bluuebunny/crossref_metadata_2025_split huggingface dataset:
Massively parallel phenotyping of variant impact in cancer with Perturb-seq reveals a shift in the spectrum of cell states induced by somatic mutations
Authors: Ursu Oana , Neal James T. , Shea Emily , Thakore Pratiksha I. , Jerby-Arnon Livnat , Nguyen Lan , Dionne Danielle , Diaz Celeste , Bauman Julia , Mosaad Mariam Mounir , Fagre Christian , Giacomelli Andrew O. , Ly Seav Huong , Rozenblatt-Rosen Orit , Hahn William C. , Aguirre Andrew J. , Berger Alice H. , Regev Aviv , Boehm Jesse S. 
Published: November 2020

AbstractGenome sequencing studies have identified millions of somatic variants in cancer, but their phenotypic impact remains challenging to predict. Current experimental approaches to distinguish between functionally impactful and neutral variants require customized phenotypic assays that often report on average effects, and are not easily scaled. Here, we develop a generalizable, high-dimensional, and scalable approach to functionally assess variant impact in single cells by pooled Perturb-seq. Specifically, we assessed the impact of 200 TP53 and KRAS variants in >300,000 single lung cancer cells, and used the profiles to categorize variants into phenotypic subsets to distinguish gain-of-function, loss-of-function and dominant negative variants, which we validated by comparison to orthogonal assays. Surprisingly, KRAS variants did not merely fit into discrete functional categories, but rather spanned a continuum of gain-of-function phenotypes driven by quantitative shifts in cell composition at the single cell level. We further discovered novel gain-of-function KRAS variants whose impact could not have been predicted solely by their occurrence in patient samples. Our work provides a scalable, gene-agnostic method for coding variant impact phenotyping, which can be applied in cancer and other diseases driven by somatic or germline coding mutations.
Temperature heterogeneity correlates with intraspecific variation in physiological flexibility in a small endotherm
Authors: Stager Maria , Senner Nathan R. , Swanson David L. , Carling Matthew D. , Eddy Douglas K. , Grieves Timothy J. , Cheviron Zachary A. 
Published: November 2020

ABSTRACTPhenotypic flexibility allows individuals to reversibly modify trait values and theory predicts an individual’s relative degree of flexibility positively correlates with the environmental heterogeneity it experiences. We tested this prediction by integrating surveys of population genetic and physiological variation with thermal acclimation experiments and indices of environmental heterogeneity in the Dark-eyed Junco (Junco hyemalis) and its congeners. We combined measures of thermogenic capacity for ~300 individuals, >21,000 single nucleotide polymorphisms genotyped in 192 individuals, and laboratory acclimations replicated on five populations. We found thatJuncopopulations: (1) differ in their thermal performance responses to temperature variationin situ; (2) exhibit intra-specific variation in their thermogenic flexibility in the laboratory that correlates with heterogeneity in their native thermal environment; and (3) harbor genetic variation that also correlates with temperature heterogeneity. These results provide comprehensive support that phenotypic flexibility corresponds with environmental heterogeneity and highlight its importance for coping with environmental change.
A versatile resource of 1500 diverse wild and cultivated soybean genomes for post-genomics research
Authors: Zhang Hengyou , Jiang He , Hu Zhenbin , Song Qijian , An Yong-qiang Charles 
Published: November 2020

