20 mmol) according to general method C as a slightly yellowish powder (320 mg, 17.12%): Mp 93°C; ^1^H NMR (DMSO-*d*~6~) δ: 6.43 (d, 1H, ^3^*J* = 1 Hz), 7.09 (dd, 1H, ^3^*J* = 7.8 Hz, ^4^*J* = 1.6 Hz), 7.22--7.27 (m, 8H), 7.29--7.32 (m, 5H), 7.39 (dd, 1H, ^3^*J* = 7.8 Hz, ^4^*J* = 1.3 Hz), MS (ESI) *m/z* calcd 338.1 \\[C~23~H~16~NO~2~\\]^+^; found 338.2 \\[C~23~H~16~NO~2~\\]^+^.\n\n*N*-\\[(2-Chlorophenyl)diphenylmethyl\\]-*N*-(3-aminopropyl)imidazoleamine (T94) was synthesized from T3-Cl (1.6 g, 5 mmol) and *N*-(3-aminopropyl)imidazole (1.88 g, 15 mmol) according to general method C as white powder (510 mg, 25.4%): Mp 89°C; ^1^H NMR (DMSO-*d*~6~) δ: 1.93--1.96 (m, 4H, 2x -CH~2~), 2.84 (t, 1H, ^3^*J* = 7.6 Hz, *N*-H), 4.03 (t, 2H, ^3^*J* = 6.8 Hz, CH~2~), 6.83 (s, 1H), 7.10 (s~broad~, 1H), 7.14 (t, 2H, ^3^*J* = 7.3 Hz), 7.25 (t, 4H, ^3^*J* = 7.7 Hz), 7.31--7.35 (m, 2H), 7.37--7.39 (m, 5H), 7.53 (dd, 1H, ^3^*J* = 7.5 Hz, ^4^*J* = 2.0 Hz), 7.56 (s~broad~, 1H); MS (ESI) *m/z* calcd 402.2 \\[M + H\\]^+^; found 402.3 \\[M + H\\]^+^; Anal. ",
"calcd for C~25~H~24~ClN~3~: C, 74.71; H, 6.02; N, 10.45; found: C, 74.06; H, 6.44; N, 10.32.",
"\n\n*N*-\\[(2-Chlorophenyl)diphenylmethyl\\]-*N*-(3-aminopropionitrile)amine (T95) was synthesized from T3-Cl (1.6 g, 5 mmol) and 3-aminopropionitrile (1.12 mL, 1.05 g, 15 mmol) according to general method C as a white yellowish powder (610 mg, 35.2%): Mp 140°C; ^1^H NMR (DMSO-d~6~) δ: 2.13 (q, 2H, ^3^*J* = 7.1 Hz, *N*H-CH~2~), 2.70 (t, 2H, ^3^*J* = 6.4 Hz, CH~2~-CN), 3.19 (t, 1H, ^3^*J* = 8.4 Hz, *N*-H), 7.18 (t, 2H, ^3^*J* = 7.3 Hz), 7.29 (t, 4H, ^3^*J* = 7.7 Hz), 7.33-7.40 (m, 3H), 7.42--7.45 (m, 4H), 7.69 (d~broad~, 1H, ^3^*J* = 7.7 Hz); HRMS (ESI) *m/z* calcd 347.1315 \\[M + H\\]^+^; found 347.1290 \\[M + H\\]^+^; Anal. ",
"calcd for C~22~H~19~ClN~2~: C, 76.18; H, 5.52; N, 8.08; found: C, 75.53; H, 5.34; N, 8.06.",
"\n\n*N*-\\[(2-Chlorophenyl)diphenylmethyl\\]-3-(trifluoromethoxy)aniline (T102) was synthesized from T3-Cl (1.6 g, 5 mmol) and 3-(trifluoromethoxy)aniline (2.0 mL, 2.66 g, 15 mmol) according to general method C and recrystallized from methanol as white powder (1.34 g, 59%): Mp 144.2°C; ^1^H NMR (CDCl~3~) δ: 6.46 (d, 1H, ^3^*J* = 8 Hz), 6.49 (s, 1H, *N*-H), 6.67 (d, 1H, ^3^*J* = 8 Hz), 7.02 (t, 1H, ^3^*J* = 8.3 Hz), 7.11 (s, 1H), 7.32 (t, 2H, ^3^*J* = 7 Hz, phenyl-Cl-H4 and -H5), 7.36-7.46 (m, 11 H), 7.66 (d, 1H, ^3^*J* = 7 Hz); HRMS (ESI) *m/z* calcd 277.0784 \\[C~19~H~14~Cl\\]^+^, 178.0480 \\[C~7~H~7~NOF~3~\\]^+^; found 277.0764 \\[C~19~H~14~Cl\\]^+^, 178.0461 \\[C~7~H~7~NOF~3~\\]^+^; Anal. ",
"calcd for C~26~H~19~ClF~3~NO: C, 68.80; H, 4.22; N, 3.09; found: C, 68.86; H, 4.02; N, 3.13.",
"\n\n*N*-\\[(2-Chlorophenyl)diphenylmethyl\\]-1,3-benzothiazol-2-amine (T103) was synthesized from T3-Cl (1.6 g, 5 mmol) and 2-aminobenzothiazole (2.25 g, 15 mmol) according to general method C and recrystallized from methanol as an off-white powder (1.12 g, 52%): Mp 156.3°C; ^1^H NMR (DMSO-*d*~6~) δ: 6.95 (t, 1H, ^3^*J* = 7.5 Hz), 7.00 (d, 1H, ^3^*J* = 8.5 Hz), 7.06 (t, 1H, ^3^*J* = 7.3 Hz), 7.20--7.23 (m, 2H), 7.28--7.31 (m, 11H), 7.49 (m, 1H), 7.60 (d, 1H, ^3^*J* = 7.5 Hz), 8.96 (s, 1H, *N*-H); HRMS (ESI) *m/z* calcd 427.1036 \\[M + H\\]^+^; found 427.1060 \\[M + H\\]^+^; Anal. ",
"calcd for C~26~H~19~ClN~2~S: C, 73.14; H, 4.49; N, 6.56; S, 7.51; found: C, 73.05; H, 4.39; N, 6.63; S, 8.07.",
"\n\n*N*-\\[(2-Chlorophenyl)diphenylmethyl\\]-2-(trifluoromethoxy)aniline (T104) was synthesized from T3-Cl (1.6 g, 5 mmol) and 2-trifluoromethoxyaniline (2.04 mL, 2.7 g, 15 mmol) according to general method C as a slightly yellowish powder (1.4 g, 62%): Mp 123.5°C; ^1^H NMR (DMSO-*d*~6~) δ: 5.91 (s, 1H, *N*-H), 6.12 (d, 1H, ^3^*J* = 7.8 Hz), 6.60 (dt, 1H, ^3^*J* = 8.2, Hz, ^4^*J* = 1.3 Hz), 6.57 (dt, 1H, ^3^*J* = 7.9 Hz, ^4^*J* = 1.3 Hz), 7.18--7.38 (m, 14H), 7.58 (d, 1H, ^3^*J* = 7.4 Hz); HRMS (ESI) *m/z* calcd 277.0784 \\[C~19~H~14~Cl\\]^+^, 178.0480 \\[C~7~H~7~NOF~3~\\]^+^; found 277.0773 \\[C~19~H~14~Cl\\]^+^, 178.0465 \\[C~7~H~7~NOF~3~\\]^+^; Anal. ",
"calcd for C~26~H~19~ClF~3~NO: C, 68.8; H, 4.22; N, 3.09; found: C, 69.19; H, 4.26; N, 3.10.",
"\n\n1-(4-{\\[(2-Chlorophenyl)diphenylmethyl\\]amino}phenyl)ethan-1-one (T105) was synthesized from T3-Cl (1.6 g, 5 mmol) and 4-aminoacetophenone (2.0 g, 15 mmol) according to general method C as a white powder (400 mg, 19.4%): Mp 166.7°C; ^1^H NMR (DMSO-*d*~6~) δ: 2.30 (s, 3H, -OCH~3~), 6.55 (s~wide~, 2H), 7.20--7.25 (m, 6H), 7.29--7.35 (m, 8H), 7.46 (d, 2H, ^3^*J* = 8.6 Hz), 7.56 (d, 1H, ^3^*J* = 7.4 Hz); HRMS (ESI) *m/z* calcd 412.1468 \\[M + H\\]^+^; found 412.1454 \\[M + H\\]^+^; Anal. ",
"calcd for C~27~H~22~ClNO: C, 78.73; H, 5.38; N, 3.40; found: C, 78.42; H, 5.48; N, 3.38.",
"\n\n*N*-\\[(2-Chlorophenyl)diphenylmethyl\\]-4-methoxyaniline (T106) was synthesized from T3-Cl (1.6 g, 5 mmol) and p-anisidine (1.85 g, 15 mmol) according to general method C and recrystallized from methanol as a slightly redish-beige powder (1.24 g, 62%): Mp 142.5°C; ^1^H NMR (DMSO-*d*~6~) δ: 3.52 (s, 3H, -OCH~3~), 6.10 (s, 1H), 6.43 (s, 4H), 7.18 (t, 2H, ^3^*J* = 6 Hz), 7.26--7.30 (m, 11H), 7.59 (d, 1H, ^3^*J* = 7.5 Hz); HRMS (ESI) *m/z* calcd: 399.13899 \\[M\\]^+^; found: 399.1381 \\[M\\]^+^; Anal. ",
"calcd for C~26~H~22~ClNO: C, 78.09; H, 5.54; N, 3.50; found: C, 77.85; H, 5.62; N, 3.53.",
"\n\n1-Chloro-2-(phenoxydiphenylmethyl)benzene (T107): To a solution of T3-Cl (0.95 g, 3 mmol) in anhydrous acetone (50 mL) phenol (282 mg, 3 mmol), K~2~CO~3~ (1.93 g, 14 mmol) and catalytic amounts of KI were added. ",
"Afterward the resulting mixture was refluxed for several hours. ",
"The progress of the reaction was monitored by TLC. ",
"After completion of the reaction K~2~CO~3~ was filtered off and the solvent was evaporated. ",
"The solid residue was dissolved in CH~2~Cl~2~ and the solution was extracted three times with NaOH (0.5 M). ",
"The pooled organic phases were dried over Na~2~SO~4~ and concentrated *in vacuo*. ",
"The residue was recrystallized from ethanol to give an off-white, slightly yellowish powder (80 mg, 7%): Mp 125°C; ^1^H NMR (DMSO-*d*) δ: 7.07 (dd, 2H, ^3^*J* = 8.1 Hz, ^4^*J* = 1.6 Hz), 7.12 (dt, 2H, ^3^*J* = 7.7 Hz, ^4^*J* = 1.4 Hz), 7.15--7.17 (m, 5H), 7.26 (dt, 2H, ^3^*J* = 7.6 Hz, ^4^*J* = 1.7 Hz), 7.29--7.31 (m, 8H); MS (FAB-NBA) *m/z* calcd 293 \\[C~19~H~14~ClO\\]^+^, 277 \\[C~19~H~14~Cl\\]^+^; found 293 \\[C~19~H~14~ClO\\]^+^, 277 \\[C~19~H~14~Cl\\]^+^.\n\n*N*-\\[(2-Chlorophenyl)diphenylmethyl\\]aniline (T109) was synthesized from T3-Cl (0.95 g, 3 mmol) and aniline (279 mg, 3 mmol) as described for T107 and recrystallized from ethanol as a yellowish-beige powder (750 mg, 2 mmol, 67.6%): Mp 131.4°C (ethanol), Lit. ",
"121°C (benzene; Gomberg and Van Slyke, [@B8]); ^1^H NMR (DMSO-d~6~) δ: 6.41--6.44 (m, 2H, *N*-H), 6.49 (d, 2H, ^3^*J* = 8.1 Hz), 6.80 (t, 2H, ^3^*J* = 7.8 Hz), 7.17--7.20 (m, 2H), 7.25--7.33 (m, 11H), 7.59 (d, 1H, ^3^*J* = 7.8 Hz); HRMS (ESI) *m/z* calcd 369.1284 \\[M\\]^+^; found 369.1277 \\[M\\]^+^.\n\n2-{\\[(2-Chlorophenyl)diphenylmethyl\\]sulfanyl}pyrimidine (T112) was synthesized from T3-Cl (1.6 g, 5 mmol) and 2-mercaptopyrimidine (1.68 g, 15 mmol) according to general method C and recrystallized from methanol as an off-white powder (1.16 g, 60%): Mp 151.6°C; ^1^H NMR (DMSO-d~6~) δ: 7.00 (t, 1H, ^3^*J* = 4.8 Hz), 7.20 (t, 2H, ^3^*J* = 7.2 Hz), 7.26 (t, 4H, ^3^*J* = 7.6 Hz), 7.33--7.37 (m, 7H), 7.81--7.82 (m, 1H), 8.28 (d, 2H, ^3^*J* = 4.9 Hz); HRMS (ESI) *m/z* calcd 389.0879 \\[M + H\\]^+^; found 389.0869 \\[M + H\\]^+^; Anal. ",
"calcd for C~23~H~17~ClN~2~S: C, 71.03; H, 4.41; N, 7.2; S, 8.24; found: C, 71.04; H, 4.26; N, 7.13; S, 8.56.",
"\n\n(2-Methoxyphenyl)diphenylmethanol (T117) was synthesized from 2-bromoanisole (3.09 mL, 4.68 g, 25 mmol) according to general method A as an off-white powder (4.9 g, 17 mmol, 67.6%): Mp 128.7°C; Lit. ",
"128--129°C (Baeyer, [@B1]); ^1^H NMR (DMSO-*d*~6~) δ: 3.67 (s, 3H, -OCH~3~), 5.28 (s, 1H, -OH), 6.54 (d, 1H, ^3^*J* = 7.7 Hz), 6.84 (t, 1H, ^3^*J* = 7.6 Hz), 6.97 (d, 1H, ^3^*J* = 8.2 Hz), 7.25--7.32 (m, 11H); HRMS (ESI) *m/z* calcd 273.12795 \\[M-OH\\]^+^; found 273.1270 \\[M-OH\\]^+^; Anal. ",
"calcd for C~20~H~18~O~2~: C, 82.73; H, 6.25; found: C, 82.45; H, 6.20.",
"\n\n*N*-\\[(2-Methoxyphenyl)diphenylmethyl\\]-1,3-thiazol-2-amine (T122): In a first-step compound T117 was chlorinated with acetyl chloride according to method B to afford 1-(chlorodiphenylmethyl)-2-methoxybenzene (T117-Cl). ",
"Without further purification and characterization T117-Cl (3.7 g, 12 mmol) was reacted with 2-aminothiazole (2.9 g, 30 mmol) according to general method C to afford T122 as an off-white powder (1.67 g, 37%): Mp 162.3°C; ^1^H NMR (DMSO-*d*~6~) δ: 3.40 (s, 3H, -OCH~3~), 6.49 (d, 1H, ^3^*J* = 3.5 Hz, thiazole-H4), 6.87 (d, 1H, ^3^*J* = 3.3, thiazole-H3), 6.89 (d, 1H, ^3^*J* = 7.5 Hz), 6.97 (d, 1H, ^3^*J* = 8.1 Hz), 7.12 (d, 1H, ^3^*J* = 7.7 Hz), 7.19--7.29 (m, 11H), 8.00 (s, 1H, *N*-H); HRMS (ESI) *m/z* calcd 373.1375 \\[M + H\\]^+^; found 373.1371 \\[M + H\\]^+^; Anal. ",
"calcd for C~23~H~20~N~2~OS: C, 74.16; H, 5.41; N, 7.52; S, 8.61; found: C, 74.26; H, 5.31; N, 7.29; S, 8.87.",
"\n\n*N*-\\[(2-Methoxyphenyl)diphenylmethyl\\]pyrimidin-2-amine (T123): T117 was chlorinated to afford T117-Cl as described for T122. ",
"In a next step T117-Cl (6.48 g, 21 mmol) and 2-aminopyrimidine (5.02 g, 52.75 mmol) were reacted according to general method C to give T123 as an off-white powder (2.15 g, 27.9%): Mp 166.5°C; ^1^H NMR (CD~3~COCD~3~) δ: 3.44 (s, 3H, -OCH~3~), 6.48 (t, 1H, ^3^*J* = 4.8 Hz), 6.83--6.86 (m, 2H, *N*-H), 6.92 (d, 1H, ^3^*J* = 7.8 Hz), 7.14--7.16 (m, 2H), 7.20--7.26 (m, 6H), 7.29--7.31 (m, 4H) 8.02 (s, 2H); HRMS (ESI) *m/z* calcd 368.1763 \\[M + H\\]^+^; found 368.1757 \\[M + H\\]^+^; Anal. ",
"calcd for C~24~H~21~N~3~O: C, 78.45; H, 5.76; N, 11.44; found: C, 78.37; H, 5.71; N, 11.18.",
"\n\n*N*-\\[(2-Methylphenyl)diphenylmethyl\\]-1,3-thiazol-2-amine (T124): (2-Methylphenyl)diphenylmethanol (T118) was synthesized from 1-bromo-2-methylbenzene (3.01 mL, 4.28 g, 25 mmol) according to general method A and then chlorinated according to method B to afford 1-(chlorodiphenylmethyl)-2-methylbenzene (T118-Cl). ",
"Without further purification and characterization T118-Cl (2.9 g, 9.9 mmol) was immediately reacted with 2-aminothiazole (2.48 g, 24.8 mmol) according to general method C. T124 was obtained as a beige powder after recrystallization from ethanol (2.69 g, 76%): Mp 158.3°C; ^1^H NMR (CDCl~3~) δ: 1.97 (s, 3H, phenyl-CH~3~), 6.26 (d, 1H, ^3^*J* = 4 Hz, thiazole-H4), 6.86 (s, 1H, *N*-H), 7.04 (d, 1H, ^3^*J* = 4 Hz, thiazole-H3), 7.12 (d, 2H, ^3^*J* = 8 Hz), 7.20-7.27 (m, 12H); HRMS (ESI) *m/z* calcd 357.1426 \\[M + H\\]^+^, 373.1375 \\[M + H~2~O\\]^+^; found 357.1420 \\[M + 1\\]^+^, 373.1357 \\[M + H~2~O\\]^+^; Anal. ",
"calcd for C~23~H~20~N~2~S: C, 77.49; H, 5.65; N, 7.86; S, 8.99; found: C, 76.87; H, 5.67; N, 7.7; S, 9.48.",
"\n\n*N*-\\[(2-Methylphenyl)diphenylmethyl\\]-pyrimidin-2-amine (T125): (2-Methylphenyl)diphenylmethanol (T118) was synthesized and afterward chlorinated (T118-Cl) as described for T124. ",
"Without further purification and characterization T118-Cl (2.9 g, 9.9 mmol) was immediately reacted with 2-aminopyrimidine (2.36 g, 24.8 mmol) according to general method C. T125 was obtained as a white powder after recrystallization from ethanol (1.46 g, 42%): Mp 183.1°C; ^1^H NMR (CDCl~3~) δ: 1.99 (s, 3H, phenyl-CH~3~), 6.43 (t, 1H, ^3^*J* = 4.8 Hz, pyrimidine-H5), 7.05 (d, 1H, ^3^*J* = 7.1 Hz), 7.08 (d, 1H, ^3^*J* = 7.7 Hz), 7.14-7.29 (m, 14H), 8.05 (s~broad~, 2H); HRMS (ESI) *m/z* calcd 352.1814 \\[M + H\\]^+^; found 352.1808 \\[M + H\\]^+^; Anal. ",
"calcd for C~24~H~21~N~3~: C, 82.02; H, 6.02; N, 11.96; found: C, 81.79; H, 5.93; N, 11.86.",
"\n\n*N*-{Diphenyl\\[2-(trifluoromethoxy)phenyl\\]methyl}-1,3-thiazol-2-amine (T126): Diphenyl\\[2-(trifluoromethoxy)phenyl\\]methanol (T119) was synthesized from 1-bromo-2-(trifluoromethoxy)benzene (3.69 mL, 6.03 g, 25 mmol) according to general method A. Without further purification and characterization T119 was chlorinated according to method B to afford 1-(chlorodiphenylmethyl)-2-(trifluoromethoxy)benzene (T119-Cl). ",
