bluuebunny/crossref_metadata_2025 huggingface dataset:
Non-alcoholic fatty liver disease (NAFLD) prevalence in Latin American and the Caribbean: Protocol for a systematic review
Authors: Rojas Yesmi Arcelia Ortega , Vidal Cuéllar Claudia Lucía , Aparicio Barrón Karina Mercedes , Larco Rodrigo Carrillo
Published: November 2020

Background

Non-alcoholic fatty liver disease (NAFLD) is the most common worldwide cause of chronic liver disease and it carries a significant economic burden for the healthcare system. The worldwide prevalence of NAFLD appears to be 25%, with the highest rates in Latin America and the Caribbean (LAC) and the middle west. Prevalence of NAFLD in LAC has not been well represented in multiple global meta-analyses because they did not include regional search engines or excluded papers in Spanish. Furthermore, older estimates may not represent the current epidemiological situation given the recent rise of several risk factors like obesity, unhealthy diet and lifestyles in LAC.

Objective

To estimate the prevalence of NAFLD in the general adult population of LAC.

Methods

Systematic review and meta-analysis. We will conduct a search in OVID (MEDLINE, Embase, Global Health), Cochrane Library, and LILACS. Search terms include those related to non-alcoholic fatty liver disease, along with countries in LAC. We seek observational studies with a random sample of the general population, closed populations, and patients; results will be presented for each of these groups. Titles and abstracts will be screened by two reviewers independently. After the screening phase, we will download the full-text of the selected publications and two reviewers will comprehensively read these papers. If there is any discrepancy in any of these two selection phases, it will be solved by consensus by the two reviewers or by a third party. An extraction data form in a spreadsheet will be developed and tested with a random sample of five selected studies. The data extracted will include study details, sample size, method of NAFLD diagnosis and prevalence of NAFLD. Data extraction will be conducted by two reviewers independently. We will use the risk of bias tool proposed by Hoy and colleagues. We will report the main features of the selected reports in tables, this will include the prevalence estimates. We will pool the prevalence estimates. We will only conduct the meta-analysis if there are three or more individual estimates and there is not large heterogeneity amongst them. We will conduct all statistical analyses using Stata 16.0

Conclusions

This systematic review and meta-analysis will provide updated evidence about the prevalence of NAFLD in LAC. Thereby, we will increase NAFLD awareness as a public health problem in LAC, and our results can inform strategies and interventions to reduce NAFLD burden in LAC. We will also pinpoint research needs and discuss future steps so that more robust evidence about NAFLD becomes available in LAC.
K-seq, an affordable, reliable, and open Klenow NGS-based genotyping technology
Authors: Ziarsolo Peio , Hasing Tomas , Hilario Rebeca , Garcia-Carpintero Victor , Blanca Jose , Bombarely Aureliano , Cañizares Joaquin
Published: November 2020

K-seq, a new genotyping methodology based on the amplification of genomic regions using two steps of Klenow amplification with short oligonucleotides, followed by standard PCR and Illumina sequencing, is presented. The protocol was accompanied by software developed to aid with primer set design. As the first examples, K-seq in species as diverse as tomato, dog and wheat was developed. K-seq provided genetic distances similar to those based on WGS in dogs. Experiments comparing K-seq and GBS in tomato showed similar genetic results, although K-seq had the advantage of finding more SNPs for the same number of Illumina reads. The technology reproducibility was tested with two independent runs of the tomato samples, and the correlation coefficient of the SNP coverages between samples was 0.8 and the genotype match was above 94%. K-seq also proved to be useful in polyploid species. The wheat samples generated specific markers for all subgenomes, and the SNPs generated from the diploid ancestors were located in the expected subgenome with accuracies greater than 80%. K-seq is an open, patent-unencumbered, easy-to-set-up, cost-effective and reliable technology ready to be used by any molecular biology laboratory without special equipment in many genetic studies.
SBGN Bricks Ontology as a tool to describe recurring concepts in molecular networks
Authors: Rougny Adrien , Touré Vasundra , Albanese John , Waltemath Dagmar , Shirshov Denis , Sorokin Anatoly , Bader Gary D. , Blinov Michael L. , Mazein Alexander
Published: November 2020

