bluuebunny/crossref_metadata_2025_split huggingface dataset:
Resolving Filament Level Mechanics in Collagen Networks using Activity Microscopy
Authors: Lissek Emanuel N. , Bartsch Tobias F. , Florin Ernst-Ludwig 
Published: August 2018

AbstractCollagen is the most abundant protein in humans and the primary component of the extracellular matrix, a meshwork of biopolymer networks, which provides structure and integrity to tissues. Its mechanical properties profoundly influence the fate of cells. The cell-matrix interaction, however, is not well understood due to a lack of experimental techniques to study the mechanical interplay between cells and their local environment. Here we introduce Activity Microscopy, a new way to visualize local network mechanics with single filament resolution. Using collagen I networksin vitro, we localize fibril positions in two-dimensional slices through the network with nanometer precision and quantify the fibrils’ transverse thermal fluctuations with megahertz bandwidth. Using a fibril’s thermal fluctuations as an indicator for its tension, we find a heterogeneous stress distribution, where “cold” fibrils with small thermal fluctuations surround regions of highly fluctuating “hot” fibrils. We seed HeLa cells into collagen networks and quantify the anisotropy in the propagation of their forces.
Failure to learn during roving, analysing the unsupervised bias hypothesis
Authors: Higgins David , Herzog Michael 
Published: August 2018

AbstractWe examine the unsupervised bias hypothesis [11] as an explanation for failure to learn two bisection tasks, when task sequencing is randomly alternating (roving). This hypothesis is based on the idea that a covariance based synaptic plasticity rule, which is modulated by a reward signal, can be biased when reward is averaged across multiple tasks of differing difficulties. We find that, in our hands, the hypothesis in its original form can never explain roving. This drives us to develop an extended mathematical analysis, which demonstrates not one but two forms of unsupervised bias. One form interacts with overlapping task representations and the other does not. We find that overlapping task representations are much more susceptible to unsupervised biases than non-overlapping representations. Biases from non-overlapping representations are more likely to stabilise learning. But this in turn is incompatible with the experimental understanding of perceptual learning and task representation, in bisection tasks. Finally, we turn to alternative network encodings and find that they also are unlikely to explain failure to learn during task roving as a result of unsupervised biases. As a solution, we present a single critic hypothesis, which is consistent with recent literature and could explain roving by a, much simpler, certainty normalised reward signalling mechanism.
Reaction times and other skewed distributions: problems with the mean and the median
Authors: Rousselet Guillaume A. , Wilcox Rand R. 
Published: August 2018

ABSTRACTTo summarise skewed (asymmetric) distributions, such as reaction times, typically the mean or the median are used as measures of central tendency. Using the mean might seem surprising, given that it provides a poor measure of central tendency for skewed distributions, whereas the median provides a better indication of the location of the bulk of the observations. However, the sample median is biased: with small sample sizes, it tends to overestimate the population median. This is not the case for the mean. Based on this observation, Miller (1988) concluded that “sample medians must not be used to compare reaction times across experimental conditions when there are unequal numbers of trials in the conditions.” Here we replicate and extend Miller (1988), and demonstrate that his conclusion was ill-advised for several reasons. First, the median’s bias can be corrected using a percentile bootstrap bias correction. Second, a careful examination of the sampling distributions reveals that the sample median is median unbiased, whereas the mean is median biased when dealing with skewed distributions. That is, on average the sample mean estimates the population mean, but typically this is not the case. In addition, simulations of false and true positives in various situations show that no method dominates. Crucially, neither the mean nor the median are sufficient or even necessary to compare skewed distributions. Different questions require different methods and it would be unwise to use the mean or the median in all situations. Better tools are available to get a deeper understanding of how distributions differ: we illustrate a powerful alternative that relies on quantile estimation. All the code and data to reproduce the figures and analyses in the article are available online.
FACT activity and histone H3-K56 acetylation promote optimal establishment of chromatin architecture independent of ongoing transcription inSaccharomyces cerevisiae
Authors: McCullough Laura , Pham Trang H. , Parnell Timothy J. , Chandrasekharan Mahesh B. , Stillman David J. , Formosa Tim 
Published: August 2018

