bluuebunny/crossref_metadata_2025_split huggingface dataset:
Systematic Integration of Structural and Functional Data into Multi-Scale Models of Mouse Primary Visual Cortex
Authors: Billeh Yazan N. , Cai Binghuang , Gratiy Sergey L. , Dai Kael , Iyer Ramakrishnan , Gouwens Nathan W. , Abbasi-Asl Reza , Jia Xiaoxuan , Siegle Joshua H. , Olsen Shawn R. , Koch Christof , Mihalas Stefan , Arkhipov Anton 
Published: June 2019

AbstractStructural rules underlying functional properties of cortical circuits are poorly understood. To explore these rules systematically, we integrated information from extensive literature curation and large-scale experimental surveys into a data-driven, biologically realistic model of the mouse primary visual cortex. The model was constructed at two levels of granularity, using either biophysically-detailed or point-neurons, with identical network connectivity. Both variants were compared to each other and to experimental recordings of neural activity during presentation of visual stimuli to awake mice. While constructing and tuning these networks to recapitulate experimental data, we identified a set of rules governing cell-class specific connectivity and synaptic strengths. These structural constraints constitute hypotheses that can be tested experimentally. Despite their distinct single cell abstraction, spatially extended or point-models, both perform similarly at the level of firing rate distributions. All data and models are freely available as a resource for the community.
Comprehensive genomic analysis of dietary habits in UK Biobank identifies hundreds of genetic loci and establishes causal relationships between educational attainment and healthy eating
Authors: Cole Joanne B. , Florez Jose C. , Hirschhorn Joel N. 
Published: June 2019

AbstractUnhealthy dietary habits are leading risk factors for life-altering diseases and mortality. Large-scale biobanks now enable genetic analysis of traits with modest heritability, such as diet. We performed genomewide association on 85 single food intake and 85 principal component-derived dietary patterns from food frequency questionnaires in UK Biobank. We identified 814 associated loci, including olfactory receptor associations with fruit and tea intake; 136 associations were only identified using dietary patterns. Mendelian randomization suggests a Western vs. prudent dietary pattern is causally influenced by factors correlated with education but is not strongly causal for coronary artery disease or type 2 diabetes.
Widespread immunogenic poly-epitope frameshift mutations in microsatellite unstable tumors
Authors: Roudko Vladimir , Bozkus Cansu Cimen , Orfanelli Theofano , Blank Stephanie V. , Greenbaum Benjamin , Bhardwaj Nina 
Published: June 2019

AbstractMicrosatellite instability-high (MSI-H) tumors are an important model system for evaluating neoantigen-based immunotherapies given their high tumor mutation burden and response to checkpoint blockade. We identified tumor-specific, frameshift peptides, encoding multiple epitopes that originated from indel mutations shared among patients with MSI-H endometrial, colorectal and stomach cancers. Epitopes derived from these shared frameshifts have high population occurrence rates, wide presence in many tumor subclones and are predicted to bind to the most frequent HLA alleles in the TCGA MSI-H patient cohorts. Neoantigens arising from these mutations are more dissimilar to both self and viral antigens, indicating the creation of peptides, that, when translated, can present truly novel antigens to the immune system. Finally, we validated the immunogenicity of common frameshift peptides from MSI-H endometrial patients in an array of T cell stimulation experiments, using peripheral blood mononuclear cells isolated from healthy donors. Our study describes for the first time the widespread occurrence and strong immunogenicity of tumor-specific antigens, derived from shared frameshift mutations in MSI-H cancer and Lynch syndrome patients, suitable for the design of common preventive “off-the-shelf” cancer vaccines.
Intertwined signatures of desiccation and drought tolerance in grasses
Authors: Pardo Jeremy , Wai Ching Man , Chay Hannah , Madden Christine F. , Hilhorst Henk W.M. , Farrant Jill M. , VanBuren Robert 
Published: June 2019