"Without further purification and characterization T119-Cl (g, 14.38 mmol) was immediately reacted with 2-aminothiazole (3.6 g, 35.94 mmol) according to general method C. T126 was obtained as an off-white powder after recrystallization from ethanol (2.25 g, 36.7%): Mp 178.8°C; ^1^H NMR (CDCl~3~) δ: 6.24 (d, 1H, ^3^*J* = 3.6 Hz, thiazole-H4), 6.82 (s, 1H, *N*-H), 6.98 (d, 1H, ^3^*J* = 3.6 Hz, thiazole-H3), 7.10--7.29 (m, 13H), 7.41 (dd, 1H, ^3^*J* = 8.1 Hz, ^4^*J* = 1.4 Hz); HRMS (ESI) *m/z* calcd 427.1092 \\[M + H\\]^+^; found 427.1087 \\[M + H\\]^+^; Anal. ",
"calcd for C~23~H~17~F~3~N~2~OS: C, 64.78; H, 4.02; N, 6.57; S, 7.52; found: C, 64.64; H, 3.89; N, 6.56; S, 8.1.",
"\n\n*N*-{Diphenyl\\[2-(trifluoromethoxy)phenyl\\]methyl}pyrimidin-2-amine (T127): Diphenyl\\[2-(trifluoromethoxy)phenyl\\]methanol (T119) was synthesized and afterward chlorinated (T119-Cl) as described for T126. ",
"Without further purification and characterization T119-Cl (5.2 g, 14.38 mmol) and 2-aminopyrimidine (3.42 g, 35.94 mmol) were reacted according to general method C. T127 was obtained as a white powder after recrystallization from ethanol (1.2 g, 19.8%): Mp 135°C; ^1^H NMR (DMSO-*d*~6~) δ: 6.54 (t, 1H, ^3^*J* = 4.8 Hz, pyrimidine-H4), 7.00 (s, 1H, *N*-H), 7.15-7.20 (m, 3H), 7.24--7.29 (m, 9H), 7.39 (ddd, 1H, ^3^*J* = 8.2 Hz, ^3^*J* = 7.4 Hz, ^4^*J* = 1.7 Hz), 7.51 (dd, 1H, ^3^*J* = 8 Hz, ^4^*J* = 1.7 Hz), 8.07 (s~broad~, 2H, pyrimidine-H3 and -H5); HRMS (ESI) *m/z* calcd 422.1480 \\[M + H\\]^+^; found 422.1471 \\[M + H\\]^+^; Anal. ",
"calcd for C~24~H~18~F~3~N~3~O: C, 68.4; H, 4.31; N, 9.97; found: C, 68.3; H, 4.58; N, 9.99.",
"\n\n*N*-\\[(2-Fluorophenyl)diphenylmethyl\\]pyrimidine-2-amine (T128): (2-Fluorophenyl)diphenylmethanol (T36) was synthesized from bromobenzene (2.63 mL, 3.93 g, 25 mmol) and 2-fluorobenzophenone (4.22 mL, 5.0 g, 25 mmol) according to general method A (yellowish solid, 6.5 g, 93.41%). ",
"Spectroscopic data were in accordance with literature (Wulff et al., [",
"@B33]). ",
"In a next step T36 was chlorinated according to method B to afford 1-(chlorodiphenylmethyl)-2-fluorobenzene (T36-Cl). ",
"Without further purification and characterization T36-Cl (3 g, 10.28 mmol) was immediately reacted with 2-aminopyrimidine (2.44 g, 25.7 mmol) according to general method C. T128 was obtained as slightly yellowish powder after recrystallization from ethanol (1.73 g, 47.3%): Mp 161.1°C; ^1^H NMR (DMSO-*d*~6~) δ: 6.53 (t, 1H, ^3^*J* = 5 Hz, pyrimidine-H4), 7.01 (dd, 1H, ^3^*J* = 12 Hz, ^3^*J* = 8 Hz), 7.11 (t, 1H, ^3^*J* = 7.9 Hz), 7.18 (t, 2H, ^3^*J* = 6.4 Hz), 7.23--7.30 (m, 9H), 7.34 (s, 1H, *N*-H), 7.40 (dt, 1H, ^3^*J* = 8 Hz, ^4^*J* = 1.3 Hz), 8.07 (s~broad~, 2H, pyrimidine-H3 and -H5); HRMS (ESI) *m/z* calcd: 356.1563 \\[M + H\\]^+^; found: 356.1563 \\[M + H\\]^+^; Anal. ",
"calcd for C~23~H~18~FN~3~: C, 77.73; H, 5.10; N, 11.82; found: C, 77.55; H, 4.95; N, 11.42.",
"\n\n*N*-\\[(3-Chlorophenyl)diphenylmethyl\\]-1,3-thiazol-2-amine (T129): (3-Chlorophenyl)diphenylmethanol (T2) was synthesized from 1-bromo-3-chlorobenzene (2.94 mL, 4.79 g, 25 mmol) according to general method A (5.0 g, 67.8%). ",
"Spectroscopic data were in accordance with literature (Wulff et al., [",
"@B33]). ",
"T2 was then chlorinated according to general method B to afford 1-chloro-3-(chlorodiphenylmethyl)benzene (T2-Cl). ",
"Without further purification and characterization T2-Cl (2.75 g, 8.78 mmol) was reacted with 2-aminothiazole (2.2 g, 21.95 mmol) according to general method C. T129 was obtained as a beige powder after recrystallization from ethanol (3.0 g, 91%): Mp 164.5°C; ^1^H NMR (DMSO-*d*~6~) δ: 6.56 (d, 1H, ^3^*J* = 3.6 Hz, thiazole-H4), 6.81 (d, 1H, ^3^*J* = 3.7 Hz, thiazole-H3), 7.18--7.31 (m, 13H), 7.35 (t, 1H, ^3^*J* = 1.8 Hz), 8.57 (s, 1H, *N*-H); HRMS (ESI) *m/z* calcd 377.0879 \\[M + H\\]^+^; found 377.0861 \\[M + H\\]^+^; Anal. ",
"calcd for C~22~H~17~ClN~2~S: C, 70.11; H, 4.55; N, 7.43; S, 8.51; found: C, 69.94; H, 4.46; N, 7.48; S, 9.09.",
"\n\n*N*-\\[(3-Chlorophenyl)diphenylmethyl\\]pyrimidin-2-amine (T130): (3-Chlorophenyl)diphenylmethanol (**T2**) was synthesized and afterward chlorinated (T2-Cl) as described for T129. ",
"Without further purification and characterization T2-Cl (2.75 g, 8.78 mmol) and 2-aminopyrimidine (2.1 g, 21.95 mmol) were reacted according to general method C. T130 was obtained as a white powder after recrystallization from ethanol (1.65 g, 51%): Mp 124.4°C; ^1^H NMR (DMSO-*d*~6~) δ: 6.53 (t, 1H, ^3^*J* = 4.8 Hz, pyrimidine-H4), 7.16 (t, 2H, ^3^*J* = 7.2 Hz), 7.22--7.28 (m, 7H), 7.30-7.32 (m, 4H), 7.35 (s~broad~, 1H), 7.87 (s, 1H, *N*-H), 8.10 (d, 2H, ^3^*J* = 4.3 Hz, pyrimidine-H3 and -H5); HRMS (ESI) *m/z* calcd 372.1262 \\[M + H\\]^+^; found 372.1253 \\[M + H\\]^+^; Anal. ",
"calcd for C~23~H~18~ClN~3~: C, 74.29; H, 4.88; N, 11.3; found: C, 74.14; H, 4.76; N, 11.21.",
"\n\n*N*-\\[(2-Bromophenyl)diphenylmethyl\\]-1,3-thiazol-2-amine (T131): (2-Bromophenyl)diphenylmethanol (T116) was synthesized according to method A (bromobenzene (2.84 mL, 4.24 g, 27 mmol) and 2-bromobenzophenone (6.52 g, 25 mmol). ",
"The crude oily T116 was chlorinated in a next step according to method B to afford 1-bromo-2-(chlorodiphenylmethyl)benzene (T116-Cl). ",
"Without further purification and characterization T116-Cl was immediately reacted with 2-aminothiazole (6.3 g, 62.5 mmol) according to general method C. T131 was obtained as white powder \\[silica column: cyclohexane/ethylacetate (8/2); 1.05 g, 10%\\]: Mp 142°C; ^1^H NMR (DMSO-*d*~6~) δ: 6.52 (d, 1H, ^3^*J* = 3.7 Hz, thiazole-H4), 6.74 (d, 1H, ^3^*J* = 3.6 Hz, thiazole-H3), 7.17--7.20 (m, 3H), 7.28 (m, 7H), 7.32--7.29 (m, 2H), 7.41 (dd, 1H, ^3^*J* = 8 Hz, ^4^*J* = 1.4 Hz), 7.52 (d, 1H, ^3^*J* = 7.8 Hz) 8.36 (s, 1H, *N*-H); HRMS (ESI) *m/z* calcd 421.0374 \\[M + H\\]^+^, 423.0353, found 421.0366 \\[M + H\\]^+^, 423.0335.",
"\n\n*N*-\\[(2-Bromophenyl)diphenylmethyl\\]-pyrimidin-2-amine (T132): (2-Bromophenyl)diphenylmethanol (T116) was synthesized and afterward chlorinated (T116-Cl) as described for T131. ",
"T116-Cl (4.5 g, 12.5 mmol) was immediately without further purification and characterization reacted with 2-aminopyrimidine (1.2 g, 12.6 mmol) according to general method C. T132 was obtained as an off-white to yellowish powder after recrystallization from ethanol (850 mg, 16%): Mp 158.7°C; ^1^H NMR (DMSO-*d*~6~) δ: 6.57 (t, 1H, ^3^*J* = 4.5 Hz, pyrimidine-H4), 7.10 (s, 1H), 7.14--7.32 (m, 13H), 7.49 (d, 2H, ^3^*J* = 8.5 Hz, pyrimidine-H3 and -H5), 8.10 (s, 1H, *N*-H); HRMS (ESI) *m/z* calcd 416.0762 \\[M + H\\]^+^, 418.0742, 419.0776; found 416.0758 \\[M + H\\]^+^, 418.0728, 419.0752; Anal. ",
"calcd for C~23~H~18~BrN~3~: C, 66.36; H, 4.36; N, 10.09; found: C, 66.16; H, 4.23; N, 9.74.",
"\n\n*N*-{diphenyl\\[3-(trifluoromethyl)phenyl\\]methyl}-1,3-thiazol-2-amine (T133): Diphenyl\\[3-(trifluoromethoxy)phenyl\\]methanol (T121) was synthesized from 1-bromo-3-(trifluoromethoxy)benzene (3.49 mL, 5.63 g, 25 mmol) and benzophenone (4.56 g, 25 mmol) according to general method A. T121 was then chlorinated according to method B to afford 1-(chlorodiphenylmethyl)-3-(trifluoromethoxy)benzene (T121-Cl). ",
"Without further purification and characterization T121-Cl (4.5 g, 12.98 mmol) was immediately reacted with 2-aminothiazole (3.25 g, 32 mmol) according to general method C. T133 was obtained as a white powder after recrystallization from ethanol (3.64 g, 68%): Mp 120.5°C; ^1^H NMR (DMSO-*d*~6~) δ: 6.56 (d, 1H, ^3^*J* = 3.7 Hz, thiazole-H4), 6.79 (d, 1H, ^3^*J* = 3.7 Hz, thiazole-H3), 7.19--7.22 (m, 2H), 7.27--7.32 (m, 8H), 7.50 (t, 1H, ^3^*J* = 8.1 Hz), 7.57 (t, 2H, ^3^*J* = 9.1 Hz), 7.67 (s, 1H), 8.64 (s, 1H, *N*-H); HRMS (ESI) *m/z* calcd 411.1137 \\[M + H\\]^+^; found 411.1137 \\[M + H\\]^+^; Anal. ",
"calcd for C~23~H~17~F~3~N~2~S: C, 67.3; H, 4.17; N, 6.82; S, 7.81; found: C, 67.39; H, 3.98; N, 6.85; S, 7.82.",
"\n\n*N*-{Diphenyl\\[3-trifluoromethyl)phenyl\\]methyl}pyrimidin-2-amine (T134): Diphenyl\\[3-(trifluoromethoxy)phenyl\\]methanol (T121) was synthesized and afterward chlorinated (T121-Cl) as described for T133. ",
"In a next step T121-Cl (4.5 g, 12.98 mmol) was immediately reacted with 2-aminopyrimidine (3.1 g, 32.4 mmol) according to general method C. T134 was obtained as an off-white powder after recrystallization from ethanol (1.95 g, 37%): Mp 161.4°C; ^1^H NMR (DMSO-*d*~6~) δ: 6.53 (t, 1H, ^3^*J* = 4.8 Hz, pyrimidine-H4), 7.17 (t, 2H, ^3^*J* = 7.18 Hz, 2× phenyl-H4), 7.25 (t, 4H, ^3^*J* = 7.7 Hz, 2× phenyl-H3 and -H5), 7.31 (d, 4H, ^3^*J* = 7.7 Hz, 2x phenyl-H2 and -H6), 7.48 (t, 1H, ^3^*J* = 7.8 Hz, phenyl-CF~3~-H5), 7.53 (d, 1H, ^3^*J* = 7.8 Hz, phenyl-CF~3~-H6), 7.62 (d, 1H, ^3^*J* = 7.9 Hz, phenyl-CF~3~-H4), 7.67 (s~wide~, 1H, phenyl-CF~3~-H2), 8.00 (s, 1H, *N*-H), 8.09 (d, 2H, ^3^*J* = 4 Hz, pyrimidine-H3 and -H5); HRMS (ESI) *m/z* calcd 406.1526 \\[M + H\\]^+^, found 406.1521 \\[M + H\\]^+^, Anal. ",
"calcd for C~24~H~18~F~3~N~3~: C, 71.1; H, 4.48; N, 10.36; found: C, 71.03; H, 4.29; N, 10.26.",
"\n\n*N*-\\[(2-Iodophenyl)diphenylmethyl\\]-1,3-thiazol-2-amine (T136): (2-Iodophenyl)diphenylmethanol (T135) was synthesized according to general method A from bromobenzene (2.1 mL, 3.13 g, 20 mmol) and 2-iodobenzophenone (6 g, 19.5 mmol). ",
"The crude oily T135 was then chlorinated according to method B to afford 1-(chlorodiphenylmethyl)-2-iodobenzene (T135-Cl). ",
"Without further purification and characterization T135-Cl was immediately reacted with 2-aminothiazole (1.5 g, 15 mmol) according to general method C. T136 was obtained as a slightly yellowish powder (silica column cyclohexane/ethylacetate (8/2); 80 mg, 2.8%): Mp 81°C; ^1^H NMR (DMSO-*d*~6~) δ: 6.52 (d, 1H, ^3^*J* = 2.6 Hz, thiazole-H4), 6.78 (d, 1H, ^3^*J* = 2.6 Hz, thiazole-H3), 6.96--6.98 (m, 1H), 7.20--7.32 (m, 12H), 7.88 (d, 1H, ^3^*J* = 7.6 Hz, phenyl-I-H3), 8.25 (s, 1H, *N*-H); HRMS (ESI) *m/z* calcd: 469.0236 \\[M + H\\]^+^; found: 469.0213 \\[M + H\\]^+^.\n\n*N*-\\[(2-Iodophenyl)diphenylmethyl\\]-pyrimidin-2-amine (T137): (2-Iodophenyl)diphenyl methanol (T135) was synthesized and afterward chlorinated (T135-Cl) as described for T136. ",
"In a next step T135-Cl (2.4 g, 6 mmol) was immediately without further purification and characterization reacted with 2-aminopyrimidine (1.43 g, 15 mmol) according to general method C. T137 was obtained as an off-white to yellowish powder \\[silica column cyclohexane/ethylacetate (8/2); 570 mg, 20.5%\\]: Mp 160.7°C; ^1^H NMR (DMSO-*d*~6~) δ: 6.58 (dt, 1H, ^3^*J* = 4.7 Hz, ^4^*J* = 1.2 Hz), 6.93 (t, 1H, ^3^*J* = 7.5 Hz), 7.05 (s~broad~, 1H), 7.19--7.32 (m, 11H), 7.44 (d, 1H, ^3^*J* = 8 Hz), 7.82 (d, 1H, ^3^*J* = 7.8 Hz), 8.1 (s~broad~, 2H, pyrimidine-H3 and -H5); MS (ESI) *m/z* calcd 469.4 \\[M + H\\]^+^; found 496.3 \\[M + H\\]^+^; Anal. ",
"calcd for C~23~H~18~IN~3~: C, 59.62; H, 3.92; N, 9.07; found: C, 60.38; H, 3.74; N, 8.84.",
"\n\n*N*-(Triphenylmethyl)pyrimidin-2-amine (T141) was synthesized from (chlorophenylmethyl)benzene (1.34 g, 4.82 mmol) and 2-aminopyrimidine (1.48 g, 15.56 mmol) according to general method C as a white powder (1.18 g, 72.4%): Mp 174.2°C; Lit. ",
"174--175°C (Dahlbom and Ekstrand, [@B6]). ",
"Spectroscopic data were in accordance with literature (Zunszain et al., [",
"@B34]).",
"\n\n1-\\[(3-Chlorophenyl)diphenylmethyl\\]-1*H*-pyrazole (T142): (3-Chlorophenyl)diphenylmethanol (T2) was synthesized and afterward chlorinated (T2-Cl) as described for T129. ",
"Without further purification and characterization T2-Cl (3.3 g, 10.54 mmol) and pyrazole (1.77 g, 26 mmol) were reacted according to general method C. T142 was obtained as a white powder after recrystallization from ethanol (3.1 g, 85.3%): Mp 127.3°C; ^1^H NMR (DMSO-*d*~6~) δ: 6.33 (t, 1H, ^3^*J* = 2.1 Hz), 6.99--7.04 (m, 5H), 7.10 (t, 1H, ^3^*J* = 1.9 Hz), 7.34--7.43 (m, 9H), 7.66 (d, 1H, ^3^*J* = 1.6 Hz); HRMS (ESI) *m/z* calcd 69.04528 \\[C~3~H~5~N~2~\\]^+^, 277.0784 \\[C~19~H~14~Cl\\]^+^, found 69.0432 \\[C~3~H~5~N~2~\\]^+^, 277.0757 \\[C~19~H~14~Cl\\]^+^; Anal. ",
"calcd for C~22~H~17~ClN~2~: C, 76.63; H, 4.97; N, 8.12; found: C, 76.13; H, 4.92; N, 8.13.",
"\n\n1-\\[(3-Chlorophenyl)diphenylmethyl\\]-1*H*-imidazole (T143): (3-Chlorophenyl)diphenylmethanol (T2) was synthesized and afterward chlorinated (T2-Cl) as described for T129. ",
