bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sex-specific gene and pathway modeling of inherited glioma risk
Authors: Ostrom Quinn T. , Coleman Warren , Huang William , Rubin Joshua B. , Lathia Justin D. , Berens Michael E. , Speyer Gil , Liao Peter , Wrensch Margaret R. , Eckel-Passow Jeanette E , Armstrong Georgina , Rice Terri , Wiencke John K. , McCoy Lucie S. , Hansen Helen M. , Amos Christopher I. , Bernstein Jonine L. , Claus Elizabeth B. , Il’yasova Dora , Johansen Christoffer , Lachance Daniel H. , Lai Rose K. , Merrell Ryan T. , Olson Sara H. , Sadetzki Siegel , Schildkraut Joellen M. , Shete Sanjay , Houlston Richard S. , Jenkins Robert B. , Andersson Ulrika , Rajaraman Preetha , Chanock Stephen J. , Linet Martha S. , Wang Zhaoming , Yeager Meredith , Melin Beatrice , Bondy Melissa L. , Barnholtz-Sloan Jill S. 
Published: December 2017

ABSTRACTBackgroundGenome-wide association studies (GWAS) have identified 25 risk variants for glioma, which explain ~30% of heritable risk. Most glioma histologies occur with significantly higher incidence in males. A sex-stratified analysis ide7ntified sex-specific glioma risk variants, and further analyses using gene- and pathway-based approaches may further elucidate risk variation by sex.MethodsResults from the Glioma International Case-Control Study were used as a testing set, and results from three GWAS were combined via meta-analysis and used as a validation set. Using summary statistics for autosomal SNPs found to be nominally significant (p<0.01) in a previous meta-analysis and X chromosome SNPs with nominally significant association (p<0.01), three algorithms (Pascal, BimBam, and GATES) were used to generate gene-scores, and Pascal was used to generate pathway scores. Results were considered significant when p<3.3x10−6in ⅔ algorithms.Results25 genes within five regions and 19 genes within six regions reached the set significance threshold in at least 2/3 algorithms in males and females, respectively.EGFRandRTEL1-TNFRSF6Bwere significantly associated with all glioma and glioblastoma in males only, and a female-specific association inTERT, all of which remained nominally significant after conditioning on known risk loci. There were nominal associations with the Telomeres, Telomerase, Cellular Aging, and Immortality pathway in both males and females.ConclusionsThese results suggest that there may be biologically relevant significant differences by sex in genetic risk for glioma. Additional gene- and pathway-based analyses may further elucidate the biological processes through which this risk is conferred.
Sex in the wild: how and why field-based studies contribute to solving the problem of sex
Authors: Neiman Maurine , Meirmans Patrick G. , Schwander Tanja , Meirmans Stephanie 
Published: December 2017

AbstractWhy and how sexual reproduction is maintained in natural populations, the so-called “queen of problems”, is a key unanswered question in evolutionary biology. Recent efforts to solve the problem of sex have often emphasized results generated from laboratory settings. Here, we use a survey of representative “sex in the wild” literature to review and synthesize the outcomes of empirical studies focused on natural populations. Especially notable results included relatively strong support for mechanisms involving niche differentiation and a near absence of attention to adaptive evolution. Support for a major role of parasites is largely confined to a single study system, and only three systems contribute most of the support for mutation accumulation hypotheses. This evidence for taxon specificity suggests that outcomes of particular studies should not be more broadly extrapolated without extreme caution. We conclude by suggesting steps forward, highlighting tests of niche differentiation mechanisms in both lab and nature and empirical evaluation of adaptive evolution-focused hypotheses in the wild. We also emphasize the value of leveraging the growing body of genomic resources for non-model taxa to address whether the clearance of harmful mutations and spread of beneficial variants in natural populations proceeds as expected under various hypotheses for sex.Author contributionsSM and MN conceived the paper idea, SM, PM, MN, and TS designed the review strategy, reviewed and analysed the literature, and wrote the manuscript. All authors gave final approval for publication.Data archival locationThe results of our literature survey are provided as electronic supplementary material.
On how the dentate gyrus contributes to memory discrimination
Authors: van Dijk Milenna T. , Fenton Andre A. 
Published: December 2017

