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10.1101/000547 | Varing chemical equilibrium gives kinetic parameters | Edward Flach;Santiago Schnell; | Edward Flach | Ronin Institute | 2013-11-16 | 1 | New Results | cc_by | Biochemistry | https://www.biorxiv.org/content/early/2013/11/16/000547.source.xml | We are interested in finding the kinetic parameters of a chemical reaction. Previous methods for finding these parameters rely on the dynamic behaviour of the system. This means that the methods are time-sensitive and often rely on non-linear curve fitting. | NA | biorxiv | 0 |
10.1101/000786 | Cycling Physicochemical Gradients as ‘Evolutionary Drivers’: From Complex Matter to Complex Living States | Jan Spitzer; | Jan Spitzer | MCP Inc | 2013-11-20 | 1 | New Results | cc_by_nc_nd | Biophysics | https://www.biorxiv.org/content/early/2013/11/20/000786.source.xml | HighlightsO_LIBiological complexity cannot be reduced to chemistry and physics\nC_LIO_LIComplex living states are: multicomponent, multiphase, crowded, and re-emergent\nC_LIO_LILiving states arise naturally only by the action of cycling physicochemical gradients\nC_LIO_LIBacterial cells can be modeled as viscoelastic capacitors with sol-gel transitions\nC_LIO_LIEvolving living states can be investigated via biotic soup experimentation\nC_LIO_LIDarwinian evolution arises from the process errors of the cell cycle\nC_LIO_LISynthetic biology heralds the transition from unintentional Darwinian evolution to intentional anthropic evolution\nC_LI\n\nAbstractWithin the overlap of physics, chemistry and biology, complex matter becomes more deeply understood when high level mathematics converts regularities of experimental data into scientific laws, theories, and models (Krakauer et al., 2011. The challenges and scope of theoretical biology. J. Theoret. Biol. 276: 269-276). The simplest kinds of complex biological matter are bacterial cells; they appear complex-from a physicochemical standpoint-because they are multicomponent, multiphase, biomacromolecularly crowded, and re-emergent; the property of re-emergence differentiates biological matter from complex chemical and physical matter.\n\nBacterial cells cannot self-reassemble spontaneously from their biomolecules and biomacromolecules (via non-covalent molecular forces) without the action of external drivers; on Earth, such drivers have been diurnal (cycling) physicochemical gradients, i.e. temperature, water activity, etc. brought about by solar radiation striking the Earths rotating surface. About 3.5 billion years ago, these cycling gradients drove complex chemical prebiotic soups toward progenotic living states from which extant bacteria evolved (Spitzer and Poolman, 2009; The role of biomacromolecular crowding, ionic strength and physicochemical gradients in the complexities of lifes emergence. Microbiol. Mol. Biol. Revs. 73:371-388). Thus there is historical non-equilibrium continuity between complex dead chemical matter and complex living states of bacterial cells. This historical continuity becomes accessible to present-day experimentation, when cycling physicochemical gradients act on dead biomacromolecules obtained from (suitably) killed bacterial populations - on a biotic soup of chemicals (Harold, 2005, Molecules into cells: specifying spatial architecture. Microbiol. Mol. Biol. Rev. 69:544-564). The making of biotic soups and recovering living states from them is briefly discussed in terms of novel concepts and experimental possibilities.\n\nIn principle, emergent living states contingently arise and evolve when cycling physicochemical gradients continuously act on complex chemical mass; once living states become dynamically stabilized, the inevitable process errors of primitive cell cycles become the roots of Darwinian evolution. | NA | biorxiv | 2 |
10.1101/000125 | A filter-flow perspective of hematogenous metastasis offers a non-genetic paradigm for personalized cancer therapy | Jacob G Scott;Alexander G Fletcher;Philip K Maini;Alexander R A Anderson;Philip Gerlee; | Jacob G Scott | H. Lee Moffitt Cancer Center and Research Institute and University of Oxford | 2013-11-07 | 1 | New Results | cc_by | Cancer Biology | https://www.biorxiv.org/content/early/2013/11/07/000125.source.xml | Translational RelevanceSince the discovery of circulating tumor cells (CTC), we have struggled for ways to use them to inform treatment. The only currently accepted method for this is a more is worse paradigm by which clinicians measure CTC burden before and after treatment to assess efficacy. Research efforts are currently focused almost entirely on genetic classification of these cells, which has yet to bear any fruit translationally. We suggest that we should shift the focus of our investigation to one driven by a physical sciences perspective. Specifically, by understanding the vascular system as a network of interconnected organs and capillary beds as filters that capture CTCs. By ascertaining the distribution of CTCs in this network for individual patients, information about the existence of subclinical metastatic disease, and therefore metastatic propensity, will come to light, and allow for better staging, prognostication and rational use of organ-directed therapy in the setting of oligometastatic disease.\n\nAbstractO_ST_ABSPurposeC_ST_ABSResearch into mechanisms of hematogenous metastasis has largely become genetic in focus, attempting to understand the molecular basis of seed-soil relationships. However, preceding this biological mechanism is the physical process of dissemination of circulating tumour cells (CTCs) in the circulatory network. We utilize a novel, network perspective of hematogenous metastasis and a large dataset on metastatic patterns to shed new light on this process.\n\nExperimental DesignThe metastatic efficiency index (MEI), previously suggested by Weiss, quantifies the process of hematogenous metastasis by taking the ratio of metastatic incidence for a given primary-target organ pair and the relative blood flow between the two sites. In this paper we extend the methodology by taking into account the reduction in CTC number that occurs in capillary beds and a novel network model of CTC flow.\n\nResultsBy applying this model to a dataset of metastatic incidence, we show that the MEI depends strongly on the assumptions of micrometastatic lesions in the lung and liver. Utilizing this framework we can represent different configurations of metastatic disease and offer a rational method for identifying patients with oligometastatic disease for inclusion in future trials.\n\nConclusionsWe show that our understanding of the dynamics of CTC flow is significantly lacking, and that this specifically precludes our ability to predict metastatic patterns in individual patients. Our formalism suggests an opportunity to go a step further in metastatic disease characterization by including the distribution of CTCs at staging, offering a rational method of trial design for oligometastatic disease. | 10.1016/j.ejca.2014.08.019 | biorxiv | 3 |
10.1101/000141 | Microenvironmental variables must influence intrinsic phenotypic parameters of cancer stem cells to affect tumourigenicity | Jacob Scott;Anita Hjelmeland;Prakash Chinnaiyan;Alexander R A Anderson;David Basanta; | Jacob Scott | H. Lee Moffitt Cancer Center and Research Institute and University of Oxford | 2013-11-07 | 1 | New Results | cc_by_nc | Cancer Biology | https://www.biorxiv.org/content/early/2013/11/07/000141.source.xml | Since the discovery of tumour initiating cells (TICs) in solid tumours, studies focussing on their role in cancer initiation and progression have abounded. The biological interrogation of these cells continues to yield volumes of information on their pro-tumourigenic behaviour, but actionable generalised conclusions have been scarce. Further, new information suggesting a dependence of tumour composition and growth on the microenvironment has yet to be studied theoretically. To address this point, we created a hybrid, discrete/continuous computational cellular automaton model of a generalised stem-cell driven tissue with a simple microenvironment. Using the model we explored the phenotypic traits inherent to the tumour initiating cells and the effect of the microenvironment on tissue growth. We identify the regions in phenotype parameter space where TICs are able to cause a disruption in homeostasis, leading to tissue overgrowth and tumour maintenance. As our parameters and model are non-specific, they could apply to any tissue TIC and do not assume specific genetic mutations. Targeting these phenotypic traits could represent a generalizable therapeutic strategy across cancer types. Further, we find that the microenvironmental variable does not strongly effect the outcomes, suggesting a need for direct feedback from the microenvironment onto stem-cell behaviour in future modelling endeavours.\n\nAuthor SummaryIn this paper, we present a mathematical/computational model of a tumour growing according to the canonical cancer stem-cell hypothesis with a simplified microenvironment. We explore the parameters of this model and find good agreement between our model and other theoretical models in terms of the intrinsic cellular parameters, which are difficult to study biologically. We find, however, disagreement between novel biological data and our model in terms of the microenvironmental changes. We conclude that future theoretical models of stem-cell driven tumours must include specific feedback from the microenvironment onto the individual cellular behavior. Further, we identify several cell intrinsic parameters which govern loss of homeostasis into a state of uncontrolled growth. | 10.1371/journal.pcbi.1003433 | biorxiv | 4 |
10.1101/000836 | Journey to the Center of the Mitochondria Guided by the Tail Anchor of Protein Tyrosine Phosphatase 1B | Julia Fueller;Mikhail Egorov;Kirstin A. Walther;Ola Sabet;Jana Mallah;Markus Grabenbauer;Ali Kinkhabwala; | Ali Kinkhabwala | Max Planck Institute of Molecular Physiology | 2013-11-22 | 1 | New Results | cc_by | Cell Biology | https://www.biorxiv.org/content/early/2013/11/22/000836.source.xml | The canonical protein tyrosine phosphatase PTP1B has traditionally been considered to exclusively reside on the endoplasmic reticulum (ER). Using confocal microscopy, we show that endogenous PTP1B actually exhibits a higher local concentration at the mitochondria in all mammalian cell lines that we tested. Fluorescently labeled chimeras containing full-length PTP1B or only its 35 amino acid tail anchor localized identically, demonstrating the complete dependence of PTP1Bs subcellular partitioning on its tail anchor. Correlative light and electron microscopy using GFP-driven photo-oxidation of DAB revealed that PTP1Bs tail anchor localizes it to the mitochondrial interior and to mitochondrial-associated membrane (MAM) sites along the ER. Heterologous expression of the tail anchor of PTP1B in the yeast S. cerevisiae surprisingly led to its exclusive localization to the ER/vacuole with no presence at the mitochondria. Studies with various yeast mutants of conserved membrane insertion pathways revealed a role for the GET/TRC40 pathway in ER insertion, but also emphasized the likely dominant role of spontaneous insertion. Further studies of modified tail isoforms in both yeast and mammalian cells revealed a remarkable sensitivity of subcellular partitioning to slight changes in transmembrane domain (TMD) length, C-terminal charge, and hydropathy. For example, addition of a single positive charge to the tail anchor was sufficient to completely shift the tail anchor to the mitochondria in mammalian cells and to largely shift it there in yeast cells, and a point mutation that increased TMD hydropathy was sufficient to localize the tail anchor exclusively to the ER in mammalian cells. Striking differences in the subcellular partitioning of a given tail anchor isoform in mammalian versus yeast cells most likely point to fundamental differences in the lipid composition of specific organelles (e.g. affecting membrane charge or thickness) in higher versus lower eukaryotes. Fluorescence lifetime imaging microscopy (FLIM) detection of the Forster Resonance Energy Transfer (FRET)-based interaction of the catalytic domain of PTP1B with the epidermal growth factor receptor (EGFR/ErbB1) at the mitochondria revealed a strong interaction on the cytosolic face of the outer mitochondrial membrane (OMM), suggesting the presence of a significant pool of PTP1B there and a novel role for PTP1B in the regulation of mitochondrial ErbB1 activity. In summary, in addition to its well-established general localization along the ER, our results reveal that PTP1B specifically accumulates at MAM sites along the ER and localizes as well to the OMM and mitochondrial matrix. Further elucidation of PTP1Bs roles in these different locations (including the identification of its targets) will likely be critical for understanding its complex regulation of general cellular responses, cell proliferation, and diseased states. | NA | biorxiv | 5 |
10.1101/000570 | Lipoproteins carry endocannabinoids that inhibit the Hedgehog pathway | Helena Khaliullina;Mesut Bilgin;Julio L. Sampaio;Andrej Shevchenko;Suzanne Eaton; | Suzanne Eaton | Max-Planck-Institute of Molecular Cell Biology and Genetics | 2013-11-18 | 1 | New Results | cc_no | Developmental Biology | https://www.biorxiv.org/content/early/2013/11/18/000570.source.xml | Hedgehog proteins are lipid-modified secreted signaling molecules that regulate tissue development and homeostasis. Lipids contained in circulating lipoproteins repress the Hedgehog signaling pathway in the absence of Hedgehog ligand, but the identity of these lipids is unknown. Here, using biochemical fractionation and lipid mass spectrometry, we identify these inhibitory lipids as endocannabinoids. Endocannabinoids are present in lipoproteins of both flies and humans, and repress the pathway in both mammalian signaling assays and Drosophila wing imaginal discs. In Drosophila, endocannabinoids are required in vivo to keep the levels of Smoothened and full-length Cubitus interruptus (Ci155) low in the absence of Hedgehog. Furthermore, elevating their endogenous levels inhibits Hedgehog-dependent accumulation of Smoothened and Ci155. Interestingly, cannabis-derived phytocannabinoids are also potent pathway inhibitors in flies and mammals. These findings constitute a novel link between organismal metabolism and local Hedgehog signaling, and suggest previously unsuspected mechanisms for the broad physiological activities of cannabinoids. | NA | biorxiv | 8 |
10.1101/000307 | Drosophila embryogenesis scales uniformly across temperature and developmentally diverse species | Steven Gregory Kuntz;Michael B Eisen; | Steven Gregory Kuntz | University of California, Berkeley | 2013-11-12 | 1 | New Results | cc_by | Developmental Biology | https://www.biorxiv.org/content/early/2013/11/12/000307.source.xml | Temperature affects both the timing and outcome of animal development, but the detailed effects of temperature on the progress of early development have been poorly characterized. To determine the impact of temperature on the order and timing of events during Drosophila melanogaster embryogenesis, we used time-lapse imaging to track the progress of embryos from shortly after egg laying through hatching at seven precisely maintained temperatures between 17.5{degrees}C and 32.5{degrees}C. We employed a combination of automated and manual annotation to determine when 36 milestones occurred in each embryo. D. melanogaster embryogenesis takes 33 hours at 17.5{degrees}C, and accelerates with increasing temperature to a low of 16 hours at 27.5{degrees}C, above which embryogenesis slows slightly. Remarkably, while the total time of embryogenesis varies over two fold, the relative timing of events from cellularization through hatching is constant across temperatures. To further explore the relationship between temperature and embryogenesis, we expanded our analysis to cover ten additional Drosophila species of varying climatic origins. Six of these species, like D. melanogaster, are of tropical origin, and embryogenesis time at different temperatures was similar for them all. D. mojavensis, a sub-tropical fly, develops slower than the tropical species at lower temperatures, while D. virilis, a temperate fly, exhibits slower development at all temperatures. The alpine sister species D. persimilis and D. pseudoobscura develop as rapidly as tropical flies at cooler temperatures, but exhibit diminished acceleration above 22.5{degrees}C and have drastically slowed development by 30{degrees}C. Despite ranging from 13 hours for D. erecta at 30{degrees}C to 46 hours for D. virilis at 17.5{degrees}C, the relative timing of events from cellularization through hatching is constant across all of the species and temperatures examined here, suggesting the existence of a previously unrecognized timer controlling the progress of embryogenesis that has been tuned by natural selection in response to the thermal environment in which each species lives.\n\nAuthor SummaryTemperature profoundly impacts the rate of development of \"cold-blooded\" animals, which proceeds far faster when it is warm. There is, however, no universal relationship. Closely related species can develop at markedly different speeds at the same temperature, likely resulting from environmental adaptation. This creates a major challenge when comparing development among species, as it is unclear whether they should be compared at the same temperature or under different conditions to maintain the same developmental rate. Facing this challenge while working with flies (Drosophila species), we found there was little data to inform this decision. So, using time-lapse imaging, precise temperature-control, and computational and manual video-analysis, we tracked the complex process of embryogenesis in 11 species at seven different temperatures. There was over a three-fold difference in developmental rate between the fastest species at its fastest temperature and the slowest species at its slowest temperature. However, our finding that the timing of events within development all scaled uniformly across species and temperatures astonished us. This is good news for developmental biologists, since we can induce species to develop nearly identically by growing them at different temperatures. But it also means flies must possess some unknown clock-like molecular mechanism driving embryogenesis forward. | 10.1371/journal.pgen.1004293 | biorxiv | 9 |
10.1101/000711 | Sap flow through petioles and petioles reveals leaf-level responses to light and vapor pressure deficit in the tropical tree Tabebuia rosea (Bignoniaceae) | Adam Roddy;Klaus Winter;Todd Dawson; | Adam Roddy | University of California, Berkeley | 2013-11-19 | 1 | New Results | cc_by | Ecology | https://www.biorxiv.org/content/early/2013/11/19/000711.source.xml | Continuous measurements of sap flow have been widely used to measure water flux through tree stems and branches. However, these measurements lack the resolution necessary for determining fine-scale, leaf-level responses to environmental variables. We used the heat ratio method to measure sap flow rates through leaf petioles and leaflet petiolules of saplings of the tropical tree Tabebuia rosea (Bignoniaceae) to determine how leaf and leaflet sap flow responds to variation in light and vapor pressure deficit (VPD). We found that in the morning sap flow rates to east-facing leaves increased 26 minutes before adjacent west-facing leaves. Although leaves had higher integrated sap flow than their largest leaflet, this difference was not proportional to the difference in leaf area, which could be due to lower conduit area in petiolules than in petioles. In contrast to measurements on main stems, integrated daily sap flow was negatively correlated with daily mean VPD. Furthermore, leaves exhibited previously undescribed patterns of hysteresis in the sap flow-VPD and sap flow-PAR relationships. When hysteresis in the sap flow-PAR relationship was clockwise, the sap flow-VPD relationship was also clockwise; however, when hysteresis in the sap flow-PAR relationship was counterclockwise, the sap flow-VPD relationship displayed an intersected loop. These pattern differences highlight how substantially leaf-level processes may vary within a canopy and how leaf-level processes may not scale predictably to the stem level. | NA | biorxiv | 11 |
10.1101/000414 | The evolution of sex differences in disease genetics | William P Gilks;Jessica K Abbott;Edward H Morrow; | Jessica K Abbott | Lund University | 2013-11-14 | 1 | New Results | cc_by | Genetics | https://www.biorxiv.org/content/early/2013/11/14/000414.source.xml | There are significant differences in the biology of males and females, ranging from biochemical pathways to behavioural responses, which are relevant to modern medicine. Broad-sense heritability estimates differ between the sexes for many common medical disorders, indicating that genetic architecture can be sex-dependent. Recent genome-wide association studies (GWAS) have successfully identified sex-specific and sex-biased effects, where in addition to sex-specific effects on gene expression, twenty-two medical traits have sex-specific or sex-biased loci. Sex-specific genetic architecture of complex traits is also extensively documented in model organisms using genome-wide linkage or association mapping, and in gene disruption studies. The evolutionary origins of sex-specific genetic architecture and sexual dimorphism lie in the fact that males and females share most of their genetic variation yet experience different selection pressures. At the extreme is sexual antagonism, where selection on an allele acts in opposite directions between the sexes. Sexual antagonism has been repeatedly identified via a number of experimental methods in a range of different taxa. Although the molecular basis remains to be identified, mathematical models predict the maintenance of deleterious variants that experience selection in a sex-dependent manner. There are multiple mechanisms by which sexual antagonism and alleles under sex-differential selection could contribute toward the genetics of common, complex disorders. The evidence we review clearly indicates that further research into sex-dependent selection and the sex-specific genetic architecture of diseases would be rewarding. This would be aided by studies of laboratory and wild animal populations, and by modelling sex-specific effects in genome-wide association data with joint, gene-by-sex interaction tests. We predict that even sexually monomorphic diseases may harbour cryptic sex-specific genetic architecture. Furthermore, empirical evidence suggests that investigating sex-dependent epistasis may be especially rewarding. Finally, the prevalent nature of sex-specific genetic architecture in disease offers scope for the development of more effective, sex-specific therapies.\n\nFundingThis work was supported by the European Research Council (WPG and EHM; Starting Grant #280632), a Royal Society University Research Fellowship (EHM), the Swedish Research Council (JKA), and the Volkswagen Foundation (JKA). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.\n\nCompeting interestsThe authors declare that they have no competing financial interests. | 10.1016/j.tig.2014.08.006 | biorxiv | 13 |
