bluuebunny/crossref_metadata_2025_split huggingface dataset:
AVADA Enables Automated Genetic Variant Curation Directly from the Full Text Literature
Authors: Birgmeier Johannes , Tierno Andrew P. , Stenson Peter D. , Deisseroth Cole A. , Jagadeesh Karthik A. , Cooper David N. , Bernstein Jonathan A. , Haeussler Maximilian , Bejerano Gill 
Published: November 2018

AbstractPurposeThe primary literature on human genetic diseases includes descriptions of pathogenic variants that are essential for clinical diagnosis. Variant databases such as ClinVar and HGMD collect pathogenic variants by manual curation. We aimed to automatically construct a freely accessible database of pathogenic variants directly from full-text articles about genetic disease.MethodsAVADA (Automatically curated VAriant DAtabase) is a novel machine learning tool that uses natural language processing to automatically identify pathogenic variants and genes in full text of primary literature and converts them to genomic coordinates for rapid downstream use.ResultsAVADA automatically curated almost 60% of pathogenic variants deposited in HGMD, a 4.4-fold improvement over the current state of the art in automated variant extraction. AVADA also contains more than 60,000 pathogenic variants that are in HGMD, but not in ClinVar. In a cohort of 245 diagnosed patients, AVADA correctly annotated 38 previously described diagnostic variants, compared to 43 using HGMD, 20 using ClinVar and only 13 (wholly subsumed by AVADA and ClinVar’s) using the best automated abstracts-only based approach.ConclusionAVADA is the first machine learning tool that automatically curates a variants database directly from full text literature. AVADA is available upon publication at http://bejerano.stanford.edu/AVADA.
Virulence gene profiles and phylogeny of Shiga toxin-positiveEscherichia colistrains isolated from FDA regulated foods during 2010-2017
Authors: Gonzalez-Escalona Narjol , Kase Julie Ann 
Published: November 2018

AbstractIllnesses caused by Shiga toxin-producingEscherichiacoli (STECs) can be life threatening, such as hemolytic uremic syndrome (HUS). The STECs most frequently identified by USDA’s Microbiological Data Program (MDP) carried toxin gene subtypesstx1aand/orstx2a. Here we describe the genome sequences of 331 STECs isolated from foods regulated by the FDA 2010-2017, determining their genomic identity, serotype, sequence type, virulence potential, and prevalence of antimicrobial resistance. Isolates were selected from the MDP archive, routine food testing by field labs (ORA), food testing by a contract company, and our laboratory (ORS). Only 276 (83%) were confirmed as STECs byin silicoanalysis. Foods from which STECs were recovered included cilantro (6%), spinach (25%), lettuce (11%), and flour (9%). Phylogenetic analysis using core genome MLST revealed these STEC genomes were highly variable, with some clustering associated with ST types and serotypes. We detected 95 different sequence types (ST); several ST were previously associated with HUS: ST21 and ST29 (O26:H11), ST11 (O157:H7), ST33 (O91:H14), ST17 (O103:H2), and ST16 (O111:H-).in silicovirulome analyses showed ~ 51% of these strains were potentially pathogenic [besidesstxgene they also carriedeae(25%) or 26%subA(26%)]. Virulence gene prevalence was also determined:stx1 only (19%) -variants a and c;stx2 only (66%) – variants a, b, c, d, e, and g; andstx1/sxt2 (15%). Our data form a new WGS database that can be used to support food safety investigations and monitor the recurrence/emergence ofE. coliin foods.ImportanceShiga toxin-producingEscherichiacoli (STECs) are associated with foodborne outbreaks worldwide; however, surveillance has not previously included genomic analyses for phylogenetics, prevalence, or potential virulence. We constructed the first genomic database of isolates from FDA-regulated foods to help monitor the emergence of new pathogenic STECs. Although only ~30 STECs were isolated per year, 50% of these carried markers associated with pathogenesis either a combination ofeaeplusstx, orsubAplusstx. Moreover, those strains also carried virulence genes associated with severe illnesses. Here we showed that WGS enabled comparisons across isolates to establish phylogeny, help in identification of antibiotic resistance by monitoring the presence of antimicrobial resistance genes, and determined the presence of known virulence genes that have been linked with illnesses. Future food safety investigations will benefit from improved source tracking and risk assessments made possible by these analyses and new WGS database.
Personalization of hybrid brain models from neuroimaging and electrophysiology data
Authors: Sanchez-Todo R. , Salvador R. , Santarnecchi E. , Wendling F. , Deco G. , Ruffini G. 
Published: November 2018

