bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic liability for internalizing versus externalizing behavior manifests in the developing and adult hippocampus: Insight from a meta-analysis of transcriptional profiling studies in a selectively-bred rat model
Authors: Birt Isabelle A. , Hagenauer Megan H. , Clinton Sarah M. , Aydin Cigdem , Blandino Peter , Stead John D. H. , Hilde Kathryn L. , Meng Fan , Thompson Robert C. , Khalil Huzefa , Stefanov Alex , Maras Pamela , Zhou Zhifeng , Hebda-Bauer Elaine K. , Goldman David , Watson Stanley J. , Akil Huda 
Published: September 2019

AbstractBackgroundFor over 16 years, we have selectively bred rats to show either high or low levels of exploratory activity within a novel environment. These “bred High Responder” (bHR) and “bred Low Responder” (bLR) rats serve as a model for temperamental extremes, exhibiting large differences in many internalizing and externalizing behaviors relevant to mood and substance abuse disorders.MethodsOur study elucidated persistent differences in gene expression related to bHR/bLR phenotype across development and adulthood in the hippocampus, a region critical for emotional regulation. We meta-analyzed eight transcriptional profiling datasets (microarray, RNA-Seq) spanning 43 generations of selective breeding (adult: n=46, P7: n=22, P14: n=49, P21: n=21; all male). We cross-referenced these results with exome sequencing performed on our colony to pinpoint candidates likely to mediate the effect of selective breeding on behavioral phenotype.ResultsGenetic and transcriptional profiling results converged to implicate two genes with previous associations with metabolism and mood: Thyrotropin releasing hormone receptor and Uncoupling protein 2. Our results also highlighted bHR/bLR functional differences in the hippocampus, including a network essential for neurodevelopmental programming, proliferation, and differentiation, containing hub genes Bone morphogenetic protein 4 and Marker of proliferation ki-67. Finally, we observed differential expression related to microglial activation, which is important for synaptic pruning, including two genes within implicated chromosomal regions: Complement C1q A chain and Milk fat globule-EGF factor 8.ConclusionThese candidate genes and functional pathways have the capability to direct bHR/bLR rats along divergent developmental trajectories and promote a widely different reactivity to the environment.
Struo: a pipeline for building custom databases for common metagenome profilers
Authors: de la Cuesta-Zuluaga Jacobo , Ley Ruth E. , Youngblut Nicholas D. 
Published: September 2019

AbstractSummaryTaxonomic and functional information from microbial communities can be efficiently obtained by metagenome profiling, which requires databases of genes and genomes to which sequence reads are mapped. However, the databases that accompany metagenome profilers are not updated at a pace that matches the increase in available microbial genomes. To address this, we developed Struo, a modular pipeline that automatizes the acquisition of genomes from public repositories and the construction of custom databases for multiple metagenome profilers. The use of custom databases that broadly represent the known microbial diversity by incorporating novel genomes results in a substantial increase in mappability of reads in synthetic and real metagenome datasets.Availability and implementationSource code available for download at https://github.com/leylabmpi/Struo. Custom GTDB databases available at http://ftp.tue.mpg.de/ebio/projects/struo/Contactnicholas.youngblut@tuebingen.mpg.de
Re-evaluation of a Tn5::gacAmutant ofPseudomonas syringaepv.tomatoDC3000 uncovers roles foruvrCandanmKin promoting virulence
Authors: O’Malley Megan R. , Weisberg Alexandra J. , Chang Jeff H. , Anderson Jeffrey C. 
Published: September 2019