SummaryWith the advance of next-generation sequencing technologies, over 15 terabytes of raw soybean genome sequencing data were generated and made available in the public. To develop a consolidated, diverse, and user-friendly genomic resource to facilitate post-genomic research, we sequenced 91 highly diverse wild soybean genomes representing the entire US collection of wild soybean accessions to increase the genetic diversity of the sequenced genomes. Having integrated and analyzed the sequencing data with the public data, we identified and annotated 32 million single nucleotide polymorphisms (32mSNPs) with a resolution of 30 SNPs/kb and 12 non-synonymous SNPs/gene in 1,556 accessions (1.5K). Population structure analysis showed that the 1.5K accessions represent the genetic diversity of the 20,087 (20K) soybean accessions in the U.S. collection. Inclusion of wild soybean genomes significantly increased the genetic diversity and shorten linkage disequilibrium distance in the panel of soybean accessions. We identified a collection of paired accessions sharing the highest genomic identity between the 1.5K and 20K accessions as genomically “equivalent” accessions to maximize the use of the genome sequences. We demonstrated that the 32mSNPs in the 1.5K accessions can be effectively used for in-silico genotyping, discovering trait QTL, gene alleles/mutations, identifying germplasms containing beneficial allele and domestication selection of trait alleles. We made the 32mSNPs and 1.5K accessions with detailed annotation available at SoyBase and Ag Data Commons. The dataset could serve as a versatile resource to release the potential of the huge amount of genome sequencing data for a variety of postgenomic research.
Rapidly self-sterilizing PPE capable of 99.9% SARS-CoV-2 deactivation in 30 seconds
Authors: Zinn Alfred A. , Izadjoo Mina , Kim Hosan , Kehn-Hall Kylene , Woodson Caitlin , Brody Rachel L. , Roth Robert R. , Vega Agustin , Nguyen Khanh K. , Ngo Nhi T. , Zinn Hannah T. , Panny Lauren , Flor Rafaela , Antonopoulos Nicholas , Stoltenberg Randall M. 
Published: November 2020

AbstractThe coronavirus disease 2019 (COVID-19) has created an acute worldwide demand for sustained broadband pathogen suppression in households, hospitals, and public spaces. The US recently passed a new sad milestone of 500,000 deaths due to COVID-19, the highest rate anywhere in the world. In response, we have created a rapid-acting, self-sterilizing PPE configurations capable of killing SARS-CoV-2 and other microbes in seconds. The highly active material destroys pathogens faster than any conventional copper configuration. The material maintains its antimicrobial efficacy over sustained use and is shelf stable. We have performed rigorous testing in accordance with guidelines from U.S. governing authorities and believe that the material could offer broad spectrum, non-selective defense against most microbes via integration into masks and other protective equipment.SummaryA novel configuration of copper offering continued fast-acting protection against viruses and bacteria, including SARS-CoV-2.
Botanical Digitization: Application of MorphoLeaf in 2D Shape Visualization, Digital Morphometrics, and Species Delimitation, using Homologous Landmarks of Cucurbitaceae Leaves as a Model
Authors: Oso Oluwatobi A. , Jayeola Adeniyi A. 
Published: November 2020

ABSTRACTMorphometrics has been applied in several fields of science including botany. Plant leaves are been one of the most important organs in the identification of plants due to its high variability across different plant groups. The differences between and within plant species reflect variations in genotypes, development, evolution, and environment. While traditional morphometrics has contributed tremendously to reducing the problems that come with the identification of plants and delimitation of species based on morphology, technological advancements have led to the creation of deep learning digital solutions that made it easy to study leaves and detect more characters to complement already existing leaf datasets. In this study, we demonstrate the use of MorphoLeaf in generating morphometric dataset from 140 leaf specimens from seven Cucurbitaceae species via scanning of leaves, extracting landmarks, data extraction, landmarks data quantification, and reparametrization and normalization of leaf contours. PCA analysis revealed that blade area, blade perimeter, tooth area, tooth perimeter, height of (each position of the) tooth from tip, and the height of each (position of the) tooth from base are important and informative landmarks that contribute to the variation within the species studied. Our results demonstrate that MorphoLeaf can quantitatively track diversity in leaf specimens, and it can be applied to functionally integrate morphometrics and shape visualization in the digital identification of plants. The success of digital morphometrics in leaf outline analysis presents researchers with opportunities to apply and carry out more accurate image-based researches in diverse areas including, but not limited to, plant development, evolution, and phenotyping.
A benchmark dataset for individual tree crown delineation in co-registered airborne RGB, LiDAR and hyperspectral imagery from the National Ecological Observation Network
Authors: Weinstein Ben. G. , Graves Sarah J. , Marconi Sergio , Singh Aditya , Zare Alina , Stewart Dylan , Bohlman Stephanie A. , White Ethan P. 
Published: November 2020