10.1101/000844 | Genomics via Optical Mapping (I): 0-1 Laws for Mapping with Single Molecules | Thomas Anantharaman;Bud (Bhubaneswar) Mishra; | Bud (Bhubaneswar) Mishra | Courant Inst., New York University | 2013-11-22 | 1 | New Results | cc_by | Genomics | https://www.biorxiv.org/content/early/2013/11/22/000844.source.xml | The genomic data that can be collected from a single DNA molecule by the best chemical and optical methods (e.g., using technologies from OpGen, BioNanoGenomics, NABSys, PacBio, etc.) are badly corrupted by many poorly understood noise processes. Thus, single molecule technology derives its utility through powerful probabilistic modeling, which can provide precise lower and upper bounds on various experimental parameters to create the correct map or validate sequence assembly. As an example, this analysis shows how as the number of \"imaged\" single molecules (i.e., coverage) is increased in the optical mapping data, the probability of successful computation of the map jumps from 0 to 1 for fairly small number of molecules. | NA | biorxiv | 20 |
10.1101/000604 | Aβ, tau, α-synuclein, huntingtin, TDP-43, PrP and AA are members of the innate immune system: a unifying hypothesis on the etiology of AD, PD, HD, ALS, CJD and RSA as innate immunity disorders | Claudiu I Bandea; | Claudiu I Bandea | Centers for Disease Control and Prevention | 2013-11-18 | 1 | Contradictory Results | cc_by_nc | Immunology | https://www.biorxiv.org/content/early/2013/11/18/000604.source.xml | Despite decades of research, thousands of studies and numerous advances, the etiologies of Alzheimers Disease (AD), Parkinsons Disease (PD), Huntingtons Disease (HD), Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Lobar Degeneration (FTLD-U), Creutzfeldt-Jakob Disease (CJD), Reactive Systemic Amyloidosis (RSA) and many other neurodegenerative and systemic amyloid diseases have not been defined, nor have the pathogenic mechanisms leading to cellular death and disease. Moreover, the biological functions of APP/amyloid-{beta} (A{beta}), tau, -synuclein, huntingtin, TAR DNA-binding protein 43 (TDP-43), prion protein (PrP), amyloid A (AA) and some of the other primary proteins implicated in amyloid diseases are not known. And, there are no successful preventive or therapeutic approaches. Based on a comprehensive analysis and new interpretation of the existing data in context of an evolutionary framework, it is proposed that: (i) A{beta}, tau, -synuclein, huntingtin, TDP-43, PrP and AA are members of the innate immune system, (ii) the isomeric conformational changes of these proteins and their assembly into various oligomers, plaques, and tangles are not protein misfolding events as defined for decades, nor are they prion-replication activities, but part of their normal, evolutionarily selected innate immune repertoire, and (iii) the immune reactions and activities associated with the function of these proteins in innate immunity lead to AD, PD, HD, ALS, CJD, RSA and other related diseases, which are innate immunity disorders. | NA | biorxiv | 21 |
10.1101/000513 | Lack of evidence for the presence of an interferon in invertebrate | Pei-Hui Wang; | Pei-Hui Wang | The University of Hong Kong | 2013-11-16 | 1 | New Results | cc_no | Immunology | https://www.biorxiv.org/content/early/2013/11/16/000513.source.xml | In vertebrates, the interferon (IFN) response is the primary form of innate antiviral defense. Previously (2005), a partial cDNA which could encode an interferon-like protein (IntlP) is reported in shrimp, later Rosa et al. (2008) argue that this partial cDNA should encode a portion of insect mitochondrial ATP synthase (MAS) B-chain. Recently (2009), it is demonstrated IntlP also possess antibacterial activity beside antiviral activity reported before. Lacking of a consensus opinion to the question of whether this gene encodes IntlP or MAS, we try to provide more evidences to identify this gene exactly. Here we obtain the full length cDNAs of IntlP/ MAS in Litopenaeus vannamei, and perform the tissue distribution and induced expression analysis. Our results confirm that IntlP is coded by a mistaken ORF and the actual protein indeed is a L. vannamei mitochondrial ATP synthase (LvMAS) whose function is unknown in antiviral responses. | NA | biorxiv | 22 |
10.1101/000679 | Differentiation-dependent telomeric long non-coding transcription in a model of skeletal myogenesis | Scott Brouilette;Samir Ounzain;Vinit Sawhney;Kenta Yashiro;Yasunori Shintani;Kunihiko Takahashi;Steven Coppen;Takuya Narita;Kelli Torsney;Martin Carrier;Niall Campbell;Ken Suzuki; | Samir Ounzain | University of Lausanne Medical School | 2013-11-18 | 1 | New Results | cc_by_nc_nd | Molecular Biology | https://www.biorxiv.org/content/early/2013/11/18/000679.source.xml | Telomeres comprise the distal ends of eukaryotic chromosomes, serve to maintain genomic integrity and are extended by the ribonucleoprotein telomerase. Recent evidence indicates that telomeres are transcribed to generate long non-coding RNAs (lncRNAs) and that these transcripts (TERRA) may inhibit telomerase activity. In this study we assessed telomerase activity and telomeric lncRNA expression in a mouse model of skeletal myogenesis. Using the C2C12 cell line we demonstrated decreased telomerase activity during differentiation into terminally-differentiated skeletal myotubes. Despite existing in a post-mitotic state, residual telomerase activity remained in C2C12 myotubes, indicating a role independent of telomere extension. Telomeric transcripts were detected in both myoblasts and myotubes, with reduced expression during differentiation correlating with reduced telomerase expression. Our data indicate that in a mouse model of skeletal myogenesis TERRA expression does not reduce telomerase activity, suggesting that their relationship is more complex than originally perceived; the role of telomeric derived lncRNAs in relation to telomerase activity may be cell-type specific. These findings raise the possibility for novel non-telomerase regulatory function for TERRA-lncRNAs during skeletal myogenesis. | NA | biorxiv | 24 |
10.1101/000224 | Water and the biology of *prions* and plaques | Graham K Steel;Phillippa M Wiggins;n/a n/a; | Graham K Steel | n/a | 2013-11-12 | 1 | New Results | cc_by | Molecular Biology | https://www.biorxiv.org/content/early/2013/11/12/000224.source.xml | This is an attempt to account for the insolubility and/or aggregation of prions and plaques in terms of a model of water consisting of an equilibrium between high density and low density microdomains. Hydrophobic molecules, including proteins, accumulate selectively into stable populations, enriched in high density water, at charged sites on biopolymers. In enriched high density water, proteins are probably partially unfolded and may precipitate out when released. All extracellular matrices contain such charged polymers. Prions, which have been shown to accumulate in soils and clays containing silicates and aluminates also probably accumulate in extracellular matrices.\n\nRelease of proteins follows hydrolysis of the charged groups by highly reactive high density water. This is normally a slow process but is greatly accelerated by urea. Plaques may form with age and disease because of accumulation of urea and, perhaps, glucose in the blood. This favours precipitation of proteins emerging from matrices, rather than refolding and solution. Dialysis should, therefore, interfere with plaque formation and impede the development of some age-related diseases. | 10.1038/npre.2007.1381.1 | biorxiv | 25 |
10.1101/000638 | Effects of metsulfuron-methyl on aquatic plant (Lemna gibba L.) and recovery from after prolonged exposure under rice cropping conditions | Raja Rajeswari;Atmakuru Ramesh; | Atmakuru Ramesh | International Institute of bio-technology and toxicology | 2013-11-22 | 2 | Contradictory Results | cc_no | Plant Biology | https://www.biorxiv.org/content/early/2013/11/22/000638.source.xml | The effects and potential recovery of aquatic plant Lemna gibba exposed to a sulfonyl urea herbicide metsulfuron-methyl (MSM) for 120 days under rice cropping condition was investigated. The frond number was decreased by day 15 at the concentration 11 {micro}g/L and 100% inhibition on growth rate of Lemna was observed. Continuous decrease of frond number by day 50 at below the detectable level of residues exhibited symptoms (chlorosis) of MSM toxicity. Toxicity was assessed on the basis of toxicity index (TI) value, growth rate, yield and pigment contents (chlorophyll, carotene, total carotenoid and xanthophyll) of treated samples compared with untreated control. The observed value of 0.698 {micro}g/g chlorophyll a, 0.263 {micro}g/g chlorophyll b, 0.147 {micro}g/g carotene, 1.620 {micro}g/g total carotenoid and 1.473 {micro}g/g xanthophyll contents in treated samples was statistically significantly different from control value of 4.366 {micro}g/g chlorophyll a, 3.132 {micro}g/g chlorophyll b, 0.796 {micro}g/g carotene, 17.755 {micro}g/g total carotenoid and 16.937 {micro}g/g xanthophyll contents by day 50 samples. After prolonged exposure, growth rate, yield and pigment content for the treated samples recovered to control levels on day 120. The obtained data indicate the application of aquatic plant Lemna gibba as sensitive biomarker of water quality as well as the significance of selected biological parameters in the reliable assessment of toxic potential of MSM under rice cropping condition. | NA | biorxiv | 27 |
10.1101/000745 | ROS accumulation in cotton ovule epidermal cells is necessary for fiber initiation | mingxiong pang;Nickolas Sanford;Thea Wilkins; | mingxiong pang | Texas Tech University | 2013-11-20 | 2 | New Results | cc_no | Plant Biology | https://www.biorxiv.org/content/early/2013/11/20/000745.source.xml | Cotton (Gossypium hirsutum) fiber, an extremely elongated and thickened single cell of the seed epidermis, is the worlds most important natural and economical textile fiber. Unlike Arabidopsis leaf trichomes, fiber initials are randomly developed and frequently form in adjacent seed epidermal cells and follow no apparent pattern. Numerous publications suggested cotton fiber development shares a similar mechanism with Arabidopsis leaf trichome development. Here we show that H2O2 accumulation in cotton ovule epidermal cells by NBT staining ovules at different development stages between TM1 and N1n2, a lintless-fuzzless doubled mutant originated from TM1. In contrast, Arabidopsis and cotton leaf trichomes do not show H2O2 content. By adding DPI (H2O2 inhibitor) and SHAM (H2O2 activator) in vitro ovule cultures, we show fiber initiation directly involves with H2O2 accumulation. We propose that the directional accumulation of H2O2 in cotton ovule epidermal cell is the drive for fiber initiation, elongation. | NA | biorxiv | 29 |
10.1101/000562 | A structural classification of candidate oscillators and multistationary systems | Franco Blanchini;Elisa Franco;Giulia Giordano; | Elisa Franco | University of California at Riverside | 2013-11-18 | 1 | New Results | cc_by_nc_nd | Systems Biology | https://www.biorxiv.org/content/early/2013/11/18/000562.source.xml | Molecular systems are uncertain: the variability of reaction parameters and the presence of unknown interactions can weaken the predictive capacity of solid mathematical models. However, strong conclusions on the admissible dynamic behaviors of a model can often be achieved without detailed knowledge of its specific parameters. In particular, starting with Thomas' conjectures, loop-based criteria have been largely used to characterize oscillatory and multistationary dynamic outcomes in systems with a sign definite Jacobian.\n\nWe build on the rich literature focused on the identification of potential oscillatory and multistationary behaviors based on parameter-free criteria. We propose a classification for sign-definite non autocatalytic biological networks which summarize several existing results in the literature, adding new results when necessary. We define candidate oscillators and multistationary systems based on their admissible transitions to instability. We introduce four categories: strong/weak candidate oscillatory/multistationary systems, which correspond to networks in which all/some of the existing feedback loops are negative/positive. We provide necessary and sufficient conditions characterizing strong and weak candidate oscillators and multistationary systems based on the exclusive or simultaneous presence of positive and negative loops in their linearized dynamics. We also consider the case in which the overall system is the connection of several stable aggregate monotone components, providing conditions in terms of positive/negative loops in a suitable network with aggregate monotone systems as nodes.\n\nMost realistic examples of biological networks fall in the gray area of systems in which both positive and negative cycles are present: therefore, both oscillatory and bistable behavior are in principle possible. Native systems with a large number of components are often interconnections of monotone modules, where negative/positive loops among modules characterize oscillatory and bistable behaviors, in agreement with our results. Finally, we note that many canonical example circuits exhibiting oscillations or bistability fall in the categories of strong candidate oscillators/multistationary systems. | 10.1007/s11538-014-0023-y | biorxiv | 31 |
10.1101/000380 | A model of flux regulation in the cholesterol biosynthesis pathway: Immune mediated graduated flux reduction versus statin-like led stepped flux reduction | Steven Watterson;Maria-Luisa Guerriero;Mathieu Blanc;Alexander Mazein;Laurence Loewe;Kevin Robertson;Holly Gibbs;Guanghou Shui;Markus Wenk;Jane Hillston;Peter Ghazal; | Steven Watterson | University of Ulster | 2013-11-14 | 1 | New Results | cc_by | Systems Biology | https://www.biorxiv.org/content/early/2013/11/14/000380.source.xml | Graphical Abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=37 SRC=\"FIGDIR/small/000380_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (14K):\[email protected]@1eac3f3org.highwire.dtl.DTLVardef@1e698f1org.highwire.dtl.DTLVardef@42fb4b_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIWe model the cholesterol biosynthesis pathway and its regulation\nC_LIO_LIThe innate immune response leads to a suppression of flux through the pathway\nC_LIO_LIStatin inhibitors show a different mode of suppression to the immune response\nC_LIO_LIStatin inhibitor suppression is less robust and less specific than immune suppression\nC_LI\n\nAsbtractThe cholesterol biosynthesis pathway has recently been shown to play an important role in the innate immune response to viral infection with host protection occurring through a coordinate down regulation of the enzymes catalyzing each metabolic step. In contrast, statin based drugs, which form the principle pharmaceutical agents for decreasing the activity of this pathway, target a single enzyme. Here, we build an ordinary differential equation model of the cholesterol biosynthesis pathway in order to investigate how the two regulatory strategies impact upon the behaviour of the pathway. We employ a modest set of assumptions: that the pathway operates away from saturation, that each metabolite is involved in multiple cellular interactions and that mRNA levels reflect enzyme concentrations. Using data taken from primary bone marrow derived macrophage cells infected with murine cytomegalovirus infection or treated with IFN{gamma}, we show that, under these assumptions, coordinate down regulation of enzyme activity imparts a graduated reduction in flux along the pathway. In contrast, modelling a statin-like treatment that achieves the same degree of down-regulation in cholesterol production, we show that this delivers a step change in flux along the pathway. The graduated reduction mediated by physiological coordinate regulation of multiple enzymes supports a mechanism that allows a greater level of specificity, altering cholesterol levels with less impact upon interactions branching from the pathway, than pharmacological step reductions. We argue that coordinate regulation is likely to show a long-term evolutionary advantage over single enzyme regulation. Finally, the results from our models have implications for future pharmaceutical therapies intended to target cholesterol production with greater specificity and fewer off target effects, suggesting that this can be achieved by mimicking the coordinated down-regulation observed in immunological responses. | 10.1016/j.biochi.2012.05.024 | biorxiv | 32 |
10.1101/000851 | Comment on “TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions” by Kim et al. | Alexander Dobin;Thomas R Gingeras; | Alexander Dobin | Cold Spring Harbor Laboratory | 2013-11-22 | 1 | Contradictory Results | cc_by_nd | Bioinformatics | https://www.biorxiv.org/content/early/2013/11/22/000851.source.xml | In the recent paper [1] (thereafter referred to as \"TopHat2paper\") the accuracy of TopHat2 was compared to other RNA-seq aligners. In this comment we re-examine most important analyses from the TopHat2paper and identify several deficiencies that significantly diminished performance of some of the aligners, including incorrect choice of mapping parameters, unfair comparison metrics, and unrealistic simulated data. Using STAR [2] as an exemplar, we demonstrate that correcting these deficiencies makes its accuracy equal or better than that of TopHat2. Furthermore, this exercise highlighted some serious issues with the TopHat2 algorithms, such as poor recall of alignments with a moderate (>3) number of mismatches, low sensitivity and high false discovery rate for splice junction detection, loss of precision for the realignment algorithm, and large number of false chimeric alignments. ... | NA | biorxiv | 34 |
10.1101/000497 | Unexpected links reflect the noise in networks | Anatoly Yambartsev;Michael Perlin;Yevgeniy Kovchegov;Natalia Shulzhenko;Karina Mine;Andrey Morgun; | Andrey Morgun | Oregon State University | 2013-11-15 | 1 | New Results | cc_by_nc | Bioinformatics | https://www.biorxiv.org/content/early/2013/11/15/000497.source.xml | Gene regulatory networks are commonly used for modeling biological processes and revealing underlying molecular mechanisms. The reconstruction of gene regulatory networks from observational data is a challenging task, especially, considering the large number of involved players (e.g. genes) and much fewer biological replicates available for analysis. Herein, we proposed a new statistical method of estimating the number of erroneous edges that strongly enhances the commonly used inference approaches. This method is based on special relationship between correlation and causality, and allows to identify and to remove approximately half of erroneous edges. Using the mathematical model of Bayesian networks and positive correlation inequalities we established a mathematical foundation for our method. Analyzing real biological datasets, we found a strong correlation between the results of our method and the commonly used false discovery rate (FDR) technique. Furthermore, the simulation analysis demonstrates that in large networks, our new method provides a more precise estimation of the proportion of erroneous links than FDR. | 10.1186/s13062-016-0155-0 | biorxiv | 35 |