A comprehensible representation of a molecular network is key to communicating and understanding scientific results in systems biology. The Systems Biology Graphical Notation (SBGN) has emerged as the main standard to represent such networks graphically. It has been implemented by different software tools, and is now largely used to communicate maps in scientific publications. However, learning the standard, and using it to build large maps, can be tedious. Moreover, SBGN maps are not grounded on a formal semantic layer and therefore do not enable formal analysis. Here, we introduce a new set of patterns representing recurring concepts encountered in molecular networks, called SBGN bricks. The bricks are structured in a new ontology, the BricKs Ontology (BKO), to define clear semantics for each of the biological concepts they represent. We show the usefulness of the bricks and BKO for both the template-based construction and the semantic annotation of molecular networks. The SBGN bricks and BKO can be freely explored and downloaded at sbgnbricks.org.
Population genetics of transposable element load: a mechanistic account of observed overdispersion
Authors: Smith Ronald D. , Puzey Joshua R. , Conradi Smith Gregory D.
Published: November 2020

In an empirical analysis of transposable element (TE) abundance within natural populations ofMimulus guttatusandDrosophila melanogaster, we found a surprisingly high variance of TE count (e.g., variance-to-mean ratio on the order of 10 to 300). To obtain insight regarding those evolutionary genetic mechanisms that are may underlie the overdispersed population distributions of TE abundance, we developed a mathematical model of TE population genetics that includes the dynamics of element proliferation and purifying selection on TE load. The modeling approach begins with a master equation for a birth-death process and extends the predictions of the classical theory of TE dynamics in several ways. In particular, moment-based analyses of time-dependent and equilibrium population distributions of TE load reveal that overdispersion is likely to arise via copy-and-paste proliferation dynamics, especially when the elementary processes of proliferation and excision are first-order and approximately balanced. Parameter studies and analytic work confirm this result and further suggest that overdispersed population distributions of TE abundance are unlikely to be a consequence of purifying selection on total element load.
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

Genome 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

Phenotypic 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

With 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

The 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.

A 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

Morphometrics 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.
Modelling the dynamics of vesicle reshaping and scission under osmotic shocks
Authors: Vanhille-Campos Christian , Šarić Anđela
Published: November 2020

We study the effects of osmotic shocks on lipid vesicles via coarse-grained molecular dynamics simulations by explicitly considering the solute in the system. We find that depending on their nature (hypo- or hypertonic) such shocks can lead to bursting events or engulfing of external material into inner compartments, among other morphology transformations. We characterize the dynamics of these processes and observe a separation of time scales between the osmotic shock absorption and the shape relaxation. Our work consequently provides an insight into the dynamics of compartmentalization in vesicular systems as a result of osmotic shocks, which can be of interest in the context of early proto-cell development and proto-cell compartmentalisation.
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

Broad 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.
Degradation of mixed-linkage (1,3;1,4)-β-D-glucan in maize is mediated by the CAL1 licheninase
Authors: Kraemer Florian J , Lunde China , Koch Moritz , Kuhn Benjamin M , Ruehl Clemens , Brown Pat , Hoffmann Philipp , Göhre Vera , Hake Sarah , Pauly Markus , Ramirez Vicente
Published: November 2020

The presence of mixed-linkage (1,3;1,4)-β-D-glucan (MLG) in plant cell walls is a key feature of grass species such as cereals - the main source of calorie intake for humans and cattle. Accumulation of this polysaccharide involves the coordinated regulation of biosynthetic and metabolic machineries. While several components of the MLG biosynthesis machinery have been identified in diverse plant species, degradation of MLG is poorly understood. A large-scale forward genetic maize screen for mutants with altered cell wall polysaccharide structural properties resulted in the identification of candy-leaf1 (cal1). Cell walls of CAL1-deficient plants contain higher amounts of MLG in several tissues, including adult leaves and senesced organs, where only trace amounts of MLG are usually detected. In addition, cal1 plants exhibit increased saccharification yields upon enzymatic digestion. Stacking cal1 with lignin-deficient mutations results in synergistic saccharification increases. Identification of the causative mutation revealed that CAL1 encodes a GH17 licheninase. Maize plants overexpressing CAL1 exhibit a 90% reduction in MLG content, indicating that CAL1 is not only required, but its expression sufficient to degrade MLG. CAL1 specifically hydrolyzes (1,3;1,4)-β-D-Glucans in vitro, and the single CAL1E262K amino acid substitution is able to block all detectable activity. Time profiling experiments indicate that wall MLG content is modulated during day/night cycles inversely correlating with CAL1 transcript accumulation. This cycling is absent in the cal1 mutant, suggesting that the mechanism involved requires MLG degradation that may in turn regulate CAL1 gene expression.
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

In 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

Background

In 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.

Methods

We 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 criterion

Results

In 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.

Conclusion

The 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

Spotted 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.

