bluuebunny/crossref_metadata_2025_split huggingface dataset:
Haplotype sharing provides insights into fine-scale population history and disease in Finland
Authors: Martin Alicia R. , Karczewski Konrad J. , Kerminen Sini , Kurki Mitja , Sarin Antti-Pekka , Artomov Mykyta , Eriksson Johan G. , Esko Tõnu , Genovese Giulio , Havulinna Aki S. , Kaprio Jaakko , Konradi Alexandra , Korányi László , Kostareva Anna , Männikkö Minna , Metspalu Andres , Perola Markus , Prasad Rashmi B. , Raitakari Olli , Rotar Oxana , Salomaa Veikko , Groop Leif , Palotie Aarno , Neale Benjamin M. , Ripatti Samuli , Pirinen Matti , Daly Mark J. 
Published: October 2017

AbstractFinland provides unique opportunities to investigate population and medical genomics because of its adoption of unified national electronic health records, detailed historical and birth records, and serial population bottlenecks. We assemble a comprehensive view of recent population history (≤100 generations), the timespan during which most rare disease-causing alleles arose, by comparing pairwise haplotype sharing from 43,254 Finns to geographically and linguistically adjacent countries with different population histories, including 16,060 Swedes, Estonians, Russians, and Hungarians. We find much more extensive sharing in Finns, with at least one ≥ 5 cM tract on average between pairs of unrelated individuals. By coupling haplotype sharing with fine-scale birth records from over 25,000 individuals, we find that while haplotype sharing broadly decays with geographical distance, there are pockets of excess haplotype sharing; individuals from northeast Finland share several-fold more of their genome in identity-by-descent (IBD) segments than individuals from southwest regions containing the major cities of Helsinki and Turku. We estimate recent effective population size changes over time across regions of Finland and find significant differences between the Early and Late Settlement Regions as expected; however, our results indicate more continuous gene flow than previously indicated as Finns migrated towards the northernmost Lapland region. Lastly, we show that haplotype sharing is locally enriched among pairs of individuals sharing rare alleles by an order of magnitude, especially among pairs sharing rare disease causing variants. Our work provides a general framework for using haplotype sharing to reconstruct an integrative view of recent population history and gain insight into the evolutionary origins of rare variants contributing to disease.
A Deep Recurrent Neural Network Discovers Complex Biological Rules to Decipher RNA Protein-Coding Potential
Authors: Hill Steven T. , Kuintzle Rachael , Teegarden Amy , Merrill Erich , Danaee Padideh , Hendrix David A. 
Published: October 2017

AbstractThe current deluge of newly identified RNA transcripts presents a singular opportunity for improved assessment of coding potential, a cornerstone of genome annotation, and for machine-driven discovery of biological knowledge. While traditional, feature-based methods for RNA classification are limited by current scientific knowledge, deep learning methods can independently discover complex biological rules in the datade novo. We trained a gated recurrent neural network (RNN) on human messenger RNA (mRNA) and long noncoding RNA (lncRNA) sequences. Our model, mRNA RNN (mRNN), surpasses state-of-the-art methods at predicting protein-coding potential. To understand what mRNN learned, we probed the network and uncovered several context-sensitive codons highly predictive of coding potential. Our results suggest that gated RNNs can learn complex and long-range patterns in full-length human transcripts, making them ideal for performing a wide range of difficult classification tasks and, most importantly, for harvesting new biological insights from the rising flood of sequencing data.
An interventional Soylent diet increases theBacteroidetestoFirmicutesratio in human gut microbiome communities: a randomized controlled trial
Authors: Hsu Ryan H. , McCormick Dylan M. , Seitz Mitchell J. , Lui Lauren M. , Rishi Harneet S. , Arkin Adam P. 
Published: October 2017

