bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Con Artist: Phenylphenoxybenzamide is not a Glycosyltransferase Inhibitor
Authors: Wybenga Gjalt G. , Wu Wei-Shen 
Published: April 2018

AbstractTo combat bacterial resistance against antibiotics, glycosyltransferase inhibiting molecules, which block the synthesis of the pre-cursor of the bacterial cell wall, need to be discovered and developed. In this study, we demonstrate that phenylphenoxybenzamide, a salicylanilide, is not a glycosyltransferase inhibiting molecule, despite claims in literature to the contrary, and through our work show that glycosyltransferase construct choice and detergent choice are crucial parameters to consider when designing glycosyltransferase assays that aim to discover and develop molecules that inhibit these types of enzymes.
Common genetic variants and health outcomes appear geographically structured in the UK Biobank sample: Old concerns returning and their implications
Authors: Haworth Simon , Mitchell Ruth , Corbin Laura , Wade Kaitlin H , Dudding Tom , Budu-Aggrey Ashley , Carslake David , Hemani Gibran , Paternoster Lavinia , Smith George Davey , Davies Neil , Lawson Dan , Timpson Nicholas 
Published: April 2018

Introductory paragraphThe inclusion of genetic data in large studies has enabled the discovery of genetic contributions to complex traits and their application in applied analyses including those using genetic risk scores (GRS) for the prediction of phenotypic variance. If genotypes show structure by location and coincident structure exists for the trait of interest, analyses can be biased. Having illustrated structure in an apparently homogeneous collection, we aimed to a) test for geographical stratification of genotypes in UK Biobank and b) assess whether stratification might induce bias in genetic association analysis.We found that single genetic variants are associated with birth location within UK Biobank and that geographic structure in genetic data could not be accounted for using routine adjustment for study centre and principal components (PCs) derived from genotype data. We found that GRS for complex traits do appear geographically structured and analysis using GRS can yield biased associations. We discuss the likely origins of these observations and potential implications for analysis within large-scale population based genetic studies.
Enchained growth and cluster dislocation: a possible mechanism for microbiota homeostasis
Authors: Bansept Florence , Schumann-Moor Kathrin , Diard Médéric , Hardt Wolf-Dietrich , Slack Emma , Loverdo Claude 
Published: April 2018

AbstractImmunoglobulin A is a class of antibodies produced by the adaptive immune system and secreted into the gut lumen to fight pathogenic bacteria. We recently demonstrated that the main physical effect of these antibodies is to enchain daughter bacteria, i.e. to cross-link bacteria into clusters as they divide, preventing them from interacting with epithelial cells, thus protecting the host. These links between bacteria may break over time. We study several models using analytical and numerical calculations. We obtain the resulting distribution of chain sizes, that we compare with experimental data. We study the rate of increase in the number of free bacteria as a function of the replication rate of bacteria. Our models show robustly that at higher replication rates, bacteria replicate before the link between daughter bacteria breaks, leading to growing cluster sizes. On the contrary at low growth rates two daughter bacteria have a high probability to break apart. Thus the gut could produce IgA against all the bacteria it has encountered, but the most affected bacteria would be the fast replicating ones, that are more likely to destabilize the microbiota. Linking the effect of the immune effectors (here the clustering) with a property directly relevant to the potential bacterial pathogeneicity (here the replication rate) could avoid to make complex decisions about which bacteria to produce effectors against.Author SummaryInside the organism, the immune system can fight generically against any bacteria. However, the lumen of the gut is home to a very important microbiota, so the host has to find alternative ways to fight dangerous bacteria while sparing beneficial ones. While many studies have focused on the complex molecular and cellular pathways that trigger an immune response, little is known about how the produced antibodies act once secreted into the intestinal lumen. We recently demonstrated that the main physical effect of these antibodies is to cross-link bacteria into clusters as they divide, preventing them from interacting with epithelial cells, thus protecting the host. These links between bacteria may break over time. Using analytical and numerical calculations, and comparing with experimental data, we studied the dynamics of these clusters. At higher replication rates, bacteria replicate before the link between daughter bacteria breaks, leading to growing cluster sizes, and conversely. Thus the gut could produce IgA against all the bacteria it has encountered, but the most affected bacteria would be the fast replicating ones, that are more likely destabilize the microbiota. Studying the mechanisms of the immune response may uncover more such processes that enable to target properties hard to escape through evolution.
Positive Cardiac Inotrope, Omecamtiv Mecarbil, Activates Muscle Despite Suppressing the Myosin Working Stroke
Authors: Woody Michael S. , Greenberg Michael J. , Barua Bipasha , Winkelmann Donald A. , Goldman Yale E. , Ostap E. Michael 
Published: April 2018

