bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multiscale causal network models of Alzheimer’s disease identify VGF as a key regulator of disease
Authors: Beckmann Noam D. , Lin Wei-Jye , Wang Minghui , Cohain Ariella T. , Wang Pei , Ma Weiping , Wang Ying-Chih , Jiang Cheng , Audrain Mickael , Comella Phillip , Hariharan Siddharth P. , Belbin Gillian M. , Levey Allan I. , Seyfried Nicholas T. , Dammer Eric B. , Duong Duc , Lah James J. , Haure-Mirande Jean-Vianney , Shackleton Ben , Charney Alexander W. , Kenny Eimear , Zhu Jun , Haroutunian Vahram , Katsel Pavel , Gandy Sam , Tu Zhidong , Ehrlich Michelle , Zhang Bin , Salton Stephen R. , Schadt Eric E. 
Published: November 2018

AbstractThough discovered over 100 years ago, the molecular foundation of sporadic Alzheimer’s disease (AD) remains elusive. To elucidate its complex nature, we constructed multiscale causal network models on a large human AD multi-omics dataset, integrating clinical features of AD, DNA variation, and gene and protein expression into probabilistic causal models that enabled detection and prioritization of high-confidence key drivers of AD, including the top predicted key driver VGF. Overexpression of neuropeptide precursor VGF in 5xFAD mice partially rescued beta-amyloid-mediated memory impairment and neuropathology. Molecular validation of network predictions downstream of VGF was achieved, with significant enrichment for homologous genes identified as differentially expressed in 5xFAD brains overexpressing VGF versus controls. Our findings support a causal and/or protective role for VGF in AD pathogenesis and progression.One sentence summaryVGF protects against Alzheimer’s disease
Genome-wide association study of piscine myocarditis virus (PMCV) robustness in Atlantic salmon (Salmo salar)
Authors: Hillestad Borghild , Moghadam Hooman K. 
Published: November 2018

AbstractCardiomyopathy syndrome is a sever, viral disease of Atlantic salmon that mostly affects farmed animals during their late production stage at sea. Caused by piscine myocarditis virus (PMCV), over the past few years, the outbreaks due to this disease have resulted in significant losses to the aquaculture industry. However, there are currently no vaccine that has proven effective against this virus. In this study, using a challenge model, we investigate the genetic variation for robustness to PMCV, by screening large number of animals using a 55 K SNP array. In particular, we aimed to identify genetic markers that are tightly linked to higher disease resistance and can potentially be used in breeding programs. Using genomic information, we estimated heritability of 0.41 ±0.05, suggesting that robustness against this virus is largely controlled by genetic factors. Through association analysis, we identified a major QTL on chromosome 27, explaining approximately 57% of the total additive genetic variation. The region harbouring this putative QTL contains various immune related candidate genes, many of which have previously been shown to have a differential expression profile between the naïve and infected animals. We also identified a suggestive association on chromosome 12, where the QTL linked markers are located within two putatively immune related genes. These findings are important as they can be readily implemented into the breeding programs but also the results can further help in fine-mapping the causative mutation, in better understanding the biology of the disease and refine the mechanics of resistance against PMCV.
pyMeSHSim: an integrative python package for biomedical named entity recognition, normalization and comparison
Authors: Luo Zhi-Hui , Shi Meng-Wei , Yang Zhuang , Zhang Hong-Yu , Chen Zhen-Xia 
Published: November 2018

ABSTRACTMotivationIncreasing disease causal genes have been identified through different methods, while there are still no uniform biomedical named entity (bio-NE) annotations of the disease phenotypes. Furthermore, semantic similarity comparison between two bio-NE annotations, like disease descriptions, has become important for data integration or system genetics analysis.MethodsThe package pyMeSHSim realizes bio-NEs recognition using MetaMap, which produces Unified Medical Language System (UMLS) concepts in natural language process. To map the UMLS concepts to MeSH, pyMeSHSim embedded a house made dataset containing the Medical Subject Headings (MeSH) main headings (MHs), supplementary concept records (SCRs) and relations between them. Based on the dataset, pyMeSHSim implemented four information content (IC) based algorithms and one graph-based algorithm to measure the semantic similarity between two MeSH terms.ResultsTo evaluate its performance, we used pyMeSHSim to parse OMIM and GWAS phenotypes. The inclusion of SCRs and the curation strategy of non-MeSH-synonymous UMLS concepts used by pyMeSHSim improved the performance of pyMeSHSim in the recognition of OMIM phenotypes. In the curation of GWAS phenotypes, pyMeSHSim and previous manual work recognized the same MeSH terms from 276/461 GWAS phenotypes, and the correlation between their semantic similarity calculated by pyMeSHSim and another semantic analysis tool meshes was as high as 0.53-0.97.ConclusionWith the embedded dataset including both MeSH MHs and SCRs, the integrative MeSH tool pyMeSHSim realized the disease recognition, normalization and comparison in biomedical text-mining.AvailabilityPackage’s source code and test datasets are available under the GPLv3 license at https://github.com/luozhhub/pyMeSHSim
The transcriptome-wide landscape and modalities of EJC binding in adult Drosophila
Authors: Obrdlik Ales , Lin Gen , Haberman Nejc , Ule Jernej , Ephrussi Anne 
Published: November 2018