AbstractOur knowledge of the relationship between the gut microbiome and health has rapidly expanded in recent years. Diet has been shown to have causative effects on microbiome composition, which can have subsequent implications on health. Soylent 2.0 is a liquid meal replacement drink that satisfies nearly 20% of all recommended daily intakes per serving. This study aims to characterize the changes in gut microbiota composition resulting from a short-term Soylent diet. Fourteen participants were separated into two groups: 5 in the regular diet group and 9 in the Soylent diet group. The regular diet group maintained a diet closely resembling self-reported regular diets. The Soylent diet group underwent three dietary phases: A) a regular diet for 2 days, B) a Soylent-only diet (five servings of Soylent daily and water as needed) for 4 days, and C) a regular diet for 4 days. Daily logs self-reporting diet, Bristol stool ratings, and any abdominal discomfort were electronically submitted. Eight fecal samples per participant were collected using fecal sampling kits, which were subsequently sent to uBiome, Inc. for sample processing and V4 16S rDNA sequencing. Reads were clustered into operational taxonomic units (OTUs) and taxonomically identified against the GreenGenes 16S database. We find that an individual’s alpha-diversity is not significantly altered during a Soylent-only diet. In addition, principal coordinate analysis using the unweighted UniFrac distance metric shows samples cluster strongly by individual and not by dietary phase. Among Soylent dieters, we find a significant increase in the ratio ofBacteroidetestoFirmicutesabundance, which is associated with several positive health outcomes, including reduced risks of obesity and intestinal inflammation.
Contrasting maternal and paternal genetic variation of hunter-gatherer groups in Thailand
Authors: Kutanan Wibhu , Kampuansai Jatupol , Changmai Piya , Flegontov Pavel , Schröeder Roland , Macholdt Enrico , Hüebner Alexander , Kangwanpong Daoroong , Stoneking Mark 
Published: October 2017

ABSTRACTThe Maniq and Mlabri are the only recorded nomadic hunter-gatherer groups in Thailand. Here, we sequenced complete mitochondrial (mt) DNA genomes and ~2.364 Mbp of non- recombining Y chromosome (NRY) to learn more about the origins of these two enigmatic populations. Both groups exhibited low genetic diversity compared to other Thai populations, and contrasting patterns of mtDNA and NRY diversity: there was greater mtDNA diversity in the Maniq than in the Mlabri, while the converse was true for the NRY. We found basal uniparental lineages in the Maniq, namely mtDNA haplogroups M21a, R21 and M17a, and NRY haplogroup K. Overall, the Maniq are genetically similar to other negrito groups in Southeast Asia. By contrast, the Mlabri haplogroups (B5a1b1 for mtDNA and O1b1a1a1b and O1b1a1a1b1a1 for the NRY) are common lineages in Southeast Asian non-negrito groups, and overall the Mlabri are genetically similar to their linguistic relatives (Htin and Khmu) and other groups from northeastern Thailand. In agreement with previous studies of the Mlabri, our results indicate that the Malbri do not directly descend from the indigenous negritos. Instead, they likely have a recent origin (within the past 1,000 years) by an extreme founder event (involving just one maternal and two paternal lineages) from an agricultural group, most likely the Htin or a closely- related group.
Combining serological and contact data to derive target immunity levels for achieving and maintaining measles elimination
Authors: Funk Sebastian , Knapp Jennifer K. , Lebo Emmaculate , Reef Susan E. , Dabbagh Alya J. , Kretsinger Katrina , Jit Mark , Edmunds W. John , Strebel Peter M. 
Published: October 2017