AbstractPersonalization is rapidly becoming standard practice in medical diagnosis and treatment. This study is part of an ambitious program towards computational personalization of neuromodulatory interventions in neuropsychiatry. We propose to model the individual human brain as a network of neural masses embedded in a realistic physical matrix capable of representing measurable electrical brain activity. We call this ahybrid brain model (HBM)to highlight that it encodes both biophysical and physiological characteristics of an individual brain. Although the framework is general, we provide here a pipeline for the integration of anatomical, structural and functional connectivity data obtained from magnetic resonance imaging (MRI), diffuse tensor imaging (DTIconnectome) and electroencephalography (EEG). We personalize model parameters through a comparison of simulated cortical functional connectivity with functional connectivity profiles derived from cortically-mapped, subject-specific EEG. We show that individual information can be represented in model space through the proper adjustment of two parameters (global coupling strength and conduction velocity), and that the underlying structural information has a strong impact on the functional outcome of the model. These findings provide a proof of concept and open the door for further advances, including the model-driven design of non-invasive brain-stimulation protocols.
Habitat loss and fragmentation increase realized predator-prey body size ratios
Authors: Hillaert Jasmijn , Vandegehuchte Martijn L. , Hovestadt Thomas , Bonte Dries 
Published: November 2018

AbstractIn the absence of predators, habitat fragmentation favors large body sizes in primary consumers with informed movement due to their high gap-crossing ability. However, the body size of primary consumers is not only shaped by such bottom-up effects, but also by top-down effects as predators prefer prey of a certain size. Therefore, higher trophic levels should be taken into consideration when studying the effect of habitat loss and fragmentation on size distributions of herbivores.We built a model to study the effect of habitat loss and fragmentation within a simple food web consisting of (i) a basal resource that is consumed by (ii) a herbivore that in turn is consumed by (iii) a predator. Our results highlight that predation may result in local accumulation of the resource via top-down control of the herbivore. As such, the temporal and spatial variation of the resource distribution is increased, selecting for increased herbivore movement. This results in selection of larger herbivores than in the scenario without predator. As predators cause herbivores to be intrinsically much larger than the optimal sizes selected by habitat fragmentation in the absence of predators, habitat fragmentation is no longer a driver of herbivore size. However, there is selection for increased predator size with habitat fragmentation as herbivores become less abundant, favoring gap-crossing ability of the predator. Since herbivore and predator body size respond differently to habitat loss and fragmentation, realized predator-herbivore body size ratios increase along this fragmentation gradient. Our model predicts the dominance of top-down forces in regulating body size selection in food webs and helps to understand how habitat destruction and fragmentation affect overall food web structure.
A requirement for neutrophil glycosaminoglycans in chemokine:receptor interactions is revealed by the streptococcal protease SpyCEP
Authors: Goldblatt Jenny , Lawrenson Richard Ashley , Muir Luke , Dattani Saloni , Tsuchiya Tomoko , Kanegasaki Shiro , Sriskandan Shiranee , Pease James Edward 
Published: November 2018

To evade the immune system, the lethal human pathogenStreptococcus pyogenesproduces SpyCEP, an enzyme that cleaves the C-terminalα-helix of CXCL8, resulting in markedly impaired recruitment of neutrophils to sites of invasive infection. The basis for chemokine inactivation by SpyCEP is, however, poorly understood, as the core domain of CXCL8 known to interact with CXCL8 receptors is unaffected by enzymatic cleavage.We examined thein vitromigration of human neutrophils and observed that their ability to efficiently navigate a CXCL8 gradient was compromised following CXCL8 cleavage by SpyCEP. SpyCEP-mediated cleavage of CXCL8 also impaired CXCL8-induced migration of transfectants expressing the human chemokine receptors CXCR1 or CXCR2. Despite possessing an intact N-terminus and preserved disulphide bonds, SpyCEP-cleaved CXCL8 had impaired binding to both CXCR1 and CXCR2, pointing to a requirement for the C terminalα-helix. SpyCEP-cleaved CXCL8 had similarly impaired binding to the glycosaminoglycan heparin. Enzymatic removal of neutrophil glycosaminoglycans was observed to ablate neutrophil navigation of a CXCL8 gradient, whilst navigation of an fMLP gradient remained largely intact.We conclude therefore, that SpyCEP cleavage of CXCL8 results in chemokine inactivation due to a requirement for glycosaminoglycan binding in productive chemokine:receptor interactions. This may inform strategies to inhibit the activity of SpyCEP, but may also influence future approaches to inhibit unwanted chemokine-induced inflammation.
Delays, behaviour and transmission: modelling the impact of effective private provider engagement on tuberculosis control in urban India
Authors: Arinaminpathy Nimalan , Deo Sarang , Singh Simrita , Khaparde Sunil , Rao Raghuram , Vadera Bhavin , Kulshrestha Niraj , Gupta Devesh , Rade Kiran , Nair Sreenivas Achuthan , Dewan Puneet 
Published: November 2018