"Without further purification and characterization T2-Cl (3.3 g, 10.54 mmol) and imidazole (1.77 g, 26 mmol) were reacted according to general method C. T143 was obtained as a white powder after recrystallization from ethanol (1.3 g, 35.77%): Mp 121.3°C, Lit. ",
"122--124°C (Bartroli et al., [",
"@B2]); ^1^H NMR (DMSO-*d*~6~) δ: 6.94 (s~broad~, 1H, imidazole-H5), 7.01 (s~broad~, 1H, imidazole-H4), 7.03--7.04 (m, 2H), 7.06 (td, 1H, ^3^*J* = 6.8 Hz, ^4^*J* = 2.1 Hz), 7.09--7.1 (m, 3H), 7.36--7.47 (m, 9H), 8.46 (s, 1H, imidazole-H2); HRMS (ESI) *m/z* calcd for C~22~H~17~ClN~2~ 345.1159 \\[M + H\\]^+^, found 345.1148 \\[M + H\\]^+^.\n\n1-\\[(4-Chlorophenyl)diphenylmethyl\\]-1*H*-imidazole (T144): (4-Chlorophenyl)diphenylmethanol (T1) was synthesized from magnesium turnings (1.2 g, 50 mmol), 1-bromo-4-chlorobenzene (11.5 g, 60 mmol) and benzophenone (9.12 g, 50 mmol) according to general method A. Spectroscopic data were in accordance with literature (Wulff et al., [",
"@B33]). ",
"The crude T1 was chlorinated according to method B to afford 1-chloro-4-(chlorodiphenylmethyl)benzene (T1-Cl). ",
"Without further purification and characterization T1-Cl (∼8 g, 25.5 mmol) was immediately reacted with imidazole (4.34 g, 63.75 mmol) according to general method C. T144 was obtained as a white powder (0.6 g, 3.5%): Mp 141.2°C, Lit. ",
"140--142°C (Bartroli et al., [",
"@B2]); ^1^H NMR (DMSO-*d*~6~) δ: 6.90 (s~broad~, 1H), 6.99 (s~broad~, 1H), 7.07--7.09 (m, 6H), 7.36 (m, 7H), 7.47 (d, 2H, ^3^*J* = 8.7 Hz); HRMS (ESI) *m/z* calcd for C~22~H~17~ClN~2~ 345.1159 \\[M + H\\]^+^, found 345.1126 \\[M + H\\]^+^.\n\n*N*-\\[(4-Chlorophenyl)diphenylmethyl\\]pyrimidin-2-amine (T145): (4-Chlorophenyl)diphenylmethanol (T1) was synthesized and afterward chlorinated (T1-Cl) as described for T144. ",
"Without further purification and characterization T1-Cl (15.7 g, 50 mmol) was reacted with 2-aminopyrimidine (11.88 g, 128 mmol) according to general method C. T145 was obtained as a white powder after recrystallization from ethanol (2.3 g, 12%): Mp 117.8°C; ^1^H NMR (DMSO-*d*~6~) δ: 6.51-6.54 (m, 3H, pyrimidne-H4), 7.15 (t, 2H, ^3^*J* = 7.2 Hz), 7.24 (t, 3H, ^3^*J* = 7.7 Hz), 7.28--7.34 (m, 6H), 7.80 (s, 1H, *N*-H), 8.09 (d, 2H, ^3^*J* = 3.5 Hz, pyrimidne-H3 and -H5), 8.19 (d, 2H, ^3^*J* = 4.8 Hz); HRMS (ESI) *m/z* calcd 372.1268 \\[M + H\\]^+^, found 372.1261 \\[M + H\\]^+^.\n\n*N*-\\[(2-Chlorophenyl)diphenylmethyl\\]-4-(trifluoromethoxy)aniline (T150) was synthesized from T3-Cl (1.6 g, 5 mmol) and 4-(trifluoromethoxy)aniline (2.01 mL, 2.66 g, 15 mmol) according to general method C and recrystallized from ethanol as an off-white powder (1.5 g, 66%): Mp 99°C; ^1^H NMR (DMSO-*d*~6~) δ: 6.54 (d, 2H, ^3^*J* = 8.9 Hz), 6.82--6.80 (m, 3H, *N*-H), 7.18-7.22 (m, 2H), 7.26--7.36 (m, 11H), 7.58 (d, 1H, ^3^*J* = 7.9 Hz, phenyl-Cl-H3); HRMS (ESI) *m/z* calcd 454.1180 \\[M + H\\]^+^, 178.0474 \\[C~7~H~6~F~3~NO + H\\]^+^, found 454.1156 \\[M + H\\]^+^, 178.0461 \\[C~7~H~6~F~3~NO + H\\]^+^; Anal. ",
"calcd for C~26~H~19~ClF~3~NO: C, 68.8; H, 4.22; N, 3.09; found: C, 68.52; H, 4.09; N, 3.05.",
"\n\n(2-Aminophenyl)diphenylmethanol (T154-OH) was synthesized from phenylmagnesium bromide (1.89 g, 15.3 mmol) and 2-aminobenzophenone (2 g, 10.2 mmol) according to general method A (125 mg, 4.5%) as a red crystalline solid: Mp 117.4--118.9°C; Lit. ",
"116--117°C (Misra et al., [",
"@B17]); ^1^H NMR (DMSO-*d*~6~) δ: 5.07 (s, 2H, -*N*H~2~) 6.23 (d, 1H, ^3^*J* = 7.8 Hz), 6.34 (t, 1H, ^3^*J* = 7.4 Hz), 6.60 (d, 1H, ^3^*J* = 8.0 Hz), 6.73 (s, 1H, -OH), 7.31--7.17 (m, 10H); MS (ESI) *m/z* calcd 258.13 \\[C~19~H~16~N\\]^+^, 180.1 \\[C~13~H~10~N\\]^+^, found 258.3 \\[C~19~H~16~N\\]^+^, 180.1 \\[C~13~H~10~N\\]^+^; Anal. ",
"calcd for C~19~H~17~NO: C, 82.88; H, 6.22; N, 5.09; found: C, 82.42; H, 6.09; N, 5.17.",
"\n\nBis-(2-methoxyphenyl)(phenyl)methanol (T165) was synthesized from magnesium turnings (0.6 g, 25 mmol), 1-bromo-2-methoxybenzene (4.0 mL, 5.99 g, 32 mmol) and 2-methoxybenzophenone (5.0 g, 23.5 mmol) according to general method A and recrystallized from ethanol as a white powder (1.2 g, 15.8%): Mp 115.8°C; Lit. ",
"115°C (Baeyer, [@B1]); ^1^H NMR (DMSO-*d*~6~) δ: 3.39 (s, 6H, -OCH~3~), 5.37 (s, 1H, -OH), 6.87 (dt, 2H, ^3^*J* = 7.3 Hz, ^4^*J* = 0.7 Hz), 6.98 (d, 2H, ^3^*J* = 7.9 Hz), 7.03 (dd, 2H, ^3^*J* = 7.8 Hz, ^3^*J* = 1.5 Hz), 7.15-7.17 (m, 3H), 7.20--7.21 (m, 2H) 7.23--7.27 (m, 2H); MS (ESI) *m/z* calcd 343.38 \\[M + Na^+^\\], 303.14 \\[M-OH\\]^+^, found 343.1 \\[M + Na^+^\\], 303.1 \\[M-OH\\]^+^; Anal. ",
"calcd for C~21~H~20~O~3~: C, 78.73; H, 6.29; found: C, 78.14; H, 6.97.",
"\n\n*N*-\\[bis(2-methoxyphenyl)(phenyl)methyl\\]-1,3-thiazol-2-amine (T166): In a first-step T165 was chlorinated according to general method B (T165-Cl). ",
"The crude T165-Cl (530 mg, 1.56 mmol) was immediately reacted with 2-aminothiazole (392 mg, 3.9 mmol) according to general method C. After recrystallization from ethanol T166 was obtained as a white powder (250 mg, 39.8%): Mp 150°C; ^1^H NMR (DMSO-*d*~6~) δ: 3.39 (s, 6H, -OCH~3~), 6.44 (d, 1H, ^3^*J* = 3.6 Hz), 6.88 (dt, 2H, ^3^*J* = 7.8 Hz, ^4^*J* = 1.0 Hz), 6.90 (d, 1H, ^3^*J* = 3.6 Hz), 6.95 (d, 2H, ^3^*J* = 8.2 Hz), 7.08 (d, 2H, ^3^*J* = 7.6 Hz), 7.16 (d, 2H, ^3^*J* = 7.1 Hz), 7.21--7.29 (m, 5H), 7.81 (s, 1H); HRMS (ESI) *m/z* calcd for C~24~H~22~N~2~O~2~S 403.1480 \\[M + H\\]^+^, found 403.1465 \\[M + H\\]^+^.\n\nCells and clones\n----------------\n\nAll electrophysiological experiments described here were performed on N2A neuroblastoma cells that were transiently co-transfected with connexin and enhanced green fluorescent protein cDNAs as described previously (Srinivas et al., [",
"@B23]). ",
"The connexins used in the study were rCx26, rCx32, rCx43, rCx46, and mCx50 (where r and m refer to rat, and mouse cDNAs, respectively). ",
"Transiently transfected cells were dissociated at 8--12 h after transfection, plated at low density on 1 cm round glass coverslips, and used within 48 h thereafter.",
"\n\nHEK-293 cells stably expressing hKCa3.1 were obtained from Khaled Houamed, University of Chicago, IL. ",
"The cloning of hKCa2.3 (19 CAG repeats) and hKCa3.1 has been previously described (Wulff et al., [",
"@B32]). ",
"The hKCa2.3 clone was later stably expressed in COS-7 cells at Aurora Biosciences Corp., San Diego, CA. ",
"Cell lines stably expressing other mammalian ion channels were gifts from several sources: hKCa1.1 in HEK-293 cells (Andrew Tinker, University College London); rKv4.2 in LTK cells (Michael Tamkun, University of Colorado, Boulder); Kv11.1 (HERG) in HEK-293 cells (Craig January, University of Wisconsin, Madison); hNav1.4 in HEK-293 cells (Frank Lehmann-Horn, University of Ulm, Germany) and Cav1.2 in HEK-293 cells (Franz Hofmann, Munich, Germany). ",
"Cells stably expressing mKv1.1, mKv1.3, hKv1.5, and mKv3.1 have been previously described (Grissmer et al., [",
"@B9]); N1E-115 neuroblastoma cells (expressing Nav1.2) were obtained from ATCC. ",
"Rat Nav1.5 in pSP64T was provided by Roland G. Kallen (University of Pennsylvania), inserted into pcDNA-3.1(+) as described (Sankaranarayanan et al., [",
"@B22]), and transiently transfected into COS-7 cells together with eGFP-C1 with Fugene-6 (Roche) according to the manufacturer's protocol. ",
"Human Kv7.2 and Kv7.3 in PTLN or pcDNA-3 was provided by Bernhard Attali (Weizmann Institute of Science, Rehovot, Israel).",
"\n\nElectrophysiology\n-----------------\n\nJunctional current measurements were performed on N2A neuroblastoma cells transiently transfected with cDNAs corresponding to individual connexins or on mouse primary lens epithelial cells isolated from postnatal day 6. ",
"Dissociation of lens epithelial was performed as described previously (White et al., [",
"@B30]). ",
"Junctional conductance was measured between cell pairs using the dual whole-cell voltage-clamp technique with Axopatch 1D patch-clamp amplifiers (Molecular Devices, CA) at room temperature. ",
"Each cell of a pair was initially held at a common holding potential of 0 mV. To evaluate junctional coupling, 200 msec hyperpolarizing pulses from the holding potential of 0 mV to −20 mV were applied to one cell to establish a transjunctional voltage gradient (*V*~j~), and junctional current was measured in the second cell (held at 0 mV). ",
"The solution bathing the cells contained 140 mM NaCl, 5 mM KCl, 2 mM CsCl, 2 mM CaCl~2~, 1 mM MgCl~2~, 5 mM HEPES, 5 mM dextrose, 2 mM pyruvate, and 1 mM BaCl~2~, pH 7.4. ",
"Patch electrodes had resistances of 3--5 MΩ when filled with internal solution containing 130 mM CsCl, 10 mM EGTA, 0.5 mM CaCl~2~, 3 mM MgATP, 2 mM Na~2~ATP, and 10 mM HEPES, pH 7.2. ",
"Macroscopic recordings were filtered at 0.2--0.5 kHz and sampled at 1--2 kHz. ",
"Data were acquired using pClamp software (Axon Instruments) and plotted using Origin 6.0 software (OriginLab Corp, Northampton, MA). ",
"Drugs were applied with a gravity-fed perfusion system. ",
"Solution exchanges were complete within 10--20 s. All compounds were applied to Cx50 expressing N2A cells at an initial concentration of 10 μM. Compounds that reduced Cx50 junctional currents by \\>80% at 10 μM were then applied at lower concentrations ranging from 0.5 to 5 μM. Concentration-response curves for drug-induced uncoupling were typically determined by exposure of each cell pair to 0.5 or 1 μM, 5 and 10 μM of each drug. ",
"Concentrations of drugs (\\[D\\]) that caused a half-maximal inhibition (IC~50~) and the Hill coefficients (*n*~h~) of concentration-response relationships were estimated by fitting the data to the equation: g~j,~% control = 1/\\[1 + (\\[D\\]/EC~50~)^*n*~h~^\\] where g~j~ (% control) is fraction of the conductance (*g*~j~) in the absence and presence of the drug. ",
"Data are presented as means ± S.E.M.\n\nExperiments on K^+^ and Na^+^ channels were performed with an EPC-10 amplifier (HEKA, Lambrecht/Pfalz, Germany) in the whole-cell configuration of the patch-clamp technique with a holding potential of --80 mV. Pipette resistances averaged 2.0 MΩ. ",
"Solutions of triarylmethanes in Ringer were freshly prepared directly before the experiments from 10 mM stock solutions in DMSO. ",
"The final DMSO concentration never exceeded 1%. ",
"For measurements of KCa2 and KCa3.1 currents we used an internal pipette solution containing (in mM): 145 K^+^ aspartate, 2 MgCl~2,~ 10 HEPES, 10 K~2~EGTA, and 5.96 (250 nM free Ca^2+^) or 8.55 CaCl~2~ (1 μM free Ca^2+^)~,~ pH 7.2, 290--310 mOsm. ",
"Free Ca^2+^ concentrations were calculated with MaxChelator assuming a temperature of 25°C, a pH of 7.2 and an ionic strength of 160 mM. To reduce currents from native chloride channels in COS-7 and HEK-293 cells, Na^+^ aspartate Ringer was used as an external solution (in mM): 160 Na^+^ aspartate, 4.5 KCl, 2 CaCl~2~, 1 MgCl~2~, 5 HEPES, pH 7.4, 290--310 mOsm. ",
"KCa2 and KCa3.1 currents were elicited by 200-ms voltage ramps from −120 to 40 mV applied every 10 s and the fold-increase of slope conductance at −80 mV by drug taken as a measure of channel activation.",
"\n\nKCa1.1 currents were elicited by 200-ms voltage steps from −80 to 60 mV applied every 10 s (1 μM free Ca^2+^), and channel modulation measured as a change in mean current amplitude. ",
"Kv1.1, Kv1.3, Kv1.4, Kv1.5, Kv3.1, Kv3.2, and Kv4.2 currents were recorded in normal Ringer solution with a Ca^2+^-free pipette solution containing (in mM): 145 KF, 10 HEPES, 10 EGTA, 2 MgCl~2~, pH 7.2, 300 mOsm. ",
"Currents were elicited by 200-ms depolarizing pulses to 40 mV applied every 10 s. HERG (Kv11.1) currents were recorded with a KCl-based pipette solution (4 mM ATP) and with a two-step pulse from --80 mV first to 20 mV for 2 s and then to --50 mV for 2 s. The reduction of both peak and tail current by the drug was determined. ",
"Current from co-expressed Kv7.2/7.3 channels was elicited by depolarizing pulses from the holding potential (−80 mV) to +40 mV for 500 ms followed by hyperpolarization to −120 mV for 200 ms. ",
"Nav1.2 currents from N1E-115 cells and Nav1.4 currents from stably transfected HEK cells were recorded with 20 ms pulses from −80 to −10 mV every 10 s with a KCl-based pipette solution and normal Ringer as an external solution. ",
"Blockade of Na^+^ current was determined by measuring the reduction of peak maximum conductance.",
