bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comprehensive Cross-Population Analysis of High-Grade Serous Ovarian Cancer Supports No More Than Three Subtypes
Authors: Way Gregory P. , Rudd James , Wang Chen , Hamidi Habib , Fridley Brooke L. , Konecny Gottfried , Goode Ellen L. , Greene Casey S. , Doherty Jennifer A. 
Published: October 2015

AbstractFour gene expression subtypes of high-grade serous ovarian cancer (HGSC) have been previously described. In these studies, a fraction of samples that did not fit well into the four subtype classifications were excluded. Therefore, we sought to systematically determine the concordance of transcriptomic HGSC subtypes across populations without removing any samples. We created a bioinformatics pipeline to independently cluster the five largest mRNA expression datasets usingk-means and non-negative matrix factorization (NMF). We summarized differential expression patterns to compare clusters across studies. While previous studies reported four subtypes, our cross-population comparison does not support four. Because these results contrast with previous reports, we attempted to reproduce analyses performed in those studies. Our results suggest that early results favoring four subtypes may have been driven by including serous borderline tumors. In summary, our analysis suggests that either two or three, but not four, gene expression subtypes are most consistent across datasets.CONFLICTS OF INTERESTThe authors do not declare any conflicts of interest.OTHER PRESENTATIONSAspects of this study were presented at the 2015 AACR Conference and the 2015 Rocky Mountain Bioinformatics Conference.
Sporadic, global linkage disequilibrium between unlinked segregating sites
Authors: Skelly Daniel A. , Magwene Paul M. , Stone Eric A. 
Published: October 2015

AbstractDemographic, genetic, or stochastic factors can lead to perfect linkage disequilibrium (LD) between alleles at two loci without respect to the extent of their physical distance, a phenomenon that Lawrenceet al. (2005a) refer to as “genetic indistinguishability”. This phenomenon can complicate genotype-phenotype association testing by hindering the ability to localize causal alleles, but has not been thoroughly explored from a theoretical perspective or using large, dense whole-genome polymorphism datasets. We derive a simple theoretical model of the prevalence of genetic indistinguishability between unlinked loci, and verify its accuracy via simulation. We show that sample size and minor allele frequency are the major determinants of the prevalence of perfect LD between unlinked loci but that demographic factors, such as deviations from random mating, can produce significant effects as well. Finally, we quantify this phenomenon in three model organisms and find thousands of pairs of moderate-frequency (> 5%) genetically indistinguishable variants in relatively large datasets. These results clarify a previously underexplored population genetic phenomenon with important implications for association studies, and define conditions under which it is likely to manifest.
IMO-HIP 2015 Report: An Evolutionary Game Theory Approach to evolutionary-enlightened application of chemotherapy in bone metastatic prostate cancer
Authors: Warman Pranav , Araujo Arturo , Lynch Conor , Basanta David 
Published: October 2015

AbstractProstate cancer metastasis to the bone is predominantly lethal and results from the ability of successful metastatic prostate cancer cells to co-opt microenvironmental cells and processes involved in bone remodelling. Understanding how the interactions between tumour and stromal cells determine successful metastases and how metastatic tumours respond to treatment is an emergent process that is hard to asses biologically and thus can benefit from mathematical models. In this work we describe a mathematical model of bone remodelling and the establishment of a prostate cancer metastasis in the bone using evolutionary game theory. We have mathematically recapitulated the current paradigm of a vicious cycle driving the tumor growth and we have used this tool to investigate the key interactions between the tumour and the bone stroma. Crucially, the model sheds light on the role that the interactions of heterogeneous tumor cells with the bone microenvironment have in the treatment of cancer. Our results show that resistant populations naturally become dominant in the metastases under a number treatment schemes and that schedules designed by an evolutionary game theory approach could be used to better control the tumour and the associated bone growth than the current standard of care.
Frequency and complexity of de novo structural mutation in autism
Authors: Brandler William M , Antaki Danny , Gujral Madhusudan , Noor Amina , Rosanio Gabriel , Chapman Timothy R , Barrera Daniel J , Lin Guan Ning , Malhotra Dheeraj , Watts Amanda C , Wong Lawrence C , Estabillo Jasper A , Gadomski Therese E , Hong Oanh , Fuentes Fajardo Karin V , Bhandari Abhishek , Owen Renius , Baughn Michael , Yuan Jeffrey , Solomon Terry , Moyzis Alexandra G , Sanders Stephan J , Reiner Gail E , Vaux Keith K , Strom Charles M , Zhang Kang , Muotri Alysson R , Akshoomoff Natacha , Leal Suzanne M , Pierce Karen , Courchesne Eric , Iakoucheva Lilia M , Corsello Christina , Sebat Jonathan 
Published: October 2015