ABSTRACTPseudomonas syringaeis a taxon of plant pathogenic bacteria that can colonize and proliferate within the interior space of leaf tissue. This process requiresP. syringaeto rapidly upregulate the production of virulence factors including a type III secretion system (T3SS) that suppress host defenses. GacS/A is a two-component system that regulates virulence of many plant and animal pathogenic bacteria includingP. syringae. We recently investigated the virulence defect of strain AC811, a Tn5::gacAmutant ofP. syringae pv.tomatoDC3000 that is less virulent on Arabidopsis. We discovered that decreased virulence of AC811 is not caused by loss of GacA function. Here, we report the molecular basis of the virulence defect of AC811. We show that AC811 possesses a nonsense mutation inanmK, a gene predicted to encode a 1,6-anhydromuramic acid kinase involved in cell wall recycling. Expression of a wild-type allele ofanmKpartially increased growth of AC811 in Arabidopsis leaves. In addition to the defectiveanmKallele, we also show that the Tn5insertion ingacAexerts a polar effect onuvrC, a downstream gene encoding a regulator of DNA damage repair. Expression of the wild-typeanmKallele together with increased expression ofuvrCfully restored the virulence of AC811 during infection of Arabidopsis. These results demonstrate that defects inanmKanduvrCare together sufficient to account for the decreased virulence of AC811, and suggest caution is warranted in assigning phenotypes to GacA function based on insertional mutagenesis of thegacA-uvrClocus.
Exploring the role of mass immunisation in influenza pandemic preparedness: a modelling study for the UK context
Authors: Grieco Luca , Panovska-Griffiths Jasmina , van Leeuwen Edwin , Grove Peter , Utley Martin 
Published: September 2019

AbstractExisting modelling work on preparedness to pandemic influenza has focused on evaluating specific countermeasures for pandemics with specific characteristics (typically based on historical instances). The aim of this study was to inform policy on preparedness planning for pandemic influenza based on the assessment of a wide range of scenarios and free from restrictive assumptions about timing and features of the next pandemic.We carried out epidemiological modelling and health economic analysis of an extensive set of scenarios, each comprising a combination of pandemic, vaccine and immunisation programme characteristics in presence or absence of access to effective antivirals. Preparedness policies that incorporate mass immunisation were evaluated on the basis of there being a given chance of a pandemic each year. To support understanding and exploration of model output, an interactive visualisation tool was devised and made available online.We evaluated over 29 million combinations of pandemic and policy characteristics. Preparedness plans incorporating mass immunisation show positive net present value for a wide range of pandemic scenarios, predominantly in the absence of effective antivirals. Plans based on the responsive purchase of vaccine have greater benefit than plans reliant on the purchase and maintenance of a stockpile if immunisation can start without extensive delays. This finding is not dependent on responsively purchased vaccine being more effective than stockpiled vaccine, but rather is driven by avoiding the costs of storing and replenishing a stockpile.While emerging technologies for rapid vaccine development and production increase the prospects for mass immunisation to be an effective countermeasure, policies based on the responsive purchase of vaccine not tailored to the pandemic should be explored. Focus is also required on the pandemic intelligence, decision, contractual and logistical processes on which timely commencement of immunisation in a pandemic is reliant.
An Inter-Species Translation Model Implicates Integrin Signaling in Infliximab-Resistant Colonic Crohn’s Disease
Authors: Brubaker Douglas. K. , Kumar Manu. P. , Vega Paige. N. , Southard-Smith Austin. N. , Simmons Alan. J. , Scoville Elizabeth. A. , Coburn Lori. A. , Wilson Keith. T. , Lau Ken. S. , Lauffenburger Douglas. A. 
Published: September 2019