"\n\nResults\n=======\n\nScreening of a \"focused\" library for Cx50 inhibitors\n----------------------------------------------------\n\nTo identify Cx50 inhibitors we first screened a small library of compounds containing known ion channel pharmacophores including the antihistamine astemizole, several psoralens and related heterocycles, benzothiazoles, triterpenes, and flavanoid glycosides as well as the antifungal agent clotrimazole. ",
"From this library we identified four novel low micromolar inhibitors of Cx50: Astemizole, rutin (a flavonoid glycoside), PAA-10 (an alkyl substituted dibenzazocinone), and clotrimazole (see Figure [1](#F1){ref-type=\"fig\"} for structures). ",
"All compounds produced significant inhibition of the Cx50 junctional current at a concentration of 10 μM (Figure [1](#F1){ref-type=\"fig\"}). ",
"The inhibition of junctional currents caused by clotrimazole, astemizole and PAA-10 was completely reversible upon washout. ",
"In contrast, the effects of rutin were only partially reversible. ",
"Of these four hits, the triarylmethane clotrimazole seemed the most drug-like and attractive compound to us. ",
"Astemizole is known to affect many other ion channels including the cardiac K^+^ channel HERG (Kv11.1; Suessbrich et al., [",
"@B26]), a liability not generally encountered with triarylmethanes (Toyama et al., [",
"@B27]). ",
"We also discarded rutin as a template since preliminary experiments showed that the rutin aglycon, quercetin, had no effect on Cx50 at 10 μM (data not shown) demonstrating that the sugar moiety is essential for connexin inhibition. ",
"The dibenzazocinone PAA-10 would of course also have been a possible lead but we preferred to perform structure activity relationship (SAR) studies around clotrimazole since our laboratory had a library of 80 triarylmethanes that were immediately available for an SAR analysis on Cx50. ",
"These compounds had been previously synthesized for an SAR study to determine the structural requirements for inhibition of the intermediate-conductance calcium-activated potassium channel KCa3.1 (a.k.a. ",
"IKCa1, SK4). ",
"By using the so-called selective optimization of side activities (SOSA) approach, which allows for the selective optimization of the side activity of an old drug (Wermuth, [@B29]), our group successfully designed a triarylmethane, TRAM-34 (T34), that selectively blocked KCa3.1 channels without affecting cytochrome P450-dependent enzymes, the main target of clotrimazole (Wulff et al., [",
"@B33]). ",
"This previous work had demonstrated that it is possible to achieve selectivity for different targets by appropriately modifying the triarylmethane (TRAM) pharmacophore, which was another reason for us to choose clotrimazole as a template for our current study on Cx50.",
"\n\n{#F1}\n\nClotrimazole reversibly inhibited Cx50 expressed in N2A cells with an IC~50~ of 5 μM and a Hill slope of ∼ 2.1 (Figure [2](#F2){ref-type=\"fig\"}). ",
"At concentrations of 10 μM clotrimazole had no effect on channels built out of Cx32, Cx36, and Cx46 (Figure [2](#F2){ref-type=\"fig\"}). ",
"GJ channel conductance in all cases was measured by using the dual whole-cell patch-clamp technique as described in the Section [\"Materials and Methods\"](#s1){ref-type=\"sec\"} (Srinivas et al., [",
"@B23]; Srinivas and Spray, [@B24]; Cruikshank et al., [",
"@B5]).",
"\n\n{#F2}\n\nProbing of the triarylmethane pharmacophore for Cx50 inhibition\n---------------------------------------------------------------\n\nUsing clotrimazole as a template we explored the SAR of the triphenylmethane scaffold according to the synthetic strategy shown in Figure [3](#F3){ref-type=\"fig\"}. ",
"In a Grignard reaction mono-substituted benzophenones and bromobenzenes were reacted in anhydrous diethyl ether to yield the corresponding triphenylmethanols. ",
"These alcohols were then either ammonolyzed, cyanated with copper cyanide or chlorinated using acetyl chloride. ",
"The triphenylmethane chlorides were further reacted in a nucleophilic substitution to give the respective triphenylmethane derivatives (further details on exact conditions and quantities are given in the see [Materials and Methods](#s1){ref-type=\"sec\"}). ",
"We first substituted the imidazole ring of clotrimazole with several other heterocycles, differently substituted carbocycles or aliphatic functional groups while keeping the 2-chlorophenyldiphenyl methane basic structure (Figure [3](#F3){ref-type=\"fig\"}). ",
"Except for T44 (pyrrol), T69 (2-aminopyridine), T89 (4-methyl-2-phenylimidazole) and the bicyclic T71 (phthalimide) and T103 (2-aminobenzothiazole), most of the heterocyclic derivatives blocked Cx50 in the low micromolar range. ",
"Spacer linked carbocycles (T102, T104, T106, T107, T109, T150) in contrast showed no effect on Cx50 at concentrations of 10 μM with the exception of T106, which was found to be a weak blocker with an IC~50~ 10 μM (Figure [4](#F4){ref-type=\"fig\"}). ",
"We next tested the heterocyclic substituted triarylmethanes for selectivity over KCa3.1 (Figure [4](#F4){ref-type=\"fig\"}). ",
"As previously reported (Wulff et al., [",
"@B33]), clotrimazole and T34 (= TRAM-34) are nanomolar KCa3.1 blockers, that exhibit IC~50~ values of 70 and 20 nM, respectively, and are therefore not useful as Cx50 inhibitors. ",
"In contrast, the aminothiazole and aminopyrimidine substituted T66 and T68 were found to be 15- to 200-fold less potent on KCa3.1 and T66 even exhibited a moderate three-fold selectivity for Cx50 over KCa3.1.",
"\n\n{#F3}\n\n{#F4}\n\nSince the alcohol T3, which is the first-step intermediate for the heterocyclic substituted triarylmethanes, was also found to reduce Cx50 currents with an IC~50~ of 2 μM we further synthesized and tested several triarylmethane alcohols, amines, nitriles, and ureas on Cx50 (Table [A1](#TA1){ref-type=\"table\"} in Appendix). ",
"While several of the alcohols including the p-chloro substituted T1, the m-chlorosubstituted T2 as well as the non-substituted triphenylmethanol and triphenylamine (T162) exhibited IC~50~ values for Cx50 in the 1--2 μM range (Table [A1](#TA1){ref-type=\"table\"} in Appendix), all these compounds lacked selectivity over KCa3.1 and were further found to inhibit other connexins like Cx43, Cx46 at similar concentrations as Cx50 (data not shown). ",
"In addition, the inhibition produced by these compounds was often enhanced by a prior application of the compounds. ",
"We therefore did not study these compounds further and instead concentrated our synthetic efforts on the heterocyclic substituted triarylmethanes and explored the substitution position of the chlorine atom on one of the phenyl rings by moving it from the ortho- to the meta- or para-position or completely removing it (Figure [5](#F5){ref-type=\"fig\"}). ",
"All four imidazole ring containing compounds (T97, clotrimazole, T143, T144) but only the o-chloro and m-chloro substituted pyrazole derivatives (T34 and T142) inhibited Cx50 channels with IC~50~s of 5--8 μM. In the 2-aminothiazole and 2-aminopyrimidine series only the o-chloro substituted T66 and T68 were active, while the other regio-isomers or the unsubstituted analogs showed no effect at 10 μM. Because the imidazole and pyrazole-substituted triarylmethanes were poorly selective for Cx50 over KCa3.1, we studied the effect of modifications of the o-chloro substituent in the 2-aminothiazole and 2-aminopyrimdine series. ",
"Specifically, we replaced the o-chloro substituent with other halogens (F, Br, I), the more lipophilic CF~3~ or OCF~3~ groups or electron-donating methyl or methoxy groups. ",
"All 14 compounds exhibited IC~50~ values in the low micromolar range (Figure [6](#F6){ref-type=\"fig\"}) with the methoxy-substituted T122 (IC~50~ 1.2 μM) and the iodo-substituted T136 (IC~50~ 2.4 μM) being the most potent (Figure [6](#F6){ref-type=\"fig\"}).",
"\n\n{#F5}\n\n{#F6}\n\nT122 and T136 are selective for Cx50\n------------------------------------\n\nThe effects of T122 and T136 on Cx50 junctional channels were further characterized using a five-point dose response curve (Figure [7](#F7){ref-type=\"fig\"}A). ",
"Non-linear least-squares fit of the individual data points to the Hill equation (see [Materials and Methods](#s1){ref-type=\"sec\"}) yielded IC~50~ values of 1.2 and 2.4 μM for the inhibition of Cx50 GJ channels by T122 and T136, respectively. ",
"In both cases, the Hill coefficients were ≈ 2 (1.6 for T122, 1.7 for T136), indicating that binding of two TRAM molecules was required to inhibit Cx50 GJ channels. ",
"Both compounds exhibited high selectivity for Cx50 channels over other connexin subtypes. ",
"The effects of T122 and T136 on GJ channels formed by several other connexins, including Cx26, Cx32, Cx40, Cx43, and Cx46 are illustrated in Figure [7](#F7){ref-type=\"fig\"}B. At a concentration of 10 μM, sufficient to cause near-maximal decreases in Cx50 junctional current, T122 and T136 did not significantly inhibit Cx26, Cx32, Cx46, or Cx43 GJ channel currents. ",
"The reduction of junction conductance was less than 20% in each of these cases. ",
"These results demonstrate that inhibition of Cx50 GJ channels by T122 and T136 is highly connexin-selective.",
"\n\n{ref-type=\"sec\"}). ",
"The EC~50~ and Hill slope values are indicated in the text. ",
"Each cell pair was exposed to only a single concentration. **(",
"B)** Bar graph illustrating that T122 (10 μM) and T136 (10 μM) has no significant effect on Cx26, Cx32, Cx43, Cx45, and Cx46 gap junction channels. ",
"Each bar represents the mean ± SEM of four to six cell pairs.](fphar-03-00106-g007){#F7}\n\nSelectivity over Kv, K~Ca~, and Nav channels\n--------------------------------------------\n\nIn order to more broadly evaluate the selectivity of T122 and T136 we further determined their effect on a panel of 12 potassium and sodium channels from various gene families (Table [1](#T1){ref-type=\"table\"}). ",
"While both compounds exerted practically no effect on the neuronal Nav1.2 and the skeletal muscle Nav1.4 channel or Kv channels from the Kv4, Kv7, Kv11, or KCa2 (SK) family, they exhibited only moderate selectivity over Kv1, Kv2, Kv3-family channels, Kv11.1 (hERG), and the calcium-activated K^+^ channels KCa1.1 and KCa3.1. ",
"T122 in particular reduced Kv1.1 currents by 65% at 10 μM, while T136 was found to have an IC~50~ of 1.3 μM for KCa3.1.",
"\n\n###### \n\n**Selectivity over other ion channels**.",
"\n\n Channel T122 (10 μM) T136 (10 μM)\n --------------- -------------------------- --------------------------\n Kv1.1 65 ± 10% block (*n* = 5) 28 ± 9% block (*n* = 5)\n Kv1.3 52 ± 2% block (*n* = 3) 18 ± 4% block (*n* = 3)\n Kv2.1 28 ± 4% block (*n* = 3) 28 ± 4% block (*n* = 3)\n Kv3.1 32 ± 12% block (*n* = 5) 37 ± 16% block (*n* = 4)\n Kv4.2 16 ± 4% block (*n* = 3) 15 ± 3% block (*n* = 3)\n Kv7.2/7.3 No effect (*n* = 3) No effect (*n* = 2)\n Kv11.1 (hERG) 42 ± 3% block (*n* = 3) 27 ± 4% block (*n* = 3)\n KCa2.3 No effect (*n* = 3) No effect (*n* = 3)\n KCa3.1 IC~50~ = 10.2 ± 0.7 μM IC~50~ = 1.3 ± 0.2 μM\n KCa1.1 (BK) 43 ± 4% (*n* = 3) 26 ± 2% (*n* = 3)\n Nav1.2 11 ± 1% block (*n* = 3) 9 ± 0.5% block (*n* = 3)\n Nav1.4 No effect (*n* = 3) No effect (*n* = 3)\n\n*Percentage of current inhibition (mean ± SD) by 10 μM T122 and T136 for a panel of cloned Kv, K~Ca~, or Nav channels. (",
"For recording conditions and pulse protocols see [Materials and Methods](#s1){ref-type=\"sec\"})*.",
"\n\nT122 and T136 inhibit coupling in the lens\n------------------------------------------\n\nCx50 is strongly expressed in the lens in both the epithelium and in fibers. ",
"In the epithelium, the functional contribution of Cx50 to epithelial cell coupling is highest during the first postnatal week (∼70--75% of total coupling on average) with the remainder being contributed by Cx43. ",
"Therefore, we determined whether T122 and T136 (10 μM) also inhibited coupling provided by Cx50 in epithelial cells (Figure [8](#F8){ref-type=\"fig\"}). ",
"The effect of T122 and T136 on junctional currents between epithelial cells isolated from mouse lenses on postnatal day 6 is shown in Figure [8](#F8){ref-type=\"fig\"}A. Both compounds strongly reduced junctional currents, an effect that was reversible on washout of the drug. ",