AbstractFACT is a histone chaperone that can destabilize or assemble nucleosomes. Acetylation of histone H3-K56 weakens a histone:DNA contact that is central to FACT activity, suggesting that this modification could affect FACT functions. We tested this by asking how mutations of H3-K56 and FACT affect nucleosome structure, chromatin integrity, and transcription output. Mimics of unacetylated or permanently acetylated H3-K56 had different effects on FACTin vitroandin vivoas expected, but H3-K56 and FACT mutations caused surprisingly similar changes in transcription of individual genes. Notably, neither the changes in transcript levels nor the effects on nucleosome occupancy resulting from mutations conformed to the model that FACT is needed to overcome nucleosomal barriers during transcription initiation or elongation. Instead, the results suggest that both FACT and H3-K56ac are involved in establishing chromatin architecture prior to transcription and restoring it afterwards. They contribute to a process that optimizes transcription frequency, especially at conditionally expressed genes, and restores chromatin integrity after transcription, especially at the +1 nucleosome to block antisense transcription, but FACT appears to be less involved than expected in directly promoting transcription.
Standardized biogeographic grouping system for annotating populations in pharmacogenetic research
Authors: Huddart Rachel , Fohner Alison E. , Whirl-Carrillo Michelle , Wojcik Genevieve L. , Gignoux Christopher R. , Popejoy Alice B. , Bustamante Carlos D. , Altman Russ B. , Klein Teri E. 
Published: August 2018

AbstractThe varying frequencies of pharmacogenetic alleles between populations have important implications for the impact of these alleles in different populations. Current population grouping methods to communicate these patterns are insufficient as they are inconsistent and fail to reflect the global distribution of genetic variability. To facilitate and standardize the reporting of variability in pharmacogenetic allele frequencies, we present seven geographically-defined groups: American, Central/South Asian, East Asian, European, Near Eastern, Oceanian, and Sub-Saharan African, and two admixed groups: African American/Afro-Caribbean and Latino. These nine groups are defined by global autosomal genetic structure and based on data from large-scale sequencing initiatives. We recognize that broadly grouping global populations is an oversimplification of human diversity and does not capture complex social and cultural identity. However, these groups meet a key need in pharmacogenetics research by enabling consistent communication of the scale of variability in global allele frequencies and are now used by PharmGKB.
Individuals with ventromedial frontal damage have more unstable but still fundamentally transitive preferences
Authors: Yu Linda Q. , Dana Jason , Kable Joseph W. 
Published: August 2018

AbstractThe ventromedial frontal lobes (VMF) are important for decision-making, but the precise causal role of the VMF in the decision process has not yet fully been established. Previous studies have suggested that individuals with VMF damage violate transitivity, a hallmark axiom of rational decisions. However, these prior studies cannot properly distinguish whether individuals with VMF damage are truly prone to choosing irrationally from whether their preferences are simply more variable. We had individuals with focal VMF damage, individuals with other frontal damage, and healthy controls make repeated choices across three categories – artwork, chocolate bar brands, and gambles. Using sophisticated tests of transitivity, we find that, without exception, individuals with VMF damage make rational decisions consistent with transitive preferences, even though they exhibit greater variability in their preferences. That is, the VMF is necessary for having strong and reliable preferences, but not for being a rational decision maker. VMF damage affects the noisiness with which value is assessed, but not the consistency with which value is sought.
Evolutionary proteomics reveals distinct patterns of complexity and divergence between Lepidopteran sperm morphs
Authors: Whittington Emma , Karr Tim , Mongue Andrew J. , Dorus Steve , Walters James R. 
Published: August 2018

AbstractSpermatozoa are one of the most strikingly diverse animal cell types. One poorly understood example of this diversity is sperm heteromorphism, where males produce multiple distinct morphs of sperm in a single ejaculate. Typically, only one morph is capable of fertilization and the function of the non-fertilizing morph, called parasperm, remains to be elucidated. Sperm heteromorphism has multiple independent origins, including Lepidoptera (moths and butterflies), where males produce a fertilizing eupyrene sperm and an apyrene parasperm, which lacks a nucleus and nuclear DNA. Here we report a comparative proteomic analysis of eupyrene and apyrene sperm between two distantly related lepidopteran species, the monarch butterfly (Danausplexippus) and Carolina sphinx month (Manduca sexta). In both species, we identified approximatey 700 sperm proteins, with half present in both morphs and the majority of the remainder specific to eupyrene sperm. Apyrene sperm thus have a distinctly less complex proteome. Gene Ontology (GO) analysis revealed proteins shared between morphs tend to be associated with canonical sperm cell structures (e.g. flagellum) and metabolism (e.g. ATP production). GO terms for morph-specific proteins broadly reflect known structural differences, but also suggest a role for apyrene sperm in modulating female neurobiology. Comparative analysis indicates that proteins shared between morphs are most conserved between species as components of sperm, while morph-specific proteins turn over more quickly, especially in apyrene sperm. The rapid divergence of apyrene sperm content is consistent with a relaxation of selective constraints associated with fertilization and karyogamy. On the other hand, parasperm exhibit greater evolutionary lability, which may reflect adaptive response to shifting regimes of sexual selection. Additionally, we provide the first (to our knowledge) scanning electron micrographs of lepidopteran sperm.
Performing Reflexive Toxin A/B Enzyme Immunoassay in a Two-Step Algorithm for the Diagnosis of Clostridium difficile Infection Has Limited Clinical Utility
Authors: Mounajjed M , Pease R , Jung-Hynes B , Safdar N , Chen D 
Published: August 2018

