bluuebunny/crossref_metadata_2025 huggingface dataset:
Virtuous and Wise: Apprehending Female Medical Practice from Hebrew Texts on Women’s Healthcare
Authors: Caballero-Navas Carmen
Published: February 2019

In this article, I analyse the attribution of remedies and therapeutic procedures to women, anonymous in the main, embedded in a number of texts belonging to the medieval Hebrew corpus of literature on women’s healthcare. By suggesting a classification of the ways in which both women and their healing activities are referred to, I intend to offer a framework that helps to identify Jewish (and non-Jewish) women’s health agency from medical texts. In addition to textual analysis, I compare some of the mentions with evidences found in a variety of historical and literary sources for the sake of helping to contextualise them.
Roseithermus sacchariphilus gen. nov., sp. nov. and proposal of Salisaetaceae fam. nov., representing new family in the order Rhodothermales
Authors: Park Mi-Jeong , Oh Ji Hye , Yang Sung-Hyun , Kwon Kae Kyoung
Published: February 2019

A novel bacterium with cells that were pinkish-cream-coloured, aerobic, rod-shaped, 0.62–1.00 µm wide and 2.3–3.3 µm long, designated as strain MEBiC09517T, was isolated from Buksung-Po, a small port in Incheon, Republic of Korea. Strain MEBiC09517T had low 16S rRNA gene sequence similarity to validly reported strains; among them,

Rubrivirga

profundi

SAORIC-476T displayed highest sequence similarity (89.9 %). Nevertheless, the novel strain shared a phylogenetic line with members of the genus

Rhodothermus

, not the genus

Rubrivirga

. Optimum growth conditions of strain MEBiC09517T were at 50–55 °C, pH 7 and in 2.0–4.0 % salt concentration. Strain MEBiC09517T was found to be an obligate marine bacterium that requires KCl, MgCl2 and CaCl2 as well as NaCl for growth. A phosphatidylethanolamine, a diphosphatidylglycerol, three glycolipids and four unidentified lipids were the strain's predominant polar lipid components. The fatty acid of the cell wall mainly consisted of carbons with 16 or 18 chain lengths such as C16 : 0, C18 : 0, C18 : 1 and summed feature 3 (C16 : 1ω6c and/or C16 : 1ω7c). The predominant menaquinone was MK-7. The DNA G+C content is 68.65 mol%. Strain MEBiC09517T differs from genera of the order

Rhodothermales

in terms of fatty acid composition, growth conditions, and range of carbon source utilization. Based on phylogenetic analysis using the strain's 16S rRNA gene sequence and results of physiological tests, strain MEBiC09517T (KCCM=43267T, JCM=32374T) is proposed as Roseithermus sacchariphilus gen. nov., sp. nov. Additionally, the novel family Salisaetaceae fam. nov. based on phylogenetic analysis and physiological characteristics is suggested.
Anti-biofilm Activity of Graphene Quantum Dots via Self-Assembly with Bacterial Amyloid Proteins
Authors: Wang Yichun , Kadiyala Usha , Qu Zhibei , Elvati Paolo , Altheim Christopher , Kotov Nicholas A. , Violi Angela , VanEpps J. Scott
Published: February 2019

Bacterial biofilms represent an essential part of Earth’s ecosystem that can cause multiple ecological, technological and health problems. The environmental resilience and sophisticated organization of biofilms are enabled by the extracellular matrix that creates a protective network of biomolecules around the bacterial community. Current anti-biofilm agents can interfere with extracellular matrix production but, being based on small molecules, are degraded by bacteria and rapidly diffuse away from biofilms. Both factors severely reduce their efficacy, while their toxicity to higher organisms create additional barriers to their practicality. In this paper we report on the ability of graphene quantum dots to effectively disperse matureStaphylococcus aureusbiofilms, interfering with the self-assembly of amyloid fibers - a key structural component of the extracellular matrix. Mimicking peptide-binding biomolecules, graphene quantum dots form supramolecular complexes with phenol soluble modulins, the peptide monomers of amyloid fibers. Experimental and computational results show that graphene quantum dots efficiently dock near theN-terminus of the peptide and change the secondary structure of phenol soluble modulins, which disrupts their fibrillation and represents a novel strategy for mitigation of bacterial communities.