AbstractGrasses are among the most resilient plants and some can survive prolonged desiccation in semi-arid regions with seasonal rainfall. This vegetative desiccation tolerance has arisen independently multiple times within the grass family, but the genetic elements that differentiate desiccation tolerant and sensitive grasses are largely unknown. Here we leveraged comparative genomic approaches with the resurrection grassEragrostis nindensisand the closely related desiccation sensitive cerealEragrostis tefto identify changes underlying desiccation tolerance. We extended the analyses to include the grasses maize, sorghum, rice, and the model desiccation tolerant grassOropetium thomaeumto identify broader evolutionary conservation and divergence. We identified changes in chromatin architecture and expression dynamics related to desiccation inE. nindensis. It was previously hypothesized that transcriptional re-wiring of seed desiccation pathways confers vegetative desiccation tolerance. We demonstrate that the majority of seed dehydration related genes show similar expression patterns in leaves of desiccation tolerant and sensitive species during dehydration. However, we discovered a small set of orthologs with expression specific to leaves of desiccation tolerant species, and seeds of sensitive species. This supports a nuanced role of seed-related genes where many overlap with typical drought responses but some crucial genes are desiccation specific in resurrection plants.
Beyond parallel evolution: when several species colonize the same environmental gradient
Authors: Le Moan Alan , Gaggiotti Oscar , Henriques Romina , Martinez Paulino , Bekkevold Dorte , Hemmer-Hansen Jakob 
Published: June 2019

AbstractGenomic signatures associated with population divergence, speciation and the evolutionary mechanisms responsible for these are key research topics in evolutionary biology. Evolutionary radiations and parallel evolution have offered opportunities to study the role of the environment by providing replicates of ecologically driven speciation. Here, we apply an extension of the parallel evolution framework to study replicates of ecological speciation where multiple species went through a process of population divergence during the colonization of a common environmental gradient. We used the conditions offered by the North Sea – Baltic Sea environmental transition zone and found clear evidence of population structure linked to the Baltic Sea salinity gradient in four flatfish species. We found highly heterogeneous signatures of population divergence within and between species, and no evidence of parallel genomic architecture across species associated with the divergence. Analyses of demographic history suggest that Baltic Sea lineages are older than the age of the Baltic Sea itself. In most cases, divergence appears to involve reticulated demography through secondary contact, and our analyses revealed that genomic patterns of divergence were likely the result of a combination of effects from past isolation and subsequent adaptation to a new environment. In one case, we identified two large structural variants associated with the environmental gradient, where populations were inferred to have diverged in the presence of gene flow. Our results highlight the heterogeneous genomic effects associated with complex interplays of evolutionary forces, and stress the importance of genomic background for studies of parallel evolution.
Transposons played a major role in the diversification between the closely related almond (Prunus dulcis) and peach (P. persica) genomes: Results from the almond genome sequence
Authors: Alioto Tyler , Alexiou Konstantinos , Bardil Amélie , Barteri Fabio , Castanera Raúl , Cruz Fernando , Dhingra Amit , Duval Henri , Fernández i Martí Ángel , Frias Leonor , Galán Beatriz , Garcia José L. , Howad Werner , Garrido Jèssica Gómez , Gut Marta , Julca Irene , Morata Jordi , Puigdomènech Pere , Ribeca Paolo , Rubio Cabetas María José , Vlasova Anna , Wirthensohn Michelle , Garcia-Mas Jordi , Gabaldón Toni , Casacuberta Josep M. , Arús Pere 
Published: June 2019

AbstractCombining both short and long-read sequencing, we have estimated the almondPrunus dulciscv. Texas genome size in 235 Mbp and assembled 227.6 Mb of its sequence. The highly heterozygous compact genome of Texas comprises eight chromosomes, to which we have anchored over 91% of the assembly. We annotated 27,042 protein-coding genes and 6,800 non-coding transcripts. High levels of genetic variability were characterized after resequencing a collection of ten almond accessions. Phylogenomic comparison with the genomes of 16 other close and distant species allowed estimating that almond and peach diverged around 5.88 Mya. Comparison between peach and almond genomes confirmed the high synteny between these close relatives, but also revealed high numbers of presence-absence variants, many attributable to the movement of transposable elements (TEs). The number and distribution of TEs between peach and almond was similar, but the history of TE movement was distinct, with peach having a larger proportion of recent transpositions and almond preserving a higher level of polymorphism in the older TEs. When focusing on specific genes involved in key characters such as the bitter vs. sweet kernel taste and the formation of a fleshy mesocarp, we found that for one gene associated with the biosynthesis of amygdalin that confers the bitter kernel taste, several TEs were inserted in its vicinity only in sweet almond cultivars but not in bitter cultivars andPrunusbitter kernel relatives, includingP. webbii,P. mume, and other species like peach and cherry. TE insertions likely to produce affects in the expression of six more genes involved in the formation of the fleshy mesocarp were also identified. Altogether, our results suggest a key role of TEs in the recent history and diversification of almond with respect to peach.
Efficient small-scale conjugation of DNA to primary antibodies for multiplexed cellular targeting
Authors: Cremers Glenn A.O. , Rosier Bas J.H.M. , Brillas Roger Riera , Albertazzi Lorenzo , de Greef Tom F.A. 
Published: June 2019