10.1101/000489 | Gappy TotalReCaller for RNASeq Base-Calling and Mapping | Bud (Bhubaneswar) Mishra; | Bud (Bhubaneswar) Mishra | New York University | 2013-11-15 | 1 | New Results | cc_by | Bioinformatics | https://www.biorxiv.org/content/early/2013/11/15/000489.source.xml | Understanding complex mammalian biology depends crucially on our ability to define a precise map of all the transcripts encoded in a genome, and to measure their relative abundances. A promising assay depends on RNASeq approaches, which builds on next generation sequencing pipelines capable of interrogating cDNAs extracted from a cell. The underlying pipeline starts with base-calling, collect the sequence reads and interpret the raw-read in terms of transcripts that are grouped with respect to different splice-variant isoforms of a messenger RNA. We address a very basic problem involved in all of these pipeline, namely accurate Bayesian base-calling, which could combine the analog intensity data with suitable underlying priors on base-composition in the transcripts. In the context of sequencing genomic DNA, a powerful approach for base-calling has been developed in the TotalReCaller pipeline. For these purposes, it uses a suitable reference whole-genome sequence in a compressed self-indexed format to derive its priors. However, TotalReCaller faces many new challenges in the transcriptomic domain, especially since we still lack a fully annotated library of all possible transcripts, and hence a sufficiently good prior. There are many possible solutions, similar to the ones developed for TotalReCaller, in applications addressing de novo sequencing and assembly, where partial contigs or string-graphs could be used to boot-strap the Bayesian priors on base-composition. A similar approach would be applicable here too, partial assembly of transcripts can be used to characterize the splicing junctions or organize them in incompatibility graphs and then used as priors for TotalReCaller. The key algorithmic techniques for this purpose have been addressed in a forthcoming paper on Stringomics. Here, we address a related but fundamental problem, by assuming that we only have a reference genome, with certain intervals marked as candidate regions for ORF (Open Reading Frames), but not necessarily complete annotations regarding the 5 or 3 termini of a gene or its exon-intron structure. The algorithms we describe find the most accurate base-calls of a cDNA with the best possible segmentation, all mapped to the genome appropriately. | NA | biorxiv | 36 |
10.1101/000158 | Functional Annotation Signatures of Disease Susceptibility Loci Improve SNP Association Analysis | Edwin S Iversen;Gary Lipton;Merlise A. Clyde;Alvaro N. A. Monteiro; | Edwin S Iversen | Duke University | 2013-11-11 | 1 | New Results | cc_by_nd | Bioinformatics | https://www.biorxiv.org/content/early/2013/11/11/000158.source.xml | We describe the development and application of a Bayesian statistical model for the prior probability of phenotype-genotype association that incorporates data from past association studies and publicly available functional annotation data regarding the susceptibility variants under study. The model takes the form of a binary regression of association status on a set of annotation variables whose coefficients were estimated through an analysis of associated SNPs housed in the GWAS Catalog (GC). The set of functional predictors we examined includes measures that have been demonstrated to correlate with the association status of SNPs in the GC and some whose utility in this regard is speculative: summaries of the UCSC Human Genome Browser ENCODE super-track data, dbSNP function class, sequence conservation summaries, proximity to genomic variants included in the Database of Genomic Variants (DGV) and known regulatory elements included in the Open Regulatory Annotation database (ORegAnno), PolyPhen-2 probabilities and RegulomeDB categories. Because we expected that only a fraction of the annotation variables would contribute to predicting association, we employed a penalized likelihood method to reduce the impact of non-informative predictors and evaluated the models ability to predict GC SNPs not used to construct the model. We show that the functional data alone are predictive of a SNPs presence in the GC. Further, using data from a genome-wide study of ovarian cancer, we demonstrate that their use as prior data when testing for association is practical at the genome-wide scale and improves power to detect associations. | 10.1186/1471-2164-15-398 | biorxiv | 37 |
10.1101/000364 | Sampling principles for biodiversity study | Xubin Pan; | Xubin Pan | Chinese Academy of Inspection and Quarantine | 2013-11-14 | 1 | New Results | cc_by | Ecology | https://www.biorxiv.org/content/early/2013/11/14/000364.source.xml | Sampling is a fundamental tool in ecology and critical for biodiversity measurement. However, basic principles of biodiversity sampling have been overlooked for many years. In this paper, I proposed and explored five principles of sampling for a specific area and biodiversity study. The first principle of sampling, species increasing with area, is that the number of species increases with the area. The second principle of sampling, individuals increasing with area, is that the number of individuals increases with the area. The third principle of sampling, sum of species number, is that the sum of species number in one area and species number in another area is no less than the total species number in the two areas. The fourth principle of sampling, individual complement, is that the sum of the mathematical expectation of individual number of one or several species in the area a and that of the same one or several species in the area A-a is the total individual number N of the same one or several species in the total area A. The fifth principle of sampling, species-area theory, is that the sum of the mathematical expectation of number of species in the area a and that of number of species lost if area A-a is cleared is the total species number M in the total area A. | NA | biorxiv | 38 |
10.1101/000315 | On the Reproducibility of TCGA Ovarian Cancer MicroRNA Profiles | Ying-Wooi Wan;Claire Mach;Genevera I. Allen;Matthew Anderson;Zhandong Liu; | Zhandong Liu | Baylor College of Medicine | 2013-11-13 | 1 | Contradictory Results | cc_by_nc_nd | Genomics | https://www.biorxiv.org/content/early/2013/11/13/000315.source.xml | Dysregulated microRNA (miRNA) expression is a well-established feature of human cancer. However, the role of specific miRNAs in determining cancer outcomes remains unclear. Using Level 3 expression data from the Cancer Genome Atlas (TCGA), we identified 61 miRNAs that are associated with overall survival in 469 ovarian cancers profiled by microarray (p<0.01). We also identified 12 miRNAs that are associated with survival when miRNAs were profiled in the same specimens using Next Generation Sequencing (miRNA-Seq) (p<0.01). Surprisingly, only 1 miRNA transcript is associated with ovarian cancer survival in both datasets. Our analyses indicate that this discrepancy is due to the fact that miRNA levels reported by the two platforms correlate poorly, even after correcting for potential issues inherent to signal detection algorithms. Further investigation is warranted. | 10.1371/journal.pone.0087782 | biorxiv | 41 |
10.1101/000216 | A Complete Public Domain Family Genomics Dataset | Manuel Corpas;Mike Cariaso;Alain Coletta;David Weiss;Andrew P Harrison;Federico Moran;Huanming Yang; | Manuel Corpas | Independent | 2013-11-12 | 1 | New Results | cc_by | Genomics | https://www.biorxiv.org/content/early/2013/11/12/000216.source.xml | BackgroundThe availability of open access genomic data is essential for the personal genomics field. Public genomic data allow comparative analyses, testing of new tools and genotype-phenotype association studies. Personal genomics data of unrelated individuals are available in the public domain, notably the Personal Genome Project; however, to date genomics family data and metadata are severely lacking, mainly due to cost, privacy concerns or restricted access to Next Generation Sequencing (NGS) technology. Family data have a lot to offer as they allow the study of heritability, something which is impossible to do just by using unrelated individuals.\n\nFindingsA whole family from Southern Spain decided to genotype, sequence and analyse their personal genomes making them publicly available under a Creative Commons 0 license (CC0; commonly denominated as public domain). These data include a) five 23andMe SNP chip genotype bed files, b) four raw exomes with their assorted bam files and VCF files, c) a metagenomic raw sequencing data file and d) derived data of likely phenotypes using SNPedia-derived tools.\n\nConclusionsTo our knowledge this is the first CC0 released set of genomic, phenotypic and metagenomic data for a whole family. This dataset is also unique in that it was obtained through direct-to-consumer genetic tests. Hence any ordinary citizen with enough budget and samples should be able to reproduce this experiment. We envisage this dataset to be a useful resource for a variety of applications in the personal genomics field as a) negative control data for trait association discovery, b) testing data for development of new software and c) sample data for heritability studies. We encourage prospective users to share with us derived results so that they can be added to our existing collection. | NA | biorxiv | 42 |
10.1101/000265 | A genome wide dosage suppressor network reveals genetic robustness and a novel mechanism for Huntington&#146;s disease | Biranchi Patra;Yoshiko Kon;Gitanjali Yadav;Anthony Sevold;Jesse P Frumkin;Ravishankar R Vallabhajosyula;Arend Hintze;Bjørn Østman;Jory Schossau;Ashish Bhan;Bruz Marzolf;Jenna K Tamashiro;Amardeep Kaur;Nitin S Baliga;Elizabeth J Grayhack;Christoph Adami;David J Galas;Alpan Raval;Eric M Phizicky;Animesh Ray; | Animesh Ray | Keck Graduate Institute | 2013-11-12 | 1 | New Results | cc_by_nd | Genomics | https://www.biorxiv.org/content/early/2013/11/12/000265.source.xml | Mutational robustness is the extent to which an organism has evolved to withstand the effects of deleterious mutations. We explored the extent of mutational robustness in the budding yeast by genome wide dosage suppressor analysis of 53 conditional lethal mutations in cell division cycle and RNA synthesis related genes, revealing 660 suppressor interactions of which 642 are novel. This collection has several distinctive features, including high co-occurrence of mutant-suppressor pairs within protein modules, highly correlated functions between the pairs, and higher diversity of functions among the co-suppressors than previously observed. Dosage suppression of essential genes encoding RNA polymerase subunits and chromosome cohesion complex suggest a surprising degree of functional plasticity of macromolecular complexes and the existence of degenerate pathways for circumventing potentially lethal mutations. The utility of dosage-suppressor networks is illustrated by the discovery of a novel connection between chromosome cohesion-condensation pathways involving homologous recombination, and Huntingtons disease. | 10.1093/nar/gkw1148 | biorxiv | 43 |
10.1101/000067 | Genetics of single-cell protein abundance variation in large yeast populations | Frank Albert;Sebastian Treusch;Arthur H Shockley;Joshua S Bloom;Leonid Kruglyak; | Leonid Kruglyak | UCLA | 2013-11-07 | 1 | New Results | cc_no | Genomics | https://www.biorxiv.org/content/early/2013/11/07/000067.source.xml | Many DNA sequence variants influence phenotypes by altering gene expression. Our understanding of these variants is limited by sample sizes of current studies and by measurements of mRNA rather than protein abundance. We developed a powerful method for identifying genetic loci that influence protein expression in very large populations of the yeast Saccharomyes cerevisiae. The method measures single-cell protein abundance through the use of green-fluorescent-protein tags. We applied this method to 160 genes and detected many more loci per gene than previous studies. We also observed closer correspondence between loci that influence protein abundance and loci that influence mRNA abundance of a given gene. Most loci cluster at hotspot locations that influence multiple proteins--in some cases, more than half of those examined. The variants that underlie these hotspots have profound effects on the gene regulatory network and provide insights into genetic variation in cell physiology between yeast strains. | 10.1038/nature12904 | biorxiv | 44 |
10.1101/000430 | Negative autoregulation matches production and demand in synthetic transcriptional networks | Elisa Franco;Giulia Giordano;Per-Ola Forsberg;Richard M Murray; | Elisa Franco | University of California at Riverside | 2013-11-15 | 2 | New Results | cc_by_nc_nd | Synthetic Biology | https://www.biorxiv.org/content/early/2013/11/15/000430.source.xml | We propose a negative feedback architecture that regulates activity of artificial genes, or \"genelets\", to meet their output downstream demand, achieving robustness with respect to uncertain open-loop output production rates. In particular, we consider the case where the outputs of two genelets interact to form a single assembled product. We show with analysis and experiments that negative autoregulation matches the production and demand of the outputs: the magnitude of the regulatory signal is proportional to the \"error\" between the circuit output concentration and its actual demand. This two-device system is experimentally implemented using in vitro transcriptional networks, where reactions are systematically designed by optimizing nucleic acid sequences with publicly available software packages. We build a predictive ordinary differential equation (ODE) model that captures the dynamics of the system, and can be used to numerically assess the scalability of this architecture to larger sets of interconnected genes. Finally, with numerical simulations we contrast our negative autoregulation scheme with a cross-activation architecture, which is less scalable and results in slower response times. | 10.1021/sb400157z | biorxiv | 48 |
10.1101/000091 | Designing Robustness to Temperature in a Feedforward Loop Circuit | Shaunak Sen;Jongmin Kim;Richard M. Murray; | Shaunak Sen | Indian Institute of Technology Delhi | 2013-11-07 | 1 | New Results | cc_by_nd | Synthetic Biology | https://www.biorxiv.org/content/early/2013/11/07/000091.source.xml | Incoherent feedforward loops represent important biomolecular circuit elements capable of a rich set of dynamic behavior including adaptation and pulsed responses. Temperature can modulate some of these properties through its effect on the underlying reaction rate parameters. It is generally unclear how to design such a circuit where the properties are robust to variations in temperature. Here, we address this issue using a combination of tools from control and dynamical systems theory as well as preliminary experimental measurements towards such a design. We formalize temperature as an uncertainty acting on system dynamics, exploring both structured and unstructured uncertainty representations. Next, we analyze a standard incoherent feedforward loop circuit, noting mechanisms that intrinsically confer temperature robustness to some of its properties. Further, we explore different negative feedback configurations that can enhance the robustness to temperature. Finally, we find that the response of an incoherent feedforward loop circuit in cells can change with temperature. These results present groundwork for the design of a temperature-robust incoherent feedforward loop circuit. | NA | biorxiv | 49 |
10.1101/000588 | On the concept of biological function, junk DNA and the gospels of ENCODE and Graur et al. | Claudiu I Bandea; | Claudiu I Bandea | Centers for Disease Control and Prevention | 2013-11-18 | 1 | Contradictory Results | cc_by_nc | Evolutionary Biology | https://www.biorxiv.org/content/early/2013/11/18/000588.source.xml | In a recent article entitled \"On the immortality of television sets: \"function\" in the human genome according to the evolution-free gospel of ENCODE\", Graur et al. dismantle ENCODEs evidence and conclusion that 80% of the human genome is functional. However, the article by Graur et al. contains assumptions and statements that are questionable. Primarily, the authors limit their evaluation of DNAs biological functions to informational roles, sidestepping putative non-informational functions. Here, I bring forward an old hypothesis on the evolution of genome size and on the role of so called junk DNA (jDNA), which might explain C-value enigma. According to this hypothesis, the jDNA functions as a defense mechanism against insertion mutagenesis by endogenous and exogenous inserting elements such as retroviruses, thereby protecting informational DNA sequences from inactivation or alteration of their expression. Notably, this model couples the mechanisms and the selective forces responsible for the origin of jDNA with its putative protective biological function, which represents a classic example of fighting fire with fire. One of the key tenets of this theory is that in humans and many other species, jDNAs serves as a protective mechanism against insertional oncogenic transformation. As an adaptive defense mechanism, the amount of protective DNA varies from one species to another based on the rate of its origin, insertional mutagenesis activity, and evolutionary constraints on genome size. | NA | biorxiv | 52 |
10.1101/000406 | Universality and predictability in molecular quantitative genetics | Armita Nourmohammad;Torsten Held;Michael Lassig; | Michael Lassig | University of Cologne | 2013-11-15 | 2 | New Results | cc_by_nc_nd | Evolutionary Biology | https://www.biorxiv.org/content/early/2013/11/15/000406.source.xml | Molecular traits, such as gene expression levels or protein binding affinities, are increasingly accessible to quantitative measurement by modern high-throughput techniques. Such traits measure molecular functions and, from an evolutionary point of view, are important as targets of natural selection. We review recent developments in evolutionary theory and experiments that are expected to become building blocks of a quantitative genetics of molecular traits. We focus on universal evolutionary characteristics: these are largely independent of a traits genetic basis, which is often at least partially unknown. We show that universal measurements can be used to infer selection on a quantitative trait, which determines its evolutionary mode of conservation or adaptation. Furthermore, universality is closely linked to predictability of trait evolution across lineages. We argue that universal trait statistics extends over a range of cellular scales and opens new avenues of quantitative evolutionary systems biology. | 10.1016/j.gde.2013.11.001 | biorxiv | 55 |
10.1101/000398 | The Origin of Human-infecting Avian Influenza A H6N1 Virus | Liangsheng Zhang;Zhenguo Zhang; | Zhenguo Zhang | Department of Biology, The Pennsylvania State University, University Park, Pennsylvania 16802, USA | 2013-11-14 | 1 | New Results | cc_by_nc_nd | Evolutionary Biology | https://www.biorxiv.org/content/early/2013/11/14/000398.source.xml | In this study, we retraced the origin of the reported avian influenza A H6N1 virus infecting a 20-year-old woman in Taiwan. As we know, this is the first reported case of human infection by the H6N1 virus, because this subtype virus usually circulates in birds and poultry. Therefore it is crucial to know how this virus attained the ability to infect humans. Using phylogenetic analysis, we found that this virus was derived from reassortments of multiple lineages of H6N1 viruses and H5N2 viruses. The results deepen our understanding of how the new human-infecting virus originated and based on these we discussed possible explanations for the H6N1 infection of humans. Our results, together with recent studies of H7N9 viruses which result in severe disorders, suggest that reassortments among avian-type viruses are quite often, which may sometimes result in fatal infections in humans. Thus a close watch on the circulation of avian influenza viruses is pretty necessary. | NA | biorxiv | 56 |
10.1101/000208 | Population genomics of parallel hybrid zones in the mimetic butterflies, H. melpomene and H. erato | Nicola Nadeau;Mayte Ruiz;Patricio Salazar;Brian Counterman;Jose Alejandro Medina;Humberto Ortiz-Zuazaga;Anna Morrison;W. Owen McMillan;Chri Jiggins;Riccardo Papa; | Chri Jiggins | Cambridge | 2013-11-12 | 1 | New Results | cc_by_nc_nd | Evolutionary Biology | https://www.biorxiv.org/content/early/2013/11/12/000208.source.xml | Hybrid zones can be valuable tools for studying evolution and identifying genomic regions responsible for adaptive divergence and underlying phenotypic variation. Hybrid zones between subspecies of Heliconius butterflies can be very narrow and are maintained by strong selection acting on colour pattern. The co-mimetic species H. erato and H. melpomene have parallel hybrid zones where both species undergo a change from one colour pattern form to another. We use restriction associated DNA sequencing to obtain several thousand genome wide sequence markers and use these to analyse patterns of population divergence across two pairs of parallel hybrid zones in Peru and Ecuador. We compare two approaches for analysis of this type of data; alignment to a reference genome and de novo assembly, and find that alignment gives the best results for species both closely (H. melpomene) and distantly (H. erato, ~15% divergent) related to the reference sequence. Our results confirm that the colour pattern controlling loci account for the majority of divergent regions across the genome, but we also detect other divergent regions apparently unlinked to colour pattern differences. We also use association mapping to identify previously unmapped colour pattern loci, in particular the Ro locus. Finally, we identify within our sample a new cryptic population of H. timareta in Ecuador, which occurs at relatively low altitude and is mimetic with H. melpomene malleti. | 10.1101/gr.169292.113 | biorxiv | 57 |