GQD mediated staphylococcal biofilm dispersal. GQDs interact with PSM peptides and frustrate the fibrillation process. The reduction in amyloid fibers prevents robust stabilization of the biofilm. In addition, there is an increase in free monomeric and oligomeric PSM peptides which trigger dispersal events.
The Crohn’s disease-associated Escherichia coli strain LF82 rely on SOS and stringent responses to survive, multiply and tolerate antibiotics within macrophages
Authors: Demarre Gaëlle , Prudent Victoria , Schenk Hanna , Rousseau Emilie , Bringer Marie-Agnes , Barnich Nicolas , Nhieu Guy Tran Van , Rimsky Sylvie , Monte Silvia De , Espéli Olivier
Published: February 2019

Adherent Invasive Escherichia coli (AIEC) strains recovered from Crohn's disease lesions survive and multiply within macrophages. A reference strain for this pathovar, AIEC LF82, forms microcolonies within phagolysosomes, an environment that prevents commensal E. coli multiplication. Little is known about the LF82 intracellular growth status, and signals leading to macrophage intra-vacuolar multiplication. We used single-cell analysis, genetic dissection and mathematical models to monitor the growth status and cell cycle regulation of intracellular LF82. We found that within macrophages, bacteria may replicate or undergo non-growing phenotypic switches. This switch results from stringent response firing immediately after uptake by macrophages or at later stages, following genotoxic damage and SOS induction during intracellular replication. Importantly, non-growers resist treatment with various antibiotics. Thus, intracellular challenges induce AIEC LF82 phenotypic heterogeneity and non-growing bacteria that could provide a reservoir for antibiotic-tolerant bacteria responsible for relapsing infections.
Adapted dandelions increase seed dispersal potential when they are attacked by root herbivores
Authors: Bont Zoe , Pfander Marc , Robert Christelle A. M. , Huber Meret , Poelman Erik H. , Raaijmakers Ciska E. , Erb Matthias
Published: February 2019

Plants allow their offspring to escape unfavourable local conditions through seed dispersal. Whether plants use this strategy to escape herbivores is not well understood. Here, we explore how differentTaraxacum officinalepopulations modify seed dispersal in response to root herbivore attack byMelolontha melolonthain the field. Root herbivore attack increases seed dispersal potential through a reduction in seed weight in populations that have evolved under high root herbivore pressure, but not in populations that have evolved under low pressure. This increase in dispersal potential is associated with reduced germination, suggesting that adapted plants trade dispersal for establishment. Analysis of vegetative growth parameters suggests that increased dispersal is not the result of stress flowering. These results suggest that root herbivory selects for genotypes that increase their dispersal ability in response to herbivore attack.
A High-Resolution Head and Brain Computer Model for Forward and Inverse EEG Simulation
Authors: Warner Alexandra , Tate Jess , Burton Brett , Johnson Christopher R.
Published: February 2019

To conduct computational forward and inverse EEG studies of brain electrical activity, researchers must construct realistic head and brain computer models, which is both challenging and time consuming. The availability of realistic head models and corresponding imaging data is limited in terms of imaging modalities and patient diversity. In this paper, we describe a detailed head modeling pipeline and provide a high-resolution, multimodal, open-source, female head and brain model. The modeling pipeline specifically outlines image acquisition, preprocessing, registration, and segmentation; three-dimensional tetrahedral mesh generation; finite element EEG simulations; and visualization of the model and simulation results. The dataset includes both functional and structural images and EEG recordings from two high-resolution electrode configurations. The intermediate results and software components are also included in the dataset to facilitate modifications to the pipeline. This project will contribute to neuroscience research by providing a high-quality dataset that can be used for a variety of applications and a computational pipeline that may help researchers construct new head models more efficiently.
Social history and exposure to pathogen signals modulate social status effects on gene regulation in rhesus macaques
Authors: Sanz Joaquin , Maurizio Paul L. , Snyder-Mackler Noah , Simons Noah D. , Voyles Tawni , Kohn Jordan , Michopoulos Vasiliki , Wilson Mark , Tung Jenny , Barreiro Luis B.
Published: February 2019