SummaryThe dentate gyrus (DG) is crucial for behaviorally discriminating similar spatial memories, predicting that dentate gyrus place cells change (“remap”) spatial tuning (“place fields”) for memory discrimination. This prediction was never tested, although DG place cells remap across similar environments without memory tasks. We confirm this prior finding, then demonstrate that DG place fields do not remap across spatial tasks that require DG-dependent memory discrimination. Instead of remapping, place-discriminating discharge is observed transiently amongst DG place cells, particularly where memory discrimination is most necessary. The DG network signals memory discrimination by expressing distinctive sub-second network patterns of co-firing amongst principal cells at memory discrimination sites. This is accompanied by increased coupling of discharge from excitatory principal cells and inhibitory interneurons. Instead of remapping, these findings identify that memory discrimination is signaled by sub-second patterns of correlated discharge within the dentate network.eTOC blurbvan Dijk and Fenton report that dentate gyrus place cells signal memory discrimination not by remapping, but by variable sub-second patterns of coordinated place cell network discharge and enhanced discharge coupling between excitatory and inhibitory neurons, at sites of memory discrimination.HighlightsDentate gyrus-dependent memory discrimination does not require place cell remappingDentate neural correlates of pattern discrimination are transient, lasting secondsSub-second dentate network discharge correlations signal memory discriminationDentate excitatory-inhibitory coupling is increased at memory discrimination sites
Statistical mechanics of cell decision-making: the cell migration force distribution
Authors: Hatzikirou Haralampos 
Published: December 2017

AbstractCell decision-making is the cellular process of responding to microenvironmental cues. This can be regarded as the regulation of cell’s intrinsic variables to extrinsic stimuli. Currently, little is known about the principles dictating cell decision-making. Regarding cells as Bayesian decision-makers under energetic constraints, I postulate the principle of least microenvironmental uncertainty (LEUP). This is translated into a free-energy principle and I develop a statistical mechanics theory for cell decision-making. I exhibit the potential of LEUP in the case of cell migration. In particular, I calculate the dependence of cell locomotion force on the steady state distribution of adhesion receptors. Finally, the associated migration velocity allows for the reproduction of the cell anomalous diffusion, as observed in cell culture experiments.
Topology independent structural matching discovers novel templates for protein interfaces
Authors: Mirabello Claudio , Wallner Björn 
Published: December 2017

AbstractMotivationProtein-protein interactions (PPI) are essential for the function of the cellular machinery. The rapid growth of protein-protein complexes with known 3D structures offers a unique opportunity to study PPI to gain crucial insights into protein function and the causes of many diseases. In particular, it would be extremely useful to compare interaction surfaces ofmonomers, as this would enable the pinpointing of potential interaction surfaces based solely on the monomer structure, without the need to predict the complete complex structure. While there are many structural alignment algorithms for individual proteins, very few have been developed for protein interfaces, and none that can align only the interface residues to other interfaces or surfaces of interacting monomer subunits in a topology independent (non-sequential) manner.ResultsWe present InterComp, a method for topology and sequence-order independent structural comparisons. The method is general and can be applied to various structural comparison applications. By representing residues as independent points in space rather than as a sequence of residues, InterComp can can be applied to a wide range of problems including: interface-surface comparisons, interface-interface comparisons and even comparisons of small molecule ligands. We demonstrate a use-case by applying InterComp to find similar protein interfaces on the surface of proteins. We show that InterComp pinpoints the correct interface for almost half of the targets (283 of 586) when considering the top 10 hits, and for 24% of the top 1, even when no templates can be found with the already available sequence-order dependent methods like TM-align.AvailabilityThe program is available from:http://wallnerlab.org/InterCompContactbjorn.wallner@liu.seSupplementary informationSupplementary data included in the pdf.
Multiplexed targeted resequencing identifies coding and regulatory variation underlying phenotypic extremes of HDL-cholesterol in humans
Authors: Khetarpal Sumeet A. , Babb Paul L. , Zhao Wei , Hancock-Cerutti William F. , Brown Christopher D. , Rader Daniel J. , Voight Benjamin F. 
Published: December 2017