"The reduction of junctional currents caused by T122 and T136 ranged from 65 to 87% of the initial conductance (means ± SEM are 67 ± 9%, *n* = 7 for T122; and 64 ± 8%, *n* = 6 for T136). ",
"These values were similar to the reduction produced by quinine, which also selectively inhibits Cx50, but not Cx43 GJ channels (Figure [8](#F8){ref-type=\"fig\"}B).",
"\n\n{#F8}\n\nDiscussion\n==========\n\nA major reason for the poorly developed pharmacology of GJ channel modulators is the intercellular location of these channels, which makes it extremely difficult to design high-throughput screening assays. ",
"In our search for Cx50 inhibitors we therefore decided to screen a small library containing known ion channel modulators using conventional dual whole-cell voltage-clamp. ",
"Our library was enriched in so-called \"privileged\" structures which are small molecule pharmacophores that are able to bind to multiple targets and which are therefore highly likely to exert biological effects (Evans et al., [",
"@B7]; Horton et al., [",
"@B10]). ",
"By appropriately decorating such \"privileged\" scaffolds their potency and selectivity can often be directed toward a single target with relatively high affinity. ",
"If the template for such an SAR study is an \"old\" drug, the approach is also called SOSA approach (selective optimization of the side activity of an old drug) as suggested by Wermuth ([@B29]). ",
"Using this approach we found four structurally very different compounds able to inhibit Cx50 channels in the low micromolar range including the triarylmethane (TRAM) clotrimazole (IC~50~ 5 μM; Figure [1](#F1){ref-type=\"fig\"}). ",
"Using clotrimazole as a template, we have tested a series of previously known or newly synthesized differently substituted TRAMs for their effects on Cx50 channels and identified several compounds inhibiting Cx50 in the low micromolar range including T122, which exhibits an IC~50~ of 1.2 μM for Cx50 and excellent selectivity over other connexins. ",
"Analyzing at the structural requirements for selective Cx50 inhibition we find that the TRAM pharmacophore should contain a heteroaromatic ring system in R1 position. ",
"Smaller, less bulky substitutions with functional groups such as OH, NH, or H also result in potent Cx50 blockers (Table [A1](#TA1){ref-type=\"table\"} in Appendix), however, these types of compounds lack selectivity over other connexins and are therefore not useful as pharmacological tools. ",
"In addition to a heteroaromatic substituent in R1 position, the second requirement is that one of the phenyl rings of the triphenylmethane should be substituted preferably in ortho-position (Figure [5](#F5){ref-type=\"fig\"}), whereby it seems to be of little consequence whether the substituent is electron withdrawing (CF3 in T72) or donating (OCH3 in T122), as long as it is lipophilic. ",
"Lastly, the heteroaromatic ring system, which can be directly attached or linked by a one-atom spacer (nitrogen or sulfur), should contain at least one hydrogen-bond accepting heteroatom, which might be directly interacting with a hydrogen-bond donor in the connexin protein (e.g., see clotrimazole with its imidazole ring versus the inactive T44 and T109). ",
"It also seems that steric bulk is a limiting factor for potency, because the bulkier bicyclic derivatives T103 and T71 are ineffective while the smaller T66 and T91 inhibit Cx50.",
"\n\nSince our compounds were derived from clotrimazole, which inhibits KCa3.1 channels with an IC~50~ of 70 nM, we also tested the more active compounds for selectivity over KCa3.1. ",
"For nanomolar KCa3.1 inhibition Wulff et al. ([",
"@B33]) previously proposed a propeller-shaped pharmacophore consisting of the triphenyl moiety with an o-halogen on one of the phenyl rings and an unsubstituted, polar π-electron-rich heterocycle of limited size such as pyrazole, tetrazole, or an even smaller nitrile group in R1 position. ",
"A similar KCa3.1-inhibiting TRAM pharmacophore was described by McNaughton-Smith et al. ([",
"@B16]) as exemplified by ICA-17043 (Senicapoc^®^), which contains a carboxamide moiety in R1 position and entered clinical trials for sickle cell anemia. ",
"Considering this knowledge about the TRAM pharmacophore for KCa3.1 inhibition in our current Cx50-focused SAR study, we could achieve a drop in potency on KCa3.1 of more than 1000-fold by inserting a one-atom linker between the triphenyl moiety and the heterocycle in R1 position. ",
"This insertion, which results in a \"kink\" in the perfect propeller shape of clotrimazole or TRAM-34 shifted selectivity toward Cx50 \\[clotrimazole (IC~50~ of 70 nM for KCa3.1 and 5 μM Cx50) versus T122 (IC~50~ of 10 μM for KCa3.1 and 1.2 μM for Cx50)\\]. ",
"At concentrations of 10 μM the two most potent compounds, T122 and T136, showed excellent selectivity over other tested connexin channels including channels built out of Cx43 and Cx46, which are also expressed in the lens (inhibition \\< 18%). ",
"In addition, T122 and T136 showed very good selectivity over sodium channels (\\<11%) and moderate selectivity over most of the tested potassium channels (18--43%), except for T122, which blocked Kv1.1 by 65%. ",
"Both compounds also inhibited Cx50 mediated coupling in primary lens epithelial cells. ",
"Thus, compared to the existing pharmacological agents such as quinine and 2-APB, which exhibit poor selectivity for Cx50 channels, T122 and T136 are likely better agents for studying the role of Cx50 in lens development and the maintenance of lens transparency.",
"\n\nTaken together, we here identified the triphenylmethane scaffold as a new pharmacophore for Cx50 inhibition and synthesized two new compounds that inhibit cloned and native Cx50 channels in the low micromolar range. ",
"Even more importantly, we were able to develop a connexin subtype specific inhibitor starting with a lead compound that exhibited several fold higher selectivity for K^+^ channels over Cx50, indicating that application of a similar approach, i.e., identification of new lead compound(s) from existing ion channel libraries followed by selective optimization of their side activities, may lead to the development of specific blockers for other connexin channels such as Cx43 or Cx26.",
"\n\nConflict of Interest Statement\n==============================\n\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.",
"\n\nThis work was supported by grants from National Institute of Neurological Disorders And Stroke \\[R21NS064417\\] and the National Eye Institute \\[RO1EY13869\\]. ",
"The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute Of Neurological Disorders And Stroke or the National Eye Institute.",
"\n\n###### \n\n**IC~50~ values for Cx50 inhibition for triarymethane alcohols, amines, nitriles and ureas**.",
"\n\n Compound IC~50~ Cx50 (μM) IC~50~ KCa3.1 (μM)\n ------------------- ------------------------------ ------------------ --------------------\n T1 ![](",
"fphar-03-00106-i001.jpg) 2.8 0.53\n T2 ![](",
"fphar-03-00106-i002.jpg) 3.6 0.55\n T3 ![](",
"fphar-03-00106-i003.jpg) 2 0.52\n T54 ![](",
"fphar-03-00106-i004.jpg) 3 0.7\n T154-OH ![](",
"fphar-03-00106-i005.jpg) No effect N/A\n T117 ![](",
"fphar-03-00106-i006.jpg) No effect N/A\n T165 ![](",
"fphar-03-00106-i007.jpg) No effect N/A\n T43 ![](",
"fphar-03-00106-i008.jpg) 2 0.75\n Triphenylmethanol ![](",
"fphar-03-00106-i009.jpg) 1 0.5\n T162 ![](",
"fphar-03-00106-i010.jpg) 1.5 5.3\n T41 ![](",
"fphar-03-00106-i011.jpg) 4 1\n T75 ![](",
"fphar-03-00106-i012.jpg) No effect 1.2\n T95 ![](",
"fphar-03-00106-i013.jpg) 6 5\n T94 ![](",
"fphar-03-00106-i014.jpg) 7.3 Not tested\n T39 ![](",
"fphar-03-00106-i015.jpg) 4 0.06\n Triphenylmethane ![](",
"fphar-03-00106-i016.jpg) 0.9 3.7\n T51 ![](",
"fphar-03-00106-i017.jpg) No effect 25\n T24 ![](",
"fphar-03-00106-i018.jpg) No effect 8\n T74 ![](",
"fphar-03-00106-i019.jpg) No effect 4\n T52 ![](",
"fphar-03-00106-i020.jpg) 10 \\>50\n T53 ![](",
"fphar-03-00106-i021.jpg) 10 \\>50\n T50 ![](",
"fphar-03-00106-i022.jpg) 10 \\>50\n T160 ![](",
"fphar-03-00106-i023.jpg) 4 8.6\n T9 ![](",
"fphar-03-00106-i024.jpg) 4 1.5\n T35 ![](",
"fphar-03-00106-i025.jpg) 10 9\n\n[^1]: Edited by: Michael Pusch, Istituto di Biofisica, Consiglio Nazionale delle Ricerche, Italy\n\n[^2]: Reviewed by: Alonso P. Moreno, Cardiovascular and Training Institute at the University of Utah, USA; Andrew L. Harris, New Jersey Medical School, USA; James Hall, University of California, Irvine, USA\n\n[^3]: ^†^Heike Wulff and Miduturu Srinivas have contributed equally to this work.",
"\n\n[^4]: This article was submitted to Frontiers in Pharmacology of Ion Channels and Channelopathies, a specialty of Frontiers in Pharmacology.",
"\n"
] |
{
"pile_set_name": "PubMed Central"
}
|
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"Testimonials\n\nTanya, NYC\n\nJayne Beilby is the Marie Kondo of technology. ",
"When I started working with Jayne I had 1,300 things on the desk top of my computer. ",
"I won't even go into what my documents and download folders looked like! ",
"At the end of two hours, my desk top was clear and I had a neat and tidy filing system. ",
"Jayne was able to take my technological mess and organize it! ",
"It was as if she came in with a filing cabinet, Manila folders and a label maker. ",
"Part techy nerd, part clutter therapist, Jayne is a joy to work with. ",
"Now I have all my old photos and documents from my old computers and phones in one place, all backed up and accessible. ",
"I feel lighter, more tech savvy than I thought possible.",
"\n\nEileen, NYC\n\nWorking with Jayne is a pleasure - she is beyond patient and helpful! ",
"My computer/life was in a desperate need of cleaning up (even more than I originally thought!) ",
"and Jayne helped me organize my files, pictures, calendars, then we backed everything up and updated my operating systems. ",
"As a busy mom of three all this tidying has made my life easier. ",
"A huge takeaway for me was Jayne's \"one touch\" philosophy - at the first moment put the file where it should live permanently. ",
"Thank you Tech Tonic!"
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"Goodbye warts, hello vitiligo: Candida antigen-induced depigmentation.",
"\nDepigmentation after the use of topical immune modulators is a rare but reported event. ",
"Herein we present what is to our knowledge the first case of vitiligo at a site of Candida antigen injection."
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"Q:\n\nNestJS throw from ExceptionFilter\n\nI try to use an ExceptionFilter to map exceptions to their HTTP counterpart.",
"\nThis is my code : \n@Catch(EntityNotFoundError)\nexport class EntityNotFoundFilter implements ExceptionFilter {\n catch(exception: EntityNotFoundError, _host: ArgumentsHost) {\n throw new NotFoundException(exception.message);\n }\n}\n\nBut, when the filter code is executed, I got a UnhandledPromiseRejectionWarning\n (node:3065) UnhandledPromiseRejectionWarning: Error: [object Object]\n at EntityNotFoundFilter.catch ([...]/errors.ts:32:15)\n at ExceptionsHandler.invokeCustomFilters ([...]/node_modules/@nestjs/core/exceptions/exceptions-handler.js:49:26)\n at ExceptionsHandler.next ([...]/node_modules/@nestjs/core/exceptions/exceptions-handler.js:13:18)\n at [...]/node_modules/@nestjs/core/router/router-proxy.js:12:35\n at <anonymous>\n at process._tickCallback (internal/process/next_tick.js:182:7)\n (node:3065) UnhandledPromiseRejectionWarning: Unhandled promise rejection. ",
"This error originated either by throwing inside of an async function without a catch block, or by rejecting a promise which was not handled with .catch(). (",
"rejection id: 5)\n\nHow can I fix this ? ",
"\n\nA:\n\nThe ExceptionFilter is always the last place that gets called before a response is sent out, it is responsible for building the response. ",
"You cannot rethrow an exception from within an ExceptionFilter.",
"\n@Catch(EntityNotFoundError)\nexport class EntityNotFoundFilter implements ExceptionFilter {\n catch(exception: EntityNotFoundError, host: ArgumentsHost) {\n const response = host.switchToHttp().getResponse();\n response.status(404).json({ message: exception.message });\n }\n}\n\nAlternatively, you can create an Interceptor that transforms your errors:\n@Injectable()\nexport class NotFoundInterceptor implements NestInterceptor {\n intercept(context: ExecutionContext, next: CallHandler): Observable<any> {\n // next.handle() is an Observable of the controller's result value\n return next.handle()\n .pipe(catchError(error => {\n if (error instanceof EntityNotFoundError) {\n throw new NotFoundException(error.message);\n } else {\n throw error;\n }\n }));\n }\n}\n\nTry it out in this codesandbox.",