Importance

Spotted 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

An 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

Aversive 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 Statement

Zebrafish exhibit low repeatability (intra-class correlation) in an aversive learning assay possibly due to past selection pressure exhausting genetic variance in this learning trait.
Gene mutations in members of the PI3K/Akt signalling pathway are related to immune thrombocytopenia pathogenesis
Authors: Sun Rui-Jie , Liu Shu-yan , Zhang Xiao-mei , Zhu Jing-jing , Yuan Dai , Shan Ning-ning
Published: November 2020

Purpose

Immune thrombocytopenic (ITP) is an autoimmune bleeding disease with genetic susceptibility. In this research, we conducted an in-depth genomic analysis of a cohort of patients and elucidated the molecular features associated with the pathogenesis of ITP.

Method

High-molecular-weight genomic DNA was extracted from freshly frozen bone marrow blood mononuclear cells (BMBMCs) from 20 active ITP patients. Next, the samples were subjected to molecular genetic analysis by whole-exome sequencing (WES), and the results were confirmed by Sanger sequencing. The signalling pathways and cellular processes associated with the mutated genes were identified with gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses.

Results

The results of this study revealed 3,998 missense mutations involving 2,269 genes in more than 10 individuals. Some unique genetic variants, including phosphatase and tensin homologue (PTEN), insulin receptor (INSR) and coagulation factor C homology (COCH) variants, were the most associated with the pathogenesis of ITP. Functional analysis revealed that these gene mutations mainly affected the phosphoinositide 3 kinase (PI3K)/protein kinase B (Akt) signalling pathways (signal transduction) and platelet activation (immune system).

Conclusions

Our findings demonstrate the functional connections between these gene variants and ITP. Although the underlying mechanisms and the impact of these genetic variants remain to be revealed through further investigation, the application of next-generation sequencing in ITP in this paper is valuable for revealing the genetic mechanisms of ITP.

Immune thrombocytopenic (ITP) is an autoimmune bleeding disease with genetic susceptibility. DNA mutation profile of ITP patient bone marrow samples (n=20) were investigated by using next-generation sequencing (NGS), and then confirmed by sanger sequencing method. Our results showed PTEN, INSR and COCH were mutated in all ITP patients. Functional analysis revealed these mutation genes mainly participate PI3K/Akt signaling pathways and platelet activation. These results suggest that genetic alterations might be involved in the pathogenesis of ITP.
Mouse eradication is required to prevent local extinction of an endangered seabird on an oceanic island
Authors: Jones Christopher W. , Risi Michelle M. , Osborne Alexis M. , Ryan Peter G. , Oppel Steffen
Published: November 2020

Petrels (Procellariidae) are a highly diverse family of seabirds, many of which are globally threatened due to the impact of invasive species on breeding populations. While predation by invasive cats and rats has led to the extinction of petrel populations, the impact of invasive house miceMus musculusis slower and less well documented. However, mice impact small burrow-nesting species such as MacGillivray’s prionPachyptila macgillivrayi,a species classified as endangered because it has been extirpated on islands in the Indian Ocean by introduced rodents. We use historic abundance data and demographic monitoring data from 2014 to 2020 to predict the population trajectory of MacGillivray’s prion on Gough Island with and without a mouse eradication using a stochastic integrated population model. Given very low annual breeding success (0.01 fledglings per breeding pair in ‘poor’ years (83%) or 0.38 in ‘good’ years (17%), n = 320 nests over 6 years) mainly due to mouse predation, our model predicted that the population collapsed from ~3.5 million pairs in 1956 to an estimated 175,000 pairs in 2020 despite reasonably high adult survival probability(ϕ= 0.901). Based on these parameters, the population is predicted to decline at a rate of 9% per year over the next 36 years without a mouse eradication, with a 31% probability that by 2057 the MacGillivray’ prion population would become extremely vulnerable to extinction. Our models predict population stability (λ = 1.01) and a lower extinction risk (<10%) if mouse eradication on Gough Island restores annual breeding success to 0.519, which is in line with that of closely-related species on predator-free islands. This study demonstrates the devastating impacts that introduced house mice can have on small burrowing petrels and highlights the urgency to eradicate invasive mammals from oceanic islands.
Streptococcus pneumoniaeserotypes carried by young children and their association with Acute Otitis Media during the period 2016 – 2019
Authors: Ekinci Esra , Desmet Stefanie , Van Heirstraeten Liesbet , Mertens Colette , Wouters Ine , Beutels Philippe , Verhaegen Jan , Malhotra-Kumar Surbhi , Theeten Heidi ,   NPcarriage group
Published: November 2020

Background

Streptococcus pneumoniae(Sp) is a major cause of acute otitis media (AOM). Pneumococcal conjugate vaccine (PCV) programs have altered pneumococcal serotype epidemiology in disease and carriage. To establish the clinical picture of AOM in young children exposed to the PCV program in Belgium and the Sp strains they carry, a cross-sectional study started in 2016.