AbstractBroad scale remote sensing promises to build forest inventories at unprecedented scales. A crucial step in this process is designing individual tree segmentation algorithms to associate pixels into delineated tree crowns. While dozens of tree delineation algorithms have been proposed, their performance is typically not compared based on standard data or evaluation metrics, making it difficult to understand which algorithms perform best under what circumstances. There is a need for an open evaluation benchmark to minimize differences in reported results due to data quality, forest type and evaluation metrics, and to support evaluation of algorithms across a broad range of forest types. Combining RGB, LiDAR and hyperspectral sensor data from the National Ecological Observatory Network’s Airborne Observation Platform with multiple types of evaluation data, we created a novel benchmark dataset to assess individual tree delineation methods. This benchmark dataset includes an R package to standardize evaluation metrics and simplify comparisons between methods. The benchmark dataset contains over 6,000 image-annotated crowns, 424 field-annotated crowns, and 3,777 overstory stem points from a wide range of forest types. In addition, we include over 10,000 training crowns for optional use. We discuss the different evaluation sources and assess the accuracy of the image-annotated crowns by comparing annotations among multiple annotators as well as to overlapping field-annotated crowns. We provide an example submission and score for an open-source baseline for future methods.
Castration delays epigenetic aging and feminises DNA methylation at androgen-regulated loci
Authors: Sugrue VJ , Zoller JA , Narayan P , Lu AT , Ortega-Recalde OJ , Grant MJ , Bawden CS , Rudiger SR , Haghani A , Bond DM , Garratt M , Sears KE , Wang N , Yang XW , Snell RG , Hore TA , Horvath S 
Published: November 2020

SUMMARYIn mammals, females generally live longer than males. Nevertheless, the mechanisms underpinning sex-dependent longevity are currently unclear. Epigenetic clocks are powerful biological biomarkers capable of precisely estimating chronological age using only DNA methylation data. These clocks have been used to identify novel factors influencing the aging rate, but few studies have examined the performance of epigenetic clocks in divergent mammalian species. In this study, we developed the first epigenetic clock for domesticated sheep (Ovis aries), and using 185 CpG sites can predict chronological age with a median absolute error of 5.1 months from ear punch and blood samples. We have discovered that castrated male sheep have a decelerated aging rate compared to intact males, mediated at least in part by the removal of androgens. Furthermore, we identified several androgen-sensitive CpG dinucleotides that become progressively hypomethylated with age in intact males, but remain stable in castrated males and females. Many of these androgen sensitive demethylating sites are regulatory in nature and located in genes with known androgen-dependent regulation, such asMKLN1, LMO4andFN1. Comparable sex-specific methylation differences inMKLN1also exist in mouse muscle (p=0.003) but not blood, indicating that androgen dependent demethylation exists in multiple mammalian groups, in a tissue-specific manner. In characterising these sites, we identify biologically plausible mechanisms explaining how androgens drive male-accelerated aging.
Methylation Quantitative Trait Loci are Largely Consistent across Disease States in Crohn’s disease
Authors: Venkateswaran Suresh , Somineni Hari K , Kilaru Varun , Katrinli Seyma , Prince Jarod , Okou David T , Hyams Jeffrey S , Denson Lee A , Kellermayer Richard , Gibson Greg , Cutler David J , Smith Alicia K , Kugathasan Subra , Conneely Karen N 
Published: November 2020