AbstractSplicing-dependent assembly of the exon junction complex (EJC) at canonical sites −20 to −24 nucleotides upstream of exon-exon junctions in mRNAs occurs in all higher eukaryotes and affects most major regulatory events in the life of a transcript. In mammalian cell cytoplasm, EJC is essential for efficient RNA surveillance, while in Drosophila the most essential cytoplasmic EJC function is in localization of oskar mRNA. Here we developed a method for isolation of protein complexes and associated RNA-targets (ipaRt), which provides a transcriptome-wide view of RNA binding sites of the fully assembled EJC in adult Drosophila. We find that EJC binds at canonical positions, with highest occupancy on mRNAs from genes comprising multiple splice sites and long introns. Moreover, the occupancy is highest at junctions adjacent to strong splice sites, CG-rich hexamers and RNA structures. These modalities have not been identified by previous studies in mammals, where more binding was seen at non-canonical positions. The most highly occupied transcripts in Drosophila have increased tendency to be maternally localized, and are more likely to derive from genes involved in differentiation or development. Taken together, we identify the RNA modalities that specify EJC assembly in Drosophila on a biologically coherent set of transcripts.
Convergent evolution inArabidopsis halleriandArabidopsis arenosaon calamine metalliferous soils
Authors: Preite Veronica , Sailer Christian , Syllwasschy Lara , Bray Sian , Krämer Ute , Yant Levi 
Published: November 2018

AbstractIt is a plausible hypothesis that parallel adaptation events to the same environmental challenge should result in genetic changes of similar or identical effects, depending on the underlying fitness landscapes. However, systematic testing of this is scarce. Here we examine this hypothesis in two closely related plant species,Arabidopsis halleriandArabidopsis arenosa, which co-occur at two calamine metalliferous sites harbouring toxic levels of the heavy metals zinc and cadmium. We conduct individual genome resequencing alongside soil elemental analysis for 64 plants from 8 populations on metalliferous and non-metalliferous soils, and identify genomic footprints of selection and local adaptation. Selective sweep and environmental association analyses indicate a modest degree of gene as well as functional network convergence, whereby the proximal molecular factors mediating this convergence mostly differ between site pairs and species. Notably, we observe repeated selection on identical SNPs in severalA. hallerigenes at two independently colonized metalliferous sites. Our data suggest that species-specific metal handling and other biological features could explain a low degree of convergence between species. The parallel establishment of plant populations on calamine metalliferous soils involves convergent evolution, which will likely be more pervasive across sites purposely chosen for maximal similarity in soil composition.
scRMD: Imputation for single cell RNA-seq data via robust matrix decomposition
Authors: Chen Chong , Wu Changjing , Wu Linjie , Wang Yishu , Deng Minghua , Xi Ruibin 
Published: November 2018

AbstractMotivationSingle cell RNA-sequencing (scRNA-seq) technology enables whole transcriptome profiling at single cell resolution and holds great promises in many biological and medical applications. Nevertheless, scRNA-seq often fails to capture expressed genes, leading to the prominent dropout problem. These dropouts cause many problems in down-stream analysis, such as significant noise increase, power loss in differential expression analysis and obscuring of gene-to-gene or cell-to-cell relationship. Imputation of these dropout values thus becomes an essential step in scRNA-seq data analysis.ResultsIn this paper, we model the dropout imputation problem as robust matrix decomposition. This model has minimal assumptions and allows us to develop a computational efficient imputation method scRMD. Extensive data analysis shows that scRMD can accurately recover the dropout values and help to improve downstream analysis such as differential expression analysis and clustering analysis.Contactruibinxi@math.pku.edu.cn
Metabolite composition of sinking particles reflects a changing microbial community and differential metabolite degradation
Authors: Johnson Winifred M. , Longnecker Krista , Kido Soule Melissa C. , Arnold William A. , Bhatia Maya P. , Hallam Steven J. , Van Mooy Benjamin A. S. , Kujawinski Elizabeth B. 
Published: November 2018