AbstractGenome-wide association studies have uncovered common variants at many loci influencing human complex traits and diseases, such as high-density lipoprotein cholesterol (HDL-C). However, the contribution of the identified genes is difficult to ascertain from current efforts interrogating common variants with small effects. Thus, there is a pressing need for scalable, cost-effective strategies for uncovering causal variants, many of which may be rare and noncoding. Here, we used a multiplexed inversion probe (MIP) target capture approach to resequence both coding and regulatory regions at seven HDL-C associated loci in 797 individuals with extremely high HDL-C vs. 735 low-to-normal HDL-C controls. Our targets included protein-coding regions of GALNT2, APOA5, APOC3, SCARB1, CCDC92, ZNF664, CETP, and LIPG (>9 kb), and proximate noncoding regulatory features (>42 kb). Exome-wide genotyping in 1,114 of the 1,532 participants yielded a >90% genotyping concordance rate with MIP-identified variants in ~90% of participants. This approach rediscovered nearly all established GWAS associations in GALNT2, CETP, and LIPG loci with significant and concordant associations with HDL-C from our phenotypic-extremes design at 0.1% of the sample size of lipid GWAS studies. In addition, we identified a novel, rare, CETP noncoding variant enriched in the extreme high HDL-C group (P<0.01, Score Test). Our targeted resequencing of individuals at the HDL-C phenotypic extremes offers a novel, efficient, and cost-effective approach for identifying rare coding and noncoding variation differences in extreme phenotypes and supports the rationale for applying this methodology to uncover rare variation—particularly non-coding variation--underlying myriad complex traits.
Size Matters: Metastatic cluster size and stromal recruitment in the establishment of successful prostate cancer to bone metastases
Authors: Araujo Arturo , Cook Leah M. , Lynch Conor C. , Basanta David 
Published: December 2017

AbstractProstate cancer (PCa) impacts over 180,000 men every year in the US alone with 26,000 patients expected to succumb to the disease (cancer.gov). The primary cause of death is metastasis, with secondary lesions most commonly occurring in the skeleton. Prostate cancer to bone metastasis is an important yet poorly understood process that is difficult to explore with experimental techniques alone. To this end we have utilized a hybrid (discrete-continuum) cellular automata (HCA) model of normal bone matrix homeostasis that allowed us to investigate how metastatic PCa can disrupt the bone microenvironment. Our previously published results showed that PCa cells can recruit mesenchymal stem cells (MSCs) that give rise to bone building osteoblasts. MSCs are also thought to be complicit in the establishment of successful bone metastases (1). Here we have explored aspects of early metastatic colonization and shown that the size of PCa clusters needs to be within a specific range to become successfully established: sufficiently large to maximize success but not too large to risk failure through competition amongst cancer and stromal cells for scarce resources. Furthermore, we show that MSC recruitment can promote the establishment of a metastasis and compensate for relatively low numbers of PCa cells seeding the bone microenvironment. Combined, our results highlight the utility of computational models that capture the complex and dynamic dialogue between cells during the initiation of active metastases.
Copy number variation and neurodevelopmental problems in females and males in the general population
Authors: Martin Joanna , Tammimies Kristiina , Karlsson Robert , Lu Yi , Larsson Henrik , Lichtenstein Paul , Magnusson Patrik 
Published: December 2017