AbstractAnti-TNF therapy resistance is a major clinical challenge in Crohn’s Disease (CD), partly due to insufficient understanding of disease-site, protein-level mechanisms of CD and anti-TNF treatment resistance. Although some proteomics data from CD mouse models exists, data type and phenotype discrepancies contribute to confounding attempts to translate between preclinical animal models of disease and human clinical cohorts. To meet this important challenge, we develop and demonstrate here an approach called Translatable Components Regression (TransComp-R) to overcome inter-species and trans-omic discrepancies between CD mouse models and human subjects. TransComp-R combines CD mouse model proteomic data with patient pre-treatment transcriptomic data to identify molecular features discernable in the mouse data predictive of patient response to anti-TNF therapy. Interrogating the TransComp-R models predominantly revealed upregulated integrin pathway signaling via collagen-binding integrin ITGA1 in anti-TNF resistant colonic CD (cCD) patients. Toward validation, we performed single-cell RNA sequencing on biopsies from a cCD patient and analyzed publicly available immune cell proteomics data to characterize the immune and intestinal cell types contributing to anti-TNF resistance. We found that ITGA1 is indeed expressed in colonic T-cell populations and that interactions between collagen-binding integrins on T-cells and colonic cell types expressing secreted collagens are associated with anti-TNF therapy resistance. Biologically, TransComp-R linked previously disparate observations about collagen and ITGA1 signaling to a potential therapeutic avenue for overcoming anti-TNF therapy resistance in cCD. Methodologically, TransComp-R provides a flexible, generalizable framework for addressing inter-species, inter-omic, and inter-phenotypic discrepancies between animal models and patients to deliver translationally relevant biological insights.One Sentence SummaryBrubaker et al. implicate dysregulated collagen-binding integrin signaling in resistance to anti-TNF therapy in Crohn’s Disease by developing a mouse-proteomic to human-transcriptomic translation model and confirm the associated inter-cellular signaling network using single-cell RNA sequencing.
Field application of the geometric framework reveals a multistep strategy of nutrient regulation in a leaf-miner
Authors: Body Mélanie J.A. , Behmer Spencer T. , Pelisson Pierre-François , Casas Jérôme , Giron David 
Published: September 2019

AbstractAnimals have evolved a vast array of behavioral and physiological strategies that allow them to achieve a nutritionally balanced diet. Plants as food for herbivores are often considered suboptimal, but phytophagous insects can employ pre- and post-ingestive mechanisms and/or symbiotic associations to help overcome food nutritional imbalances. This is particularly crucial for permanent multivoltine leaf-miner insects such as the caterpillarPhyllonorycter blancardellawhich completes development within a restricted area of a single leaf and use deciduous leaves to fuel growth and reproduction even under senescing autumnal conditions. Using the geometric framework for nutrition under natural field conditions, we show that this insect has multiple strategies to deal with inadequate food supply from the plant. First, larvae manipulate the protein-sugar content of both normal, photosynthetically active, and senescing, photosynthetically inactive, leaf tissues. Control of nutritional homeostasis of mined tissues is however higher for late instars, which differ from younger larval instars in their feeding mode (fluid-vs.tissue-feeder). Second, slight differences in the protein-sugar environment remain between mined tissues on green and yellow leaves despite this manipulation of the leaf physiology. This insect uses post-ingestive mechanisms to achieve similar body protein, sugar and lipid composition. This study demonstrates, for the first time under natural conditions, the ability of an insect herbivore to practice a combination of pre- and post-ingestive compensatory mechanisms to attain similar growth and metabolic outcomes in fundamentally different nutritional environments. Additionally, a comparison of larval nutritional requirements of 117 species from various insect groups further reinforces the hypothesis of a close association betweenP. blancardellaand endosymbiotic bacteria for nutritional purposes.
Environmentally sensitive hotspots in the methylome of the early human embryo
Authors: Silver Matt J. , Saffari Ayden , Kessler Noah J. , Chandak Giriraj R. , Fall Caroline H.D. , Issarapu Prachand , Dedaniya Akshay , Betts Modupeh , Moore Sophie E. , Routledge Michael N. , Herceg Zdenko , Cuenin Cyrille , Derakhshan Maria , James Philip T. , Monk David , Prentice Andrew M. 
Published: September 2019

AbstractIn humans, DNA methylation marks inherited from gametes are largely erased following fertilisation, prior to construction of the embryonic methylome. Exploiting a natural experiment of seasonal variation including changes in diet and nutritional status in rural Gambia, we analysed two independent child cohorts and identified 259 CpGs showing consistent associations between season of conception (SoC) and DNA methylation. SoC effects were most apparent in early infancy, with evidence of attenuation by mid-childhood. SoC-associated CpGs were enriched for metastable epialleles, parent-of-origin specific methylation and germline DMRs, supporting a periconceptional environmental influence. Many SoC-sensitive CpGs overlapped enhancers or sites of active transcription in H1 ESCs and fetal tissues. Half were influenced but not determined by measured genetic variants that were independent of SoC. Environmental ‘hotspots’ providing a record of environmental influence at periconception constitute a valuable resource for investigating epigenetic mechanisms linking early exposures to lifelong health and disease.
Comparative evolutionary analysis and prediction of deleterious mutation patterns between sorghum and maize
Authors: Lozano Roberto , Gazave Elodie , dos Santos Jhonathan P.R. , Stetter Markus , Valluru Ravi , Bandillo Nonoy , Fernandes Samuel B. , Brown Patrick J. , Shakoor Nadia , Mockler Todd C. , Ross-Ibarra Jeffrey , Buckler Edward S. , Gore Michael A. 
Published: September 2019