AbstractBackgroundVaccination has reduced the global incidence of measles to the lowest rates in history. However, local interruption of measles virus transmission requires sustained high levels of population immunity that can be challenging to achieve and maintain. The herd immunity threshold for measles is typically stipulated at 90–95%. This figure does not easily translate into age-specific immunity levels required to interrupt transmission. Previous estimates of such levels were based on speculative contact patterns based on historical data from high-income countries. The aim of this study was to determine age-specific immunity levels that would ensure elimination of measles when taking into account empirically observed contact patterns.MethodsWe combined estimated immunity levels from serological data in 17 countries with studies of age-specific mixing patterns to derive contact-adjusted immunity levels. We then compared these to case data from the 10 years following the seroprevalence studies to establish a contact-adjusted immunity threshold for elimination. We lastly combined a range of hypothetical immunity profiles with contact data from a wide range of socioeconomic and demographic settings to determine whether they would be sufficient for elimination.ResultsWe found that contact-adjusted immunity levels were able to predict whether countries would experience outbreaks in the decade following the serological studies in about 70% of countries. The corresponding threshold level of contact-adjusted immunity was found to be 93%, corresponding to an average basic reproduction number of approximately 14. Testing different scenarios of immunity with this threshold level using contact studies from around the world, we found that 95% immunity would have to be achieved by the age of five and maintained across older age groups to guarantee elimination. This reflects a greater level of immunity required in 5–9 year olds than established previously.ConclusionsThe immunity levels we found necessary for measles elimination are higher than previous guidance. The importance of achieving high immunity levels in 5–9 year olds presents both a challenge and an opportunity. While such high levels can be difficult to achieve, school entry provides an opportunity to ensure sufficient vaccination coverage. Combined with observations of contact patterns, further national and sub-national serological studies could serve to highlight key gaps in immunity that need to be filled in order to achieve national and regional measles elimination.
Identification of genetic factors controlling domestication-related traits in cowpea (Vigna unguiculataL. Walp)
Authors: Lo Sassoum , Muñoz-Amatriaín María , Boukar Ousmane , Herniter Ira , Cisse Ndiaga , Guo Yi-Ning , Roberts Philip A. , Xu Shizhong , Fatokun Christian , Close Timothy J. 
Published: October 2017

AbstractCowpea (Vigna unguiculataL. Walp) is a warm-season legume with a genetically diverse gene-pool composed of wild and cultivated forms. Cowpea domestication involved considerable phenotypic changes from the wild progenitor, including reduction of pod shattering, increased organ size, and changes in flowering time. Little is known about the genetic basis underlying these changes. In this study, 215 recombinant inbred lines derived from a cross between a cultivated and a wild cowpea accession were used to evaluate nine domestication-related traits (pod shattering, peduncle length, flower color, flowering time, 100-seed weight, pod length, leaf length, leaf width and seed number per pod). A high-density genetic map containing 17,739 single nucleotide polymorphisms was constructed and used to identify 16 quantitative trait loci (QTL) for these nine domestication-related traits. Candidate genes underlying each of those 16 QTL were identified. Four regions with clusters of QTL were identified, including one on chromosome 8 related to increased organ size. This study provides new knowledge of the genomic regions controlling domestication-related traits in cowpea as well as candidate genes underlying those QTL. This information can help to exploit wild relatives in cowpea breeding programs.Key messageThis study identified regions of the cowpea genome that played an important role in cowpea domestication, including a hotspot region for increased organ size
Modularity of genes involved in local adaptation to climate despite physical linkage
Authors: Lotterhos Katie E. , Yeaman Sam , Degner Jon , Aitken Sally , Hodgins Kathryn A. 
Published: October 2017

AbstractThis preprint has been reviewed and recommended by Peer Community In Evolutionary Biology (https://doi.org/10.24072/pci.evolbiol.100050)BackgroundLinkage among genes experiencing different selection pressures can make natural selection less efficient. Theory predicts that when local adaptation is driven by complex and non-covarying stresses, increased linkage is favoured for alleles with similar pleiotropic effects, with increased recombination favoured among alleles with contrasting pleiotropic effects. Here, we introduce a framework to test these predictions with a co-association network analysis, which clusters loci based on differing associations. We use this framework to study the genetic architecture of local adaptation to climate in lodgepole pine (Pinus contorta), based on associations with environments.ResultsWe identified many clusters of candidate genes and SNPs associated with distinct environments (aspects of aridity, freezing, etc.), and discovered low recombination rates among some candidate genes in different clusters. Only a few genes contained SNPs with effects on more than one distinct aspect of climate. There was limited correspondence between co-association networks and gene regulatory networks. We further showed how associations with environmental principal components can lead to misinterpretation. Finally, simulations illustrated both benefits and caveats of co-association networks.ConclusionsOur results supported the prediction that different selection pressures favored the evolution of distinct groups of genes, each associating with a different aspect of climate. But our results went against the prediction that loci experiencing different sources of selection would have high recombination among them. These results give new insight into evolutionary debates about the extent of modularity, pleiotropy, and linkage in the evolution of genetic architectures.
Shared High Value Research Resources: The CamCAN Human Lifespan Neuroimaging Dataset Processed on the Open Science Grid
Authors: Krieger Don , Shepard Paul , Zusman Ben , Jana Anirban , Okonkwo David 
Published: October 2017