ABSTRACTThe combination of the specificity of antibodies and the programmability of DNA nanotechnology has provided the scientific community with a powerful tool to label and unambiguously distinguish a large number of subcellular targets using fluorescence-based read-out methods. While primary antibodies are commercially available for a large class of targets, a general stoichiometric site-specific DNA labeling strategy for this affinity reagent is lacking. Here, we present a universal, site-selective, conjugation method using a small photocrosslinkable protein G adaptor that allows labeling of antibodies of different host species with a controlled number of short oligonucleotides (ODNs). Importantly, we illustrate that this conjugation method can be directly performed on commercially-available primary antibodies, on a small scale and without cross-reactivity towards other proteins, such as bovine serum albumin. In addition, we present a general, benchtop-compatible strategy to purify DNA-labeled antibodies without loss of function. The application of protein G-ODN labeled primary antibodies is demonstrated by employing three well-known methods for detecting subcellular targets using fluorescent read-out, including flow cytometry, DNA-PAINT, and dSTORM. This work thus establishes a general and efficient platform for the synthesis of a library of unique ODN-antibody conjugates, facilitating the broader use of DNA-based programmable tags for multiplexed labeling to identify subcellular features with nanometer-precision, improving our understanding of cellular structure and function.
Coordination difficulties, IQ and psychopathology in children with high-risk Copy Number Variants
Authors: Cunningham Adam C , Hall Jeremy , Owen Michael J , van den Bree Marianne B M 
Published: June 2019

AbstractBackgroundThe prevalence and impact of motor coordination difficulties in children with Copy Number Variants that are associated with high risk of neurodevelopmental disorder (ND-CNVS) remain unknown. The present study aims to advance understanding of motor coordination difficulties in children with ND-CNVs and establish relationships with IQ and psychopathology.Methods169 children with a ND-CNV (67% male, median age 8.88 years, range 6.02-14.81) and 57 closest-in-age unaffected siblings (controls; 55% male, median age 10.41 years, SD=3.04, range 4.89-14.75) were assessed with the Developmental Coordination Disorder Questionnaire, alongside psychiatric interviews, and standardised assessments of IQ.Results91% of children with an ND-CNV screened positive for coordination problems, compared to 19% of unaffected sibling controls (OR=42.53, p<.001). There was no difference in coordination ability between ND-CNV genotypes (F=1.47, p=.184). Poorer motor coordination in the ND-CNV group was associated with greater numbers of ADHD (p=.021) and autism spectrum disorder trait (p<.001) symptoms, along with lower full-scale (p=.011), performance (p=.015), and verbal IQ (p=.036). Mediation analysis indicated that coordination ability was a full mediator of anxiety symptoms (69% mediated, p=.012), and a partial mediator of ADHD (51%, p=.001) and ASD trait symptoms (66%, p<.001) along with FSIQ (40%, p=.002) PIQ (40%, p=.005) and VIQ (38%, p=.006) scores.ConclusionsThe findings indicate that poor motor coordination is highly prevalent and closely linked to risk of mental health disorder and lower intellectual function. Future research should explore whether early interventions for poor coordination ability could ameliorate neurodevelopmental risk more generally.
Retroviral integration into nucleosomes through DNA looping and sliding along the histone octamer
Authors: Wilson Marcus D. , Renault Ludovic , Maskell Daniel P. , Ghoneim Mohamed , Pye Valerie E. , Nans Andrea , Rueda David S. , Cherepanov Peter , Costa Alessandro 
Published: June 2019