AbstractGenetic studies of Autism Spectrum Disorder (ASD) have established thatde novoduplications and deletions contribute to risk. However, ascertainment of structural variation (SV) has been restricted by the coarse resolution of current approaches. By applying a custom pipeline for SV discovery, genotyping andde novoassembly to genome sequencing of 235 subjects, 71 cases, 26 sibling controls and their parents, we present an atlas of 1.2 million SVs (5,213/genome), comprising 11 different classes. We demonstrate a high diversity ofde novomutations, a majority of which were undetectable by previous methods. In addition, we observe complex mutation clusters where combinations ofde novoSVs, nucleotide substitutions and indels occurred as a single event. We estimate a high rate of structural mutation in humans (20%). Genetic risk for ASD is attributable to an elevated frequency of gene-disruptingde novoSVs but not an elevated rate of genome rearrangement.
SimpleSBML: A Python package for creating and editing SBML models
Authors: Cannistra Caroline , Medley Kyle , Sauro Herbert M. 
Published: October 2015

AbstractSummaryIn this technical report we describe a simple extension to python-libSBML that allows users of Python to more easily construct SBML based models. The most commonly used package for constructing SBML models in Python is python-libSBML based on the C/C++ library libSBML. python-libSBML supports a comprehensive set of model types, but is difficult for new users to learn and requires long scripts to create even the simplest models. We present SimpleSBML, a package that allows users to add species, parameters, reactions, events, and rules to a libSBML model with only one command for each. Models can be exported to SBML format, and SBML files can be imported and converted to SimpleSBML commands that creates each element in a new model. This allows users to create new models and edit existing models for use with other software.Accessibility and ImplementationSimpleSBML is publicly available and licensed under the liberal Apache 2.0 open source license. It supports SBML levels 2 and 3. Its only dependency is libSBML. It is supported on Windows and Mac OS X. All code has been deposited at the GitHub sitehttps://github.com/sys-bio/simplesbmlContactcarolc24@u.washington.eduorhsauro@u.washington.edu
Analysis of protein-coding genetic variation in 60,706 humans
Authors:   Exome Aggregation Consortium, Lek Monkol , Karczewski Konrad J , Minikel Eric V , Samocha Kaitlin E , Banks Eric , Fennell Timothy , O’Donnell-Luria Anne H , Ware James S , Hill Andrew J , Cummings Beryl B , Tukiainen Taru , Birnbaum Daniel P , Kosmicki Jack A , Duncan Laramie E , Estrada Karol , Zhao Fengmei , Zou James , Pierce-Hoffman Emma , Berghout Joanne , Cooper David N , Deflaux Nicole , DePristo Mark , Do Ron , Flannick Jason , Fromer Menachem , Gauthier Laura , Goldstein Jackie , Gupta Namrata , Howrigan Daniel , Kiezun Adam , Kurki Mitja I , Moonshine Ami Levy , Natarajan Pradeep , Orozco Lorena , Peloso Gina M , Poplin Ryan , Rivas Manuel A , Ruano-Rubio Valentin , Rose Samuel A , Ruderfer Douglas M , Shakir Khalid , Stenson Peter D , Stevens Christine , Thomas Brett P , Tiao Grace , Tusie-Luna Maria T , Weisburd Ben , Won Hong-Hee , Yu Dongmei , Altshuler David M , Ardissino Diego , Boehnke Michael , Danesh John , Donnelly Stacey , Elosua Roberto , Florez Jose C , Gabriel Stacey B , Getz Gad , Glatt Stephen J , Hultman Christina M , Kathiresan Sekar , Laakso Markku , McCarroll Steven , McCarthy Mark I , McGovern Dermot , McPherson Ruth , Neale Benjamin M , Palotie Aarno , Purcell Shaun M , Saleheen Danish , Scharf Jeremiah M , Sklar Pamela , Sullivan Patrick F , Tuomilehto Jaakko , Tsuang Ming T , Watkins Hugh C , Wilson James G , Daly Mark J , MacArthur Daniel G 
Published: October 2015