AbstractThe CamCAN Lifespan Neuroimaging Dataset [1,2], Cambridge (UK) Centre for Ageing and Neuroscience, was acquired and processed beginning in December, 2016. The referee consensus solver deployed to the Open Science Grid [3,4] was used for this task. The dataset includes demographic and screening measures, a high-resolution MRI scan of the brain, and whole-head magnetoencephalographic (MEG) recordings during eyes closed rest (560 sec), a simple task (540 sec), and passive listening/viewing (140 sec). The data were collected from 619 neurologically normal individuals, ages 18-87. The processed results from the resting recordings are completed and available for download at http://stash.osgconnect.net/+krieger/. These constitute ≈1.7 TBytes of data including the location within the brain (1 mm resolution), time stamp (1 msec resolution), and 80 msec time course for each of 3.7 billion validated neuroelectric events, i.e. mean 6.1 million events for each of the 619 participants.The referee consensus solver provides high yield (mean 11,000 neuroelectric currents/sec; standard deviation (sd): 3500/sec) high confidence (p < 10−12 for each identified current) measures of the neuroelectric currents whose magnetic fields are detected in the MEG recordings. We describe the solver, the implementation of the solver deployed on the Open Science Grid, the workflow management system, the opportunistic use of high performance computing (HPC) resources to add computing capacity to the Open Science Grid reserved for this project, and our initial findings from the recently completed processing of the resting recordings. This required ≈14 million core hours, i.e. ≈40 core hours per second of data.
Passenger mutations can accelerate tumor suppressor gene inactivation in cancer evolution
Authors: Wodarz Dominik , Newell Alan C. , Komarova Natalia L. 
Published: October 2017

AbstractCarcinogenesis is an evolutionary process whereby cells accumulate multiple mutations. Besides the “driver mutations” that cause the disease, cells also accumulate a number of other mutations with seemingly no direct role in this evolutionary process. They are called passenger mutations. While it has been argued that passenger mutations render tumors more fragile due to reduced fitness, the role of passenger mutations remains understudied. Using evolutionary computational models, we demonstrate that in the context of tumor suppressor gene inactivation (and hence fitness valley crossing), the presence of passenger mutations can accelerate the rate of evolution by reducing overall population fitness and increasing the relative fitness of intermediate mutants in the fitness valley crossing pathway. Hence, the baseline rate of tumor suppressor gene inactivation might be faster than previously thought. Conceptually, parallels are found in the field of turbulence and pattern formation, where instabilities can be driven by perturbations that are damped (disadvantageous), but provide a richer set of pathways such that a system can achieve some desired goal more readily. This highlights, through a number of novel parallels, the relevance of physical sciences in oncology.
Simulating human sleep spindle MEG and EEG from ion channel and circuit level dynamics
Authors: Rosen B.Q. , Krishnan G.P. , Sanda P. , Komarov M. , Sejnowski T. , Rulkov N. , Ulbert I. , Eross L. , Madsen J. , Devinsky O. , Doyle W. , Fabo D. , Cash S. , Bazhenov M. , Halgren E. 
Published: October 2017

AbstractBackgroundAlthough they form a unitary phenomenon, the relationship between extracranial M/EEG and transmembrane ion flows is understood only as a general principle rather than as a well-articulated and quantified causal chain.MethodWe present an integrated multiscale model, consisting of a neural simulation of thalamus and cortex during stage N2 sleep and a biophysical model projecting cortical current densities to M/EEG fields. Sleep spindles were generated through the interactions of local and distant network connections and intrinsic currents within thalamocortical circuits. 32,652 cortical neurons were mapped onto the cortical surface reconstructed from subjects’ MRI, interconnected based on geodesic distances, and scaled-up to current dipole densities based on laminar recordings in humans. MRIs were used to generate a quasi-static electromagnetic model enabling simulated cortical activity to be projected to the M/EEG sensors.ResultsThe simulated M/EEG spindles were similar in amplitude and topography to empirical examples in the same subjects. Simulated spindles with more core-dominant activity were more MEG weighted.Comparison with Existing MethodsPrevious models lacked either spindle-generating thalamic neural dynamics or whole head biophysical modeling; the framework presented here is the first to simultaneously capture these disparate scales simultaneously.ConclusionsThis multiscale model provides a platform for the principled quantitative integration of existing information relevant to the generation of sleep spindles, and allows the implications of future findings to be explored. It provides a proof of principle for a methodological framework allowing large-scale integrative brain oscillations to be understood in terms of their underlying channels and synapses.
A novel core promoter element induces bidirectional transcription in CpG island
Authors: Mahpour Amin , Smiraglia Dominic , Scruggs Benjamin S. , Gelman Irwin H. , Ouchi Toru 
Published: October 2017