Material/methods

In three collection periods from February 2016 to May 2018, nasopharyngeal swabs and background characteristics were collected from children aged 6-30 months either presenting at their physician with AOM (AOM-group) or healthy and attending day care (DCC-group). Sp was detected, quantified, and characterized using both conventional culture and qPCR. Clinical signs of AOM episodes and treatment were registered by the physicians.

Results

Among 3264 collected samples, overall pneumococcal carriage and density were similar in AOM (79.2% and 0.50 ×106copies/μl) and DCC (77.5% and 0.42 ×106copies/μl). Non-vaccine serotypes were most frequent: 23B (AOM: 12.3%; DCC: 17.4%), 11A (AOM: 7.5%; DCC: 7.4%) and 15B (AOM: 7.5%; DCC: 7.1%). Serotypes 3, 6C, 7B, 9N, 12F, 17F and 29 were more frequent in AOM than in DCC, whereas 23A and 23B frequencies were lower. Antibiotic susceptibility of Sp strains was similar in both groups . No predictors of AOM severity were identified, and 77.3% received an antibiotic prescription.

Conclusion

Young children with AOM did not carry Sp more frequently or at higher load than healthy children in day care, but some ST were more frequent in AOM and are not included in the currently used vaccines.
Combined polygenic risk scores of different psychiatric traits predict general and specific psychopathology in childhood
Authors: Neumann Alexander , Jolicoeur-Martineau Alexia , Szekely Eszter , Sallis Hannah M. , O’Donnel Kieran , Greenwood Celia M.T. , Levitan Robert , Meaney Michael J. , Wazana Ashley , Evans Jonathan , Tiemeier Henning
Published: November 2020

Background

Polygenic risk scores (PRSs) operationalize genetic propensity towards a particular mental disorder and hold promise as early predictors of psychopathology, but before a PRS can be used clinically, explanatory power must be increased and the specificity for a psychiatric domain established. To enable early detection it is crucial to study these psychometric properties in childhood. We examined whether PRSs associate more with general or with specific psychopathology in school-aged children. Additionally, we tested whether psychiatric PRSs can be combined into a multi-PRS score for improved performance.

Methods

We computed 16 PRSs based on GWASs of psychiatric phenotypes, but also neuroticism and cognitive ability, in mostly adult populations. Study participants were 9247 school-aged children from three population-based cohorts of the DREAM-BIG consortium: ALSPAC (UK), The Generation R Study (Netherlands) and MAVAN (Canada). We associated each PRS with general and specific psychopathology factors, derived from a bifactor model based on self-, parental-, teacher-, and observer reports. After fitting each PRS in separate models, we also tested a multi-PRS model, in which all PRSs are entered simultaneously as predictors of the general psychopathology factor.

Results

Seven PRSs were associated with the general psychopathology factor after multiple testing adjustment, two with specific externalizing and five with specific internalizing psychopathology. PRSs predicted general psychopathology independently of each other, with the exception of depression and depressive symptom PRSs. Most PRSs associated with a specific psychopathology domain, were also associated with general child psychopathology.

Conclusions

The results suggest that PRSs based on current GWASs of psychiatric phenotypes tend to be associated with general psychopathology, or both general and specific psychiatric domains, but not with one specific psychopathology domain only. Furthermore, PRSs can be combined to improve predictive ability. PRS users should therefore be conscious of non-specificity and consider using multiple PRSs simultaneously, when predicting psychiatric disorders.
Biochemical and Biophysical Characterization of the dsDNA packaging motor from theLactococcus lactisbacteriophage asccphi28
Authors: Reyes-Aldrete Emilio , Dill Erik A. , Bussetta Cecile , Szymanski Michal R. , Diemer Geoffrey , Maindola Priyank , White Mark A. , Bujalowski Wlodzimierz M. , Choi Kyung H. , Morais Marc C.
Published: November 2020