AbstractRetroviral integrase can efficiently utilise nucleosomes for insertion of the reverse-transcribed viral DNA. In face of the structural constraints imposed by the nucleosomal structure, integrase gains access to the scissile phosphodiester bonds by lifting DNA off the histone octamer at the site of integration. To clarify the mechanism of DNA looping by integrase, we determined a 3.9 Å resolution structure of the prototype foamy virus intasome engaged with a nucleosome core particle. The structural data along with complementary single-molecule Förster resonance energy transfer measurements reveal twisting and sliding of the nucleosomal DNA arm proximal to the integration site. Sliding the nucleosomal DNA by approximately two base pairs along the histone octamer accommodates the necessary DNA lifting from the histone H2A-H2B subunits to allow engagement with the intasome. Thus, retroviral integration into nucleosomes involves the looping-and-sliding mechanism for nucleosomal DNA repositioning, bearing unexpected similarities with chromatin remodelers.
RedMed: Extending drug lexicons for social media applications
Authors: Lavertu Adam , Altman Russ B 
Published: June 2019

AbstractSocial media has been identified as a promising potential source of information for pharmacovigilance. The adoption of social media data has been hindered by the massive and noisy nature of the data. Initial attempts to use social media data have relied on exact text matches to drugs of interest, and therefore suffer from the gap between formal drug lexicons and the informal nature of social media. The Reddit comment archive represents an ideal corpus for bridging this gap. We trained a word embedding model, RedMed, to facilitate the identification and retrieval of health entities from Reddit data. We compare the performance of our model trained on a consumer-generated corpus against publicly available models trained on expert-generated corpora. Our automated classification pipeline achieves an accuracy of 0.88 and a specificity of >0.9 across four different term classes. Of all drug mentions, an average of 79% (±0.5%) were exact matches to a generic or trademark drug name, 14% (±0.5%) were misspellings, 6.4% (±0.3%) were synonyms, and 0.13% (±0.05%) were pill marks. We find that our system captures an additional 20% of mentions; these would have been missed by approaches that rely solely on exact string matches. We provide a lexicon of misspellings and synonyms for 2,978 drugs and a word embedding model trained on a health-oriented subset of Reddit.
Kappa Opioid Receptor and Dynorphin Signaling in the Central Amygdala Regulates Alcohol Intake
Authors: Bloodgood Daniel W. , Pati Dipanwita , Pina Melanie M. , Neira Sofia , Hardaway J. Andrew , Desai Shivani , Boyt Kristen M. , Palmiter Richard D. , Kash Thomas L. 
Published: June 2019

AbstractExcessive alcohol drinking has been shown to modify brain circuitry to predispose individuals for future alcohol abuse. Previous studies have implicated the central nucleus of the amygdala (CeA) as an important site for mediating the somatic symptoms of withdrawal and for regulating alcohol intake. In addition, recent work has established a role for both the Kappa Opioid Receptor (KOR) and its endogenous ligand dynorphin in mediating these processes. However, it is unclear whether these effects are due to dynorphin or KOR arising from within the CeA itself or other input brain regions. To directly examine the role of preprodynorphin (PDYN) and KOR expression in CeA neurons, we performed region-specific conditional knockout of these genes and assessed the effects on the Drinking in the Dark (DID) and Intermittent Access (IA) paradigms. We then examined the effects of DID on PDYN and KOR modulation of CeA circuit physiology. Conditional gene knockout resulted in sex-specific responses wherein PDYN knockout decreased alcohol drinking in both male and female mice, whereas KOR knockout decreased drinking in males only. We also found that neither PDYN nor KOR knockout protected against anxiety caused by alcohol drinking. Lastly, a history of alcohol drinking did not alter synaptic transmission in PDYN neurons in the CeA of either sex, but excitability of PDYN neurons was increased in male mice only. Taken together, our findings indicate that PDYN and KOR signaling in the CeA plays an important role in regulating excessive alcohol consumption and highlight the need for future studies to examine how this is mediated through downstream effector regions.
Patterns of microbial colonization of human bone from surface-decomposed remains
Authors: Emmons Alexandra L. , Mundorff Amy Z. , Keenan Sarah W. , Davoren Jonathan , Andronowski Janna , Carter David O. , DeBruyn Jennifer M. 
Published: June 2019