AbstractObjectiveNeurodevelopmental problems (NPs) are childhood phenotypes that are more common in males. Conversely, anxiety and depression (which are frequently comorbid with NPs) are more common in females. Rare copy number variants (CNVs) have been implicated in clinically-defined NPs. Here, we aimed to characterise the relationship between rare CNVs with NPs and anxiety/depression in a population sample of twin children. Additionally, we examined whether sex-specific CNV effects underlie the sex bias of these disorders.MethodWe analysed a sample of N=12,982 children, of whom 5.3% had narrowly-defined NPs (clinically-diagnosed), 20.9% had broadly-defined NPs (based on validated screening measures, but no diagnosis) and 3.0% had clinically-diagnosed anxiety or depression. Rare (<1% frequency) CNVs were categorised by size (medium: 100-500kb or large: >500kb), type (duplication or deletion) and putative relevance to NPs (affecting previously implicated loci or evolutionarily-constrained genes). We tested for associations between the different CNV categories with NPs and anxiety/depression, followed by examination of sex-specific effects.ResultsMedium deletions (OR(CI)=1.18(1.05-1.33),p=0.0053) and large duplications (OR(CI)=1.45(1.19-1.75),p=0.00017) were associated with broadly-defined NPs. Large deletions (OR(CI)=1.85(1.14-3.01),p=0.013) were associated with narrowly-defined NPs. The effect sizes increased for large NP-relevant CNVs (broadly-defined: OR(CI)=1.60(1.06-2.42),p=0.025; narrowly-defined: OR(CI)=3.64(2.16-6.13),p=1.2E-6). No sex differences in CNV burden were found in individuals with NPs (p>0.05). In individuals diagnosed with anxiety or depression, females were more likely to have large CNVs (OR(CI)=3.75(1.45-9.68),p=0.0064).ConclusionRare CNVs are significantly associated with both narrowly- and broadly-defined NPs in a general population sample of children. Our results also suggest that large, rare CNVs may show sex-specific phenotypic effects.
Replay of Stimulus Specific Temporal Patterns during Associative Memory Formation
Authors: Michelmann Sebastian , Bowman Howard , Hanslmayr Simon 
Published: December 2017

AbstractForming a memory often entails the association of recent experience with present events. This recent experience is usually an information rich and dynamic representation of the world around us. We here show that associating a static cue with a previously shown dynamic stimulus, yields a detectable, dynamic representation of this stimulus in working memory. We further implicate this representation in the decrease of low-frequency power (∼4-30 Hz) in the ongoing electroencephalogram (EEG), which is a well-known correlate of successful memory formation. The maintenance of content specific patterns in desynchronizing brain oscillations was observed in two sensory domains, i.e. in a visual and in an auditory condition. Together with previous results, these data suggest a mechanism that generalizes across domains and processes, in which the decrease in oscillatory power allows for the dynamic representation of information in ongoing brain oscillations.
Human Herpes Virus 6 (HHV-6) - Pathogen or Passenger? A pilot study of clinical laboratory data and next generation sequencing
Authors: Sharp Colin , Golubchik Tanya , Gregory William F. , McNaughton Anna L. , Gow Nicholas , Selvaratnam Mathyruban , Mirea Alina , Foster Dona , Andersson Monique , Klenerman Paul , Jeffery Katie , Matthews Philippa C. 
Published: December 2017

ABSTRACTBackgroundHuman herpes virus 6 (HHV-6) is a ubiquitous organism that can cause a variety of clinical syndromes ranging from short-lived rash and fever through to life-threatening encephalitis.ObjectivesWe set out to generate observational data regarding the epidemiology of HHV-6 infection in clinical samples from a UK teaching hospital and to compare different diagnostic approaches.Study designFirst, we scrutinized HHV-6 detection in samples submitted to our hospital laboratory through routine diagnostic pathways. Second, we undertook a pilot study using Illumina next generation sequencing (NGS) to determine the frequency of HHV-6 in CSF and respiratory samples that were initially submitted to the laboratory for other diagnostic tests.ResultsOf 72 samples tested for HHV-6 by PCR at the request of a clinician, 24 (33%) were positive for HHV-6. The majority of these patients were under the care of the haematology team (30/41, 73%), and there was a borderline association between HHV-6 detection and both Graft versus Host Disease (GvHD) and Central nervous system (CNS) disease (p=0.05 in each case). We confirmed detection of HHV-6 DNA using NGS in 4/20 (20%) CSF and respiratory samples.ConclusionsHHV-6 is common in clinical samples submitted from a high-risk haematology population, and enhanced screening of this group should be considered. NGS can be used to identify HHV-6 from a complex microbiomee, but further controls are required to define the sensitivity and specificity, and to correlate these results with clinical disease. Our results underpin ongoing efforts to develop NGS technology for viral diagnostics.
CLIQ-BID: A method to quantify bacteria-induced damage to eukaryotic cells by automated live-imaging of bright nuclei
Authors: Wallez Yann , Bouillot Stéphanie , Soleilhac Emmanuelle , Huber Philippe , Attrée Ina , Faudry Eric 
Published: December 2017