Double-stranded DNA viruses package their genomes into pre-assembled protein procapsids. This process is driven by macromolecular motors that transiently assemble at a unique vertex of the procapsid and utilize homomeric ring ATPases to couple genome encapsidation to ATP hydrolysis. Here we describe biochemical and biophysical characterization of the packaging ATPase from Lactococcus lactis phage asccφ28. Size-exclusion chromatography, analytical ultracentrifugation, small angle x-ray scattering, and negative stain TEM indicate that the ~45 kDa protein formed a 443 kDa cylindrical assembly with a maximum dimension of ~155 Å and radius of gyration of ~54 Å. Together with the dimensions of the crystallographic asymmetric unit from preliminary X-ray diffraction experiments, these results indicate that gp11 forms a decameric D5-symmetric complex consisting of two pentameric rings related by 2-fold symmetry. Additional kinetic analysis shows that recombinantly expressed gp11 has ATPase activity comparable to that of functional ATPase rings assembled on procapsids in other genome packaging systems. Hence, gp11 forms rings in solution that likely reflect the fully assembled ATPases in active virus-bound motor complexes. Whereas ATPase functionality in other dsDNA phage packaging systems requires assembly on viral capsids, the ability to form functional rings in solution imparts gp11 with significant advantages for high resolution structural studies and rigorous biophysical/biochemical analysis.
Dissection of barrier dysfunction in organoid-derived human intestinal epithelia induced byGiardia duodenalis
Authors: Kraft Martin , Holthaus David , Krug Susanne M. , Holland Gudrun , Schulzke Joerg-Dieter , Aebischer Toni , Klotz Christian
Published: November 2020

Background and aims

The protozoaGiardia duodenalisis a major cause of gastrointestinal illness worldwide, but underlying pathophysiological mechanisms remain obscure, partly due to the absence of adequate cellular models. We aimed to overcome these limitations and to recapitulate the authentic series of events in the primary human duodenal tissue by using the human organoid system.

Methods

We established a compartmentalized cellular transwell system with electrophysiological and barrier properties akin to duodenal mucosa and dissected the events leading toG. duodenalis-induced barrier breakdown by functional analysis of transcriptional, electrophysiological and tight junction components.

Results

Organoid-derived cell layers of different donors showed a time- and parasite load-dependent leak flux indicated by collapse of epithelial barrier uponG. duodenalisinfection. Transcriptomic analysis suggested major expression changes in genes contributing to ion transport and tight junction structure. SLC12A2/NKCC1- and CFTR-dependent chloride secretion was reduced early after infection, while changes in the tight junction composition, localization and structural organization occurred later as revealed by immunofluorescence analysis and freeze fracture electron microscopy.

Conclusion

Data suggest a previously unknown sequence of events culminating in intestinal barrier dysfunction uponG. duodenalisinfection ignited by alterations of cellular ion transport followed by breakdown of the tight junctional complex and loss of epithelial integrity. The newly established organoid-derived model to studyG. duodenalisinfection will help enable further molecular dissection of the disease mechanism and, thus, can help to find new options treating disease and infection, in particular relevant for chronic cases of giardiasis.
UniBind: maps of high-confidence direct TF-DNA interactions across nine species
Authors: Puig Rafael Riudavets , Boddie Paul , Khan Aziz , Castro-Mondragon Jaime Abraham , Mathelier Anthony
Published: November 2020

Transcription factors (TFs) bind specifically to TF binding sites (TFBSs) at cis-regulatory regions to control transcription. Hence, it is critical to locate these TF-DNA interactions to understand transcriptional regulation. The availability of datasets generated by chromatin immunoprecipitation followed by sequencing (ChIP-seq) empowers our efforts to predict the specific locations of TFBSs with greater confidence than previously possible by fusing computational and experimental approaches. In this work, we processed ~10,000 public ChIP-seq datasets from nine species to provide high-quality TFBS predictions. After quality control, it culminated with the prediction of ~56 million TFBSs with experimental and computational evidence for direct TF-DNA interactions for 644 TFs in >1,000 cell lines and tissues. These TFBSs were used to predict >198,000 cis-regulatory modules representing clusters of binding events in the corresponding genomes. The high-quality of the TFBSs was reinforced by their evolutionary conservation, enrichment at active cis-regulatory regions, and capacity to predict combinatorial binding of TFs. Further, we confirmed that the cell type and tissue specificity of enhancer activity was correlated with the number of TFs with binding sites predicted in these regions. All the data is provided to the community through the UniBind database that can be accessed through its web-interface (https://unibind.uio.no/), a dedicated RESTful API, and as genomic tracks. Finally, we provide an enrichment tool, available as a web-service and an R package, for users to find TFs with enriched TFBSs in a set of provided genomic regions. UniBind is the first resource of its kind, providing the largest collection of high-confidence direct TF-DNA interactions in nine species.