"\n\nA:\n\nBase on Kim Kern solution I've created this abstract class \nexport abstract class AbstractErrorInterceptor<T> implements NestInterceptor {\n protected interceptedType: new (...args) => T;\n\n intercept(\n context: ExecutionContext,\n call$: Observable<any>,\n ): Observable<any> | Promise<Observable<any>> {\n return call$.pipe(\n catchError(exception => {\n if (exception instanceof this.interceptedType) {\n this.handleError(exception);\n }\n throw exception;\n }),\n );\n }\n\n abstract handleError(exception: T);\n}\n\nAnd some implementations\nexport class EntityNotFoundFilter extends AbstractErrorInterceptor<EntityNotFoundError> {\n interceptedType = EntityNotFoundError;\n\n handleError(exception: EntityNotFoundError) {\n throw new NotFoundException(exception.message);\n }\n}\n\n"
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"The Latimers\n\nThe Latimers : A Tale of the Western Insurrection of 1794 is an historical novel by the American writer and Presbyterian clergyman Henry Christopher McCook (1837–1911) set in 1790s Pittsburgh, Pennsylvania.",
"\n\nThe novel tells the story of Scotch-Irish American pioneers during the Whiskey Rebellion.",
"\n\nSee also\n\nOther novels that employ events of the Whiskey Rebellion:\n The Whiskey Rebels (2008)\n Wilderness Boy (1955)\n The Delectable Country (1939)\n\nReferences\n\nExternal links\nThe Latimers : A Tale of the Western Insurrection of 1794 (1898) (Historic Pittsburgh e-text)\n\nCategory:1898 American novels\nCategory:Novels set in Pittsburgh\nCategory:Scotch-Irish American culture in Pennsylvania\nCategory:Fiction set in the 1790s"
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"###### Summary box\n\n- China has made considerable achievements in controlling hepatitis B and C through multiple strategies with efforts focused on prevention and increased treatment financing.",
"\n\n- Formidable challenges remain in combating hepatitis by 2030. ",
"Key health system barriers, including a fragmented governance system, insufficient funding, inadequate service coverage and unstandardised treatment, and flawed information systems, have compromised the effective control of viral hepatitis.",
"\n\n- To tackle these challenges, China must take five immediate actions: restructuring the governance system of viral hepatitis, optimising resource allocation and increasing the efficiency of funding, improving access to and the quality of the health benefits package, strengthening information systems and boosting investment on hepatitis research and development.",
"\n\nIntroduction {#s1}\n============\n\nInfection with chronic viral hepatitis can be caused by exposure to five different types of viruses (hepatitis A, B, C, D, E). ",
"Hepatitis B virus (HBV) and hepatitis C virus (HCV) account for 96% of all deaths related to viral hepatitis.[@R1] China is the country experiencing the highest burden of these infections,[@R2] with the WHO estimating that in 2016, 90 million people were living with chronic HBV infection and 10 million with chronic HCV infection in China, accounting for one-third and 7% of the global infections, respectively.[@R4] Chronic HBV and HCV infection can progress to cirrhosis, hepatocellular carcinoma and premature death without proper treatment.[@R5] Chronic HBV infections are associated with increased risk of other cancers including stomach cancer, colorectal cancer, oral cancer, pancreatic cancer and lymphoma.[@R6] Among people living with chronic HBV and HCV, around 7 million and 2.5 million needed urgent treatment in China due to advanced liver diseases or the high risk of developing into cancer, respectively, in 2016.[@R4] In 2017, there were an estimated 310 079 and 124 645 deaths due to chronic HBV and HCV infections, respectively, in China, according to the Global Burden of Diseases (GBD) 2017 Study.[@R7]\n\nViral hepatitis control in China is governed by the Bureau of Disease Prevention and Control, National Health Commission (NHC) and overseen by health commissions at the provincial, prefecture and county levels across the country. ",
"Under the regulatory supervision of NHC, the Chinese Center for Disease Control and Prevention (China CDC) is responsible for disease prevention and management, while hospitals provide clinical diagnosis and treatment. ",
"The Division of Immunization Planning Management and Division of HIV/AIDS Prevention and Control within NHC is responsible for hepatitis B and C control, respectively. ",
"The same governance structure for hepatitis B and C control has been put in place at the China CDC system nationwide.",
"\n\nViral hepatitis is increasingly garnering global attention and is included in the United Nations' 2030 Agenda for Sustainable Development Goals (SDGs) where SDG 3.3 calls for 'combat viral hepatitis'.[@R8] At the same time, in 2016, WHO published its first Global Health Sector Strategy on Viral Hepatitis 2016--2021, which established nine quantitative global targets, such as 'reducing new cases of chronic viral hepatitis B and C infections by 90% and deaths by 65% by 2030'.[@R9] The first Action Plan for the Prevention and Treatment of Viral Hepatitis in China (2017--2020) was jointly published by 11 ministries in 2017, which set out 6 targets, 4 of which corresponded with WHO's targets ([table 1](#T1){ref-type=\"table\"}).[@R10] Despite the priorities and action recommendations put forward by the international community to eliminate hepatitis globally and analysis of eliminating hepatitis B in China,[@R11] we present key achievements, identify gaps and challenges, and proposes next steps to specifically help China end hepatitis B and C as a major public health threat by 2030.",
"\n\n###### \n\nThe hepatitis targets set by WHO and China\n\n ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------\n Target area WHO 2020 targets\\ WHO 2030 targets\\ China 2020 targets\n (base year: 2015) (base year: 2015) \n ------------------------------------------------------------------------------------------------------------------------------------------------- ------------------------------------------------------------------------------------------------ --------------------------------------------------------- ---------------------------------------------------------\n Impact targets \n\n Incidence: new cases of chronic viral hepatitis B and C infections 30% reduction\\ 90% reduction\\ Keeping \\<1% prevalence of HBsAg among children under 5\n (equivalent to 1% prevalence of HBsAg among children) (equivalent to 0.1% prevalence of HBsAg among children) \n\n Mortality: viral hepatitis B and C deaths 10% reduction 65% reduction No quantitative target\n\n Service coverage targets \n\n HBV vaccination: childhood third dose vaccination coverage 90% 90% Keeping \\>95%\n\n Prevention of HBV mother-to-child transmission: HBV birth-dose vaccination coverage or other approaches to prevent mother-to-child transmission 50% 90% Keeping \\>90%\n\n Blood safety 95% of donations screened in a quality-assured manner 100% of donations screened in a quality-assured manner 100% of donations screened in a quality-assured manner\n\n Safe injections: percentage of injections administered with safety-engineered devices in and out of health facilities 50% 90% No quantitative target\n\n Harm reduction: number of sterile needles and syringes provided per person who injects drugs per year 200 300 No quantitative target\n\n Viral hepatitis B and C diagnosis 30% 90% No quantitative target\n\n Viral hepatitis B and C treatment Globally 5 million people receiving HBV treatment and 3 million people receiving HCV treatment 80% No quantitative target\n\n China-specific service coverage targets \n\n Public awareness of viral hepatitis prevention and control knowledge \\>50%\n\n Drug dependence treatment coverage to opioid users \\>70%\n ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------\n\nSources: Global health sector strategy on viral hepatitis 2016--2021: towards ending viral hepatitis & Action plan for the prevention and treatment of viral hepatitis in China (2017--2020).",
"\n\nHBsAg, HBV surface antigen; HBV, Hepatitis B virus; HCV, hepatitis C virus.",
"\n\nApproach {#s2}\n========\n\nThis article collected quantitative and qualitative data for analysis. ",
"Quantitative data were collected from published literature in Chinese and English, GBD 2017 Study estimates,[@R3] the infectious diseases surveillance reporting system (IDSRS) and reports published by related governmental agencies. ",
"The health outcome projection results are estimated using the adjusted model developed by the GBD SDG team.[@R13] Also, this paper includes qualitative findings from nine interviews purposively conducted among key stakeholders, including policy-makers, hepatitis control professionals and clinicians at national and provincial levels from Jiangsu, Hubei and Yunnan provinces representing eastern, central and western China, respectively, in 2017. ",
"The current study is part of a large-scale project assessing the progress of China in achieving health-related SDGs, and which has published detailed methods on the qualitative data collection and analysis and the projection model.[@R14]\n\nAchievements in hepatitis B and C control in China {#s3}\n==================================================\n\nChina has made substantial progress in controlling HBV and HCV infections over the past few decades. ",
"Based on the national seroepidemiology surveys conducted by China CDC since the 1990s, the seroprevalence of HBV surface antigen (HBsAg) among children \\<15 years old has declined from 10.5% in 1992 to 0.8% in 2014, and reached 0.3% among children under age 5 in 2014.[@R15] The overall seroprevalence of anti-HCV antibody fell from 3.2% in 1996 to 0.43% in 2006.[@R16] These achievements in China may, to a large extent, be attributed to the four national programmes or policies as outlined below.",
"\n\nFirst, China's HBV childhood immunisation programme has been recognised by WHO for its remarkable success.[@R18] China was among the first developing countries to establish an HBV immunisation programme in 1992, recommending timing the first dose vaccination within 24 hours of birth and the second and third doses at 1 month and 6 months of birth, respectively.[@R19] In 2002, with financial support from both the GAVI Alliance and the Chinese Government, the HBV vaccine was included in the National Immunization Program and made available free of charge to all newborns by 2005.[@R20] An estimated total of ¥20.3 billion (¥1≈ US\\$0.14) was allocated by the central government to support the programme between 1992 and 2005.[@R21] In 2009, the programme was further expanded to vaccinate children aged ≤15 years, with 68 million children successfully vaccinated.[@R22] Thanks to the effective implementation of this policy, the three-dose vaccine coverage tripled from 30.0% in 1992 to 99.6% in 2015 with the timely first dose rate increasing from 22.2% to 95.6% during the same period.[@R23]\n\nSecond, comprehensive programmes to prevent mother-to-child transmission boosted HBV transmission control. ",
"Mother-to-child transmission is estimated to be responsible for 40%--50% of new HBV infections in China.[@R24] Beginning in 2011, China initiated a national programme for integrated prevention of mother-to-child transmission (PMTCT) of HIV, syphilis and HBV. ",
"The programme includes free HBV screening services during pregnancy and administration of hepatitis B immunoglobulin within 12 hours of birth for babies born to HBV-infected mothers. ",
"It was expanded nationwide in 2015, and around ¥1.4 billion has been invested annually to cover the HBV-related services, which reached 95.6% coverage in 2015.[@R25]\n\nThird, full coverage of nucleic acid amplification testing (NAT) in all blood stations substantially improved blood safety and prevented transfusion-transmitted infections, including HBV and HCV. ",