10.1101/000240 | Genome-wide targets of selection: female response to experimental removal of sexual selection in Drosophila melanogaster | Paolo Innocenti;Ilona Flis;Edward H Morrow; | Edward H Morrow | University of Sussex | 2013-11-12 | 1 | New Results | cc_by | Evolutionary Biology | https://www.biorxiv.org/content/early/2013/11/12/000240.source.xml | Despite the common assumption that promiscuity should in general be favored in males, but not in females, to date there is no consensus on the general impact of multiple mating on female fitness. Notably, very little is known about the genetic and physiological features underlying the female response to sexual selection pressures. By combining an experimental evolution approach with genomic techniques, we investigated the effects of single and multiple matings on female fecundity and gene expression. We experimentally manipulated the mating system in replicate populations of Drosophila melanogaster by removing sexual selection, with the aim of testing differences in short term post-mating effects of females evolved under different mating strategies. We show that monogamous females suffer decreased fecundity, a decrease that was partially recovered by experimentally reversing the selection pressure back to the ancestral promiscuous state. The post-mating gene expression profiles of monogamous females differ significantly from promiscuous females, involving 9% of the genes tested. These transcripts are active in several tissues, mainly ovaries, neural tissues and midgut, and are involved in metabolic processes, reproduction and signaling pathways. Our results demonstrate how the female post-mating response can evolve under different mating systems, and provide novel insights into the genes targeted by sexual selection in females, by identifying a list of candidate genes responsible for the decrease in female fecundity in the absence of promiscuity. | NA | biorxiv | 58 |
10.1101/000109 | Speciation and introgression between Mimulus nasutus and Mimulus guttatus | Yaniv Brandvain;Amanda M Kenney;Lex Fagel;Graham Coop;Andrea L Sweigart; | Yaniv Brandvain | Department of Evolution and Ecology & Center for Population Biology, University of California -Davis | 2013-11-07 | 1 | New Results | cc_by | Evolutionary Biology | https://www.biorxiv.org/content/early/2013/11/07/000109.source.xml | Mimulus guttatus and M. nasutus are an evolutionary and ecological model sister species pair differentiated by ecology, mating system, and partial reproductive isolation. Despite extensive research on this system, the history of divergence and differentiation in this sister pair is unclear. We present and analyze a novel population genomic data set which shows that M. nasutus "budded" off of a central Californian M. guttatus population within the last 200 to 500 thousand years. In this time, the M. nasutus genome has accrued numerous genomic signatures of the transition to predominant selfing. Despite clear biological differentiation, we document ongoing, bidirectional introgression. We observe a negative relationship between the recombination rate and divergence between M. nasutus and sympatric M. guttatus samples, suggesting that selection acts against M. nasutus ancestry in M. guttatus. | 10.1371/journal.pgen.1004410 | biorxiv | 60 |
10.1101/001495 | A coarse-grained elastic network atom contact model and its use in the simulation of protein dynamics and the prediction of the effect of mutations | Vincent Frappier;Rafael Najmanovich; | Rafael Najmanovich | Université de Sherbrooke | 2013-12-20 | 1 | New Results | cc_by_nd | Bioinformatics | https://www.biorxiv.org/content/early/2013/12/20/001495.source.xml | Normal mode analysis (NMA) methods are widely used to study dynamic aspects of protein structures. Two critical components of NMA methods are coarse-graining in the level of simplification used to represent protein structures and the choice of potential energy functional form. There is a trade-off between speed and accuracy in different choices. In one extreme one finds accurate but slow molecular-dynamics based methods with all-atom representations and detailed atom potentials. On the other extreme, fast elastic network model (ENM) methods with Conly representations and simplified potentials that based on geometry alone, thus oblivious to protein sequence. Here we present ENCoM, an Elastic Network Contact Model that employs a potential energy function that includes a pairwise atom-type non-bonded interaction term and thus makes it possible to consider the effect of the specific nature of amino-acids on dynamics within the context of NMA. ENCoM is as fast as existing ENM methods and outperforms such methods in the generation of conformational ensembles. Here we introduce a new application for NMA methods with the use of ENCoM in the prediction of the effect of mutations on protein stability. While existing methods are based on machine learning or enthalpic considerations, the use of ENCoM, based on vibrational normal modes, is based on entropic considerations. This represents a novel area of application for NMA methods and a novel approach for the prediction of the effect of mutations. We compare ENCoM to a large number of methods in terms of accuracy and self-consistency. We show that the accuracy of ENCoM is comparable to that of the best existing methods. We show that existing methods are biased towards the prediction of destabilizing mutations and that ENCoM is less biased at predicting stabilizing mutations. | 10.1371/journal.pcbi.1003569 | biorxiv | 65 |
10.1101/001230 | libRoadRunner: A High Performance SBML Compliant Simulator | Herbert M Sauro;Totte T Karlsson;Maciej Swat;Michal Galdzicki;Andy Somogyi; | Herbert M Sauro | University of Washington | 2013-12-12 | 1 | New Results | cc_by | Bioinformatics | https://www.biorxiv.org/content/early/2013/12/12/001230.source.xml | SummaryWe describe libRoadRunner, a cross-platform, open-source, high performance C++ library for running and analyzing SBML-compliant models. libRoadRunner was created primarily to achieve high performance, ease of use, portability and an extensible architecture. libRoadRunner includes a comprehensive API, Plugin support, Python scripting and additional functionality such as stoichio-metric and metabolic control analysis.\n\nAccessibility and ImplementationTo maximize collaboration, we made libRoadRunner open source and released it under the Apache License, Version 2.0. To facilitate reuse, we have developed comprehensive Python bindings using SWIG (swig.org) and a C API. Li-bRoadRunner uses a number of statically linked third party libraries including: LLVM [4], libSBML [1], CVODE, NLEQ2, LAPACK and Poco. LibRoadRunner is supported on Windows, Mac OS X and Linux.\n\nSupplementary informationOnline documentation, build instructions and git source repository are available at http://www.libroadrunner.org | 10.1093/bioinformatics/btv363 | biorxiv | 67 |
10.1101/000984 | A Bayesian Method to Incorporate Hundreds of Functional Characteristics with Association Evidence to Improve Variant Prioritization | Sarah A Gagliano;Michael R Barnes;Michael E Weale;Jo Knight; | Jo Knight | Centre for Addiction and Mental Health | 2013-12-04 | 1 | New Results | cc_no | Bioinformatics | https://www.biorxiv.org/content/early/2013/12/04/000984.source.xml | The increasing quantity and quality of functional genomic information motivate the assessment and integration of these data with association data, including data originating from genome-wide association studies (GWAS). We used previously described GWAS signals (\"hits\") to train a regularized logistic model in order to predict SNP causality on the basis of a large multivariate functional dataset. We show how this model can be used to derive Bayes factors for integrating functional and association data into a combined Bayesian analysis. Functional characteristics were obtained from the Encyclopedia of DNA Elements (ENCODE), from published expression quantitative trait loci (eQTL), and from other sources of genome-wide characteristics. We trained the model using all GWAS signals combined, and also using phenotype specific signals for autoimmune, brain-related, cancer, and cardiovascular disorders. The non-phenotype specific and the autoimmune GWAS signals gave the most reliable results. We found SNPs with higher probabilities of causality from functional characteristics showed an enrichment of more significant p-values compared to all GWAS SNPs in three large GWAS studies of complex traits. We investigated the ability of our Bayesian method to improve the identification of true causal signals in a psoriasis GWAS dataset and found that combining functional data with association data improves the ability to prioritise novel hits. We used the predictions from the penalized logistic regression model to calculate Bayes factors relating to functional characteristics and supply these online alongside resources to integrate these data with association data.\n\nAuthor SummaryLarge-scale genetic studies have had success identifying genes that play a role in complex traits. Advanced statistical procedures suggest that there are still genetic variants to be discovered, but these variants are difficult to detect. Incorporating biological information that affect the amount of protein or other product produced can be used to prioritise the genetic variants in order to identify which are likely to be causal. The method proposed here uses such biological characteristics to predict which genetic variants are most likely to be causal for complex traits. | 10.1371/journal.pone.0098122 | biorxiv | 68 |
10.1101/001081 | PyRAD: assembly of de novo RADseq loci for phylogenetic analyses | Deren A. R. Eaton; | Deren A. R. Eaton | University of Chicago | 2013-12-03 | 1 | New Results | cc_by | Bioinformatics | https://www.biorxiv.org/content/early/2013/12/03/001081.source.xml | Restriction-site associated genomic markers are a powerful tool for investigating evolutionary questions at the population level, but are limited in their utility at deeper phylogenetic scales where fewer orthologous loci are typically recovered across disparate taxa. While this limitation stems in part from mutations to restriction recognition sites that disrupt data generation, an alternative source of data loss comes from the failure to identify homology during bioinformatic analyses. Clustering methods that allow for lower similarity thresholds and the inclusion of indel variation will perform better at assembling RADseq loci at the phylogenetic scale.\n\nPyRAD is a pipeline to assemble de novo RADseq loci with the aim of optimizing coverage across phylogenetic data sets. It utilizes a wrapper around an alignment-clustering algorithm which allows for indel variation within and between samples, as well as for incomplete overlap among reads (e.g., paired-end). Here I compare PyRAD with the program Stacks in their performance analyzing a simulated RADseq data set that includes indel variation. Indels disrupt clustering of homologous loci in Stacks but not in PyRAD, such that the latter recovers more shared loci across disparate taxa. I show through re-analysis of an empirical RADseq data set that indels are a common feature of such data, even at shallow phylogenetic scales. PyRAD utilizes parallel processing as well as an optional hierarchical clustering method which allow it to rapidly assemble phylogenetic data sets with hundreds of sampled individuals.\n\nAvailabilitySoftware is written in Python and freely available at http://www.dereneaton.com/software/\n\nSupplementScripts to completely reproduce all simulated and empirical analyses are available in the Supplementary Materials. | 10.1093/bioinformatics/btu121 | biorxiv | 69 |
10.1101/001065 | A null model for Pearson coexpression networks | Andrea Gobbi;Giuseppe Jurman; | Giuseppe Jurman | Fondazione Bruno Kessler | 2013-12-03 | 2 | New Results | cc_by_nd | Bioinformatics | https://www.biorxiv.org/content/early/2013/12/03/001065.source.xml | Gene coexpression networks inferred by correlation from high-throughput profiling such as microarray data represent a simple but effective technique for discovering and interpreting linear gene relationships. In the last years several approach have been proposed to tackle the problem of deciding when the resulting correlation values are statistically significant. This is mostly crucial when the number of samples is small, yielding a non negligible chance that even high correlation values are due to random effects. Here we introduce a novel hard thresholding solution based on the assumption that a coexpression network inferred by randomly generated data is expected to be empty. The theoretical derivation of the new bound by geometrical methods is shown together with applications in onco- and neurogenomics. | 10.1371/journal.pone.0128115 | biorxiv | 71 |
10.1101/001461 | RNA Structure Refinement using the ERRASER-Phenix pipeline | Fang-Chieh Chou;Nathaniel Echols;Thomas C. Terwilliger;Rhiju Das; | Rhiju Das | Stanford | 2013-12-19 | 1 | New Results | cc_by_nd | Biophysics | https://www.biorxiv.org/content/early/2013/12/19/001461.source.xml | The final step of RNA crystallography involves the fitting of coordinates into electron density maps. The large number of backbone atoms in RNA presents a difficult and tedious challenge, particularly when experimental density is poor. The ERRASER-Phenix pipeline can improve an initial set of RNA coordinates automatically based on a physically realistic model of atomic-level RNA interactions. The pipeline couples diffraction-based refinement in Phenix with the Rosetta-based real-space refinement protocol ERRASER (Enumerative Real-Space Refinement ASsisted by Electron density under Rosetta). The combination of ERRASER and Phenix can improve the geometrical quality of RNA crystallographic models while maintaining or improving the fit to the diffraction data (as measured by Rfree). Here we present a complete tutorial for running ERRASER-Phenix through the Phenix GUI, from the command-line, and via an application in the Rosetta On-line Server that Includes Everyone (ROSIE). | 10.1007/978-1-4939-2763-0_17 | biorxiv | 72 |
10.1101/001396 | Parametric inference in the large data limit using maximally informative models | Justin B. Kinney;Gurinder S. Atwal; | Justin B. Kinney | Cold Spring Harbor Laboratory | 2013-12-13 | 1 | New Results | cc_by_nc_nd | Biophysics | https://www.biorxiv.org/content/early/2013/12/13/001396.source.xml | Motivated by data-rich experiments in transcriptional regulation and sensory neuro-science, we consider the following general problem in statistical inference. When exposed to a high-dimensional signal S, a system of interest computes a representation R of that signal which is then observed through a noisy measurement M. From a large number of signals and measurements, we wish to infer the \"filter\" that maps S to R. However, the standard method for solving such problems, likelihood-based inference, requires perfect a priori knowledge of the \"noise function\" mapping R to M. In practice such noise functions are usually known only approximately, if at all, and using an incorrect noise function will typically bias the inferred filter. Here we show that, in the large data limit, this need for a pre-characterized noise function can be circumvented by searching for filters that instead maximize the mutual information I[M; R] between observed measurements and predicted representations. Moreover, if the correct filter lies within the space of filters being explored, maximizing mutual information becomes equivalent to simultaneously maximizing every dependence measure that satisfies the Data Processing Inequality. It is important to note that maximizing mutual information will typically leave a small number of directions in parameter space unconstrained. We term these directions \"diffeomorphic modes\" and present an equation that allows these modes to be derived systematically. The presence of diffeomorphic modes reflects a fundamental and nontrivial substructure within parameter space, one that is obscured by standard likelihood-based inference. | 10.1162/NECO_a_00568 | biorxiv | 73 |
10.1101/001263 | Climate change triggers morphological and life-history evolution in response to predators | Edmund Hart;Nicholas Gotelli; | Edmund Hart | National Ecological Observatory Network | 2013-12-10 | 1 | New Results | cc_by_nc_nd | Ecology | https://www.biorxiv.org/content/early/2013/12/10/001263.source.xml | Although climate change is expected to reorganize entire communities, this restructuring might reflect either direct ecological or evolutionary responses to abiotic conditions or indirect effects mediated through altered species interactions. We tested the hypothesis that changes in trophic interaction strength due to altered predator abundance have a cascading evolutionary response in a prey species (Daphnia pulex). Using a multiyear / multigenerational field experiment, we manipulated 12 open aquatic mesocosms to simulate hydrological conditions under climate change. After a three-year press manipulation, we collected Daphnia pulex from each pond and raised them in a common garden. Using quantitative genetic methods, we measured a series of quantitative traits every other day on 108 individuals for eight weeks. There was a significant decrease in tail spine length and population growth rate in groups exposed to the most extreme future climate scenarios. Structural equation models demonstrated that trait changes were best explained as an indirect effect of climate change treatments mediated through changes in predator abundance. Our results suggest climate change can trigger a cascade of ecological and evolutionary forces by reducing predator density, which in turn acts as a selective force leading to evolutionary change in prey morphology and life history. | NA | biorxiv | 80 |
10.1101/001032 | Mechanism of β-Aminobutyric Acid-Induced Resistance in Wheat to the Grain Aphid, Sitobion avenae | He-He Cao;Meng Zhang;Hui Zhao;Yi Zhang;Xing-Xing Wang;Shan-Shan Guo;Zhan-Feng Zhang;Tong-Xian Liu; | He-He Cao | Northwest A&F University | 2013-12-02 | 1 | New Results | cc_by_nc_nd | Ecology | https://www.biorxiv.org/content/early/2013/12/02/001032.source.xml | The non-protein amino acid {beta}-aminobutyric acid (BABA) could induce plant resistance to a broad spectrum of biotic and abiotic stresses. However, BABA-induced plant resistance to insects is less well-studied, especially its underlying mechanism. In this research, we applied BABA to wheat seedlings and tested its effects on Sitobion avenae. When applied as a soil drench, BABA significantly reduced weight of S. avenae, whereas foliar spray and seed treatment had no such effects. BABA-mediated suppression of S. avenae growth is dose dependent and could last at least for 7 days. The aminobutyric acid concentration in phloem sap of BABA-treated plants accumulated to high levels and increased with BABA concentrations applied. Moreover, after 10 days of treatment, the aminobutyric acid content in BABA-treated plants was still higher than that in control treatment. S. avenae could not discriminate artificial diet containing BABA from standard diet, indicating that BABA itself is not a deterrent to this aphid. Also S. avenae did not show preference for control plants or BABA-treated plants. Consistent with choice test results, S. avenae had similar feeding activities on control and BABA-treated plants, suggesting that BABA did not induce antifeedants in wheat seedlings. In addition, aminobutyric acid concentration in S. avenae feeding on BABA-treated plants was significantly higher than those feeding on control palnts. S. avenae growth rate was reduced on artificial diet containing BABA, indicating direct toxic effects of BABA to this aphid. These results suggest that BABA application could enhance wheat plant resistance to S. avenae and the mechanism is possibly due to direct toxicity of high BABA contents in plant phloem. | 10.1371/journal.pone.0091768 | biorxiv | 81 |
10.1101/000893 | The Effectiveness of China’s National Forest Protection Program and National-level Nature Reserves, 2000 to 2010: PREPRINT | Guopeng Ren;Stephen S. Young;Lin Wang;Wei Wang;Yongcheng Long;Ruidong Wu;Junsheng Li;Jianguo Zhu;Douglas W. Yu; | Douglas W. Yu | Kunming Institute of Zoology | 2013-11-25 | 1 | New Results | cc_no | Ecology | https://www.biorxiv.org/content/early/2013/11/25/000893.source.xml | There is profound interest in knowing the degree to which Chinas institutions are capable of protecting its natural forests and biodiversity in the face of economic and political change. Chinas two most important forest protection policies are its National Forest Protection Program (NFPP) and its National-level Nature Reserves (NNRs). The NFPP was implemented in 17 provinces starting in the year 2000 in response to deforestation-caused flooding. We used MODIS data (MOD13Q1) to estimate forest cover and forest loss across mainland China, and we report that 1.765 million km2 or 18.7% of mainland China was covered in forest (12.3%, canopy cover > 70%) and woodland (6.4%, 40% [≤] canopy cover < 70%) in 2000. By 2010, a total of 480,203 km2 of forest + woodland was lost, amounting to an annual deforestation rate of 2.7%. The forest-only loss was 127,473 km2, or 1.05% annually. The three most rapidly deforested provinces were outside NFPP jurisdiction, in the southeast. Within the NFPP provinces, the annual forest + woodland loss rate was 2.26%, and the forest-only rate was 0.62%. Because these loss rates are likely overestimates, China appears to have achieved, and even exceeded, its NFPP target of reducing deforestation to 1.1% annually in the target provinces. We also assemble the first-ever polygon dataset for Chinas forested NNRs (n = 237), which covered 74,030 km2 in 2000. Conventional unmatched and covariate-matching analyses both find that about two-thirds of Chinas NNRs exhibit effectiveness in protecting forest cover and that within-NNR deforestation rates are higher in provinces that have higher overall deforestation. | 10.1111/cobi.12561 | biorxiv | 82 |