AbstractIn India, the country with the world’s largest burden of tuberculosis (TB), most patients first seek care in the private healthcare sector, which is fragmented and unregulated. Ongoing initiatives are demonstrating effective approaches for engaging with this sector, and form a central part of India’s recent National Strategic Plan: here we aimed to address their potential impact on TB transmission in urban settings, when taken to scale. We developed a mathematical model of TB transmission dynamics, calibrated to urban populations in Mumbai and Patna, two major cities in India where pilot interventions are currently ongoing.We found that, when taken to sufficient scale to capture 75% of patient-provider interactions, the intervention could reduce incidence by upto 21.3% (95% Bayesian credible interval (CrI) 13.0 – 32.5%) and 15.8% (95% CrI 7.8 – 28.2%) in Mumbai and Patna respectively, between 2018 and 2025. There is a stronger impact on TB mortality, with a reduction of up to 38.1% (95% CrI 20.0 – 55.1%) in the example of Mumbai. The incidence impact of this intervention alone may be limited by the amount of transmission that has already occurred by the time a patient first presents for care: model estimates suggest an initial patient delay of 4-5 months before first seeking care, followed by a diagnostic delay of 1-2 months before ultimately initiating TB treatment. Our results suggest that the transmission impact of such interventions could be maximised by additional measures to encourage early uptake of TB services.
Oligodendrocyte Precursor Cells Are Co-Opted by the Immune System to Cross-Present Antigen and Mediate Cytotoxicity
Authors: Kirby Leslie , Jin Jing , Cardona Jaime Gonzalez , Smith Matthew D. , Martin Kyle A. , Wang Jingya , Strasburger Hayley , Herbst Leyla , Alexis Maya , Karnell Jodi , Davidson Todd , Dutta Ranjan , Goverman Joan , Bergles Dwight , Calabresi Peter A. 
Published: November 2018

AbstractOligodendrocyte precursor cells (OPCs) are abundant in the adult CNS and can be recruited to form new oligodendrocytes and myelin in response to injury or disease. However, in multiple sclerosis (MS), oligodendrocyte regeneration and remyelination are often incomplete, suggesting that recruitment and maturation of OPCs is impaired. MS and the rodent model experimental autoimmune encephalomyelitis (EAE) are characterized by infiltration of activated T-cells into the CNS. To investigate the mechanisms by which this neuroinflammatory process influences OPC mobilization, we performed in vivo fate tracing in an inflammatory demyelinating animal model. Results of our studies showed that the OPC differentiation and myelin production are inhibited by either adoptive transfer of CNS infiltrating cytokine producing effector T-cells or CNS production of interferon gamma (IFNγ), using an astrocyte specific IFNγ transgene model. In both systems, IFNγ changes the profile of OPCs by inducing functional expression of the immunoproteasome and upregulation of MHC class I. OPCs exposed to IFNγ are shown to cross present exogenous antigen to cytotoxic CD8 T-cells, which then produce proteases and FasL that results in subsequent caspase 3/7 activation and OPC death, both in vitro and in vivo. Cross presentation by OPCs is dependent on the cytosolic processing pathway and can be inhibited by small molecules targeting MHC class I antigen processing and the immunoproteasome subunits. Finally, the immunoproteasome subunit, PSMB8, is shown to be markedly increased on Sox10+oligodendrocyte lineage cells only in the demyelinated white matter lesions from patients with MS. These findings support the notion that OPCs have multiple functions beyond differentiation into myelinating cells and adapt to their microenvironment by responding to local cues. In MS, OPCs may be co-opted by the immune system to perpetuate the autoimmune response. Strategies aimed at inhibiting the aberrant immune activation pathways in OPCs may allow more efficient remyelination in MS.
Timing polymerase pausing with TV-PRO-seq: dissecting the interplay of pausing duration and location, and gene expression
Authors: Zhang Jie , Cavallaro Massimo , Hebenstreit Daniel 
Published: November 2018