"The probability of transmitting via blood is especially high for HCV, and NAT can detect low levels of virus during a window period. ",
"NAT was included in routine donor screenings and piloted in 14 selected blood stations of 11 provinces since 2010.[@R27] This practice was expanded nationwide in 2014 and received 1 billion RMB from the central budget to fund implementation in all blood stations.[@R28]\n\nLastly, China has made remarkable progress in implementing effective financing policies to make HBV and HCV drugs affordable over the past few years. ",
"Entecavir and tenofovir, two WHO-recommended first-line HBV drugs, were included in the updated National List of Reimbursable Medicines (NLRM) in February 2017.[@R29] The two drugs were further selected into the '4+7 Cities Centralized Drug Procurement Document', published in November 2018, a novel procurement pilot scheme aiming to dramatically cut the price paid for generic drugs through centralised joint procurement.[@R30] Due to these efforts, the prices of entecavir and tenofovir have been substantially reduced, especially in the '4+7 Cities' where it only takes around ¥18 (less than US\\$3) to complete 1 month entecavir or tenofovir treatment. ",
"By 2017, all the antiviral drugs recommended by the Chinese guidelines to treat HBV, including interferon-alfa, pegylated interferon-alfa and five nucleoside analogues, had been included in the NLRM.[@R28] Remarkably, in recent years, treatment for HCV has vastly improved, and the sustained virological response rate of pan-genotypic Direct-Acting Antivirals (DAAs) has reached over 95%.[@R31] Elbasvir--grazoprevir, ledipasvir--sofosbuvir and sofosbuvir--velpatasvir tablets can cure two, four and six main genotypes of HCV, respectively, though these medications are very expensive. ",
"They received expedited approval from the National Medical Products Administration to be marketed in China in 2018.[@R32] The recent NLRM updated on 28 November 2019 has included the three HCV drugs, and the prices are expected to drop by 85% on average.[@R33]\n\nGaps and challenges {#s4}\n===================\n\nChina has almost reached WHO's targets for HBsAg prevalence (0.3% in 2014 among children under 5), HBV vaccination (99.6% in 2015), PMTCT (95.6% in 2015) and blood safety (100% blood screening since 2014; See [table 1](#T1){ref-type=\"table\"} for specific target definition).[@R15] However, progress has been much slower in reaching the remaining five targets surrounding deaths, diagnosis and treatment of hepatitis B and C, and safe injections and harm reduction. ",
"China's Hepatitis Action Plan has not established any quantitative goals to close this gap. ",
"Based on data available, we were only able to project the number of expected deaths. ",
"It is estimated that the total number of deaths due to hepatitis B and C would increase from 434 724 in 2017 to 527 829 in 2030. ",
"Particularly, mortality will be predominately driven by liver cancer caused by hepatitis B and C ([figure 1](#F1){ref-type=\"fig\"}). ",
"Based on our interviews, reversing this trend cannot be done without addressing the following challenges.",
"\n\n{#F1}\n\nThe governance system of viral hepatitis control is fragmented in China. ",
"There is no specific single department or unit within the NHC or CDC to plan and lead hepatitis control work centrally. ",
"Currently, viral hepatitis is managed by different departments at the NHC or CDC based on similar transmission patterns or control strategies with other diseases. ",
"The Division of Immunization Planning Management leads HBV prevention through the vaccination programme, while the Division of HIV/AIDS Prevention and Control leads hepatitis C prevention given similar transmission patterns between HIV and HCV. ",
"The fragmented governance system has resulted in a lack of central strategic planning and leadership, which has further led to inadequate financial and personnel support. ",
"For example, we found through our interviews that hepatitis C control is highly dependent on the work plan, budget, skills and personnel of HIV/AIDS.",
"\n\nHealth financing is insufficient to fund the elimination of hepatitis B and C in China. ",
"Prevention and control strategies rely on domestic governmental funding that currently covers vaccination and PMTCT services of hepatitis B. However, a minimal amount of funding is explicitly allocated to hepatitis C, except for that bundled within HIV/AIDS control. ",
"Consequently, there is a massive gap in funding for crucial routine work such as disease surveillance (eg, the HBV seroepidemiology surveys have been funded by the Ministry of Science and Technology through research project applications), and the gap is even more massive for hepatitis C control with little support to implement effective prevention strategies. ",
"Although recommended HBV drugs have been included in the NLRM for over 3 years, the actual reimbursement rates vary greatly across China due to the decentralised management and risk pooling across Chinese health insurance schemes. ",
"This policy poses formidable challenges in achieving universal hepatitis treatment. ",
"It will be the same case for the HCV drugs recently added into the NLRM if no effective actions are taken.",
"\n\nThe delivery of comprehensive health services for hepatitis B and C, including prevention, testing, diagnosis and treatment, has not achieved its ideal coverage and standardisation. ",
"Hospital-acquired infections have not been prevented in low-tiered hospitals or hospitals in remote areas, which may follow less strict sterilisation procedures and skip testing HCV before surgical operations. ",
"The coverage of harm reduction practices to prevent HCV infection among drug users is low given stigma, discrimination and legality of using drugs.[@R11] HBV testing was removed from routine health check-ups for new employees and students in 2010 to avoid discrimination against people infected with HBV.[@R35] The diagnosis and treatment rate of hepatitis B and C remains extremely low according to our interviews, though there is no public data available to confirm this. ",
"For people who are diagnosed and treated, overtreatment is common with hospitals in China incentivised to prescribe drugs, particularly auxiliary medications to generate income.",
"\n\nThe information system of viral hepatitis is unable to provide adequate data on the hepatitis epidemic for strategic planning. ",
"The current information system, IDSRS, primarily captures HBV and HCV new infections and deaths while providing little information on critical indicators such as service coverage, diagnosis and treatment. ",
"Duplication of data undermines its quality and accuracy.",
"\n\nOptions for actions towards eliminating viral hepatitis B and C in China {#s5}\n========================================================================\n\nIn light of the above challenges and taking into account recommendations from literature and key stakeholder interviews, we propose five strategic priority actions to help achieve the international and domestic targets and eliminate viral hepatitis in China.",
"\n\nFirst, restructure the governance system for viral hepatitis control within NHC and the China CDC to change the current fragmented management situation. ",
"It is suggested that the NHC establish a separate and independent division for viral hepatitis under the Disease Control Bureau to lead the national viral hepatitis control effort, with the Health Commission and CDC at different administrative levels making similar structural changes. ",
"The department should have its own team, budget and work plan with performance indicators to ensure successful operation.",
"\n\nSecond, optimise resource allocation and increase the efficiency of funding to ensure sufficient and sustainable health financing for hepatitis elimination. ",
"It is essential that the NHC identify the funding required to achieve targets, and develop a comprehensive and feasible hepatitis control budget to cover the continuum of health services. ",
"The NHC worked with WHO to develop an investment plan for hepatitis in 2016, though it remains unclear if and how this plan will be used for strategic planning. ",
"Meanwhile, the NHC can work with the Ministry of Finance and the National Healthcare Security Administration on funding resource mobilisation and reallocation for sustained viral hepatitis health financing, ideally under the designated leadership of the State Council. ",
"It is essential to standardise treatment and reduce drug prices to increase funding efficiency. ",
"Regional disparities in health insurance coverage need to be assessed and addressed through central budgeting compensations.",
"\n\nThird, improve access to and quality of the health benefits package for patients with viral hepatitis, especially for high-risk groups. ",
"The five core interventions proposed by WHO ([box 1](#B1){ref-type=\"boxed-text\"}) to be included in benefits packages are available in China, while extra efforts need to be invested in strengthening surgical safety and other sources of hospital-acquired infections and harm reduction services.[@R9] It is critical to increase the identification of the number of infected individuals with an effective disease surveillance system using better testing and diagnosis accuracy, coverage and reporting. ",
"It is vital to increase the treatment rate by developing a standard treatment package with sufficient financial coverage, particularly for low-income populations, and an individualised patient management system, especially for HBV lifelong treatment ([box 2](#B2){ref-type=\"boxed-text\"}). ",
"High-risk populations, including healthcare workers, people born to mothers with hepatitis B, injection drug users, indigenous peoples and ethnic minorities, prisoners, migrants, men who have sex with men, persons coinfected with HIV and hepatitis, and blood donors need to be identified and prioritised for specific prevention, testing, diagnosis, care and treatment.[@R9] Tailored interventions for these high-risk populations can be implemented to microeliminate hepatitis within the discrete group.[@R36] It is important to address HBV and HCV-related stigma and discrimination, through identifying the drivers of this discrimination, alongside population-wide health education programmes.",
"\n\n###### Five core viral hepatitis interventions proposed by WHO\n\n- HBV vaccination;\n\n- Injection, blood and surgical safety and universal precautions;\n\n- Prevention of mother-to-child transmission of hepatitis B virus;\n\n- Harm reduction services for people who inject drugs;\n\n- Treatment of chronic hepatitis B virus and hepatitis C virus infection.",
"\n\nSource: Global Health Sector Strategy on Viral Hepatitis, 2016--2021, WHO\n\n###### Hepatitis B and C treatment challenges and proposed options for actions in China\n\nEffective prevention interventions have reduced new hepatitis B virus (HBV) infections and put new hepatitis C virus (HCV) infections under control in China. ",
"Treating the large number of people with HBV and HCV needs to be prioritised to meet viral hepatitis elimination targets.",
"\n\nAddressing low hepatitis B and C treatment rates largely due to inadequate case identification and high patient financial burden face formidable challenges with respect to service coverage, service quality and financial protection. ",
"The treatment success rate is an issue for people infected with hepatitis B, who have to receive lifelong treatment despite the asymptotic nature and side effects. ",
"The quality of service provided varies by hospital, and there are no standardised treatment packages. ",
"Overprescription of medicines is prevalent, especially auxiliary medicines, as a way to generate revenues. ",
"Effective financing strategies have improved the financial protections for patients with hepatitis, especially for patients with hepatitis B in the '4+7 Cities'.",
"\n\nLooking ahead, China must take urgent actions to improve the treatment service coverage, quality and affordability for people infected with HBV and HCV. ",