AbstractMarine sinking particles transport carbon from the surface and bury it in deep sea sediments where it can be sequestered on geologic time scales. The combination of the surface ocean food web that produces these particles and the particle-associated microbial community that degrades these particles, creates a complex set of variables that control organic matter cycling. We use targeted metabolomics to characterize a suite of small biomolecules, or metabolites, in sinking particles and compare their metabolite composition to that of the suspended particles in the euphotic zone from which they are likely derived. These samples were collected in the South Atlantic subtropical gyre, as well as in the equatorial Atlantic region and the Amazon River plume. The composition of targeted metabolites in the sinking particles was relatively similar throughout the transect, despite the distinct oceanic regions in which they were generated. Metabolites possibly derived from the degradation of nucleic acids and lipids, such as xanthine and glycine betaine, were an increased mole fraction of the targeted metabolites in the sinking particles relative to surface suspended particles, while algal-derived metabolites like the osmolyte dimethylsulfoniopropionate were a smaller fraction of the observed metabolites on the sinking particles. These compositional changes are shaped both by the removal of metabolites associated with detritus delivered from the surface ocean and by production of metabolites by the sinking particle-associated microbial communities. Further, they provide a basis for examining the types and quantities of metabolites that may be delivered to the deep sea by sinking particles.
Absence of pathogenic mutations in CD59 in chronic inflammatory demyelinating polyradiculoneuropathy
Authors: Duchateau Lena , Martin-Aguilar Lorena , Lleixà Cinta , Cortese Andrea , Dols-Icardo Oriol , Cervera-Carles Laura , Pascual-Goñi Elba , Diaz-Manera Jordi , Calegari Ilaria , Franciotta Diego , Rojas-Garcia Ricard , Illa Isabel , Clarimon Jordi , Querol Luis 
Published: November 2018

ABSTRACTObjectiveMutations inCD59cause CIDP-like polyneuropathy in children with inherited chronic hemolysis. We hypothesized that mutations inCD59might be found in a subset of sporadic CIDP patients.Methods5 patients from two centers, fulfilling the EFNS/PNS diagnostic criteria for CIDP were included.CD59coding region was amplified by PCR and Sanger sequenced.ResultsOne rare variant was detected in a patient which resulted in a synonymous change and predicted to be neutral. Pathogenic variants were absent in our cohort.InterpretationOur pilot study suggests that mutations inCD59are absent in adult-onset sporadic CIDP.
In vivo widefield calcium imaging of the mouse cortex for analysis of network connectivity in health and brain disease
Authors: Cramer Julia V , Gesierich Benno , Roth Stefan , Dichgans Martin , Düring Marco , Liesz Arthur 
Published: November 2018