AbstractSorghum and maize share a close evolutionary history that can be explored through comparative genomics. To perform a large-scale comparison of the genomic variation between these two species, we analyzed 13 million variants identified from whole genome resequencing of 468 sorghum lines together with 25 million variants previously identified in 1,218 maize lines. Deleterious mutations in both species were prevalent in pericentromeric regions, enriched in non-syntenic genes, and present at low allele frequencies. A comparison of deleterious burden between sorghum and maize revealed that sorghum, in contrast to maize, departed from the “domestication cost” hypothesis that predicts a higher deleterious burden among domesticates compared to wild lines. Additionally, sorghum and maize population genetic summary statistics were used to predict a gene deleterious index with an accuracy higher than 0.5. This research represents a key step towards understanding the evolutionary dynamics of deleterious variants in sorghum and provides a comparative genomics framework to start prioritizing them for removal through genome editing and breeding.
Strain-level identification of bacterial tomato pathogens directly from metagenomic sequences
Authors: Mechan Llontop Marco E. , Sharma Parul , Flores Marcela Aguilera , Yang Shu , Pollock Jill , Tian Long , Huang Chenjie , Rideout Steve , Heath Lenwood S. , Li Song , Vinatzer Boris A. 
Published: September 2019

AbstractRoutine strain-level identification of plant pathogens directly from symptomatic tissue could significantly improve plant disease control and prevention. Here we tested the Oxford Nanopore Technologies (ONT) MinION™ sequencer for metagenomic sequencing of tomato plants either artificially inoculated with a known strain of the bacterial speck pathogenPseudomonas syringaepv.tomato(Pto), or collected in the field and showing bacterial spot symptoms caused by either one of fourXanthomonasspecies. After species-level identification using ONT’s WIMP software and the third party tools Sourmash and MetaMaps, we used Sourmash and MetaMaps with a custom database of representative genomes of bacterial tomato pathogens to attempt strain-level identification. In parallel, each metagenome was assembled and the longest contigs were used as query with the genome-based microbial identification Web service LINbase. Both the read-based and assembly-based approaches correctly identifiedPtostrain T1 in the artificially inoculated samples. The pathogen strain in most field samples was identified as a member ofXanthomonas perforansgroup 2. This result was confirmed by whole genome sequencing of colonies isolated from one of the samples. Although in our case, metagenome-based pathogen identification at the strain-level was achieved, caution still needs to be exerted when interpreting strain-level results because of the challenges inherent to assigning reads to specific strains and the error rate of nanopore sequencing.
Metagenomics and stable isotope probing offer insights into metabolism of polycyclic aromatic hydrocarbons degraders in chronically polluted seawater
Authors: Sieradzki Ella T. , Morando Michael , Fuhrman Jed A. 
Published: September 2019