ABSTRACTThe differentiation of Clostridium difficile infection (CDI) from colonization is challenged by the suboptimal clinical specificity of nucleic acid amplification tests (NAAT). In this study, we examined the utility of testing for toxin via enzyme immunoassay (EIA) in specimens already tested by NAAT for the diagnosis of CDI in an attempt to differentiate colonization from infection. We tested 59 stool samples for the presence of C. difficile toxin B gene by NAAT followed by EIAs for glutamate dehydrogenase (GDH EIA) and toxins A and B (Toxin EIA). Two infectious disease physicians independently reviewed the patients’ electronic medical records retrospectively to categorize each patient as CDI-Likely, CDI-Unlikely, or CDI-Indeterminate. Clinical sensitivities and specificities were calculated using 3 definitions of “true” CDI status, being: (1) concordance between both reviewers, (2) concordance, and CDI-Indeterminate/discordant cases classified as CDI-Likely, and (3) concordance, and CDI-Indeterminate/discordant cases classified as CDI-Unlikely. Based on these definitions, clinical sensitivity and specificity for NAAT was 100% and 49-94%, GDH EIA was 83-85% and 43-89%, and Toxin EIA was 39-42% and 83-100%, respectively. 85% (22 of 26) of patients who were NAAT-positive but Toxin EIA-negative symptomatically benefited from treatment for CDI. The addition of EIA to NAAT for CDI diagnosis had limited utility for differentiating colonization from CDI and could have led to under treatment of patients with CDI.
Mathematical modeling supports fate restriction in neurogenic progenitors of the embryonic ventral spinal cord
Authors: Azaïs Manon , Agius Eric , Blanco Stéphane , Gautrais Jacques , Molina Angie , Pituello Fabienne , Tregan Jean-Marc 
Published: August 2018

AbstractIn the developing neural tube in chicken and mammals, neural stem cells proliferate and differentiate according to a stereotyped spatio-temporal pattern. Several actors have been identified in the control of this process, from tissue-scale morphogens patterning (Shh, BMP) to intrinsic determinants in neural progenitor cells. In a previous study (Bonnet et al. eLife 7, 2018), we have shown that the CDC25B phosphatase promotes the transition from proliferation to differentiation in a cell-cycle independent fashion. In this study, we set up a mathematical model linking progenitor modes of division to the dynamics of progenitors and differentiated populations. Here, we build on this previous model to propose a complete dynamical picture of this process. We start from the standard model in which progenitors are homogeneous and can perform any type of divisions (proliferative division yielding two progenitors, asymmetric neurogenic divisions yielding one progenitor and one neuron, and terminal symmetric divisions yielding two neurons). We constraint this model using published data about mode of divisions and population dynamics of progenitors/neurons at different developmental stages (Saade et al. Cell Reports 4, 2013), and check the effect of CDC25B gain of function in this context. Next, we explore the scenarios in which progenitors population is actually split into two different pools, one of which composed of cells that have lost the capacity to perform proliferative divisions (fate restriction). We show that one such scenario appears relevant and calls for further identification of the alternative role of CDC25B in such a fate restriction.
Orthogonal linear separation analysis: an approach to decompose the complex effects of a perturbagen
Authors: Mizuno Tadahaya , Kinoshita Setsuo , Maedera Shotaro , Ito Takuya , Kusuhara Hiroyuki 
Published: August 2018

AbstractDrugs have multiple, not single, effects. Decomposition of drug effects into basic components helps us to understand the pharmacological properties of a drug and contributes to drug discovery. We have extended factor analysis and developed a novel profile data analysis method, orthogonal linear separation analysis (OLSA). OLSA contracted 11,911 genes to 118 factors from transcriptome data of MCF7 cells treated with 318 compounds in Connectivity Map. Ontology of the main genes constituting the factors detected significant enrichment of the ontology in 65 of 118 factors and similar results were obtained in two other data sets. One factor discriminated two Hsp90 inhibitors, geldanamycin and radicicol, while clustering analysis could not. Doxorubicin was estimated to inhibit Na+/K+ATPase, one of the suggested mechanisms of doxorubicin-induced cardiotoxicity. Based on the factor including PI3K/AKT/mTORC1 inhibition activity, 5 compounds were predicted to be novel autophagy inducers, and other analysis including western blotting revealed that 4 of the 5 actually induced autophagy. These findings indicate the potential of OLSA to decompose the effects of a drug and identify its basic components. (<175 words)
Processing of eukaryotic Okazaki fragments by redundant nucleases can be uncoupled from ongoing DNA replicationin vivo
Authors: Kahli Malik , Osmundson Joseph S. , Yeung Rani , Smith Duncan J. 
Published: August 2018