AbstractHow TATA-less promoters such as those within CpG islands (CGI) control gene expression is still a subject of active research. Here, we have identified the “CGCG element”, a ten-base pair motif with a consensus sequence of TCTCGCGAGA present in a group of promoter-associated CGIs of ribosomal protein and housekeeping genes. This element is evolutionarily conserved in vertebrates, found in DNase-accessible regions and employs RNA polymerase 2 to activate gene expression. Through extensive analysis of several endogenous promoters, we demonstrate that this element activates bidirectional transcription through divergent start sites. Methylation of this element abrogates the associated promoter activity. When coincident with a TATA-box directional transcription remains CGCG-dependent. Because the CGCG element is sufficient to drive transcription, we propose that its unmethylated form functions as a core promoter of TATA-less CGI-associated promoters.
Unsupervised detection of cell-assembly sequences with edit similarity score
Authors: Watanabe Keita , Haga Tatsuya , Euston David R , Tatsuno Masami , Fukai Tomoki 
Published: October 2017

SUMMARYCell assembly is a hypothetical functional unit of information processing in the brain. While technologies for recording large-scale neural activity have been advanced, mathematical methods to analyze sequential activity patterns of cell-assembly are severely limited. Here, we propose a method to extract cell-assembly sequences repeated at multiple time scales and various precisions from irregular neural population activity. The key technology is to combine “edit similarity” in computer science with machine-learning clustering algorithms, where the former defines a “distance” between two strings as the minimal number of operations required to transform one string to the other. Our method requires no external references for pattern detection, and is tolerant of spike timing jitters and length irregularity in assembly sequences. These virtues enabled simultaneous automatic detections of hippocampal place-cell sequences during locomotion and their time-compressed replays during resting states. Furthermore, our method revealed previously undetected cell-assembly structure in the rat prefrontal cortex during goal-directed behavior. Thus, our method expands the horizon of cell-assembly analysis.
Induction of autophagy by trehalose limits opportunistic mycobacterial infections in HIV-infected macrophages
Authors: Sharma Vartika , Makhdoomi Muzamil , Kumar Purnima , Khan Nabab , Singh Sarman , Verma H N , Luthra Kalpana , Sarkar Sovan , Kumar Dhiraj 
Published: October 2017

AbstractOpportunistic bacterial infections amongst HIV-infected individuals pose serious health challenge. While immediate control of bacterial pathogens is typically attributed to innate defense mechanisms, whether HIV-mediated modulation of innate mechanisms like autophagy promote opportunistic infections, remains obscure. Using U1.1 and U937 macrophages, we show, HIV activation or infection inhibits autophagy and helps survival of pathogenicMycobacterium tuberculosisand non-pathogenic non-tuberculous mycobacterial strains (NTMs) likeMycobacterium aviumcomplex andMycobacterium fortuitum. HIV achieves this by blocking xenophagy flux, which could be reversed by the autophagy inducer trehalose that kills intracellularMtband NTMs. We found trehalose acts as a PI (3,5) P2agonist and activates TRPML1 to induce autophagy. Remarkably, trehalose treatment significantly reduced p24 levels in PBMCs infected with clinical HIV strains and in PBMCs derived from treatment-naive HIV patients. Taken together, our study highlights the immense potential of autophagy modulators in the therapeutic intervention of HIV and associated opportunistic infection.