"Key recommendations are:\n\n- Increase identification of infected individuals through a better surveillance system and improved testing and diagnosis accuracy. ",
"Resource-rich provinces and cities can implement active patient identification strategies, while working on removing stigma and discrimination through population-wide health education programs.",
"\n\n- Develop a standardised treatment package and ensure it is well implemented at different levels of clinical institutions. ",
"Considering the root cause of overprescription, strategies to rationalise physicians' salary and apply the diagnosis-related groups or capitation payment need to be in place. ",
"Capacity training for physicians and carefully designed performance evaluation indicators are also essential to ensure the successful implementation.",
"\n\n- Strengthen patient management to improve medication adherence. ",
"This is especially important for patients with hepatitis B. Hospitals should apply individual patient management to them, similar to the treatment and management of patients with HIV/AIDs.",
"\n\n- Decrease patient financial burden due to treatment, especially for low-income groups. ",
"Economic analysis has demonstrated high cost effectiveness of investing HBV and HCV treatment drugs in many countries. ",
"Despite the huge progress, continuing investment needs to be made on reducing drug price and increasing reimbursement rate especially for the low-income patients to increase equity.",
"\n\nFourth, strengthen information systems to obtain high-quality hepatitis epidemiological data. ",
"A well-designed quality control system needs to be established and implemented to avoid inaccurate and duplicate cases of hepatitis infection and hepatitis-related death. ",
"The system should also integrate process indicators for service coverage to capture data throughout the continuum of care, making it possible to assess the national hepatitis burden and monitor access to, uptake of and quality of services delivered.",
"\n\nLastly, boost investment for hepatitis research and development (R&D) innovations. ",
"It is unlikely for either the world or China to eliminate the viral hepatitis burden unless significant progress is made to develop new medicines, technologies and innovative service delivery approaches. ",
"Continuing and increasing investment is necessary to improve the prevention, testing, diagnostics, treatment and patient management of chronic viral hepatitis. ",
"Particularly, priority should be placed on R&D in effective HCV vaccination and short-course HBV curative treatments.",
"\n\nConclusion {#s6}\n==========\n\nThis article highlights recent improvements in the control of hepatitis B and C in China and how they can be furthered. ",
"Given projections for increased deaths due to hepatitis B and C in China and the large numbers of individuals infected with hepatitis B and C, it is critical to urgently develop and implement a set of concerted actions, as proposed above, with adequate resources put in place to support the effective implementation of these actions. ",
"Inaction, or delay in taking these actions, would have to make a negative impact on a large number of Chinese households and society.",
"\n\nThe work reported in this publication is part of the research \\'Achieving Health-related SDGs in China: Developing Evidence-based Policy Options for Action\\' supported by the Bill & Melinda Gates Foundation. ",
"The authors are grateful for all the interviewees from national and provincial government agencies and hospitals who took the time to answer our questions. ",
"They also want to sincerely thank their collaborating universities and their faculty and students who made significant contributions to this study, particularly Rae Jean Proeschold-Bell from Duke Global Health Institute (DGHI) for her insightful comments as a hepatitis expert, John S Ji from Duke Kunshan University (DKU) for his language edits, Guanshen Dou from Fudan University, Xiyu Ding from DKU and Jiyan Ma from DGHI for their research assistance.",
"\n\n**Handling editor:** Alberto L Garcia-Basteiro\n\n**Contributors:** SC, WM, JZ and ST conceptualised the manuscript. ",
"SC, WM and LG did investigation, developed methodology, collected, analysed and visualised the data. ",
"JZ and ST supervised the research team. ",
"ST acquired the funding and is the guarantor of the article. ",
"SC wrote the original draft. ",
"All authors reviewed and edited the manuscript.",
"\n\n**Funding:** This research is funded by the Bill and Melinda Gates Foundation (OPP1148464).",
"\n\n**Disclaimer:** The funder did not play any role in the study design, data analysis, data interpretation, writing or submission for this publication.",
"\n\n**Competing interests:** None declared.",
"\n\n**Patient and public involvement:** Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.",
"\n\n**Patient consent for publication:** Not required.",
"\n\n**Ethics approval:** This study obtained ethical approval from the Duke University Institutional Review Board (IRB number: 2017-1359) in 2017.",
"\n\n**Provenance and peer review:** Not commissioned; externally peer reviewed.",
"\n\n**Data availability statement:** All quantitative data in this manuscript are publicly available. ",
"The results from GBD 2017 can be found at the Global Health Data Exchange website (<http://ghdx.healthdata.org/gbd-results-tool>). ",
"Other quantitative data can be found through their references.",
"\n"
] |
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[
"Chris Bosh Appreciation Thread\n\nYeah I know, Chris Bosh did not leave the organisation under the best of terms but lets put that aside for now and apperciate the player that played for the Raptors for 7 seasons and represented the team while arguably being the best player they ever had in the long haul.",
"\n\nYou're right he didn't leave as quietly as most would've liked but you still can't ignore the fact that he played hard and well for most of the games he played in while he was here. ",
"He leaves the Raptors to as its all-time leader in points, rebounds, blocks, double doubles, free throws made and attempted, and minutes played.",
"\n\nI think he really liked playing in Toronto but with the team as it is now how can you blame him for not wanting to try someplace else?",
"\n\nI can't believe how much flack Bosh gets. ",
"He had the worst point guards possible. ",
"Why doesn't Jose ever get it for his inability to create for the big men? ",
"Has anybody ever seen Jose throw an oop? ",
"Good luck Bosh, I hope your talents are exploited like they should be!",
"\n\nI can't believe how much flack Bosh gets. ",
"He had the worst point guards possible. ",
"Why doesn't Jose ever get it for his inability to create for the big men? ",
"Has anybody ever seen Jose throw an oop? ",
"Good luck Bosh, I hope your talents are exploited like they should be!",
"\n\nI will wish Bosh (aka RuPaul ) well because he answered my prayers and left Toronto. ",
"I cannot stand his game, and I'm glad to see him move on to another team as it's second ranked player ( for now). ",
"I also wish him well and will cheer when he is in Toronto and he gets the ball only to hold it indecisively for 10 seconds before he tries to drive and gets rejected by one of our bigs. ",
"I will also cheer when one of our bigs, or athletic wingmen drives right over RuPaul to slam the ball. ",
"I will however save the biggest cheers for when Bosh ( RuPaul) makes the playoffs, and sees a real defense and does his usual .....absolutely nothing. ",
"I would cheer even louder if RuPaul was somehow lucky enough to make it to the finals where Gasol would eat him up and spit him out on both ends of the floor. ",
"I will also cheer during the last couple of years of RuPaul's contract when he is playing about 55 games a year and plays like the pussy we all know him to be. ",
"Oh and no he is not the greatest Raptor of all time as he's not even close to the talent or accomplishments of Vince Carter regardless of what happened with him, and yes I will boo him when he returns to the ACC for being such a lying sack of shit media whore and screwing the Raptors in the process. ",
"What happened to wanting to be The Man?? ",
"He's just accepted a job as Wade's bitch, and if by chance LBJ signs there too RuPaul will be washing their laundry after games.",
"\n\nIt goes to show what kind of people you are, taking time out of your day to to write hateful things about someone that you don't know or probably have never met. ",
"You all post the same shit every post. ",
"Fuckin give it up, its getting old fast. ",
"Good luck Chris, I had hope you departure would have been a little smoother but for seven years you were a professional that represented yourself and the franchise as well as can be expected. ",
"I don't know what happned between you and the raptors management but as long as your'e not playing against Toronto you are the only one on that team I will cheer for. ",
"Hope you find what you are looking for professionaly. ",
"Thanks for the good and bad times afterall its only sports.",
"\n\nBosh is gonna be booed but he really doesnt need to be. ",
"its bs that we arent gonna get anything for him but thats not really his fault nor is it his fault we havent been winning. ",
"We are gonna look like a bunch of whiners if we do to him what we do to VC\n\nI feel very \"meh\" about this. ",
"I remember when the whole VC thing was going down, I had all kinds of venom for him. ",
"But CB4 leaving? ",
"It doesn't stir up much of an emotional response. ",
"I don't wish him well or wish him harm. ",
"He's gone and that's that. ",
"Didn't lead the Raptors to anything significant. ",
"A stat-machine who's not much of a winner. ",
"Mediocre defender, mediocre leader. ",
"He reminds me of Shareef Abdur Rahim. ",
"Miami is probably the right fit for him. ",
"Looking forward to next season without a sword over the collective team's heads though. ",
"Good luck Chris, I guess."
] |
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| 5
|
[
"Fed says economy grows ‘modestly’ as housing, autos improve\n\nThe Federal Reserve said today that the U.S. economy was expanding “modestly” last month, supported by improvements in housing and auto sales, even as the labor market showed little change.",
"\n\n“Consumer spending was generally reported to be flat to up slightly since the last report,” the Fed said in its Beige Book business survey, which is based on accounts from the 12 district Fed banks. ",
"Conditions in manufacturing were “somewhat improved,” according to the report, which provides anecdotal evidence on the health of the economy two weeks before the Federal Open Market Committee meets in Washington on Oct. 23-24.",
"\n\nThe Fed on Sept. 13 announced a third round of quantitative easing, with purchases of $40 billion a month of mortgage debt, and said its benchmark interest rate was likely to stay low through the middle of 2015.",
"\n\nThe report’s description of the economy is not as positive as Beige Books earlier in the year, which used the word “moderate” to describe the pace of expansion, said Dana Saporta, U.S. economist at Credit Suisse Group AG in New York. “",
"In Fed parlance, modest is a step down from moderate,” she said.",
"\n\nWhile “employment conditions were little changed since the last report,” several districts reported shortages of highly skilled workers, the Beige Book said.",
"\n\nThe New York district reported economic activity had “leveled off” and Kansas City indicated “some slowing in the pace of growth.” ",
"The Fed said that “in general, other districts reported that growth continued at a modest pace.”",
"\n\nThe housing market showed “widespread improvement since the last report,” according to the Fed with all twelve districts reporting that “existing home sales strengthened, in some cases substantially.”",
"\n\nThe Fed’s previous Beige Book report said six districts reported “modest” growth, while three called it “moderate.” ",
"The Philadelphia and Richmond Feds said growth was slow in most industries while manufacturing declined. ",
"The Boston Fed cited “some slowdown.”"
] |
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| 5
|
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