AbstractTranscription of many genes in metazoans is subject to polymerase pausing, which is the transient stop of transcriptionally-engaged polymerases. This is known to mainly occur in promoter proximal regions but it is not well understood. In particular, a genome-wide measurement of pausing times at high resolution has been lacking. We present here the time-variant precision nuclear run-on and sequencing (TV-PRO-seq) assay, an extension of the standard PRO-seq that allows us to estimate genome-wide pausing times at single-base resolution. Its application to human cells demonstrates that, proximal to promoters, polymerases pause more frequently but for shorter times than in other genomic regions. Pausing release by the detergent sarkosyl, previously believed to be linked to the factor NELF at the promoter proximal region only, is independent of the latter. Comparison with single-cell gene expression data reveals that the polymerase pausing times are longer in highly expressed genes, while transcriptionally noisier genes have higher pausing frequencies and slightly longer pausing times. Analyses of histone modifications suggest that the marker H3K36me3 is related to the polymerase pausing.
De novo transcriptome assembly of the Italian white truffle (Tuber magnatum Pico)
Authors: Vita Federico , Alpi Amedeo , Bertolini Edoardo 
Published: November 2018

AbstractThe Italian white truffle (Tuber magnatum Pico) is a gastronomic delicacy that dominates the worldwide truffle market. Despite its importance, the genomic resources currently available for this species are still limited. Here we present the first de novo transcriptome assembly of T. magnatum. Illumina RNA-seq data were assembled using a single-k-mer approach into 22,932 transcripts with N50 of 1,524 bp. Our approach allowed to predict and annotate 12,367 putative protein coding sequences, reunited in 6,723 loci. In addition, we identified 2,581 gene-based SSR markers. This work provides the first publicly available reference transcriptome for genomics and genetic studies providing insight into the molecular mechanisms underlying the biology of this important species.
Inhibition of tetrameric Patched1 by Sonic Hedgehog through an asymmetric paradigm
Authors: Qian Hongwu , Cao Pingping , Hu Miaohui , Gao Shuai , Yan Nieng , Gong Xin 
Published: November 2018

AbstractThe Hedgehog (Hh) pathway controls embryonic development and postnatal tissue maintenance and regeneration. Inhibition of oligomeric Hh receptor Patched (Ptch) by the secreted and post-translationally modified ligand Hh relieves suppression of the signaling cascades. Here, we report the cryo-EM structure of tetrameric Ptch1 in complex with palmitoylated N-terminal signaling domain of human Sonic hedgehog (ShhNp). The structure shows that four Ptch1 protomers are organized as a loose dimer of dimers and each dimer binds to one ShhNp through two distinct inhibitory interfaces. Ptch1-A binds to ShhNp through the well-characterized Ca2+-mediated interface on the globular domain of ShhNp, and Ptch1-B primarily interacts with the N-terminal peptide and the palmitoyl moiety. Map comparison reveals that the cholesteryl moiety of native ShhN occupies a recently identified extracellular steroid binding pocket in Ptch1-B. Our structure elucidates the tetrameric assembly of Ptch1 and suggests asymmetric mode of actions of the Hh ligands for inhibiting the potential cholesterol transport activity of Ptch1.
Distinguishing multiple-merger from Kingman coalescence using two-site frequency spectra
Authors: Fenton Eliot F. , Rice Daniel P. , Novembre John , Desai Michael M. 
Published: November 2018

ABSTRACTDemographic inference methods in population genetics typically assume that the ancestry of a sample can be modeled by the Kingman coalescent. A defining feature of this stochastic process is that it generates genealogies that are binary trees: no more than two ancestral lineages may coalesce at the same time. However, this assumption breaks down under several scenarios. For example, pervasive natural selection and extreme variation in offspring number can both generate genealogies with “multiple-merger” events in which more than two lineages coalesce instantaneously. Therefore, detecting multiple mergers (and other violations of the Kingman assumptions) is important both for understanding which forces have shaped the diversity of a population and for avoiding fitting misspecified models to data. Current methods to detect multiple mergers in genomic data rely primarily on the site frequency spectrum (SFS). However, the signatures of multiple mergers in the SFS are also consistent with a Kingman coalescent with a time-varying population size. Here, we present a new statistical test for determining whether the Kingman coalescent with any population size history is consistent with population data. Our approach is based on information contained in the two-site joint frequency spectrum (2-SFS) for pairs of linked sites, which has a different dependence on the topologies of genealogies than the SFS. Our statistical test is global in the sense that it can detect when the genome-wide genetic diversity is inconsistent with the Kingman model, rather than detecting outlier regions, as in selection scan methods. We validate this test using simulations, and then apply it to demonstrate that genomic diversity data fromDrosophila melanogasteris inconsistent with the Kingman coalescent.
Ventral hippocampal projections to the medial prefrontal cortex regulate social memory
Authors: Phillips Mary L. , Robinson Holly A. , Pozzo-Miller Lucas 
Published: November 2018