AbstractBackgroundIn a recent study, we identified 1189 CpG sites whose DNA methylation (DNAm) level in blood distinguished Crohn’s disease (CD) cases from controls. We also demonstrated that the vast majority of these differences were a consequence of disease, rather than a cause of CD. Since methylation can be influenced by both genetic and environmental factors, here we focus on CpGs under demonstrable genetic control (methylation quantitative trait loci, or mQTLs). By comparing mQTL patterns across disease states and tissue (blood vs. ileum), we may distinguish patterns unique to CD. Such DNAm patterns may be relevant for the developmental origins of CD.MethodsWe investigated three datasets: (i) 402 blood samples from 164 newly diagnosed pediatric CD patients taken at two time points, and 74 non-IBD controls (ii) 780 blood samples from a non-CD adult population and (iii) 40 ileal biopsies (17 CD cases and 23 non-IBD controls) from group (i). Genome-wide DNAm profiling and genotyping were performed using the Illumina MethylationEPIC and Illumina Multi-Ethnic arrays. SNP-CpG associations were tested via linear models adjusted for age, gender, disease status, disease subtype, estimated cell type and three genotype-based principal components. We used a Bonferroni-adjusted significance threshold to identify significantly associated SNP-CpG pairs, but also considered larger sets identified by a false discovery rate criterionResultsIn total, we observed 535,448 SNP-CpG associations between 287,881 SNPs and 12,843 CpG sites (P<8.21×10−14). These associations and their effects are highly consistent across different ages, races, disease states, and tissue types, suggesting that the vast majority of these mQTLs participate in common gene regulation. However, genes near CpGs associated with IBD SNPs were enriched for 18 KEGG pathways relevant to IBD-linked immune function and inflammatory responses. We observed suggestive evidence for a small number of tissue-specific associations and disease-specific ileal associations in ileum, though larger studies will be needed to confirm these results.ConclusionThe vast majority of blood derived mQTLs are commonly shared across individuals. However, we have identified a subset of such, which may be involved in processes related to CD. Independent cohort studies will be required to validate these findings.
Endothelial exosome plays functional role during rickettsial infection
Authors: Liu Yakun , Zhou Changcheng , Su Zhengchen , Chang Qing , Qiu Yuan , Bei Jiani , Gaitas Angelo , Xiao Jie , Drelich Alexandra , Khanipov Kamil , Jin Yang , Golovko Georgiy , Saito Tais B. , Gong Bin 
Published: November 2020

AbstractSpotted fever group rickettsioses (SFRs) are devastating human infections. Vascular endothelial cells (ECs) are the primary targets of infection. Edema resulting from EC barrier dysfunction occurs in the brain and lungs in most cases of lethal SFR, but the underlying mechanisms remain unclear. The aim of the study is to explore the potential role ofRickettsia(R)-infected, EC-derived exosomes (Exos) during infection. Using size-exclusion chromatography (SEC), we purified Exos from conditioned, filtered, bacteria-free media collected fromR-infected human umbilical vein ECs (HUVECs) (R-ECExos) and plasma ofR-infected mice (R-plsExos). We observed that rickettsial infection increases the release of heterogeneous plsExos, but endothelial exosomal size, morphology, and production were not significantly altered following infection. Compared to normal plsExos and ECExos, bothR-plsExos andR-ECExos induced dysfunction of recipient normal brain microvascular Ecs (BMECs). The effect ofR-plsExos on mouse recipient BMEC barrier function is dose-dependent. The effect ofR-ECExos on human recipient BMEC barrier function is dependent on exosomal RNA cargo. Next-generation sequencing analysis and stem-loop quantitative reverse transcription PCR (RT-qPCR) validation revealed thatRinfection triggered the selective enrichment of endothelial exosomal mir-23a and mir-30b, which target the endothelial barrier. To our knowledge, this is the first report on the functional role of extracellular vesicles following infection by obligately intracellular bacteria.ImportanceSpotted fever group rickettsioses are devastating human infections. Vascular endothelial cells are the primary targets of infection. Edema resulting from endothelial barrier dysfunction occurs in the brain and lungs in most cases of lethal rickettsioses, but the underlying mechanisms remain unclear. The aim of the study is to explore the potential role ofRickettsia-infected, endothelial cell-derived exosomes during infection. We observed that rickettsial infection increases the release of heterogeneous plasma Exos, but endothelial exosomal size, morphology, and production were not significantly altered following infection.Rickettsia-infected, endothelial cell-derived exosomes induced dysfunction of recipient normal brain microvascular endothelial cells. The effect is dependent on exosomal RNA cargo. Next-generation sequencing analysis revealed that rickettsial infection triggered the selective enrichment of endothelial exosomal mir-23a and mir-30b, which target the endothelial barrier. To our knowledge, this is the first report on the functional role of extracellular vesicles following infection by obligately intracellular bacteria.
Investigating the shared genetic architecture between multiple sclerosis and inflammatory bowel diseases
Authors: Yang Yuanhao , Musco Hannah , Simpson-Yap Steve , Zhu Zhihong , Wang Ying , Lin Xin , Zhang Jiawei , Taylor Bruce , Gratten Jacob , Zhou Yuan 
Published: November 2020