ABSTRACTOmecamtiv mecarbil (OM) is a positive cardiac inotrope in phase-3 clinical trials for treatment of heart failure. Although initially described as a direct myosin activator, subsequent studies are at odds with this description and do not explain OM-mediated increases in cardiac output. Single-molecule, biophysical experiments on cardiac myosin show that OM suppresses myosin’s working stroke and prolongs actomyosin attachment 5-fold, which explain inhibitory actions of the drug observedin vitro. Surprisingly, the increased myocardial force output in the presence of OM can be explained by cooperative thin filament activation by OM-inhibited myosin molecules. Selective suppression of myosin is an unanticipated route to muscle activation that may guide future development of therapeutic drugs.
Multiplex Enrichment and Detection of Rare KRAS Mutations in Liquid Biopsy Samples using Digital Droplet Pre-Amplification
Authors: Pratt Erica D. , Cowan Robert W. , Manning Sara L. , Qiao Edmund , Cameron Heather , Schradle Kara , Simeone Diane , Zhen David B. 
Published: April 2018

AbstractOncology research is increasingly incorporating molecular detection of circulating tumor DNA (ctDNA) as a tool for cancer surveillance and early detection. However, non-invasive monitoring of conditions with low tumor burden remains challenging, as the diagnostic sensitivity of most ctDNA assays is inversely correlated with total DNA concentration and ctDNA abundance. Here we present the Multiplex Enrichment using Droplet Pre-Amplification (MED-Amp) method, which com-bines single-molecule emulsification and short-round PCR preamplification with digital droplet PCR (ddPCR) detection of mutant DNA template. The MED-Amp assay increased mutant signal by over 50-fold with minimal distortion in allelic frequency. We demonstrate detection of as few as 3 mutant copies in wild-type DNA concentrations ranging from 5 to 50ng. The MED-Amp assay successfully detected KRAS mutant ctDNA in 86% plasma samples obtained from patients with metastatic pancreatic ductal adenocarcinoma. This assay for high-sensitivity rare variant detection is appropriate for liquid biopsy samples, or other limited clinical biospecimens
Science Podcasts: Analysis of Global Production and Output From 2004 to 2018
Authors: MacKenzie Lewis E. 
Published: April 2018

1.SummarySince 2004, podcasts have emerged as a decentralised medium for science communication to the global public. However, to-date, there have been no large-scale quantitative studies of the production and dissemination of science podcasts. This study identified 952 English language science podcasts available between January and February 2018 and analysed online textual and visual data related to the podcasts and classified and noted key production parameters. It was found that the total number of science podcast series available grew linearly between 2004 and 2010, and then exponentially between 2010 and 2018. 65% of science podcast series were hosted by scientists and 77% were targeted to public audiences. Although a wide range of primarily single-subject science podcasts series were noted, 34% of science podcast series were not dedicated to a science subject. Compared to biology and physics, chemistry may be under-represented by science podcasts. Only 24% of science podcast series had any overt financial income. 62% of science podcast series were affiliated to an organisation; producing a greater number of episodes (median = 24, average = 96) than independent science podcast series (median = 16, average = 48). This study provides the first ‘snapshot’ of how science podcasts are being used to communicate science to public audiences around the globe.
Cross-fostering in rodents causes region-specific alterations in entorhinal cortical gamma rhythms associated with NMDA receptor dysfunction
Authors: Hall Stephen , Hawkins Karen , Laws Grace , Akitt Thomas , Simon Anna , Davies Ceri H. , Whittington Miles A. , Cunningham Mark O. 
Published: April 2018

ABSTRACTThere has recently been a large increase in the number of children placed in foster care in the United States and Europe. While this is ‘the least worst scenario’ for those with a lack of appropriate biological care, it is recognised that these children are exposed to major stressors correlated with behavioural changes, particularly in the realm of social cognition into adulthood. Here we model foster care in rodents: rat pups are removed from their biological mother and placed with a non-genetically related dam. This prevented the entorhinal cortex from generating patterns of gamma rhythms required for normal parahippocampal function relevant to social interaction. These changes correlated with a reduction in NMDA receptor-mediated excitation, and changes in parvalbumin expression in interneurons. These data suggest that early life care delivered by a non-biological parent may disrupt social behaviour but, in contrast, generate neurobiological changes antagonistic to those currently associated with psychosis.Significance StatementCross fostering is an effective approach for delineating the effect of environment from genetic influences upon behavior. This involves removal of pups from one mother and transfer to another lactating dam. This manipulation is considered as a mild form of early life stress, producing neurobehavioral changes such as alterations in social interaction. We demonstrate that cross fostering produces changes in the ability of cortical microcircuits to generate oscillatory rhythms, in particular the gamma rhythm, in brain regions important for social cognition. This reduction in gamma rhythmogenesis is related to a reduction in synaptic drive provided by the NMDA receptor. One implication of this work is that the modulation of NMDA receptors offers a potential therapeutic strategy for disorders involving impaired sociability.
Reproducible genomics analysis pipelines with GNU Guix
Authors: Wurmus Ricardo , Uyar Bora , Osberg Brendan , Franke Vedran , Gosdschan Alexander , Wreczycka Katarzyna , Ronen Jonathan , Akalin Altuna 
Published: April 2018