AbstractBacterial biodegradation is a significant contributor to remineralization of polycyclic aromatic hydrocarbons (PAHs): toxic and recalcitrant components of crude oil as well as byproducts of partial combustion chronically introduced into seawater via atmospheric deposition. The Deepwater Horizon oil spill demonstrated the speed at which a seed PAH-degrading community maintained by low chronic inputs can respond to an acute pollution. We investigated the diversity and functional potential of a similar seed community in the Port of Los Angeles, a chronically polluted site, using stable isotope probing with naphthalene, deep-sequenced metagenomes and carbon incorporation rate measurements at the port and in two sites further into the San Pedro Channel. We show a switch in the composition of the PAH degrading community from diverse early-responding generalists to late-blooming specialized degraders. This switch demonstrates the ability of the local seed community of degraders at the Port of LA to incorporate carbon from PAHs independently of a labile-hydrocarbon degrading succession. We were able to directly show that assembled genomes belonged to naphthalene degraders by matching their 16S-rRNA gene with experimental stable isotope probing data. Surprisingly, we did not find a full PAH degradation pathway in any of those genomes and even when combining genes from the entire microbial community. We use metabolic pathways identified in those genomes to generate metagenomic-based recommendations for future optimization of PAHs bioremediation.
Combinatorial analysis of Saccharomyces cerevisiae regulatory elements
Authors: Dhillon N. , Shelansky R. , Townshend B. , Jain M. , Boeger H. , Endy D. , Kamakaka R.T. 
Published: September 2019

AbstractGene expression in Saccharomyces cerevisiae is regulated at multiple levels. Genomic and epigenomic mapping of transcription factors and chromatin components has led to the definition and delineation of various regulatory elements. Enhancers, promoters, 5’ untranslated regions (5’UTR) and transcription terminators/3’ untranslated regions (3’UTR) have all been defined. However, the specific contributions of each of these features as part of a regulatory unit and the functional communications between these regulatory elements remains under explored.We built a combinatorial library of 26 different enhancers, core promoters, 5’UTRs and transcription terminators/3’UTRs. This library was analyzed with respect to gene expression in order to better understand the interactions between different regulatory elements. In the process we developed new methods to estimate the contribution of individual regulatory parts from just a few simple measurements. Our data show that different pairs of regulatory parts follow specific interaction rules affecting overall activity either positively or negatively. We find that while enhancers are the initiators of gene activity, core promoters modulate the levels of enhancer mediated expression. Cluster analysis based on expression show that TATA-box containing core promoters appear to increase enhancer-driven transcription to a greater extent than TATA-less promoters. Principal component analysis highlight outliers and suggest differences in mechanisms of regulation. These results provide a system to characterize regulatory elements and use these elements in the design of synthetic regulatory circuits.
Inferring the Genetic Influences on Psychological Traits Using MRI Connectivity Predictive Models: Demonstration with Cognition
Authors: Hatoum Alexander S. , Reineberg Andrew E. , Kragel Philip A. , Wager Tor D. , Friedman Naomi P. 
Published: September 2019

AbstractGenetic correlations between brain and behavioral phenotypes in analyses from major genetic consortia have been weak and mostly non-significant. fMRI models of systems-level brain patterns may help improve our ability to link genes, brains, and behavior by identifying reliable and reproducible endophenotypes. Work using connectivity-based predictive modeling (CBPM) has generated brain-based proxies of behavioral and neuropsychological variables. If such models capture activity in inherited brain systems, they may offer a more powerful link between genes and behavior. As a proof of concept, we develop models predicting intelligence (IQ) based on fMRI connectivity and test their effectiveness as endophenotypes. We link brain and IQ in a model development dataset of N=3,000 individuals; and test the genetic correlations between brain models and measured IQ in a genetic validation sample of N=13,092 individuals from the UKBiobank. We compare an additive connectivity-based model to multivariate LASSO and ridge models phenotypically and genetically. We also compare these approaches to single “candidate” brain areas. We find that predictive brain models were significantly phenotypically correlated with IQ and showed much stronger correlations than individual edges. Further, brain models were more heritable than single brain regions (h2=.155-.181) and capture about half of the genetic variance in IQ (rG=.422-.576), while rGs with single brain measures were smaller and non-significant. For the different approaches, LASSO and Ridge were similarly predictive, with slightly weaker performance of the additive model. LASSO model weights were highly theoretically interpretable and replicated known brain IQ associations. Finally, functional connectivity models trained in midlife showed genetic correlations with early life correlates of IQ, suggesting some stability in the prediction of fMRI models. We conclude that multi-system predictive models hold promise as imaging endophenotypes that offer complex and theoretically relevant conclusions for future imaging genetics research.