AbstractMicrobial colonization of bone is an important mechanism of post-mortem skeletal degradation. However, the types and distributions of bone and tooth colonizing microbes are not well characterized. It is unknown if microbial communities vary in abundance or composition between bone element types, which could help explain patterns of human DNA preservation. The goals of the present study were to (1) identify the types of microbes capable of colonizing different human bone types and (2) relate microbial abundances, diversity, and community composition to bone type and human DNA preservation. DNA extracts from 165 bone and tooth samples from three skeletonized individuals were assessed for bacterial loading and microbial community composition and structure. Random forest models were applied to predict operational taxonomic units (OTUs) associated with human DNA concentration. Dominant bacterial bone colonizers were from the phyla Proteobacteria (36%), Actinobacteria (23%), Firmicutes (13%), Bacteroidetes (12%), and Planctomycetes (4.4%). Eukaryotic bone colonizers were from Ascomycota (40%), Apicomplexa (21%), Annelida (19%), Basidiomycota (17%), and Ciliophora (14%). Bacterial loading was not a significant predictor of human DNA concentration in two out of three individuals. Random forest models were minimally successful in identifying microbes related to patterns of DNA preservation, complicated by high variability in community structure between individuals and body regions. This work expands on our understanding of the types of microbes capable of colonizing human bone and contributing to human skeletal DNA degradation.
Development of a multi-locus typing scheme for anEnterobacteriaceaelinear plasmid that mediates inter-species transfer of flagella
Authors: Robertson James , Lin Janet , Wren-Hedegus Amie , Arya Gitanjali , Carrillo Catherine , Nash John H.E. 
Published: June 2019

AbstractDue to the public health importance of flagellar genes for typing, it is important to understand mechanisms that could alter their expression or presence. Phenotypic novelty in flagellar genes arise predominately through accumulation of mutations but horizontal transfer is known to occur. A linear plasmid termed pBSSB1 previously identified inSalmonellaTyphi, was found to encode a flagellar operon that can mediate phase variation, which results in the rare z66 flagella phenotype. The identification and tracking of homologs of pBSSB1 is limited because it falls outside the normal replicon typing schemes for plasmids. Here we report the generation of nine new pBSSB1-family sequences using Illumina and Nanopore sequence data. Homologs of pBSSB1 were identified in 154 genomes representing 25 distinct serotypes from 67,758Salmonellapublic genomes. Pangenome analysis of pBSSB1-family contigs was performed using Roary and we identified three core genes amenable to a minimal MLST scheme. Population structure analysis based on the newly developed MLST scheme identified three major lineages representing 35 sequence types, and the distribution of these sequence types was found to span multiple serovars across the globe. This MLST scheme has shown utility in tracking and subtyping pBSSB1-family plasmids and it has been incorporated into the plasmid MLST database under the name “pBSSB1-family”.
Satellite glial cells modulate cholinergic transmission between sympathetic neurons
Authors: Enes Joana , Sona Surbhi , Gerard Nega , Mitchell Alexander C. , Haburcak Marian , Birren Susan J. 
Published: June 2019

AbstractPostganglionic sympathetic neurons and satellite glial cells are the two major cell types of the peripheral sympathetic ganglia. Sympathetic neurons project to and provide neural control of peripheral organs and have been implicated in human disorders ranging from cardiovascular disease to peripheral neuropathies. Here we show that satellite glia regulate postnatal development and activity of sympathetic neurons, providing evidence for local ganglionic control of sympathetic drive. We show changes in the cellular architecture of the rat sympathetic ganglia during the postnatal period, with satellite glia enwrapping sympathetic neuronal somata during a period of neuronal hypertrophy. In culture, satellite glia contribute to neuronal survival, promote synapse formation and play a modulatory role in neuron-to-neuron cholinergic neurotransmission, consistent with the close contact seen within the ganglia. Cultured satellite glia make and release neurotrophins, which can partially rescue the neurons from nerve growth factor deprivation. Electrophysiological recordings and immunocytochemical analysis on cultured sympathetic neurons show that satellite glial cells influence synapse number and total neuronal activity with little effect on neuronal intrinsic excitability. Thus, satellite glia play an early and ongoing role within the postnatal sympathetic ganglia, expanding our understanding of the contributions of local and target-derived factors in the regulation of sympathetic neuron function.