AbstractIn bioinformatics, as well as other computationally-intensive research fields, there is a need for workflows that can reliably produce consistent output, independent of the software environment or configuration settings of the machine on which they are executed. Indeed, this is essential for controlled comparison between different observations or for the wider dissemination of workflows. Providing this type of reproducibility, however, is often complicated by the need to accommodate the myriad dependencies included in a larger body of software, each of which generally come in various versions. Moreover, in many fields (bioinformatics being a prime example), these versions are subject to continual change due to rapidly evolving technologies, further complicating problems related to reproducibility. Here, we propose a principled approach for building analysis pipelines and managing their dependencies. As a case study to demonstrate the utility of our approach, we present a set of highly reproducible pipelines for the analysis of RNA-seq, ChIP-seq, Bisulfite-seq, and single-cell RNA-seq. All pipelines process raw experimental data, and generate reports containing publication-ready plots and figures, with interactive report elements and standard observables. Users may install these highly reproducible packages and apply them to their own datasets without any special computational expertise beyond the use of the command line. We hope such a toolkit will provide immediate benefit to laboratory workers wishing to process their own data sets or bioinformaticians seeking to automate all, or parts of, their analyses. In the long term, we hope our approach to reproducibility will serve as a blueprint for reproducible workflows in other areas. Our pipelines, along with their corresponding documentation and sample reports, are available at http://bioinformatics.mdc-berlin.de/pigx
Multiple brain networks mediating stimulus-pain relationships in humans
Authors: Geuter Stephan , Losin Elizabeth A. Reynolds , Roy Mathieu , Atlas Lauren Y. , Schmidt Liane , Krishnan Anjali , Koban Leonie , Wager Tor D. , Lindquist Martin A. 
Published: April 2018

AbstractThe brain transforms nociceptive input into a complex pain experience comprised of sensory, affective, motivational, and cognitive components. However, it is still unclear how pain arises from nociceptive input, and which brain networks coordinate to generate pain experiences. We introduce a new high-dimensional mediation analysis technique to estimate distributed, network-level patterns mediating the relationship between stimulus intensity and pain. In a large-scale analysis of functional magnetic resonance imaging data (N=284), we identify both traditional mediators in somatosensory brain regions and additional mediators located in prefrontal, midbrain, striatal, and default-mode regions unrelated to nociception in standard analyses. The whole brain mediators are specific for pain vs. aversive sounds and are organized in five functional networks. Brain mediators explain 32% more within-subject variance of single-trial pain ratings than previous brain-based models. Our results provide a new, broader view of the networks underlying pain experience, as well as distinct targets for interventions.
Test-retest reliability and convergent validity of (R)-[11C]PK11195 outcome measures without arterial input function
Authors: Plavén-Sigray Pontus , Matheson Granville James , Cselényi Zsolt , Jučaite Aurelija , Farde Lars , Cervenka Simon 
Published: April 2018

BackgroundThe positron emission tomography radioligand (R)-[11C]PK11195 can be used to quantify the expression of translocator protein (TSPO), which is considered a marker for activation of glial cells. TSPO is expressed throughout the brain, and for this reason no true reference region exists. When a radioligand does not have a reference region, an arterial input function (AIF) is usually required in order to quantify binding. However, obtaining an AIF can be difficult as well as uncomfortable for participants. Alternative methods have therefore been proposed with the aim of estimating (R)-[11C]PK11195 binding without arterial measurements, such as standardized uptake values (SUVs), supervised-cluster analysis (SVCA), or the use of a pseudo-reference region. The objective of this study was to evaluate the test-retest reliability and convergent validity of these techniques.MethodsData from a previously published (R)-[11C]PK11195 test-retest study in six healthy male subjects were reanalysed. Non-displaceable binding potential (BPND) was calculated for a set of cortical and subcortical brain regions using the simplified reference tissue model, with either cerebellum as reference region or a reference input derived using SVCA. SUVs were estimated for the time interval of 40-60 minutes. For comparison, total distribution volume (VT), specific distribution volume (VS) and BPNDwere estimated from the two-tissue-compartment model (2TCM) using AIF. Test-retest reliability was then assessed for all outcome measures. Convergent validity was examined by correlating all measures derived without an AIF to those derived using 2TCM.ResultsTest-retest reliability for BPNDestimates were poor (80% of all regional ICCs<0.5). SUVs showed, on average, moderate reliability. BPNDestimates derived without an AIF were not correlated with VT, VSor BPNDfrom the 2TCM (all R2<12%). SUVs were not correlated with any other outcome (all R2<9%).DiscussionBPNDestimated using cerebellum or SVCA as reference input showed poor reliability and little to no convergent validity with outcomes derived using an AIF. SUVs showed moderate reliability but no convergent validity with any other outcome. Caution is warranted for interpreting patient-control comparisons employing (R)-[11C]PK11195 outcome measures obtained without an AIF.
A Cut/cohesin axis alters the chromatin landscape to facilitate neuroblast death
Authors: Arya Richa , Gyonjyan Seda , Harding Katherine , Sarkissian Tatevik , Li Ying , Zhou Lei , White Kristin 
Published: April 2018