SummaryLarge-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. Here we describe the aggregation and analysis of high-quality exome (protein-coding region) sequence data for 60,706 individuals of diverse ethnicities generated as part of the Exome Aggregation Consortium (ExAC). The resulting catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence for the presence of widespread mutational recurrence. We show that this catalogue can be used to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; we identify 3,230 genes with near-complete depletion of truncating variants, 72% of which have no currently established human disease phenotype. Finally, we demonstrate that these data can be used for the efficient filtering of candidate disease-causing variants, and for the discovery of human “knockout” variants in protein-coding genes.
DBSIM: A Platform of Simulation Resources for Genetic Epidemiology Studies
Authors: Yao Po-Ju , Chung Ren-Hua 
Published: October 2015

AbstractComputer simulations are routinely conducted to evaluate new statistical methods, to compare the properties among different methods, and to mimic the real data in genetic epidemiology studies. Conducting simulation studies can become a complicated task as several challenges can occur, such as the selection of an appropriate simulation tool and the specification of parameters in the simulation model. Although abundant simulated data have been generated for human genetic research, currently there is no public database designed specifically as a repository for these simulated data. With the lack of such database, for similar studies, similar simulations may have been repeated, which resulted in redundant works. We created an online platform, DBSIM, for simulation data sharing and discussion of simulation techniques for human genetic studies. DBSIM has a database containing simulation scripts, simulated data, and documentations from published manuscripts, as well as a discussion forum, which provides a platform for discussion of the simulated data and exchanging simulation ideas. DBSIM will be useful in three aspects. Moreover, summary statistics such as the simulation tools that are most commonly used and datasets that are most frequently downloaded are provided. The statistics will be very informative for researchers to choose an appropriate simulation tool or select a common dataset for method comparisons. DBSIM can be accessed athttp://dbsim.nhri.org.tw.
The Genetic cost of Neanderthal introgression
Authors: Harris Kelley , Nielsen Rasmus 
Published: October 2015

AbstractApproximately 2-4% of genetic material in human populations outside Africa is derived from Neanderthals who interbred with anatomically modern humans. Recent studies have shown that this Neanderthal DNA is depleted around functional genomic regions; this has been suggested to be a consequence of harmful epistatic interactions between human and Neanderthal alleles. However, using published estimates of Neanderthal inbreeding and the distribution of mutational fitness effects, we infer that Neanderthals had at least 40% lower fitness than humans on average; this increased load predicts the reduction in Neanderthal introgression around genes without the need to invoke epistasis. We also predict a residual Neanderthal mutational load in non-Africans, leading to a fitness reduction of at least 0.5%. This effect of Neanderthal admixture has been left out of previous debate on mutation load differences between Africans and non-Africans. We also show that if many deleterious mutations are recessive, the Neanderthal admixture fraction could increase over time due to the protective effect of Neanderthal haplotypes against deleterious alleles that arose recently in the human population. This might partially explain why so many organisms retain gene flow from other species and appear to derive adaptive benefits from introgression.
Post‐Democracy, Press, Politics and Power
Authors: Fenton Natalie 
Published: October 2015