10.1101/001487 | Hawkish but helpful: When cultural group selection favors within-group aggression | Ben Hanowell; | Ben Hanowell | Department of Anthropology, University of Washington | 2013-12-20 | 1 | New Results | cc_by_nc_nd | Evolutionary Biology | https://www.biorxiv.org/content/early/2013/12/20/001487.source.xml | The origin of cooperation is a central problem in evolutionary biology and social science. Cultural group selection and parochial altruism are popular but controversial evolutionary explanations for large-scale cooperation. Proponents of the cultural group selection hypothesis argue that the human tendency to conform--a consequence of our reliance on social learning--maintained sufficient between-group variation to allow group selection (which favors altruism) to overpower individual selection (which favors selfishness), whereupon large-scale altruism could emerge. Proponents of the parochial altruism hypothesis argue that altruism could emerge in tandem with hostility toward other groups if the combination of the two traits increased success in inter-group contests. Proponents of both hypotheses assume that cooperation is altruistic and that within-group conflict is antithetical to cooperation, implying that group selection for cooperation reduces within-group conflict. Yet within-group conflict need not be antithetical to cooperation. This essay uses a mathematical model to show that selection between groups can lead to greater within-group aggression if within-group aggression enhances the value of individually costly public goods contributions. This model may help to explain cross-cultural associations between warfare, socialization for aggression, aggressive sports, and interpersonal violence among humans. It may also apply to other forms of inter-group conflict among humans. Finally, the model suggests that group selection can lead to disharmony within groups, a caveat to the use of group selection models to inform social policy. | NA | biorxiv | 85 |
10.1101/001446 | Direct Reciprocity Under Uncertainty Does Not Explain One-Shot Cooperation, But It Can Explain Norm Psychology | Matthew Zefferman; | Matthew R Zefferman | National Institute for Mathematical and Biological Synthesis | 2013-12-17 | 1 | New Results | cc_by_nc_nd | Evolutionary Biology | https://www.biorxiv.org/content/early/2013/12/17/001446.source.xml | Humans in many societies cooperate in economic experiments at much higher levels than would be expected if their goal was maximizing economic returns even when interactions are anonymous and one-shot. This is a puzzle because paying a cost to benefit another player in one-shot interactions has no direct benefit to the cooperator. This paper explores the logic of two competing evolutionary hypotheses to explain this behavior. The \"norm psychology\" hypothesis holds that a players choice of strategy is heavily influenced by socially-learned cultural norms. Its premise is that over the course of human evolutionary history, cultural norms varied considerably across human societies and through a process of gene-culture co-evolution, humans evolved mechanisms to learn and adopt the norms of their particular society. The \"evolutionary mismatch\" hypothesis holds that pro-social preferences evolved genetically in our hunter-gatherer past where one-shot anonymous interactions were rare and these evolved \"protocols\" for cooperation are misapplied in modern, laboratory, conditions. I compare these hypotheses by adopting a well-known model of the mismatch hypothesis. I show that the cooperation generated by the model is based on a flawed assumption - that the best thing to do is cooperate in a repeated game. I show that repeated games generate a great diversity of behavioral equilibria, in support of the norm psychology hypothesiss premise. When interaction is repeated, adopting local norms is a more evolutionarily successful strategy than automatically cooperating. If various groups are at different behavioral equilibria, then cultural selection between groups tends to select for cooperative behavior. | NA | biorxiv | 86 |
10.1101/001289 | An Adaptive Threshold in Mammalian Neocortical Evolution | Eric Lewitus;Iva Kelava;Alex T Kalinka;Pavel Tomancak;Wieland B Huttner; | Wieland B Huttner | Max Planck Institute of Molecular Cell Biology and Genetics | 2013-12-16 | 2 | New Results | cc_no | Evolutionary Biology | https://www.biorxiv.org/content/early/2013/12/16/001289.source.xml | Expansion of the neocortex is a hallmark of human evolution. However, it remains an open question what adaptive mechanisms facilitated its expansion. Here we show, using gyrencephaly index (GI) and other physiological and life-history data for 102 mammalian species, that gyrencephaly is an ancestral mammalian trait. We provide evidence that the evolution of a highly folded neocortex, as observed in humans, requires the traversal of a threshold of [~]109 neurons, and that species above and below the threshold exhibit a bimodal distribution of physiological and life-history traits, establishing two phenotypic groups. We identify, using discrete mathematical models, proliferative divisions of pro-genitors in the basal compartment of the developing neocortex as evolutionarily necessary and sufficient for generating a fourteen-fold increase in daily prenatal neuron production and thus traversal of the neuronal threshold. Finally, using RNA-seq data from fetal human neocortical germinal zones, we show a genomic correlate to the neuron threshold in the differential conservation of long intergenic non-coding RNA. (see arXiv:1304.5412) | 10.1371/journal.pbio.1002000 | biorxiv | 88 |
10.1101/001404 | The importance of population growth and regulation in human life history evolution | Ryan Baldini; | Ryan Baldini | UC Davis | 2013-12-14 | 1 | New Results | cc_by_nc_nd | Evolutionary Biology | https://www.biorxiv.org/content/early/2013/12/14/001404.source.xml | Explaining the evolution of human life history characteristics remains an outstanding problem to evolutionary anthropologists. Progress is hindered by common misunderstandings of how selection works in age-structured populations. I review two important results of life history theory related to demography. First, different life history strategies evolve under density-independent and density-dependent population growth. Second, and more poorly appreciated, different kinds of density-dependence also select for different life history strategies; assuming zero population growth alone is insufficient to determine the optimal strategy. I show that these facts are more than methodological niceties by reanalyzing the model by Kaplan et al. (2000) and showing that the results depend strongly on the form of population regulation assumed. This analysis suggests that progress in human life history theory requires better understanding of the demography of our ancestors. I close with a discussion of empirical implications. | 10.1371/journal.pone.0119789 | biorxiv | 89 |
10.1101/001354 | A Tale of Two Hypotheses: Genetics and the Ethnogenesis of Ashkenazi Jewry | Aram Yardumian; | Aram Yardumian | University of Pennsylvania | 2013-12-12 | 1 | Contradictory Results | cc_no | Genetics | https://www.biorxiv.org/content/early/2013/12/12/001354.source.xml | The debate over the ethnogenesis of Ashkenazi Jewry is longstanding, and has been hampered by a lack of Jewish historiographical work between the Biblical and the early Modern eras. Most historians, as well as geneticists, situate them as the descendants of Israelite tribes whose presence in Europe is owed to deportations during the Roman conquest of Palestine, as well as migration from Babylonia, and eventual settlement along the Rhine. By contrast, a few historians and other writers, most famously Arthur Koestler, have looked to migrations following the decline of the little-understood Medieval Jewish kingdom of Khazaria as the main source for Ashkenazi Jewry. A recent study of genetic variation in southeastern European populations (Elhaik 2012) also proposed a Khazarian origin for Ashkenazi Jews, eliciting considerable criticism from other scholars investigating Jewish ancestry who favor a Near Eastern origin of Ashkenazi populations. This paper re-examines the genetic data and analytical approaches used in these studies of Jewish ancestry, and situates them in the context of historical, linguistic, and archaeological evidence from the Caucasus, Europe and the Near East. Based on this reanalysis, it appears not only that the Khazar Hypothesis per se is without serious merit, but also the veracity of the Rhineland Hypothesis may also be questionable. | NA | biorxiv | 93 |
10.1101/001099 | OTX2 Dosage Sensitivity is Implicated in Hemifacial Microsomia | Dina Zielinski;Barak Markus;Mona Sheikh;Melissa Gymrek;Clement Chu;Marta Zaks;Balaji Srinivasan;Jodi D. Hoffman;Dror Aizenbud;Yaniv Erlich; | Yaniv Erlich | Whitehead Institute | 2013-12-03 | 1 | New Results | cc_by | Genetics | https://www.biorxiv.org/content/early/2013/12/03/001099.source.xml | Hemifacial microsomia (HFM) is the second most common facial anomaly after cleft lip and palate. The phenotype is highly variable and most cases are sporadic. Here, we investigated the disorder in a large pedigree with five affected individuals spanning eight meioses. We performed whole-exome sequencing and a genome-wide survey of segmental variations. Analysis of the exome sequencing results indicated the absence of a pathogenic coding point mutation. Inspection of segmental variations identified a 1.3Mb duplication of chromosome 14q22.3 in all affected individuals that was absent in more than 1000 chromosomes of ethnically matched controls. The duplication was absent in seven additional sporadic HFM cases, which is concordant with the known heterogeneity of the disorder. To find the critical gene in the duplicated region, we analyzed signatures of human craniofacial disease networks, mouse expression data, and predictions of dosage sensitivity. All of these approaches implicated OTX2 as the most likely causal gene. Moreover, OTX2 is a known oncogenic driver in medulloblastoma, a condition that was diagnosed in the proband during the course of our study. Our findings highlight dosage sensitivity of OTX2 in human craniofacial development and suggest a possible shared etiology between a subtype of hemifacial microsomia and medulloblastoma. | 10.1371/journal.pone.0096788 | biorxiv | 94 |
10.1101/001073 | Variational Inference of Population Structure in Large SNP Datasets | Anil Raj;Matthew Stephens;Jonathan K Pritchard; | Anil Raj | Stanford University | 2013-12-02 | 1 | New Results | cc_by_nc_nd | Genetics | https://www.biorxiv.org/content/early/2013/12/02/001073.source.xml | Tools for estimating population structure from genetic data are now used in a wide variety of applications in population genetics. However, inferring population structure in large modern data sets imposes severe computational challenges. Here, we develop efficient algorithms for approximate inference of the model underlying the STRUCTURE program using a variational Bayesian framework. Variational methods pose the problem of computing relevant posterior distributions as an optimization problem, allowing us to build on recent advances in optimization theory to develop fast inference tools. In addition, we propose useful heuristic scores to identify the number of populations represented in a dataset and a new hierarchical prior to detect weak population structure in the data. We test the variational algorithms on simulated data, and illustrate using genotype data from the CEPH-Human Genome Diversity Panel. The variational algorithms are almost two orders of magnitude faster than STRUCTURE and achieve accuracies comparable to those of ADMIXTURE. Furthermore, our results show that the heuristic scores for choosing model complexity provide a reasonable range of values for the number of populations represented in the data, with minimal bias towards detecting structure when it is very weak. Our algorithm, fastSTRUCTURE, is freely available online at http://pritchardlab.stanford.edu/structure.html. | 10.1534/genetics.114.164350 | biorxiv | 95 |
10.1101/001511 | The causal meaning of genomic predictors and how it affects the construction and comparison of genome-enabled selection models | Bruno D Valente;Gota Morota;Guilherme JM Rosa;Daniel Gianola;Kent Weigel; | Bruno D Valente | University of Wisconsin - Madison | 2013-12-21 | 1 | New Results | cc_no | Genomics | https://www.biorxiv.org/content/early/2013/12/21/001511.source.xml | The additive genetic effect is arguably the most important quantity inferred in animal and plant breeding analyses. The term effect indicates that it represents causal information, which is different from standard statistical concepts as regression coefficient and association. The process of inferring causal information is also different from standard statistical learning, as the former requires causal (i.e. non-statistical) assumptions and involves extra complexities. Remarkably, the task of inferring genetic effects is largely seen as a standard regression/prediction problem, contradicting its label. This widely accepted analysis approach is by itself insufficient for causal learning, suggesting that causality is not the point for selection. Given this incongruence, it is important to verify if genomic predictors need to represent causal effects to be relevant for selection decisions, especially because applying regression studies to answer causal questions may lead to wrong conclusions. The answer to this question defines if genomic selection models should be constructed aiming maximum genomic predictive ability or aiming identifiability of genetic causal effects. Here, we demonstrate that selection relies on a causal effect from genotype to phenotype, and that genomic predictors are only useful for selection if they distinguish such effect from other sources of association. Conversely, genomic predictors capturing non-causal signals provide information that is less relevant for selection regardless of the resulting predictive ability. Focusing on covariate choice decision, simulated examples are used to show that predictive ability, which is the criterion normally used to compare models, may not indicate the quality of genomic predictors for selection. Additionally, we propose using alternative criteria to construct models aiming for the identification of the genetic causal effects. | 10.1534/genetics.114.169490 | biorxiv | 96 |
10.1101/001479 | Massively differential bias between two widely used Illumina library preparation methods for small RNA sequencing | Jeanette Baran-Gale;Michael R Erdos;Christina Sison;Alice Young;Emily E Fannin;Peter S Chines;Praveen Sethupathy; | Praveen Sethupathy | University of North Carolina at Chapel HIll | 2013-12-19 | 1 | Confirmatory Results | cc_by_nc_nd | Genomics | https://www.biorxiv.org/content/early/2013/12/19/001479.source.xml | Recent advances in sequencing technology have helped unveil the unexpected complexity and diversity of small RNAs. A critical step in small RNA library preparation for sequencing is the ligation of adapter sequences to both the 5 and 3 ends of small RNAs. Two widely used protocols for small RNA library preparation, Illumina v1.5 and Illumina TruSeq, use different pairs of adapter sequences. In this study, we compare the results of small RNA-sequencing between v1.5 and TruSeq and observe a striking differential bias. Nearly 100 highly expressed microRNAs (miRNAs) are >5-fold differentially detected and 48 miRNAs are >10-fold differentially detected between the two methods of library preparation. In fact, some miRNAs, such as miR-24-3p, are over 30-fold differentially detected. The results are reproducible across different sequencing centers (NIH and UNC) and both major Illumina sequencing platforms, GAIIx and HiSeq. While some level of bias in library preparation is not surprising, the apparent massive differential bias between these two widely used adapter sets is not well appreciated. As increasingly more laboratories transition to the newer TruSeq-based library preparation for small RNAs, researchers should be aware of the extent to which the results may differ from previously published results using v1.5. | 10.3389/fgene.2015.00352 | biorxiv | 97 |
10.1101/001388 | Bayesian inference of infectious disease transmission from whole genome sequence data | Xavier Didelot;Jennifer Gardy;Caroline Colijn; | Xavier Didelot | Imperial College London | 2013-12-16 | 1 | New Results | cc_by_nc_nd | Genomics | https://www.biorxiv.org/content/early/2013/12/16/001388.source.xml | Genomics is increasingly being used to investigate disease outbreaks, but an important question remains unanswered - how well do genomic data capture known transmission events, particularly for pathogens with long carriage periods or large within-host population sizes? Here we present a novel Bayesian approach to reconstruct densely-sampled outbreaks from genomic data whilst considering within-host diversity. We infer a time-labelled phylogeny using BEAST, then infer a transmission network via a Monte-Carlo Markov Chain. We find that under a realistic model of within-host evolution, reconstructions of simulated outbreaks contain substantial uncertainty even when genomic data reflect a high substitution rate. Reconstruction of a real-world tuberculosis outbreak displayed similar uncertainty, although the correct source case and several clusters of epidemiologically linked cases were identified. We conclude that genomics cannot wholly replace traditional epidemiology, but that Bayesian reconstructions derived from sequence data may form a useful starting point for a genomic epidemiology investigation. | 10.1093/molbev/msu121 | biorxiv | 98 |
10.1101/000802 | Generation of high-resolution a priori Y-chromosome phylogenies using &#147;next-generation&#148; sequencing data | Gregory R Magoon;Raymond H Banks;Christian Rottensteiner;Bonnie E Schrack;Vincent O Tilroe;Terry Robb;Andrew J Grierson; | Gregory R Magoon | Aerodyne Research, Inc. | 2013-12-13 | 5 | New Results | cc_no | Genomics | https://www.biorxiv.org/content/early/2013/12/13/000802.source.xml | An approach for generating high-resolution a priori maximum parsimony Y-chromosome (chrY) phylogenies based on SNP and small INDEL variant data from massively-parallel short-read (next-generation) sequencing data is described; the tree-generation methodology produces annotations localizing mutations to individual branches of the tree, along with indications of mutation placement uncertainty in cases for which \"no-calls\" (through lack of mapped reads or otherwise) at particular site precludes a precise placement of the mutation. The approach leverages careful variant site filtering and a novel iterative reweighting procedure to generate high-accuracy trees while considering variants in regions of chrY that had previously been excluded from analyses based on short-read sequencing data. It is argued that the proposed approach is also superior to previous region-based filtering approaches in that it adapts to the quality of the underlying data and will automatically allow the scope of sites considered to expand as the underlying data quality improves (e.g. through longer read lengths). Key related issues, including calling of genotypes for the hemizygous chrY, reliability of variant results, read mismappings and \"heterozygous\" genotype calls, and the mutational stability of different variants are discussed and taken into account. The methodology is demonstrated through application to a dataset consisting of 1292 male samples from diverse populations and haplogroups, with the majority coming from low-coverage sequencing by the 1000 Genomes Project. Application of the tree-generation approach to these data produces a tree involving over 120,000 chrY variant sites (about 45,000 sites if singletons are excluded). The utility of this approach in refining the Y-chromosome phylogenetic tree is demonstrated by examining results for several haplogroups. The results indicate a number of new branches on the Y-chromosome phylogenetic tree, many of them subdividing known branches, but also including some that inform the presence of additional levels along the trunk of the tree. Finally, opportunities for extensions of this phylogenetic analysis approach to other types of genetic data are examined. | NA | biorxiv | 101 |
10.1101/000042 | Routes for breaching and protecting genetic privacy | Yaniv Erlich;Arvind Narayanan; | Yaniv Erlich | Whitehead Institute | 2013-12-01 | 3 | New Results | cc_by | Genomics | https://www.biorxiv.org/content/early/2013/12/01/000042.source.xml | We are entering the era of ubiquitous genetic information for research, clinical care, and personal curiosity. Sharing these datasets is vital for rapid progress in understanding the genetic basis of human diseases. However, one growing concern is the ability to protect the genetic privacy of the data originators. Here, we technically map threats to genetic privacy and discuss potential mitigation strategies for privacy-preserving dissemination of genetic data.\n\nAbout the AuthorsYaniv Erlich is a Fellow at the Whitehead Institute for Biomedical Research. Erlich received his Ph.D. from Cold Spring Harbor Laboratory in 2010 and B.Sc. from Tel-Aviv University in 2006. Prior to that, Erlich worked in computer security and was responsible for conducting penetration tests on financial institutes and commercial companies. Dr. Erlichs research involves developing new algorithms for computational human genetics.\n\nArvind Narayanan is an Assistant Professor in the Department of Computer Science and the Center for Information Technology and Policy at Princeton. He studies information privacy and security. His research has shown that data anonymization is broken in fundamental ways, for which he jointly received the 2008 Privacy Enhancing Technologies Award. His current research interests include building a platform for privacy-preserving data sharing.\n\nSummaryO_LIBroad data dissemination is essential for advancements in genetics, but also brings to light concerns regarding privacy.\nC_LIO_LIPrivacy breaching techniques work by cross-referencing two or more pieces of information to gain new, potentially undesirable knowledge on individuals or their families.\nC_LIO_LIBroadly speaking, the main routes to breach privacy are identity tracing, attribute disclosure, and completion of sensitive DNA information.\nC_LIO_LIIdentity tracing exploits quasi-identifiers in the DNA data or metadata to uncover the identity of an unknown genetic dataset.\nC_LIO_LIAttribute disclosure techniques work on known DNA datasets. They use the DNA information to link the identity of a person with a sensitive phenotype.\nC_LIO_LICompletion techniques also work on known DNA data. They try to uncover sensitive genomic areas that were masked to protect the participant.\nC_LIO_LIIn the last few years, we have witnessed a rapid growth in the range of techniques and tools to conduct these privacy-breaching attacks. Currently, most of the techniques are beyond the reach of the general public, but can be executed by trained persons with varying degrees of effort.\nC_LIO_LIThere is considerable debate regarding risk management. One camp supports a pragmatic, ad-hoc approach of privacy by obscurity and the other supports a systematic, mathematically-backed approach of privacy by design.\nC_LIO_LIPrivacy by design algorithms include access control, differential privacy, and cryptographic techniques. So far, data custodians of genetic databases mainly adopted access control as a mitigation strategy.\nC_LIO_LINew developments in cryptographic techniques may usher in an additional arsenal of security by design techniques.\nC_LI | 10.1038/nrg3723 | biorxiv | 102 |