AbstractThe organization of brain areas in functionally connected networks, their dynamic changes, and perturbations in disease states are subject of extensive investigations. Research on functional networks in humans predominantly uses functional magnetic resonance imaging (fMRI). However, adopting fMRI and other functional imaging methods to mice, the most widely used model to study brain physiology and disease, poses major technical challenges and faces important limitations. Hence, there is great demand for alternative imaging modalities for network characterization. Here, we present a refined protocol for in vivo widefield calcium imaging of both cerebral hemispheres in mice expressing a calcium sensor in excitatory neurons. We implemented a stringent protocol for minimizing anesthesia and excluding movement artifacts which both imposed problems in previous approaches. We further adopted a method for unbiased identification of functional cortical areas using independent component analysis (ICA) on resting-state imaging data. Biological relevance of identified components was confirmed using stimulus-dependent cortical activation. To explore this novel approach in a model of focal brain injury, we induced photothrombotic lesions of the motor cortex, determined changes in inter- and intrahemispheric connectivity at multiple time points up to 56 days post-stroke and correlated them with behavioral deficits. We observed a severe loss in interhemispheric connectivity after stroke, which was partially restored in the chronic phase and associated with corresponding behavioral motor deficits. Taken together, we present an improved widefield calcium imaging tool accounting for anesthesia and movement artifacts, adopting an advanced analysis pipeline based on human fMRI algorithms and with superior sensitivity to recovery mechanisms in mouse models compared to behavioral tests. This tool will enable new studies on interhemispheric connectivity in murine models with comparability to human imaging studies for a wide spectrum of neuroscience applications in health and disease.
Fibroblast activation protein enzyme deficiency prevents liver steatosis, insulin resistance and glucose intolerance and increases fibroblast growth factor-21 in diet induced obese mice
Authors: Chowdhury Sumaiya , Song Sunmi , Zhang Hui Emma , Wang Xin Maggie , Gall Margaret G. , Tse Yu Denise Ming , Lay Angelina J. , Wen Xiang Michelle Sui , Evans Kathryn A. , Wetzel Stefanie , Liu Yolanda , Yau Belinda , Coppage Andrew L. , Lo Lisa , Stokes Rebecca A. , Hawthorne Wayne J. , Cooney Gregory J. , McLennan Susan V. , Gunton Jenny E. , Bachovchin William W. , Turner Nigel , Kebede Melkam A. , McCaughan Geoffrey W. , Twigg Stephen M. , Gorrell Mark D. 
Published: November 2018

AbstractBackground & AimsFibroblast activation protein-a (FAP) is a post-proline peptidase closely related to dipeptidyl peptidase-4. FAP degrades bioactive peptides including fibroblast growth factor-21 (FGF-21) and neuropeptide Y. We examined metabolic outcomes of specific genetic ablation of FAP and its enzyme activity in a mouse model of diet-induced obesity (DIO) causing fatty liver.MethodsWildtype (WT) and genetically modified FAP deficient mice that specifically lacked either the FAP protein or FAP enzyme activity received chow, or an atherogenic diet for 8 to 20 weeks of DIO.ResultsFAP deficient male and female mice in the DIO model were more metabolically healthy than controls. The FAP deficient mice had less glucose intolerance, liver lipid, adiposity, insulin resistance, pancreatic and plasma insulin, pancreatic β-cell hyperplasia, serum alanine transaminase and circulating cholesterol compared to wild type controls. Furthermore, FAP deficiency lowered respiratory exchange ratio and greatly increased intrahepatic non-esterified free fatty acids, indicative of increased lipolysis and β-oxidation. Concordantly, lipogenic genes (Pparg, Gck, Acc, Fasn) and hepatic triglyceride and fatty acid uptake genes (Cd36, Apoc3, Ldlr) and plasma low-density lipoprotein cholesterol were downregulated. Glucagon like peptide-1 levels were unaltered. FAP was localized to human pancreatic β-cells and pancreas from diabetes mellitus patients contained elevated FAP activity. Comparable data from a FAP gene knockout mouse and a novel mouse lacking FAP enzyme activity indicated that these metabolic changes depended upon the enzymatic activity of FAP. These changes may be driven by FGF-21, which was upregulated in livers of FAP deficient DIO mice.ConclusionThis is the first study to show that specific genetic ablation of FAP activity or protein protects against DIO-driven glucose intolerance, hyperinsulinaemia, insulin resistance, hypercholesterolaemia and liver steatosis in mice and provide mechanistic insights.
let-7controls the transition to adulthood by releasing select transcriptional regulators from repression by LIN41
Authors: Aeschimann Florian , Neagu Anca , Rausch Magdalene , Großhans Helge 
Published: November 2018

ABSTRACTDevelopment of multicellular organisms relies on faithful temporal control of cell fates. InCaenorhabditis elegans, the heterochronic pathway governs temporal patterning of somatic cells. This function may be phylogenetically conserved as several heterochronic genes have mammalian orthologues, and as the heterochroniclet-7miRNA and its regulator LIN28 appear to time the onset of puberty in mice and humans. Here, we have investigated howlet-7promotes the transition to adulthood inC. elegans. We find thatlet-7controls each of three relevant processes, namely male and female sexual organ morphogenesis as well as changes in skin progenitor cell fates, through the same single target,lin-41. LIN41 in turn silences two pairs of targets post-transcriptionally, by binding and silencing their mRNAs. The EGR-type transcription factor LIN-29a and its co-factor, the NAB1/2 orthologous MAB-10, mediate control of progenitor cell fates and vulval integrity. By contrast, male tail development depends on regulation of the DM domain-containing transcription factors DMD-3 and MAB-3. Our results provide mechanistic insight into an exemplary temporal patterning pathway, demonstrate thatlet-7– LIN41 function as a versatile regulatory module that can be connected to different outputs, and reveal how several levels of post-transcriptional regulation ultimately achieve effects through controlling transcriptional outputs.
Systems approaches provide new insights into Arabidopsis thaliana root growth under mineral nutrient limitation
Authors: Bouain Nadia , Korte Arthur , Satbhai Santosh B. , Rhee Seung Y. , Busch Wolfgang , Rouached Hatem 
Published: November 2018