AbstractTransnational media corporations now wield enormous power and influence. Never has this been displayed so starkly and so shockingly as in the revelations that emerged during the Leveson Inquiry into the culture and ethics of the press in the UK. This paper considers the implications of the relationship between media elites and political elites for democratic culture and media reform. The paper argues that the culture of press–politician mutual interest in which media executives and party leaders collude will continue as long as the solutions proffered focus on the ethical constraints of professional journalists rather than wider structural issues relating to plurality of ownership and control and funding of news in the public interest.
Is Liberal Democracy Sliding into ‘Democratic Despotism’?
Authors: Pabst Adrian 
Published: October 2015

AbstractPost‐democracy and cognate concepts suggest that the postwar period of democratisation has given way to a concentration of power in the hands of small groups that are unrepresentative and unaccountable, as exemplified by the rise of multinational corporations and their influence on democratic politics. This article goes further to argue that this does not fully capture the triple threat facing liberal democracy: first, the rise of a new oligarchy that strengthens executive power at the expense of parliament and people; second, the resurgence of populism and demagogy linked to a backlash against technocratic rule and procedural politics; third, the emergence of anarchy associated with the atomisation of society and a weakening of social ties and civic bonds. In consequence, liberal democracy risks sliding into a form of ‘democratic despotism’ that maintains the illusion of free choice while instilling a sense of ‘voluntary servitude’ as conceptualised by Tocqueville.
Occupancy estimation for rare species using a spatially‐adaptive sampling design
Authors: Pacifici Krishna , Reich Brian J. , Dorazio Robert M. , Conroy Michael J. 
Published: October 2015

Summary

Spatially clustered populations create unique challenges for conservation monitoring programmes. Advances in methodology typically are focused on either the design or the modelling stage of the study but do not involve integration of both.

We integrate adaptive cluster sampling and spatial occupancy modelling by developing two models to handle the dependence induced by cluster sampling. We compare these models to scenarios using simple random sampling and traditional occupancy models via simulation and data collected on a rare plant species, Tamarix ramosissima, found in China.

Our simulations show a marked improvement in confidence interval coverage for the new models combined with cluster sampling compared to simple random sampling and traditional occupancy models, with greatest improvement in the presence of low detection probability and spatial correlation in occupancy.

Accounting for the design using the simple cluster random‐effects model reduces bias considerably, and full spatial modelling reduces bias further, especially for large n when the spatial covariance parameters can be estimated reliably. Both new models build on the strength of occupancy modelling and adaptive sampling and perform at least as well, and often better, than occupancy modelling alone.

We believe our approach is unique and potentially useful for a variety of studies directed at patchily distributed, clustered or rare species exhibiting spatial variation.
Peer‐led interventions to prevent tobacco, alcohol and/or drug use among young people aged 11–21 years: a systematic review and meta‐analysis
Authors: MacArthur Georgie J. , Harrison Sean , Caldwell Deborah M. , Hickman Matthew , Campbell Rona 
Published: October 2015

AbstractBackground and AimsPeer‐led interventions may offer a beneficial approach in preventing substance use, but their impact has not yet been quantified. We conducted a systematic review to investigate and quantify the effect of peer‐led interventions that sought to prevent tobacco, alcohol and/or drug use among young people aged 11–21 years.MethodsMedline, EMBASE, PsycINFO, CINAHL, ERIC and the Cochrane Library were searched from inception to July 2015 without language restriction. We included randomized controlled trials only. Screening and data extraction were conducted in duplicate and data from eligible studies were pooled in a random effects meta‐analysis.ResultsWe identified 17 eligible studies, approximately half of which were school‐based studies targeting tobacco use among adolescents. Ten studies targeting tobacco use could be pooled, representing 13 706 young people in 220 schools. Meta‐analysis demonstrated that the odds of smoking were lower among those receiving the peer‐led intervention compared with control [odds ratio (OR) = 0.78, 95% confidence interval (CI) = 0.62–0.99, P = 0.040]. There was evidence of heterogeneity (I2 = 41%, χ2 15.17, P = 0.086). Pooling of six studies representing 1699 individuals in 66 schools demonstrated that peer‐led interventions were also associated with benefit in relation to alcohol use (OR = 0.80, 95% CI = 0.65–0.99, P = 0.036), while three studies (n = 976 students in 38 schools) suggested an association with lower odds of cannabis use (OR = 0.70, 0.50–0.97, P = 0.034). No studies were found that targeted other illicit drug use.ConclusionsPeer interventions may be effective in preventing tobacco, alcohol and possibly cannabis use among adolescents, although the evidence base is limited overall, and is characterized mainly by small studies of low quality.
Transplacental Transfer of Interleukin‐1 Receptor Agonist and Antagonist Following Maternal Immune Activation
Authors: Girard Sylvie , Sebire Guillaume 
Published: October 2015