AbstractPrecise control of cell death in the nervous system is essential for development. Spatial and temporal factors activate the death of Drosophila neural stem cells (neuroblasts) by controlling the transcription of multiple cell death genes through a shared enhancer, enh1. The activity of enh1 is controlled byabdominalAandNotch, but additional inputs are needed for proper specificity. Here we show that the Cut DNA binding protein is required for neuroblast death, acting downstream of enh1. In the nervous system, Cut promotes an open chromatin conformation in the cell death gene locus, allowing cell death gene expression in response toabdominalA. We demonstrate a temporal increase in global H3K27me3 levels in neuroblasts, which is enhanced bycutknockdown. Furthermore,cutregulates the expression of the cohesin subunit Stromalin in the nervous system. The cohesin components Stromalin and NippedB are required for neuroblast death, and knockdown of Stromalin increases repressive histone modifications in neuroblasts. Thus Cut and cohesin regulate apoptosis in the developing nervous system by altering the chromatin landscape.Summary statementCut regulates the programmed death of neural stem cells by altering cohesin levels and promoting a more open chromatin conformation to allow cell death gene expression.
Marginal Effects of Systemic CCR5 Blockade with Maraviroc on Oral Simian Immunodeficiency Virus Transmission to Infant Macaques
Authors: Brocca-Cofano Egidio , Xu Cuiling , Wetzel Katherine S. , Cottrell Mackenzie L. , Policicchio Benjamin B. , Raehtz Kevin D. , Ma Dongzhu , Dunsmore Tammy , Haret-Richter George S. , Musaitif Karam , Keele Brandon F. , Kashuba Angela D. , Collman Ronald G. , Pandrea Ivona , Apetrei Cristian 
Published: April 2018

AbstractCurrent approaches do not eliminate all HIV-1 maternal-to-infant transmissions (MTIT); new prevention paradigms might help avert new infections. We administered Maraviroc (MVC) to rhesus macaques (RMs) to block CCR5-mediated entry, followed by repeated oral exposure of a CCR5-dependent clone of simian immunodeficiency virus (SIV)mac251 (SIVmac766). MVC significantly blocked the CCR5 coreceptor in peripheral blood mononuclear cells and tissue cells. All control animals and 60% of MVC-treated infant RMs became infected by the 6th challenge, with no significant difference between the number of exposures (p=0.15). At the time of viral exposures, MVC plasma and tissue (including tonsil) concentrations were within the range seen in humans receiving MVC as a therapeutic. Both treated and control RMs were infected with only a single transmitted/founder variant, consistent with the dose of virus typical of HIV-1 infection. The uninfected RMs expressed the lowest levels of CCR5 on the CD4+ T cells. Ramp-up viremia was significantly delayed (p=0.05) in the MVC-treated RMs, yet peak and postpeak viral loads were similar in treated and control RMs. In conclusion, in spite of apparent effective CCR5 blockade in infant RMs, MVC had marginal impact on acquisition and only a minimal impact on post infection delay of viremia following oral SIV infection. Newly developed, more effective CCR5 blockers may have a more dramatic impact on oral SIV transmission than MVC.ImportanceWe have previously suggested that the very low levels of simian immunodeficiency virus (SIV) maternal-to-infant transmissions (MTIT) in African nonhuman primates that are natural hosts of SIVs are due to a low availability of target cells (CCR5+ CD4+ T cells) in the oral mucosa of the infants, rather than maternal and milk factors. To confirm this new MTIT paradigm, we performed a proof of concept study, in which we therapeutically blocked CCR5 with maraviroc (MVC) and orally exposed MVC treated and naïve infant rhesus macaques to SIV. MVC had only a marginal effect on oral SIV transmission. However, the observation that the infant RMs that remained uninfected at the completion of the study, after 6 repeated viral challenges, had the lowest CCR5 expression on the CD4+ T cells prior to the MVC treatment, appear to confirm our hypothesis, also suggesting that the partial effect of MVC is due to a limited efficacy of the drug. Newly, more effective CCR5 inhibitors may have a better effect in preventing SIV and HIV transmission.