AbstractThe molecular genetic mechanisms by which plants modulate their root growth rate (RGR) in response to nutrient deficiency are largely unknown. Using a panel of Arabidopsis thaliana natural accessions, we provide a comprehensive combinatorial analysis of RGR variation under macro- and micronutrient deficiency, namely phosphorus (P), iron (Fe), and zinc (Zn), which affect root growth in opposite directions. We found that while -P stimulates early RGR of most accessions, -Fe or -Zn reduces it. The combination of either -P-Fe or -P-Zn leads to suppression of the growth inhibition exerted by -Fe or -Zn alone. Surprisingly, Arabidopsis reference accession Columbia (Col-0) is not representative of the species under -P and -Zn. Using a genome wide association study, we identify candidate genes that control RGR under the assayed nutrient deficiency conditions. By using a network biology driven search using these candidate genes, we further identify a functional module enriched in regulation of cell cycle, DNA replication and chromatin modification that possibly underlies the suppression of root growth reduction in -P-Fe conditions. Collectively, our findings provide a framework for understanding the regulation of RGR under nutrient deficiency, and open new routes for the identification of both large effect genes and favorable allelic variations to improve root growth.
The evolution of egg trading in simultaneous hermaphrodites
Authors: Peña Jorge , Nöldeke Georg , Puebla Oscar 
Published: November 2018

AbstractEgg trading, whereby simultaneous hermaphrodites exchange each other’s eggs for fertilization, constitutes one of the few rigorously documented and most widely cited examples of direct reciprocity among unrelated individuals. Yet how egg trading may initially invade a population of non-trading simultaneous hermaphrodites is still unresolved. Here, we address this question with an analytical model that considers mate encounter rates and costs of egg production in a population that may include traders (who provide eggs for fertilization only if their partners also have eggs to reciprocate), providers (who provide eggs regardless of whether their partners have eggs to reciprocate), and withholders (“cheaters” who only mate in the male role and just use their eggs to elicit egg release from traders). Our results indicate that a combination of inter-mediate mate encounter rates, sufficiently high costs of egg production, and a sufficiently high probability that traders detect withholders (in which case eggs are not provided) is conducive to the evolution of egg trading. Under these conditions traders can invade—and resist invasion from—providers and withholders alike. The prediction that egg trading evolves only under these specific conditions is consistent with the rare occurrence of this mating system among simultaneous hermaphrodites.
Functional heterogeneity within the developing zebrafish epicardium
Authors: Weinberger Michael , Simões Filipa C. , Patient Roger , Sauka-Spengler Tatjana , Riley Paul R. 
Published: November 2018

AbstractThe epicardium is essential during cardiac development, homeostasis and repair and yet fundamental insights into its underlying cell biology, notably epicardium formation, lineage heterogeneity and functional cross-talk with other cell types in the heart, are currently lacking. In this study, we investigated epicardial heterogeneity and the functional diversity of discrete epicardial subpopulations in the developing zebrafish heart. Single-cell RNA-sequencing uncovered three epicardial subpopulations with specific genetic programmes and distinctive spatial distribution within the developing heart. Perturbation of unique gene signatures uncovered distinct functions associated with each subpopulation and established novel epicardial roles in cell adhesion, migration, and chemotaxis as a mechanism for recruitment of leukocytes into the heart. This work elucidates the mutual spatiotemporal relationships between different epicardial subpopulations and assigns unique function to each during cardiac development. Understanding which mechanisms cells employ to establish a functional epicardium and to communicate with other cardiovascular cell types during development will bring us closer to repairing cellular relationships that are disrupted during cardiovascular disease.