ProblemPrenatal exposure to inflammation increases the incidence of neonatal brain injury. This raise the question whether maternally produced cytokines, especially interleukin (IL)‐1 elevated in pathological pregnancies and known to alter fetal development, can cross the placental barrier and affect the fetus directly.Method of studyWe addressed if IL‐1 agonist/antagonist could cross the placenta.ResultsRadiolabelled‐IL‐1 injected maternally reached the fetus in minimal amount. 3% of the amount detected within the placenta was transferred into the fetal liver and less than 1% recovered in the fetal brain 30 min after the injection Importantly, transfer of IL‐1 was not affected by maternal exposure to LPS. Maternal administration of IL‐1 receptor antagonist also reached the fetus in low concentration.ConclusionsThis suggests that minimal amount of maternally produced IL‐1 family members cross the placental barrier. Their negative effects are likely indirect, through their deleterious placental actions.
Suboptimal bonding impairs hormonal, epigenetic and neuronal development in preterm infants, but these impairments can be reversed
Authors: Kommers D , Oei G , Chen W , Feijs L , Bambang Oetomo S 
Published: October 2015

AbstractThis review aimed to raise awareness of the consequences of suboptimal bonding caused by prematurity. In addition to hypoxia–ischaemia, infection and malnutrition, suboptimal bonding is one of the many unnatural stimuli that preterm infants are exposed to, compromising their physiological development. However, the physiological consequences of suboptimal bonding are less frequently addressed in the literature than those of other threatening unnatural stimuli.ConclusionThis review found that suboptimal bonding significantly impaired hormonal, epigenetic and neuronal development, but these impairments could be reversed by bonding interventions. This suggests that neonatal intensive care units should focus more on interventions that optimise bonding.
Prediction of human fetal pharmacokinetics using ex vivo human placenta perfusion studies and physiologically based models
Authors: De Sousa Mendes Maïlys , Hirt Deborah , Vinot Cécile , Valade Elodie , Lui Gabrielle , Pressiat Claire , Bouazza Naïm , Foissac Frantz , Blanche Stephane , Lê Minh Patrick , Peytavin Gilles , Treluyer Jean‐Marc , Urien Saik , Benaboud Sihem 
Published: October 2015

AIMSPregnant women can be exposed to numerous drugs during the gestational period. For obvious ethical reasons, in vivo studies of fetal exposure to drugs are limited. Information about the transplacental transfer of drugs prior to their administration to pregnant women would be highly useful. In the present study, a novel approach was developed quantitatively predict or to predict the fetal exposure to drugs administered to the mother quantitatively.MethodsTransplacental parameters estimated from ex vivo human placenta perfusion experiments were implemented in pregnancy–physiologically based pharmacokinetic (p‐PBPK) models in order to predict fetal PK. Thereafter, fetal PK profiles for two antiretroviral drugs, tenofovir (TFV) and emtricitabine (FTC) were simulated. These predictions were then compared to observed cord blood concentrations, to validate these models.ResultsParameters obtained from the ex vivo experiments enabled a good prediction of observed cord blood concentrations without additional a scaling factor. Moreover, a sensitivity analysis showed that fetal predictions were sensitive to changes in transplacental parameters values obtained ex vivo.ConclusionThe integration of ex vivo human placental perfusion parameters in a p‐PBPK model should be a promising new approach for predicting human fetal exposure to xenobiotics.