SUMMARYInputs from the ventral hippocampus (vHIP) to the medial prefrontal cortex (mPFC) have been implicated in several neuropsychiatric disorders. Here, we show that the long-range vHIP-mPFC projection is hyperactive in the Mecp2 knockout (KO) mouse model of the autism spectrum disorder Rett syndrome, which has deficits in social memory. Chronically mimicking vHIP-mPFC hyperexcitability in wild-type mice impaired social memory, whereas chronic inhibition of mPFC-projecting vHIP neurons in Mecp2 KO mice rescued social memory deficits; the extent of memory rescue was negatively correlated with the strength of vHIP input to the mPFC. Acute manipulations of the vHIP-mPFC projection also affected social memory in a specific and selective manner, suggesting that proper vHIP-mPFC signaling is necessary to recall social memories. In addition, we identified an altered vHIP-mPFC innervation pattern and increased synaptic strength onto layer 5 pyramidal neurons as contributing factors in aberrant vHIP-mPFC signaling in Mecp2 KO mice.
Multiple mechanisms link prestimulus neural oscillations to sensory responses
Authors: Iemi Luca , Busch Niko A , Laudini Annamaria , Haegens Saskia , Samaha Jason , Villringer Arno , Nikulin Vadim V 
Published: November 2018

AbstractSpontaneous fluctuations of neural activity may explain why sensory responses vary across repeated presentations of the same physical stimulus. To test this hypothesis, we recorded electroencephalography in humans during stimulation with identical visual stimuli and analyzed how prestimulus neural oscillations modulate different stages of sensory processing reflected by distinct components of the event-related potential (ERP). We found that strong prestimulus alpha- and beta-band power resulted in a suppression of early ERP components (C1 and N150) and in an amplification of late components (after 0.4 s), even after controlling for fluctuations in 1/f aperiodic signal and sleepiness. Whereas functional inhibition of sensory processing underlies the reduction of early ERP responses, we found that the modulation of non-zero-mean oscillations (baseline shift) accounted for the amplification of late responses. Distinguishing between these two mechanisms is crucial for understanding how internal brain states modulate the processing of incoming sensory information.
Loss of cytoplasmic incompatibility and minimal fecundity effects explain relatively lowWolbachiafrequencies inDrosophila mauritiana
Authors: Meany Megan K. , Conner William R. , Richter Sophia V. , Bailey Jessica A. , Turelli Michael , Cooper Brandon S. 
Published: November 2018

ABSTRACTMaternally transmittedWolbachiabacteria infect about half of all insect species. ManyWolbachiacause cytoplasmic incompatibility (CI), reduced egg hatch when uninfected females mate with infected males. Although CI produces a frequency-dependent fitness advantage that leads to high equilibriumWolbachiafrequencies, it does not aidWolbachiaspread from low frequencies. Indeed, the fitness advantages that produce initialWolbachiaspread and maintain non-CIWolbachiaremain elusive.wMauWolbachiainfectingDrosophila mauritianado not cause CI, despite being very similar to CI-causingwNo fromD. simulans(0.068% sequence divergence over 682,494 bp), suggesting recent CI loss. Using draftwMau genomes, we identify a deletion in a CI-associated gene, consistent with theory predicting that selection within host lineages does not act to increase or maintain CI. In the laboratory,wMau shows near-perfect maternal transmission; but we find no significant effect on host fecundity, in contrast to published data. IntermediatewMau frequencies on the island Mauritius are consistent with a balance between unidentified small, positive fitness effects and imperfect maternal transmission. Our phylogenomic analyses suggest that group-BWolbachia, includingwMau andwPip, diverged from group-AWolbachia, such aswMel andwRi, 6–46 million years ago, more recently than previously estimated.