AbstractAn epidemiological association between multiple sclerosis (MS) and inflammatory bowel disease (IBD) is well-established, but whether this reflects a shared genetic aetiology, and whether consistent genetic relationships exist between MS and the two predominant subtypes of IBD, ulcerative colitis (UC) and Crohn’s disease (CD), remains unclear. Here, we used genome-wide association study (GWAS) summary data to estimate genetic correlations (rg) between MS and each of IBD, UC and CD, finding that the rg between MS and UC was approximately twice that between MS and CD. On the basis of these genetic correlations, we performed cross-trait meta-analysis of GWAS summary data for MS and each of IBD, UC and CD, identifying a total of 42 novel SNPs shared between MS and IBD (N=19), UC (N=14), and CD (N=18). We then used multiple Mendelian randomization (MR) methods to investigate causal relationships between these diseases, finding suggestive but inconclusive evidence for a causal effect of MS on UC and IBD, and no or weak and inconsistent evidence for a causal effect of IBD or UC on MS. There was also no evidence for causality in bidirectional analyses of MS and CD. We also investigated tissue- and cell-type-specific enrichment of SNP heritability for each disease using stratified LD score regression. At the tissue level, we observed largely consistent patterns of enrichment for all four diseases in immune system-related tissues, including lung, spleen and whole blood, and in contrast to prior studies, small intestine. At the cell-type level, we identified significant enrichment for all diseases in CD4+ T cells in lung, and for MS, IBD and CD in CD8+ cytotoxic T cells in both lung and spleen, and regulatory T cells in lung. Our study sheds new insights into the biological basis of comorbidity between MS and both UC and CD.
Low Repeatability of Aversive Learning in Zebrafish (Danio rerio)
Authors: Mason Dominic , Zajitschek Susanne , Anwer Hamza , O’Dea Rose E , Hesselson Daniel , Nakagawa Shinichi 
Published: November 2020

AbstractAversive learning – avoiding certain situations based on negative experiences – can profoundly increase fitness in animal species. The extent to which this cognitive mechanism could evolve depends upon individual differences in aversive learning being stable through time, and heritable across generations, yet no published study has quantified the stability of individual differences in aversive learning using the repeatability statistic,R(also known as the intra-class correlation). We assessed the repeatability of aversive learning by conditioning approximately 100 zebrafish(Danio rerio)to avoid a colour cue associated with a mild electric shock. Across eight different colour conditions zebrafish did not show consistent individual differences in aversive learning (R= 0.04). Within conditions, when zebrafish were twice conditioned to the same colour, blue conditioning was more repeatable than green conditioning (R= 0.15 andR= 0.02). In contrast to the low repeatability estimates for aversive learning, zebrafish showed moderately consistent individual differences in colour preference during the baseline period (i.e. prior to aversive conditioning;R~ 0.45). Overall, aversive learning responses of zebrafish were weak and variable (difference in time spent near the aversive cue <6 seconds per minute), but individual differences in learning ability did not explain substantial variability. We speculate that either the effect of aversive learning was too weak to quantify consistent individual differences, or directional selection might have eroded additive genetic variance. Finally, we discuss how confounded repeatability assays and publication bias could have inflated average estimates of repeatability in animal behaviour publications.Summary StatementZebrafish exhibit low repeatability (intra-class correlation) in an aversive learning assay possibly due to past selection pressure exhausting genetic variance in this learning trait.