ABSTRACTPathogenic bacteria induce eukaryotic cell damage which range from discrete modifications of signalling pathways, to morphological alterations and even to cell death. Accurate quantitative detection of these events is necessary for studying host-pathogen interactions and for developing strategies to protect host organisms from bacterial infections. Investigation of morphological changes is cumbersome and not adapted to high-throughput and kinetics measurements. Here, we describe a simple and cost-effective method based on automated analysis of live cells with stained nuclei, which allows real-time quantification of bacteria-induced eukaryotic cell damage at single-cell resolution. We demonstrate that this automated high-throughput microscopy approach permits screening of libraries composed of interference-RNA, bacterial strains, antibodies and chemical compounds in ex vivo infection settings. The use of fluorescently-labelled bacteria enables the concomitant detection of changes in bacterial growth. Using this method named CLIQ-BID (Cell Live Imaging Quantification of Bacteria Induced Damage), we were able to distinguish the virulence profiles of different pathogenic bacterial species and clinical strains.
Antenatal microbial colonisation of mammalian gut
Authors: Borghi Elisa , Massa Valentina , Severgnini Marco , Fazio Grazia , Avagliano Laura , Menegola Elena , Bulfamante Gaetano , Morace Giulia , Borgo Francesca 
Published: December 2017

ABSTRACTThe widely accepted dogma of intrauterine sterility and initial colonisation of the newborn during birth has been blurred by recent observations of microbial presence in meconium, placenta and amniotic fluid. Given the importance of a maternal-derived in utero infant seeding, it is crucial to exclude potential environmental or procedural contaminations, and to assess foetal colonisation before parturition. To ascertain antenatal microbial colonisation in mammals, we analysed sterilely collected intestinal tissues from rodent foetuses in parallel with experimental controls, and tissues from autoptic human foetuses. Next generation sequencing (NGS) showed the presence of pioneer microbes in both rat and human intestines, as well as in rodent placentas and amniotic fluids. Live microbes were isolated from culture-dependent analyses from homogenized rat foetal intestines.Microbial communities showed foetus- and dam-dependent clustering, confirming the high interindividual variability of microbiota even in the antenatal period. Fluorescent in situ hybridisation analysis confirmed the microbes’ existence in the lumen of the developing gut.These findings have vast implications for an emerging field of enhancing the management of healthy pregnancies, and for understanding how the infant microbiome starts and it is thus shaped.
Importance of homo-dimerization of Fanconi-associated nuclease 1 in DNA flap cleavage
Authors: Rao Timsi , Longerich Simonne , Zhao Weixing , Aihara Hideki , Sung Patrick , Xiong Yong 
Published: December 2017

SUMMARYFanconi-associated nuclease 1 (FAN1) removes interstrand DNA crosslinks (ICLs) through its DNA flap endonuclease and exonuclease activities. Crystal structures of human and bacterial FAN1 bound to a DNA flap have been solved. The Pseudomonas aeruginosa bacterial FAN1 and human FAN1 (hFAN1) missing a flexible loop are monomeric, while intact hFAN1 is homo-dimeric in structure. Importantly, the monomeric and dimeric forms of FAN1 exhibit very different DNA binding modes. Here, we interrogate the functional differences between monomeric and dimeric forms of FAN1 and provide an explanation for the discrepancy in oligomeric state between the two hFAN1 structures. Specifically, we show that the flexible loop in question is needed for hFAN1 dimerization. While monomeric and dimeric bacterial or human FAN1 proteins cleave a short 5’ flap strand with similar efficiency, optimal cleavage of a long 5’ flap strand is contingent upon protein dimerization. Our study therefore furnishes biochemical evidence for a role of hFAN1 homodimerization in biological processes that involve 5’ DNA Flap cleavage.