ABSTRACTPrior to ligation, each Okazaki fragment synthesized on the lagging strand in eukaryotes must be nucleolytically processed. Nuclease cleavage takes place in the context of 5’ flap structures generated via strand-displacement synthesis by DNA polymerase delta. At least three DNA nucleases: Rad27 (Fen1), Dna2, and Exo1, have been implicated in processing Okazaki fragment flaps. However, neither the contributions of individual nucleases to lagging-strand synthesis nor the structure of the DNA intermediates formed in their absence have been clearly definedin vivo.By conditionally depleting lagging-strand nucleases and directly analyzing Okazaki fragments synthesizedin vivoinS. cerevisiae, we conduct a systematic evaluation of the impact of Rad27, Dna2 and Exo1 on lagging-strand synthesis. We find that Rad27 processes the majority of lagging-strand flaps, with a significant additional contribution from Exo1 but not from Dna2. When nuclease cleavage is impaired, we observe a reduction in strand-displacement synthesis as opposed to the widespread generation of long Okazaki fragment 5’ flaps, as predicted by some models. Further, using cell cycle-restricted constructs, we demonstrate that both the nucleolytic processing and the ligation of Okazaki fragments can be uncoupled from DNA replication and delayed until after synthesis of the majority of the genome is complete.
A Transcriptome Wide Association Study implicates specific pre- and post-synaptic abnormalities in Schizophrenia
Authors: Hall Lynsey S , Medway Christopher W , Pardinas Antonio F , Rees Elliott G , Escott-Price Valentina , Pocklington Andrew , Holmans Peter A , Walters James TR , Owen Michael J , O’Donovan Michael C 
Published: August 2018

AbstractSchizophrenia is a complex highly heritable disorder. Genome-wide association studies have identified multiple loci that influence the risk of developing schizophrenia, although the causal variants driving these associations and their impacts on specific genes are largely unknown. Here we link genetic findings to gene expression in the human brain by performing a transcriptome-wide association study (TWAS) in which we integrate the largest published genome-wide association dataset of schizophrenia, with publically available post mortem expression data from the dorsolateral prefrontal cortex (DLPFC). We identify a significant correlation between schizophrenia risk and expression at eighty-nine genes in DLPFC, including forty-two genes not identified in earlier TWAS of this transcriptomic resource. Genes whose expression correlate with schizophrenia were enriched for those involved in nervous system development, abnormal synaptic transmission, reduced long term potentiation, and calcium-dependent cell-cell adhesion. Previous genetic studies have implicated post-synaptic glutamatergic and gabaergic processes in schizophrenia; here we extend this to include molecules that regulate presynaptic transmitter release. We identify specific candidate genes to which we assign predicted directions of effect in terms of expression level, facilitating downstream experimental studies geared towards a better mechanistic understanding of schizophrenia pathogenesis.
Sfp1 regulates the SAGA component Tra1 in response to proteotoxic stress inSaccharomyces cerevisiae
Authors: Jiang Yuwei , Berg Matthew D. , Genereaux Julie , Ahmed Khadija , Duennwald Martin L. , Brandl Christopher J. , Lajoie Patrick 
Published: August 2018

ABSTRACTProteotoxic stress triggers transcriptional responses that allow cells to compensate for the accumulation of toxic misfolded proteins. Chromatin remodeling regulates gene expression in response to the accumulation of misfolded polyQ proteins associated with Huntington’s disease (HD). Tra1 is an essential component of both the SAGA/SLIK and NuA4 transcription co-activator complexes and is linked to multiple cellular processes associated with misfolded protein stress, including the heat shock response. Cells with compromised Tra1 activity display phenotypes distinct from deletions encoding components of the SAGA and NuA4 complexes, indicating a potentially unique regulatory role of Tra1 in the cellular response to protein misfolding. Here, we employed a yeast model of HD to define how the expression of toxic polyQ expansion proteins affects Tra1 expression and function. Expression of expanded polyQ proteins, mimics deletion of SAGA/NuA4 components and results in growth defects under stress conditions. Moreover, deleting genes encoding SAGA and, to a lesser extent, NuA4 components exacerbates polyQ toxicity. Also, cells carrying a mutant Tra1 allele displayed increased sensitivity to polyQ toxicity. Interestingly, expression of polyQ proteins also upregulated the expression ofTRA1and other genes encoding SAGA components, revealing a feedback mechanism aimed at maintaining Tra1and SAGA functional integrity. Moreover, deleting the TORC1 (Target of Rapamycin) effectorSFP1specifically abolished upregulation ofTRA1upon expression of polyQ proteins. While Sfp1 is known to adjust ribosome biogenesis and cell size in response to stress, we identified a new role for Sfp1 in the control of Tra1, linking TORC1 and cell growth regulation to functions of the SAGA acetyltransferase complex during misfolded protein stress.