10.1101/000935 | The-LHON-Enigma: explaining the behaviour of Leber&#146;s Hereditary Optic Neuropathy by the use of a simple computer model | IAN S Logan; | IAN S Logan | - | 2013-11-25 | 1 | New Results | cc_by | Genomics | https://www.biorxiv.org/content/early/2013/11/25/000935.source.xml | Lebers Hereditary Optic Neuropathy (LHON) appears as an enigmatic condition; affecting only certain families and often causing a severe loss of vision seemingly at random amongst family members. The first breakthrough came in 1988 with the linking of the condition to a mutation in the mitochondrial DNA (mtDNA). Now it is known that about 90% of cases are linked to 3 mutations. In this paper the hypothesis is suggested that a LHON mutation decreases the function of the mitochondrial enzyme, Complex I, by 50% and this alone critically endangers the survival of cells - especially the fragile cells of the optic nerves. A computer model has been written to illustrate how the hypothesis can produce a natural history for the condition of LHON that has features similar to those observed in practice; thereby successfully explaining the behaviour of this enigmatic condition. | NA | biorxiv | 103 |
10.1101/001362 | Extensive Phenotypic Changes Associated with Large-scale Horizontal Gene Transfer | Kevin Dougherty;Brian A Smith;Autum F Moore;Shannon Maitland;Chris Fanger;Rachel Murillo;David A Baltrus; | David A Baltrus | University of Arizona | 2013-12-12 | 1 | New Results | cc_by_nc_nd | Microbiology | https://www.biorxiv.org/content/early/2013/12/12/001362.source.xml | Horizontal gene transfer often leads to phenotypic changes within recipient organisms independent of any immediate evolutionary benefits. While secondary phenotypic effects of horizontal transfer (i.e. changes in growth rates) have been demonstrated and studied across a variety of systems using relatively small plasmid and phage, little is known about how size of the acquired region affects the magnitude or number of such costs. Here we describe an amazing breadth of phenotypic changes which occur after a large-scale horizontal transfer event (~1Mb megaplasmid) within Pseudomonas stutzeri including sensitization to various stresses as well as changes in bacterial behavior. These results highlight the power of horizontal transfer to shift pleiotropic relationships and cellular networks within bacterial genomes. They also provide an important context for how secondary effects of transfer can bias evolutionary trajectories and interactions between species. Lastly, these results and system provide a foundation to investigate evolutionary consequences in real time as newly acquired regions are ameliorated and integrated into new genomic contexts. | 10.1371/journal.pone.0102170 | biorxiv | 104 |
10.1101/000968 | Functional connectivity networks with and without global signal correction | Satoru Hayasaka; | Satoru Hayasaka | Wake Forest School of Medicine | 2013-12-19 | 2 | New Results | cc_by_nc_nd | Neuroscience | https://www.biorxiv.org/content/early/2013/12/19/000968.source.xml | In functional connectivity analyses in BOLD (blood oxygenation level dependent) fMRI data, there is an ongoing debate on whether to correct global signals in fMRI time series data. Although the discussion has been ongoing in the fMRI community since the early days of fMRI data analyses, this subject has gained renewed attention in recent years due to the surging popularity of functional connectivity analyses, in particular graph theory-based network analyses. However, the impact of correcting (or not correcting) for global signals has not been systematically characterized in the context of network analyses. Thus, in this work, I examined the effect of global signal correction on an fMRI network analysis. In particular, voxel-based resting-state fMRI networks were constructed with and without global signal correction. The resulting functional connectivity networks were compared. Without global signal correction, the distributions of the correlation coefficients were positively biased. I also found that, without global signal correction, nodes along the interhemisphic fissure were highly connected whereas some nodes and subgraphs around white-matter tracts became disconnected from the rest of the network. These results from this study show differences between the networks with or without global signal correction. | 10.3389/fnhum.2013.00880 | biorxiv | 107 |
10.1101/001198 | Genomic architecture of human neuroanatomical diversity | Roberto Toro;Jean-Baptiste Poline;Guillaume Huguet;Eva Loth;Vincent Frouin;Tobias Banaschewski;Gareth J Barker;Arun Bokde;Christian Büchel;Fabiana Carvalho;Patricia Conrod;Mira Fauth-Bühler;Herta Flor;Jürgen Gallinat;Hugh Garavan;Penny Gowloan;Andreas Heinz;Bernd Ittermann;Claire Lawrence;Hervé Lemaître;Karl Mann;Frauke Nees;Tomá Paus;Zdenka Pausova;Marcella Rietschel;Trevor Robbins;Michael Smolka;Andreas Ströhle;Gunter Schumann;Thomas Bourgeron; | Roberto Toro | Institut Pasteur | 2013-12-10 | 1 | New Results | cc_no | Neuroscience | https://www.biorxiv.org/content/early/2013/12/10/001198.source.xml | Human brain anatomy is strikingly diverse and highly inheritable: genetic factors may explain up to 80% of its variability. Prior studies have tried to detect genetic variants with a large effect on neuroanatomical diversity, but those currently identified account for <5% of the variance. Here we show, based on our analyses of neuroimaging and whole-genome genotyping data from 1,765 subjects, that up to 54% of this heritability is captured by large numbers of single nucleotide polymorphisms of small effect spread throughout the genome, especially within genes and close regulatory regions. The genetic bases of neuroanatomical diversity appear to be relatively independent of those of body size (height), but shared with those of verbal intelligence scores. The study of this genomic architecture should help us better understand brain evolution and disease. | 10.1038/mp.2014.99 | biorxiv | 111 |
10.1101/001156 | Influence of walking speed on locomotor time production | Fabrice MEGROT;Carole MEGROT; | Fabrice MEGROT | French Red Cross | 2013-12-04 | 1 | Contradictory Results | cc_by_nc | Neuroscience | https://www.biorxiv.org/content/early/2013/12/04/001156.source.xml | The aim of the present study was to determine whether or not walking speed affects temporal perception. It was hypothesized that fast walking would reduce the perceived length of time while slow walking increase production estimates. 16 healthy subjects were included. After a first << calibration >> phase allowing the determination of different walking speeds, the subjects were instructed to demonstrate periods of time or << target times >> of 3s and 7s, by a walking movement. Then, subjects were asked to simulate walking by raising one foot after the other without advancing. Finally, a third condition, Motionless, involved producing the target times while standing without movement. The results of this study suggest that movement does influence the perception of time, causing an overestimation of time. In agreement with the results of Denner et al. (1963) the subjects produced times which were longer than the target times. | NA | biorxiv | 112 |
10.1101/001123 | Analysis of the study of the cerebellar pinceau by Korn and Axelrad | Antonin Blot;Boris Barbour; | Boris Barbour | Ecole Normale Supérieure | 2013-12-03 | 1 | Contradictory Results | cc_by | Neuroscience | https://www.biorxiv.org/content/early/2013/12/03/001123.source.xml | The axon initial segment of each cerebellar Purkinje cell is ensheathed by basket cell axons in a structure called the pinceau, which is largely devoid of chemical synapses and gap junctions. These facts and ultrastructural similarities with the axon cap of the teleost Mauthner cell led to the conjecture that the pinceau mediates ephaptic (via the extracellular field) inhibition. Korn and Axelrad published a study in 1980 in which they reported confirmation of this conjecture. We have analysed their results and show that most are likely to be explained by an artefactual signal arising from the massive stimulation of parallel fibres they employed. We reproduce their experiments and confirm that all of their results are consistent with this artefact. Their data therefore provide no evidence regarding the operation of the pinceau. | NA | biorxiv | 113 |
10.1101/001438 | DCL1, a Protein that Produces Plant MicroRNA, Coordinates Meristem Activity | Stephen E. Schauer;Teresa A. Golden;Delwin S. Merchant;Biranchi N. Patra;Jean D. Lang;Sumita Ray;Bulbul Chakravarti;Deb N. Chakravarti;Animesh Ray; | Animesh Ray | Keck Graduate Institute | 2013-12-21 | 2 | New Results | cc_by_nd | Plant Biology | https://www.biorxiv.org/content/early/2013/12/21/001438.source.xml | Abstract Abstract Introduction Results Discussion Materials and Methods Authors' contributions Funding References The ubiquity and importance of short duplex RNAs, termed microRNA (miRNA), for normal development in higher eukaryotes are becoming increasingly clear. We had previously shown that reduction-of-function mutations in Arabidopsis thaliana DCL1 (DICER-LIKE1) gene, affecting the nucleus-localized protein that produces 19-25 nucleotides long miRNA species from longer double stranded RNA precursors, cause a delay in flowering by prolonging the period of juvenile organ development. Here we show that DCL1 transcription is increased at the critical phase of juvenile to reproductive developmental transition, and that DCL1 protein is localized in meri ... | NA | biorxiv | 118 |
10.1101/001248 | A conserved oomycete CRN effector targets and modulates tomato TCP14-2 to enhance virulence | Remco Stam;Graham Motion;Petra C. Boevink;Edgar Huitema; | Edgar Huitema | University of Dundee | 2013-12-11 | 1 | New Results | cc_by_nc_nd | Plant Biology | https://www.biorxiv.org/content/early/2013/12/11/001248.source.xml | Phytophthora spp. secrete vast arrays of effector molecules upon infection. A main class of intracellular effectors are the CRNs. They are translocated into the host cell and specifically localise to the nucleus where they are thought to perturb many different cellular processes. Although CRN proteins have been implicated as effectors, direct evidence of CRN mediated perturbation of host processes has been lacking. Here we show that a conserved CRN effector from P. capsici directly binds to tomato transcription factor SlTCP14-2. Previous studies in Arabidopsis thaliana have revealed that transcription factor TCP14 may be key immune signalling protein, targeted by effectors from divergent species. We extend on our understanding of TCP targeting by pathogen effectors by showing that the P. capsici effector CRN12_997 binds to SlTCP14-2 in plants. SlTCP14-2 over-expression enhances immunity to P. capsici, a phenotypic outcome that can be abolished by co-expression of CRN12_997.\n\nWe show that in the presence of CRN12_997, SlTCP14-2 association with nuclear chromatin is diminished, resulting in altered SlTCP14 subnuclear localisation. These results suggest that CRN12_997 prevents SlTCP14 from positively regulating defence against P. capsici. Our work demonstrates a direct interaction between an oomycete CRN and a host target required for suppression of immunity. Collectively, our results hint at a virulence strategy that is conserved within the oomycetes and may allow engineering of resistance to a wide range of crop pathogens. | NA | biorxiv | 119 |
10.1101/000927 | Investigating the relation between stochastic differentiation and homeostasis in intestinal crypts via multiscale modeling | Alex Graudenzi;Giulio Caravagna;Giovanni De Matteis;Marco Antoniotti; | Alex Graudenzi | Dept. of Informatics, Systems and Communication | 2013-11-25 | 1 | New Results | cc_no | Systems Biology | https://www.biorxiv.org/content/early/2013/11/25/000927.source.xml | Colorectal tumors originate and develop within intestinal crypts. Even though some of the essential phenomena that characterize crypt structure and dynamics have been effectively described in the past, the relation between the differentiation process and the overall crypt homeostasis is still partially understood. We here investigate this relation and other important biological phenomena by introducing a novel multiscale model that combines a morphological description of the crypt with a gene regulation model: the emergent dynamical behavior of the underlying gene regulatory network drives cell growth and differentiation processes, linking the two distinct spatio-temporal levels. The model relies on a few a priori assumptions, yet accounting for several key processes related to crypt functioning, such as: dynamic gene activation patterns, stochastic differentiation, signaling pathways ruling cell adhesion properties, cell displacement, cell growth, mitosis, apoptosis and the presence of biological noise.\n\nWe show that this modeling approach captures the major dynamical phenomena that characterize the regular physiology of crypts, such as cell sorting, coordinate migration, dynamic turnover, stem cell niche maintenance and clonal expansion. All in all, the model suggests that the process of stochastic differentiation might be sufficient to drive the crypt to homeostasis, under certain crypt configurations. Besides, our approach allows to make precise quantitative inferences that, when possible, were matched to the current biological knowledge and it permits to investigate the role of gene-level perturbations, with reference to cancer development. We also remark the theoretical framework is general and may applied to different tissues, organs or organisms. | 10.1371/journal.pone.0097272 | biorxiv | 120 |
10.1101/000349 | Filling up the tree: considering the self-organization of avian roosting behavior | Bradly J Alicea; | Bradly J Alicea | Michigan State University | 2013-12-01 | 2 | New Results | cc_by_nc | Zoology | https://www.biorxiv.org/content/early/2013/12/01/000349.source.xml | In this paper, models for understanding bird roosting will be considered for purposes of developing better Artificial Life models of complex behavior. Roosting involves multiple flocks of birds picking a single tree limb to rest on for the night, and can be considered an iterative, time-dependent process that unfolds over a 45-minute interval roughly corresponding to twilight. Two models will be used to better understand the main components of this behavior. The constrained dynamics model, which represents continuous random absorption on a one-dimensional lattice, will be used to characterize the dynamics of crowding in the tree structure over time. A second approach involves the relationships between complex networks and roosting behaviors, in particular the evolution of structured networks via rules of incorporation and interaction. Finally, the percolation model will be proposed as a way to bridge behaviors explained by the constrained dynamics and complex network models. | NA | biorxiv | 121 |
10.1101/001024 | Exploring DNA structures in real-time polymerase kinetics using Pacific Biosciences sequencer data | Sterling Sawaya;James Boocock;Mik Black;Neil Gemmell; | Sterling Sawaya | University of Otago | 2013-12-02 | 1 | New Results | cc_by_nc_nd | Bioinformatics | https://www.biorxiv.org/content/early/2013/12/02/001024.source.xml | Pausing of DNA polymerase can indicate the presence of a DNA structure that differs from the canonical double-helix. Here we detail a method to investigate how polymerase pausing in the Pacific Biosciences sequencer reads can be related to DNA structure. The Pacific Biosciences sequencer uses optics to view a polymerase and its interaction with a single DNA molecule in real-time, offering a unique way to detect potential alternative DNA structures. We have developed a new way to examine polymerase kinetics and relate it to the DNA sequence by using a wavelet transform of read information from the sequencer. We use this method to examine how polymerase kinetics are related to nucleotide base composition. We then examine tandem repeat sequences known for their ability to form different DNA structures: (CGG)n and (CG)n repeats which can, respectively, form G-quadruplex DNA and Z-DNA. We find pausing around the (CGG)n repeat that may indicate the presence of G-quadruplexes in some of the sequencer reads. The (CG)n repeat does not appear to cause polymerase pausing, but its kinetics signature nevertheless suggests the possibility that alternative nucleotide conformations may sometimes be present. We discuss the implications of using our method to discover DNA sequences capable of forming alternative structures. The analyses presented here can be reproduced on any Pacific Biosciences kinetics data for any DNA pattern of interest using an R package that we have made publicly available.\n\nAuthor SummaryDNA can be found in various forms that differ from the double-helix first discovered by Watson and Crick in 1953. These alternative DNA structures depend on the DNA sequence, and researchers continue to explore which sequences have the potential to form alternative structures. Here we advance the use of Pacific Biosciences sequencer data to explore potential alternative DNA structures. The Pacific Bio-sciences sequencer provides an unprecedented way to examine the interaction between DNA polymerase and DNA by following a single polymerase in real time as it copies a DNA molecule. The pausing of DNA polymerase is a common method for exploring the DNA sequences that have the potential to form alternative DNA structures, and Pacific Biosciences data has previously been used to measure polymerase pausing at a slipped strand structure. DNA polymerase is known to pause at some of these alternative structures, such as the structure known as the G-quadruplex, a DNA structure that has potentially importing regulatory significance. We examine polymerase kinetics around a G-quadruplex, and find evidence of polymerase pausing in the Pacific Biosciences kinetics. We provide a method, with publicly available code, so that others can examine these polymerase kinetics for any sequence of interest. | 10.1186/s12859-014-0449-0 | biorxiv | 122 |
10.1101/000448 | Design and implementation of a synthetic biomolecular concentration tracker | Victoria Hsiao;Emmanuel LC de los Santos;Weston R Whitaker;John E Dueber;Richard M Murray; | Victoria Hsiao | California Institute of Technology | 2013-12-10 | 2 | New Results | cc_by_nc_nd | Synthetic Biology | https://www.biorxiv.org/content/early/2013/12/10/000448.source.xml | As a field, synthetic biology strives to engineer increasingly complex artificial systems in living cells. Active feedback in closed loop systems offers a dynamic and adaptive way to ensure constant relative activity independent of intrinsic and extrinsic noise. In this work, we design, model, and implement a biomolecular concentration tracker, in which an output protein tracks the concentration of an input protein. Synthetic modular protein scaffold domains are used to colocalize a two-component system, and a single negative feedback loop modulates the production of the output protein. Using a combination of model and experimental work, we show that the circuit achieves real-time protein concentration tracking in Escherichia coli and that steady state outputs can be tuned. | 10.1021/sb500024b | biorxiv | 125 |
10.1101/000661 | Natural Allelic Variations of Xenobiotic Enzymes Pleiotropically Affect Sexual Dimorphism in Oryzias latipes | Takafumi Katsumura;Shoji Oda;Shigeki Nakagome;Tsunehiko Hanihara;Hiroshi Kataoka;Hiroshi Mitani;Shoji Kawamura;Hiroki Oota; | Hiroki Oota | Kitasato University School of Medicine | 2013-11-25 | 3 | New Results | cc_by_nc_nd | Evolutionary Biology | https://www.biorxiv.org/content/early/2013/11/25/000661.source.xml | Summary Summary Highlights Results and Discussion Accession Numbers Reference Sexual dimorphisms, which are phenotypic differences between males and females, are driven by sexual selection [1, 2]. Interestingly, sexually selected traits show geographic variations within species despite strong directional selective pressures [3, 4]. However, genetic factors that regulate varied sexual differences remain unknown. In this study, we show that polymorphisms in cytochrome P450 (CYP) 1B1, which encodes a xenobiotic-metabolising enzyme, are associated with local differences of sexual dimorphisms in the anal fin morphology of medaka fish (Oryzias latipes). High and low activity CYP1B1 alleles increased and decreased differences in anal fin sizes ... | 10.1098/rspb.2014.2259 | biorxiv | 132 |