Social experiences are an important predictor of disease susceptibility and survival in humans and other social mammals. Chronic social stress is thought to generate a pro-inflammatory state characterized by elevated antibacterial defenses and reduced investment in antiviral defense. Here, we manipulated long-term social status in female rhesus macaques to show that social subordination alters the gene expression response to ex vivo bacterial and viral challenge. As predicted by current models, bacterial lipopolysaccharide polarizes the immune response such that low status corresponds to higher expression of genes in NF-κB-dependent pro-inflammatory pathways and lower expression of genes involved in the antiviral response and type I interferon (IFN) signaling. Counter to predictions, however, low status drives more exaggerated expression of both NF-κB and IFN-associated genes after cells are exposed to the viral mimic Gardiquimod. Status-driven gene expression patterns are not only linked to social status at the time of sampling, but also to social history (i.e., past social status), especially in unstimulated cells. However, for a subset of genes, we observed interaction effects in which females who fell in rank were more strongly affected by current social status than those who climbed the social hierarchy. Together, our results indicate that the effects of social status on immune cell gene expression depend on pathogen exposure, pathogen type, and social history – in support of social experience-mediated biological embedding in adulthood, even in the conventionally memory-less innate immune system.
Distinct Regulation of Bioenergetics and Translation by Group I mGluR and NMDAR
Authors: Dastidar Sudhriti Ghosh , Sharma Shreya Das , Chakraborty Sumita , Chattarji Sumantra , Bhattacharya Aditi , Muddashetty Ravi S
Published: February 2019

Neuronal activity is responsible for large energy consumption within the brain. However, the cellular mechanisms draining ATP upon the arrival of a stimulus are yet to be explored systematically at the post-synapse. Here we provide evidence that a significant fraction of ATP is consumed upon glutamate stimulation to energize the mGluR-induced protein synthesis. We find that both mGluR and NMDAR alter protein synthesis and ATP consumption with distinct kinetics at the synaptic-dendritic compartments. While mGluR activation leads to a rapid and sustained reduction in the neuronal ATP level, NMDAR activation has no immediate impact on the same. ATP consumption correlates inversely to the kinetics of protein synthesis for both the receptors. We observe a persistent elevation in protein synthesis within 5 minutes of mGluR activation and robust inhibition of the same within 2 minutes of NMDAR activation, assessed by the phosphorylation status of eEF2 and metabolic labeling. However, a delayed protein synthesis-dependent ATP expenditure ensues after 15 minutes of NMDAR activation. We identify a central role for AMPK in this correlation between protein synthesis and ATP consumption. AMPK is dephosphorylated and inhibited upon mGluR activation while it was rapidly phosphorylated upon NMDAR activation. Perturbing AMPK activity disrupts the receptor-specific modulations of eEF2 phosphorylation and protein synthesis. Therefore, our observations suggest that the glutamate receptors required modulating the AMPK-eEF2 signaling axis to alter neuronal protein synthesis and bioenergetics.

Short Summary

Stimulation of glutamate receptors induces robust protein synthesis within cortical neurons and consumes a significantly large fraction of cellular ATP. Glutamate receptors viz. mGlulR and NMDAR modulate AMPK-eEF2 signaling uniquely leading to the dynamic regulation of protein synthesis and bioenergetics.

Key Highlights

Protein synthesis following glutamate receptor activation is responsible for the bulk of the activity-induced ATP consumption in cortical neurons.

mGluR and NMDAR regulate protein synthesis with distinct kinetics and dictate the subsequent impacts over neuronal ATP level.

Dynamic modulation of AMPK and eEF2 phosphorylation is key to create unique temporal features of receptor-specific protein synthesis and bioenergetics.
Functional characterization of genes mediating cell wall metabolism and responses to plant cell wall integrity impairment
Authors: Engelsdorf Timo , Kjaer Lars , Gigli-Bisceglia Nora , Vaahtera Lauri , Bauer Stefan , Miedes Eva , Wormit Alexandra , James Lucinda , Chairam Issariya , Molina Antonio , Hamann Thorsten
Published: February 2019

Plant cell walls participate in all plant-environment interactions. Maintaining cell wall integrity (CWI) during these interactions is essential. This realization led to increased interest in CWI and resulted in knowledge regarding early perception and signalling mechanisms active during CWI maintenance. By contrast, knowledge regarding processes mediating changes in cell wall metabolism upon CWI impairment is very limited. To identify genes involved and to investigate their contributions to the processes we selected 23 genes with altered expression in response to CWI impairment and characterized the impact of T-DNA insertions in these genes on cell wall composition using Fourier-Transform Infrared Spectroscopy (FTIR) in Arabidopsis thaliana seedlings. Insertions in 14 genes led to cell wall phenotypes detectable by FTIR. A detailed analysis of four genes found that their altered expression upon CWI impairment is dependent on THE1 activity, a key component of CWI maintenance. Phenotypic characterizations of insertion lines suggest that the four genes are required for particular aspects of CWI maintenance, cell wall composition or resistance to Plectosphaerella cucumerina infection in adult plants. Taken together, the results implicate the genes in responses to CWI impairment, cell wall metabolism and/or pathogen defence, thus identifying new molecular components and processes relevant for CWI maintenance.
Window to the Fluorescence: TheWhiteEye-Color Gene of Western Corn Rootworm,Diabrotica virgifera virgifera
Authors: Grubbs Nathaniel , Chu Fu-Chyun , Lorenzen Marcé D.
Published: February 2019