10.1101/001040 | High Genetic Diversity and Adaptive Potential of Two Simian Hemorrhagic Fever Viruses in a Wild Primate Population | Adam L. Bailey;Michael Lauck;Andrea Weiler;Samuel D. Sibley;Jorge M. Dinis;Zachary Bergman;Chase W. Nelson;Michael Correll;Michael Gleicher;David Hyeroba;Alex Tumukunde;Geoffrey Weny;Colin Chapman;Jens Kuhn;Austin Hughes;Thomas C. Friedrich;Tony L. Goldberg;David H. O'Connor; | David H. O'Connor | University of Wisconsin - Madison | 2013-12-03 | 1 | New Results | cc_no | Microbiology | https://www.biorxiv.org/content/early/2013/12/03/001040.source.xml | Key biological properties such as high genetic diversity and high evolutionary rate enhance the potential of certain RNA viruses to adapt and emerge. Identifying viruses with these properties in their natural hosts could dramatically improve disease forecasting and surveillance. Recently, we discovered two novel members of the viral family Arteriviridae: simian hemorrhagic fever virus (SHFV)-krc1 and SHFV-krc2, infecting a single wild red colobus (Procolobus rufomitratus tephrosceles) in Kibale National Park, Uganda. Nearly nothing is known about the biological properties of SHFVs in nature, although the SHFV type strain, SHFV-LVR, has caused devastating outbreaks of viral hemorrhagic fever in captive macaques. Here we detected SHFV-krc1 and SHFV-krc2 in 40% and 47% of 60 wild red colobus tested, respectively. We found viral loads in excess of 106 - 107 RNA copies per milliliter of blood plasma for each of these viruses. SHFV-krc1 and SHFV-krc2 also showed high genetic diversity at both the inter- and intra-host levels. Analyses of synonymous and non-synonymous nucleotide diversity across viral genomes revealed patterns suggestive of positive selection in SHFV open reading frames (ORF) 5 (SHFV-krc2 only) and 7 (SHFV-krc1 and SHFV-krc2). Thus, these viruses share several important properties with some of the most rapidly evolving, emergent RNA viruses. | 10.1371/journal.pone.0090714 | biorxiv | 133 |
10.1101/001669 | Algorithms in Stringomics (I): Pattern-Matching against "Stringomes" | Paolo Ferragina;Bud (Bhubaneswar) Mishra; | Bud (Bhubaneswar) Mishra | New York University | 2014-01-02 | 1 | New Results | cc_by | Bioinformatics | https://www.biorxiv.org/content/early/2014/01/02/001669.source.xml | This paper reports an initial design of new data-structures that generalizes the idea of pattern-matching in stringology, from its traditional usage in an (unstructured) set of strings to the arena of a well-structured family of strings. In particular, the object of interest is a family of strings composed of blocks/classes of highly similar \"stringlets,\" and thus mimic a population of genomes made by concatenating haplotype-blocks, further constrained by haplotype-phasing. Such a family of strings, which we dub \"stringomes,\" is formalized in terms of a multi-partite directed acyclic graph with a source and a sink. The most interesting property of stringomes is probably the fact that they can be represented efficiently with compression up to their k-th order empirical entropy, while ensuring that the compression does not hinder the pattern-matching counting and reporting queries - either internal to a block or spanning two (or a few constant) adjacent blocks. The solutions proposed here have immediate applications to next-generation sequencing technologies, base-calling, expression profiling, variant-calling, population studies, onco-genomics, cyber security trace analysis and text retrieval. | NA | biorxiv | 134 |
10.1101/000422 | On the optimal trimming of high-throughput mRNAseq data | Matthew D MacManes; | Matthew D MacManes | University of New Hampshire | 2014-01-14 | 3 | New Results | cc_by | Bioinformatics | https://www.biorxiv.org/content/early/2014/01/14/000422.source.xml | The widespread and rapid adoption of high-throughput sequencing technologies has afforded researchers the opportunity to gain a deep understanding of genome level processes that underlie evolutionary change, and perhaps more importantly, the links between genotype and phenotype. In particular, researchers interested in functional biology and adaptation have used these technologies to sequence mRNA transcriptomes of specific tissues, which in turn are often compared to other tissues, or other individuals with different phenotypes. While these techniques are extremely powerful, careful attention to data quality is required. In particular, because high-throughput sequencing is more error-prone than traditional Sanger sequencing, quality trimming of sequence reads should be an important step in all data processing pipelines. While several software packages for quality trimming exist, no general guidelines for the specifics of trimming have been developed. Here, using empirically derived sequence data, I provide general recommendations regarding the optimal strength of trimming, specifically in mRNA-Seq studies. Although very aggressive quality trimming is common, this study suggests that a more gentle trimming, specifically of those nucleotides whose PO_SCPLOWHREDC_SCPLOW score <2 or <5, is optimal for most studies across a wide variety of metrics. | 10.3389/fgene.2014.00013 | biorxiv | 136 |
10.1101/001297 | Aerodynamic characteristics of a feathered dinosaur measured using physical models. Effects of form on static stability and control effectiveness. | Dennis Evangelista;Griselda Cardona;Eric Guenther-Gleason;Tony Huynh;Austin Kwong;Dylan Marks;Neil Ray;Adrian Tisbe;Kyle Tse;Mimi Kohl; | Dennis Evangelista | UC Berkeley | 2014-01-16 | 3 | New Results | cc_by_nc_nd | Biophysics | https://www.biorxiv.org/content/early/2014/01/16/001297.source.xml | We report the effects of posture and morphology on the static aerodynamic stability and control effectiveness of physical models based on the feathered dinosaur, {dagger}Microraptor gui, from the Cretaceous of China. Postures had similar lift and drag coefficients and were broadly similar when simplified metrics of gliding were considered, but they exhibited different stability characteristics depending on the position of the legs and the presence of feathers on the legs and the tail. Both stability and the function of appendages in generating maneuvering forces and torques changed as the glide angle or angle of attack were changed. These are significant because they represent an aerial environment that may have shifted during the evolution of directed aerial descent and other aerial behaviors. Certain movements were particularly effective (symmetric movements of the wings and tail in pitch, asymmetric wing movements, some tail movements). Other appendages altered their function from creating yaws at high angle of attack to rolls at low angle of attack, or reversed their function entirely. While {dagger}M. gui lived after {dagger}Archaeopteryx and likely represents a side experiment with feathered morphology, the general patterns of stability and control effectiveness suggested from the manipulations of forelimb, hindlimb and tail morphology here may help understand the evolution of flight control aerodynamics in vertebrates. Though these results rest on a single specimen, as further fossils with different morphologies tested, the findings here could be applied in a phylogenetic context to reveal biomechanical constraints on extinct flyers arising from the need to maneuver. | 10.1371/journal.pone.0085203 | biorxiv | 137 |
10.1101/001651 | Power-law Null Model for Bystander Mutations in Cancer | Loes Olde Loohuis;Andreas Witzel;Bud Mishra; | Loes Olde Loohuis | City University New York | 2014-01-02 | 1 | New Results | cc_no | Cancer Biology | https://www.biorxiv.org/content/early/2014/01/02/001651.source.xml | In this paper we study Copy Number Variation (CNV) data. The underlying process generating CNV segments is generally assumed to be memory-less, giving rise to an exponential distribution of segment lengths. In this paper, we provide evidence from cancer patient data, which suggests that this generative model is too simplistic, and that segment lengths follow a power-law distribution instead. We conjecture a simple preferential attachment generative model that provides the basis for the observed power-law distribution. We then show how an existing statistical method for detecting cancer driver genes can be improved by incorporating the power-law distribution in the null model. | NA | biorxiv | 138 |
10.1101/001602 | p97-dependent retrotranslocation and proteolytic processing govern formation of active Nrf1 upon proteasome inhibition | Senthil K Radhakrishnan;Willem den Besten;Raymond J Deshaies; | Raymond J Deshaies | California Institute of Technology | 2014-01-23 | 3 | New Results | cc_no | Cell Biology | https://www.biorxiv.org/content/early/2014/01/23/001602.source.xml | Proteasome inhibition elicits an evolutionarily conserved response wherein proteasome subunit mRNAs are upregulated, resulting in recovery of proteasome activity. We previously demonstrated that the transcription factor Nrf1 mediates this homeostatic response in mammalian cells. We show here that Nrf1 is initially translocated into the lumen of the ER, but is rapidly and efficiently retrotranslocated to the cytosolic side of the membrane in a manner that depends on p97/VCP. Normally, retrotranslocated Nrf1 is degraded by the proteasome and active species do not accumulate. However, in cells with compromised proteasomes, retrotranslocated Nrf1 escapes degradation and is cleaved N-terminal to Leu-104 to yield a fragment that is no longer tethered to the ER-membrane. Importantly, this cleavage event is essential for Nrf1-dependent activation of proteasome gene expression upon proteasome inhibition. Our data uncover an unexpected role for p97 in activation of a transcription factor by relocalizing it from the ER lumen to the cytosol. | 10.7554/eLife.01856.001 | biorxiv | 141 |
10.1101/001610 | Black rhinoceros demography should be stage, not age, based. | Peter R Law;Wayne L Linklater; | Peter R Law | na | 2013-12-30 | 1 | New Results | cc_by_nc_nd | Ecology | https://www.biorxiv.org/content/early/2013/12/30/001610.source.xml | Biologically meaningful and standardized definitions of life stages are essential for demographic studies, especially for endangered and intensively managed species such as rhinoceros. Focusing on the black rhinoceros Diceros bicornis, we argue that standardized biological definitions of calf, subadult, and adult, rather than age classes, provide the appropriate basis for black rhinoceros demography. Age classes do not correlate well with the risks of mortality nor characterize, at least for females, the attainment of reproductive maturity. Black rhinoceros demography based on age classes, typical of existing literature, obscures the significance of studies of mortality and fecundity. Comparison of studies also requires standardized definitions. We propose biologically meaningful definitions of life stages appropriate for the demography of the black rhinoceros and encourage the community of rhinoceros researchers to reach consensus on standardized, demographically appropriate definitions for adoption for each rhinoceros species. | 10.1111/aje.12148 | biorxiv | 145 |
10.1101/001537 | Assessing the Use of Antiviral Treatment to Control Influenza | Sarah C Kramer;Shweta Bansal; | Shweta Bansal | Georgetown University; National Institutes of Health | 2013-12-26 | 1 | New Results | cc_no | Ecology | https://www.biorxiv.org/content/early/2013/12/26/001537.source.xml | Vaccines are the cornerstone of influenza control policy, but can suffer from several drawbacks. Seasonal influenza vaccines are prone to production problems and low efficacies, while pandemic vaccines are unlikely to be available in time to slow a rapidly spreading global outbreak. Antiviral therapy was found to be beneficial during the influenza A(H1N1)pdm09 pandemic even with limited use; however, antiviral use has decreased further since then. We seek to determine the role antiviral therapy can play in pandemic and seasonal influenza control on the population level, and to find optimized strategies for more efficient use of treatment. Using an age-structured contact network model for an urban population, we find that while a conservative antiviral therapy strategy cannot replace a robust influenza vaccine, it can play a role in reducing attack rates and eliminating outbreaks. | 10.1017/S0950268814002520 | biorxiv | 146 |
10.1101/001172 | Species Delimitation using Genome-Wide SNP Data | Adam Leache;Matthew Fujita;Vladimir Minin;Remco Bouckaert; | Adam Leache | University of Washington | 2014-01-04 | 2 | New Results | cc_by_nc_nd | Evolutionary Biology | https://www.biorxiv.org/content/early/2014/01/04/001172.source.xml | The multi-species coalescent has provided important progress for evolutionary inferences, including increasing the statistical rigor and objectivity of comparisons among competing species delimitation models. However, Bayesian species delimitation methods typically require brute force integration over gene trees via Markov chain Monte Carlo (MCMC), which introduces a large computation burden and precludes their application to genomic-scale data. Here we combine a recently introduced dynamic programming algorithm for estimating species trees that bypasses MCMC integration over gene trees with sophisticated methods for estimating marginal likelihoods, needed for Bayesian model selection, to provide a rigorous and computationally tractable technique for genome-wide species delimitation. We provide a critical yet simple correction that brings the likelihoods of different species trees, and more importantly their corresponding marginal likelihoods, to the same common denominator, which enables direct and accurate comparisons of competing species delimitation models using Bayes factors. We test this approach, which we call Bayes factor delimitation (*with genomic data; BFD*), using common species delimitation scenarios with computer simulations. Varying the numbers of loci and the number of samples suggest that the approach can distinguish the true model even with few loci and limited samples per species. Misspecification of the prior for population size{theta} has little impact on support for the true model. We apply the approach to West African forest geckos (Hemidactylus fasciatus complex) using genome-wide SNP data data. This new Bayesian method for species delimitation builds on a growing trend for objective species delimitation methods with explicit model assumptions that are easily tested. | 10.1093/sysbio/syu018 | biorxiv | 147 |
10.1101/001529 | Revisiting the effect of population size on cumulative cultural evolution | Ryan Baldini; | Ryan Baldini | UC Davis | 2013-12-31 | 2 | New Results | cc_by_nc_nd | Evolutionary Biology | https://www.biorxiv.org/content/early/2013/12/31/001529.source.xml | Henrich (2004) argued that larger populations can better maintain complex technologies because they contain more highly skilled people whom others can imitate. His original model, however, did not distinguish the effects of population size from population density or network size; a learners social network included the entire population. Does population size remain important when populations are subdivided and networks are realistically small? I use a mathematical model to show that population size has little effect on equilibrium levels of mean skill under a wide range of conditions. The effects of network size and transmission error rate usually overshadow that of population size. Population size can, however, affect the rate at which a population approaches equilibrium, by increasing the rate at which innovations arise. This effect is small unless innovation is very rare. Whether population size predicts technological complexity in the real world, then, depends on whether technological evolution is innovation-limited and short of equilibrium. The effect of population \"connectedness,\" via migration or trade, is similar. I discuss the results of this analysis in light of the current empirical debate. | 10.1163/15685373-12342153 | biorxiv | 148 |
10.1101/001636 | Hippocampal Motifs | Zahra Aghajan;Lavanya Acharya;Jesse Cushman;Cliff Vuong;Jason Moore;Mayank Mehta; | Mayank Mehta | UCLA | 2013-12-31 | 1 | New Results | cc_no | Neuroscience | https://www.biorxiv.org/content/early/2013/12/31/001636.source.xml | Dorsal Hippocampal neurons provide an allocentric map of space1, characterized by three key properties. First, their firing is spatially selective1-3, termed a rate code. Second, as animals traverse through place fields, neurons sustain elevated firing rates for long periods, however this has received little attention. Third the theta-phase of spikes within this sustained activity varies with animals location, termed phase-precession or a temporal code4-10. The precise relationship between these properties and the mechanisms governing them are not understood, although distal visual cues (DVC) are thought to be sufficient to reliably elicit them2,3. Hence, we measured rat CA1 neurons activity during random foraging in two-dimensional VR--where only DVC provide consistent allocentric location information-- and compared it with their activity in real world (RW). Surprisingly, we found little spatial selectivity in VR. This is in sharp contrast to robust spatial selectivity commonly seen in one-dimensional RW and VR7-11, or two-dimensional RW1-3. Despite this, neurons in VR generated approximately two-second long phase precessing spike sequences, termed \"hippocampal motifs\". Motifs, and \"Motif-fields\", an aggregation of all motifs of a neuron, had qualitatively similar properties including theta-scale temporal coding in RW and VR, but the motifs were far less spatially localized in VR. These results suggest that intrinsic, network mechanisms generate temporally coded hippocampal motifs, which can be dissociated from their spatial selectivity. Further, DVC alone are insufficient to localize motifs spatially to generate a robust rate code. | 10.1038/nn.3884 | biorxiv | 149 |
10.1101/001586 | Embodied cognition, embodied regulation, and the Data Rate Theorem | Rodrick Wallace; | Rodrick Wallace | New York State Psychiatric Institute | 2014-01-13 | 2 | New Results | cc_by_nd | Neuroscience | https://www.biorxiv.org/content/early/2014/01/13/001586.source.xml | The Data Rate Theorem carries deep implications for theories of embodied cognition, extensions providing a spectrum of necessary conditions dynamic statistical models useful in empirical studies. A large deviations argument, however, implies that the regulation and stabilization of such systems is itself an interpenetrating phenomenon necessarily convoluted with embodied cognition. For humans, the central regulatory role of culture has long been known. Although a ground-state collapse analogous to generalized anxiety appears ubiquitous to such systems, lack of cultural modulation in real-time automatons or distributed cognition man-machine cockpits makes them subject to a pathology under which all possible targets are enemies. | 10.1016/j.bica.2014.02.003 | biorxiv | 150 |
10.1101/000950 | An XA21-Associated Kinase (OsSERK2) regulates immunity mediated by the XA21 and XA3 immune receptors | Xuewei Chen;Shimin Zuo;Benjamin Schwessinger;Mawsheng Chern;Patrick Canlas;Deling Ruan;Arsalan Daudi;Xiaogang Zhang;Jing Wang;Christopher Petzold;Joshua Heazlewood;Pamela C Ronald; | Pamela C Ronald | Department of Plant Pathology and the Genome Center, University of California, Davis, California 956 | 2013-12-25 | 2 | New Results | cc_by_nc_nd | Plant Biology | https://www.biorxiv.org/content/early/2013/12/25/000950.source.xml | The rice XA21 immune receptor kinase and the structurally related XA3 receptor, confer immunity to Xanthomonas oryzae pv. oryzae (Xoo), the causal agent of bacterial leaf blight. Here we report the isolation of OsSERK2 (rice somatic embryogenesis receptor kinase 2) and demonstrate that OsSERK2 positively regulates immunity mediated by XA21 and XA3 as well as the rice immune receptor FLS2 (OsFLS2). Rice plants silenced for OsSerk2 display altered morphology and reduced sensitivity to the hormone brassinolide. OsSERK2 interacts with the intracellular domains of each immune receptor in the yeast-two-hybrid system in a kinase activity dependent manner. OsSERK2 undergoes bidirectional trans-phosphorylation with XA21 in vitro and forms a constitutive complex with XA21 in vivo. These results demonstrate an essential role for OsSERK2 in the function of three rice immune receptors and suggest that direct interaction with the rice immune receptors is critical for their function. Taken together, our findings suggest that the mechanism of OsSERK2-meditated regulation of rice XA21, XA3 and FLS2 differs from that of AtSERK3/BAK1-mediated regulation of Arabidopsis FLS2 and EFR. | 10.1093/mp/ssu003 | biorxiv | 151 |
10.1101/000778 | Quantifying the turnover of transcriptional subclasses of HIV-1-infected cells | Christian L Althaus;Beda Joos;Alan S Perelson;Huldrych F Günthard; | Christian L Althaus | University of Bern | 2014-01-18 | 2 | New Results | cc_by_nc_nd | Systems Biology | https://www.biorxiv.org/content/early/2014/01/18/000778.source.xml | HIV-1-infected cells in peripheral blood can be grouped into different transcriptional subclasses. Quantifying the turnover of these cellular subclasses can provide important insights into the viral life cycle and the generation and maintenance of latently infected cells. We used previously published data from five patients chronically infected with HIV-1 that initiated combination antiretroviral therapy (cART). Patient-matched PCR for unspliced and multiply spliced viral RNAs combined with limiting dilution analysis provided measurements of transcriptional profiles at the single cell level. Furthermore, measurement of intracellular transcripts and extracellular virion-enclosed HIV-1 RNA allowed us to distinguish productive from non-productive cells. We developed a mathematical model describing the dynamics of plasma virus and the transcriptional subclasses of HIV-1-infected cells. Fitting the model to the data allowed us to better understand the phenotype of different transcriptional subclasses and their contribution to the overall turnover of HIV-1 before and during cART. The average number of virus-producing cells in peripheral blood is small during chronic infection (25.7 cells ml-1). We find that 14.0%, 0.3% and 21.2% of infected cells become defectively, latently and persistently infected cells, respectively. Assuming that the infection is homogenous throughout the body, we estimate an average in vivo viral burst size of 2.1 x 104 virions per cell. Our study provides novel quantitative insights into the turnover and development of different subclasses of HIV-1-infected cells. The model predicts that the pool of latently infected cells becomes rapidly established during the first months of acute infection and continues to increase slowly during the first years of chronic infection. Having a detailed understanding of this process will be useful for the evaluation of viral eradication strategies that aim to deplete the latent reservoir of HIV-1.\n\nAuthor SummaryGaining a quantitative understanding of the development and turnover of different HIV-1-infected subpopulations of cells is crucial to improve the outcome of patients on combination antiretroviral therapy (cART). The population of latently infected cells is of particular interest as they represent the major barrier to a cure of HIV-1 infection. We developed a mathematical model that describes the dynamics of different transcriptionally active subclasses of HIV-1-infected cells and the viral load in peripheral blood. The model was fitted to previously published data from five chronically HIV-1-infected patients starting cART. This allowed us to estimate critical parameters of the within-host dynamics of HIV-1, such as the the number of virions produced by a single infected cell. The model further allowed investigation of HIV-1 dynamics during the acute phase. Computer simulations predict that latently infected cells become rapidly established during the first months of acute infection and continue to increase slowly during the first years of chronic infection. This illustrates the opportunity for strategies that aim to eradicate the virus during early cART as the pool of HIV-1 infected cells is substantially smaller during acute infection than during chronic infection. | 10.1371/journal.pcbi.1003871 | biorxiv | 152 |
10.1101/001594 | Morphometrics of a wild Asian elephant exhibiting disproportionate dwarfism | Shermin de Silva;Udaya S Weerathunga;Tennekoon Pushpakumara; | Shermin de Silva | Colorado State University, EFECT, Trunks & Leaves (Inc.) | 2013-12-24 | 1 | New Results | cc_by_nc_nd | Zoology | https://www.biorxiv.org/content/early/2013/12/24/001594.source.xml | Dwarfism is a condition characterized by shorter stature, at times accompanied by differential skeletal growth pro-portions relative to the species-typical physical conformation. Causes vary and well-documented in humans as well as certain mammalian species in captive or laboratory conditions, but rarely observed in the wild. Here we report on a single case of apparent dwarfism in a free-ranging adult male Asian elephant (Elephas maximus) in Sri Lanka, comparing physical dimensions to those of other males in the same population, males in other populations, and records in previous literature. The subject was found to have a shoulder height of approximately 195cm, is shorter than the average height of typical mature males, with a body length of 218cm. This ratio of body length to height deviates from what is typically observed, which is approximately 1:1. In absolute height the subject was similar to the attributes of a captive elephant documented in 1955 in Sri Lanka, also said to be a dwarf, however the two specimens differed in the relative proportions of height vs. body length. The subject also exhibits a slight elongation of the skull. We discuss how this phenotype compares to cases of dwarfism in other non-human animals. | 10.1186/1756-0500-7-933 | biorxiv | 153 |
10.1101/001693 | A statistical mechanics model for the collective epigenetic histone modification dynamics | Hang Zhang;XIAO-JUN TIAN;Abhishek Mukhopadhyay;Kenneth S Kim;Jianhua Xing; | Jianhua Xing | Virginia Tech | 2014-01-08 | 2 | New Results | cc_no | Biophysics | https://www.biorxiv.org/content/early/2014/01/08/001693.source.xml | Epigenetic histone modifications play an important role in the maintenance of different cell phenotypes. The exact molecular mechanism for inheritance of the modification patterns over cell generations remains elusive. We construct a Potts-type model based on experimentally observed nearest-neighbor enzyme lateral interactions and nucleosome covalent modification state biased enzyme recruitment. The model can lead to effective nonlocal interactions among nucleosomes suggested in previous theoretical studies, and epigenetic memory is robustly inheritable against stochastic cellular processes.\n\nPACS numbers: 82.39.Rt, 87.17.Aa, 87.16.Yc, 87.16.A | 10.1103/PhysRevLett.112.068101 | biorxiv | 156 |
10.1101/001727 | SIANN: Strain Identification by Alignment to Near Neighbors | Samuel Minot;Stephen D Turner;Krista L Ternus;Dana R Kadavy; | Samuel Minot | Signature Science, LLC | 2014-01-10 | 1 | New Results | cc_by_nc_nd | Bioinformatics | https://www.biorxiv.org/content/early/2014/01/10/001727.source.xml | Next-generation sequencing is increasingly being used to study samples composed of mixtures of organisms, such as in clinical applications where the presence of a pathogen at very low abundance may be highly important. We present an analytical method (SIANN: Strain Identification by Alignment to Near Neighbors) specifically designed to rapidly detect a set of target organisms in mixed samples that achieves a high degree of species- and strain-specificity by aligning short sequence reads to the genomes of near neighbor organisms, as well as that of the target. Empirical benchmarking alongside the current state-of-the-art methods shows an extremely high Positive Predictive Value, even at very low abundances of the target organism in a mixed sample. SIANN is available as an Illumina BaseSpace app, as well as through Signature Science, LLC. SIANN results are presented in a streamlined report designed to be comprehensible to the non-specialist user, providing a powerful tool for rapid species detection in a mixed sample. By focusing on a set of (customizable) target organisms and their near neighbors, SIANN can operate quickly and with low computational requirements while delivering highly accurate results. | NA | biorxiv | 158 |
10.1101/001743 | OPPOSING MICROTUBULE MOTORS CONTROL MOTILITY, MORPHOLOGY, AND CARGO SEGREGATION DURING ER-TO-GOLGI TRANSPORT. | Anna K Brown;Sylvie D Hunt;David J Stephens; | David J Stephens | University of Bristol | 2014-01-10 | 1 | New Results | cc_by | Cell Biology | https://www.biorxiv.org/content/early/2014/01/10/001743.source.xml | We recently demonstrated that dynein and kinesin motors drive multiple aspects of endosomal function in mammalian cells. These functions include driving motility, maintaining morphology (notably through providing longitudinal tension to support vesicle fission), and driving cargo sorting. Microtubule motors drive bidirectional motility during traffic between the endoplasmic reticulum (ER) and Golgi. Here, we have examined the role of microtubule motors in transport carrier motility, morphology, and domain organization during ER-to-Golgi transport. We show that consistent with our findings for endosomal dynamics, microtubule motor function during ER-to-Golgi transport of secretory is required for motility, morphology of, and cargo sorting within vesicular tubular carriers en route to the Golgi. Our data are consistent with previous findings that defined roles for dynein-1 and kinesin-1 (KIF5B) and kinesin-2 in this trafficking step. Our high resolution tracking data identify some intriguing aspects. Depletion of kinesin-1 reduces the number of motile structures seen which is in line with other findings relating to the role of kinesin-1 in ER export. However, those transport carriers that were produced had a much greater run length suggesting that this motor can act as a brake on anterograde motility. Kinesin-2 depletion did not significantly reduce the number of motile transport carriers but did cause a similar increase in run length. These data suggest that kinesins act as negative regulators of ER-to-Golgi transport. Depletion of dynein not only reduced the number of motile carriers formed but also caused tubulation of carriers similar to that seen for SNX-coated early endosomes. Our data indicated that the previously observed anterograde-retrograde polarity of transport carriers in transit to the Golgi from the ER is maintained by microtubule motor function. | 10.1242/bio.20147633 | biorxiv | 159 |
10.1101/001768 | Quantification of nuclear transport in single cells | Lucía Durrieu;Rikard Johansson;Alan Bush;David L.I. Janzén;Martin Gollvik;Gunnar Cedersund;Alejandro Colman-Lerner; | Alejandro Colman-Lerner | IFIByNE, DFBMC, FCEN, UBA, Buenos Aires, Argentine | 2014-01-13 | 1 | New Results | cc_by_nc_nd | Biophysics | https://www.biorxiv.org/content/early/2014/01/13/001768.source.xml | Nuclear transport is an essential part of eukaryotic cell function. Several assays exist to measure the rate of this process, but not at the single-cell level. Here, we developed a fluorescent recovery after photobleaching (FRAP)- based method to determine nuclear import and export rates independently in individual live cells. To overcome the inherent noise of single-cell measurements, we performed sequential FRAPs on the same cell. We found large cell-to-cell variation in transport rates within isogenic yeast populations. Our data suggest that a main determinant of this heterogeneity may be variability in the number of nuclear pore complexes (NPCs). For passive transport, this component explained most of the variability. Actively transported proteins were influenced by variability in additional components, including general factors such as the Ran-GTP gradient as well as specific regulators of the export rate. By considering mother-daughter pairs, we showed that mitotic segregation of the transport machinery is too noisy to control cellular inheritance. Finally, we studied mother-daughter cell asymmetry in the localization of the transcription factor Ace2, which is specifically concentrated in daughter cell nuclei. We found that this asymmetry is the outcome of a higher ratio of import rate to export rate in daughters. Interestingly, rather than reduced export in the daughter cell, as previously hypothesized, rates of both import and export are faster in daughter cells than in mother cells, but the magnitude of increase is greater for import. These results shed light into cell-to-cell variation in cellular dynamics and its sources. | 10.1016/j.isci.2022.105906 | biorxiv | 165 |
10.1101/001792 | Human paternal and maternal demographic histories: insights from high-resolution Y chromosome and mtDNA sequences | Sebastian Lippold;Hongyang Xu;Albert Ko;Mingkun Li;Gabriel Renaud;Anne Butthof;Roland Schroeder;Mark Stoneking; | Mark Stoneking | MPI-EVA | 2014-01-13 | 1 | New Results | cc_by_nc_nd | Genetics | https://www.biorxiv.org/content/early/2014/01/13/001792.source.xml | To investigate in detail the paternal and maternal demographic histories of humans, we obtained [~]500 kb of non-recombining Y chromosome (NRY) sequences and complete mtDNA genome sequences from 623 males from 51 populations in the CEPH Human Genome Diversity Panel (HGDP). Our results: confirm the controversial assertion that genetic differences between human populations on a global scale are bigger for the NRY than for mtDNA; suggest very small ancestral effective population sizes (<100) for the out-of-Africa migration as well as for many human populations; and indicate that the ratio of female effective population size to male effective population size (Nf/Nm) has been greater than one throughout the history of modern humans, and has recently increased due to faster growth in Nf. However, we also find substantial differences in patterns of mtDNA vs. NRY variation in different regional groups; thus, global patterns of variation are not necessarily representative of specific geographic regions. | 10.1186/2041-2223-5-13 | biorxiv | 167 |
10.1101/001776 | Chromothripsis-like patterns are recurring but heterogeneously distributed features in a survey of 22,347 cancer genome screens | Haoyang Cai;Nitin Kumar;Homayoun C Bagheri;Christian von Mering;Mark Robinson;Michael Baudis; | Michael Baudis | University of Zurich | 2014-01-13 | 2 | New Results | cc_by_nc | Genomics | https://www.biorxiv.org/content/early/2014/01/13/001776.source.xml | BackgroundChromothripsis is a recently discovered phenomenon of genomic rearrangement, possibly arising during a single genome-shattering event. This could provide an alternative paradigm in cancer development, replacing the gradual accumulation of genomic changes with a \"one-off\" catastrophic event. However, the term has been used with varying operational definitions, with the minimal consensus being a large number of locally clustered copy number aberrations. The mechanisms underlying these chromothripsis-like patterns (CTLP) and their specific impact on tumorigenesis are still poorly understood.\n\nResultsHere, we identified CTLP in 918 cancer samples, from a dataset of more than 22,000 oncogenomic arrays covering 132 cancer types. Fragmentation hotspots were found to be located on chromosome 8, 11, 12 and 17. Among the various cancer types, soft-tissue tumors exhibited particularly high CTLP frequencies. Genomic context analysis revealed that CTLP rearrangements frequently occurred in genomes that additionally harbored multiple copy number aberrations (CNAs). An investigation into the affected chromosomal regions showed a large proportion of arm-level pulverization and telomere related events, which would be compatible to a number of underlying mechanisms. We also report evidence that these genomic events may be correlated with patient age, stage and survival rate.\n\nConclusionsThrough a large-scale analysis of oncogenomic array data sets, this study characterized features associated with genomic aberrations patterns, compatible to the spectrum of \"chromothripsis\"-definitions as previously used. While quantifying clustered genomic copy number aberrations in cancer samples, our data indicates an underlying biological heterogeneity behind these chromothripsis-like patterns, beyond a well defined \"chromthripsis\" phenomenon. | 10.1186/1471-2164-15-82 | biorxiv | 169 |
10.1101/001818 | Emergence of structural and dynamical properties of ecological mutualistic networks | Samir Suweis;Filippo Simini;Jayanth Banavar;Amos Maritan; | Samir Suweis | Universiyt of Padova | 2014-01-14 | 1 | New Results | cc_by_nc_nd | Ecology | https://www.biorxiv.org/content/early/2014/01/14/001818.source.xml | Mutualistic networks are formed when the interactions between two classes of species are mutually beneficial. They are important examples of cooperation shaped by evolution. Mutualism between animals and plants plays a key role in the organization of ecological communities1-3. Such networks in ecology have generically evolved a nested architecture4,5 independent of species composition and latitude6,7 - specialists interact with proper subsets of the nodes with whom generalists interact1. Despite sustained efforts5,8,9,10 to explain observed network structure on the basis of community-level stability or persistence, such correlative studies have reached minimal consensus11,12,13. Here we demonstrate that nested interaction networks could emerge as a consequence of an optimization principle aimed at maximizing the species abundance in mutualistic communities. Using analytical and numerical approaches, we show that because of the mutualistic interactions, an increase in abundance of a given species results in a corresponding increase in the total number of individuals in the community, as also the nestedness of the interaction matrix. Indeed, the species abundances and the nestedness of the interaction matrix are correlated by an amount that depends on the strength of the mutualistic interactions. Nestedness and the observed spontaneous emergence of generalist and specialist species occur for several dynamical implementations of the variational principle under stationary conditions. Optimized networks, while remaining stable, tend to be less resilient than their counterparts with randomly assigned interactions. In particular, we analytically show that the abundance of the rarest species is directly linked to the resilience of the community. Our work provides a unifying framework for studying the emergent structural and dynamical properties of ecological mutualistic networks2,5,10,14. | NA | biorxiv | 172 |
10.1101/001909 | The shrinking human protein coding complement: are there fewer than 20,000 genes? | Iakes Ezkurdia;David Juan;Jose Manuel Rodriguez;Adam Frankish;Mark Deikhans;Jennifer L Harrow;Jesus Vazquez;Alfonso Valencia;Michael Tress; | Michael Tress | Spanish National Cancer Research Centre | 2014-01-17 | 1 | New Results | cc_by_nc | Genomics | https://www.biorxiv.org/content/early/2014/01/17/001909.source.xml | Determining the full complement of protein-coding genes is a key goal of genome annotation. The most powerful approach for confirming protein coding potential is the detection of cellular protein expression through peptide mass spectrometry experiments. Here we map the peptides detected in 7 large-scale proteomics studies to almost 60% of the protein coding genes in the GENCODE annotation the human genome. We find that conservation across vertebrate species and the age of the gene family are key indicators of whether a peptide will be detected in proteomics experiments. We find peptides for most highly conserved genes and for practically all genes that evolved before bilateria. At the same time there is almost no evidence of protein expression for genes that have appeared since primates, or for genes that do not have any protein-like features or cross-species conservation. We identify 19 non-protein-like features such as weak conservation, no protein features or ambiguous annotations in major databases that are indicators of low peptide detection rates. We use these features to describe a set of 2,001 genes that are potentially non-coding, and show that many of these genes behave more like non-coding genes than protein-coding genes. We detect peptides for just 3% of these genes. We suggest that many of these 2,001 genes do not code for proteins under normal circumstances and that they should not be included in the human protein coding gene catalogue. These potential non-coding genes will be revised as part of the ongoing human genome annotation effort. | 10.1093/hmg/ddu309 | biorxiv | 173 |
10.1101/001883 | Tracking global changes induced in the CD4 T cell receptor repertoire by immunization with a complex antigen using short stretches of CDR3 protein sequence. | Niclas Thomas;Katharine Best;Mattia Cinelli;Shlomit Reich-Zeliger;Hila Gal;Eric Shifrut;Asaf Madi;Nir Friedman;John Shawe-Taylor;Benny Chain; | Benny Chain | UCL | 2014-01-17 | 1 | New Results | cc_no | Immunology | https://www.biorxiv.org/content/early/2014/01/17/001883.source.xml | The clonal theory of adaptive immunity proposes that immunological responses are encoded by increases in the frequency of lymphocytes carrying antigen-specific receptors. In this study, we measure the frequency of different TcRs in CD4+ T cell populations of mice immunized with a complex antigen, killed Mycobacterium tuberculosis, using high throughput parallel sequencing of the TcR beta chain. In order to track the changes induced by immunisation within this very heterogeneous repertoire, the sequence data were classified by counting the frequency of different clusters of short (3 or 4) continuous stretches of amino acids within the CDR3 repertoire of different mice. Both unsupervised (hierarchical clustering) and supervised (support vector machine) analysis of these different distributions of sequence clusters differentiated between immunised and unimmunised mice with 100% efficiency. The CD4+ T cell receptor repertoires of mice 5 and 14 days post immunisation were clearly different from that of unimmunised mice, but were not distinguishable from each other. However, the repertoires of mice 60 days post immunisation were distinct both from unimmunised mice, and the day 5/14 animals. Our results reinforce the remarkable diversity of the T cell receptor repertoire, resulting in many diverse private TcRs contributing to the T cell response even in genetically identical mice responding to the same antigen. Finally, specific motifs defined by short sequences of amino acids within the CDR3 region may have a major effect on TcR specificity. The results of this study provide new insights into the properties of the CD4+ adaptive T cell response. | 10.1093/bioinformatics/btu523 | biorxiv | 174 |
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bioRxiv Paper Metadata Dataset
This dataset includes metadata of all papers (297,902) from bioRxiv between November 16, 2013, and March 17, 2025. To access the full text, please visit the official website by searching the paper title or DOI: https://www.biorxiv.org/ , or retrieve the paper using the official API: https://api.biorxiv.org/ .
Dataset Fields
- doi: Digital Object Identifier.
- title: Paper title.
- authors: List of authors.
- author_corresponding: Corresponding author.
- author_corresponding_institution: Corresponding author's institution.
- date: Publication date.
- version: Version information.
- type: Paper type.
- license: License information.
- category: Subject category.
- jatsxml: Content in JATS XML format.
- abstract: Abstract.
- published: Publication status.
- server: Server information.
- index_level_0: Index.
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