Eye-color mutations have proven useful in multiple insect species to help facilitate the development and use of transgenic tools for functional genomics. While there is species-specific variation in the pigments used to color insect eyes, every species studied thus far requires an ortholog of the ABC transporter genewhitefor proper pigmentation of the eyes. Previously, we generated transgenic western corn rootworm,Diabrotica virgifera virgifera, and found that their wild-type eye color obscured our ability to visualize a fluorescent marker driven by the widely used 3xP3 eye-specific promoter. Therefore, we sought to identify theD. v. virgiferaortholog ofwhite(Dvvw). Here we report the discovery, cloning, and analysis ofDvvwcDNA and promoter. We also utilize RNA interference to knock downDvvwmRNA in a transgenic strain, thereby demonstrating the utility of eye-color mutations when developing transgenic technologies.
The intersectional genetics landscape for human
Authors: Macedo Andre , Gontijo Alisson M.
Published: February 2019

The human body is made up of hundreds, perhaps thousands of cell types and states, most of which are currently inaccessible genetically. Genetic accessibility carries significant diagnostic and therapeutic potential by allowing the selective delivery of genetic messages or cures to cells. Research in model organisms has shown that single regulatory element (RE) activities are seldom cell type specific, limiting their usage in genetic systems designed to restrict gene expression posteriorly to their delivery to cells. Intersectional genetic approaches can increase the number of genetically accessible cells. A typical intersectional method acts like an AND logic gate by converting the input of two or more active REs into a single synthetic output, which becomes unique for that cell. Here, we systematically assessed the intersectional genetics landscape of human using a curated subset of cells from a large RE usage atlas obtained by Cap Analysis of Gene Expression Sequencing (CAGE-Seq) of thousands of primary and cancer cells (the FANTOM5 consortium atlas). We developed the heuristics and algorithms to retrieve and quality rank AND gate intersections intra- and inter-individually. We find that >90% of the 154 primary cell types surveyed can be distinguished from each other with as little as 3 to 4 active REs, with quantifiable safety and robustness. We call these minimal intersections of active REs with cell-type diagnostic potential “Versatile Entry Codes” (VEnCodes). We show that VEnCodes could be found for 100% of the 158 cancer cell types surveyed, and that most of these are highly robust to intra- and interindividual variation. Our tools for generating and quality-ranking VEnCodes can be adapted to other RE usage databases and to other intersectional methods using alternative Boolean logic operations. Our work demonstrate the potential of intersectional approaches for future gene delivery technologies in human.
Repeated evolution of asymmetric genitalia and right-sided mating behavior in theDrosophila nannopteraspecies group
Authors: Acurio Andrea , Rhebergen Flor T. , Paulus Sarah , Courtier-Orgogozo Virginie , Lang Michael
Published: February 2019

Background

Male genitals have repeatedly evolved left-right asymmetries, and the causes of such evolution remain unclear. TheDrosophila nannopteragroup contains four species, among which three exhibit left-right asymmetries of distinct genital organs. In the most studied species,Drosophila pachea, males display asymmetric genital lobes and they mate right-sided on top of the female. Copulation position of the other species is unknown.

Results

To assess whether the evolution of genital asymmetry could be linked to the evolution of one-sided mating, we examined phallus morphology and copulation position inD. pacheaand closely related species. The phallus was found to be symmetric in all investigated species exceptD. pachea, which display an asymmetric phallus with a right-sided gonopore, andD. acanthoptera, which harbor an asymmetrically bent phallus. In all examined species, males were found to position themselves symmetrically on top of the female, except inD. pacheaandD. nannoptera, where males mated right-sided, in distinctive, species-specific positions. In addition, the copulation duration was found to be increased innannopteragroup species compared to closely related outgroup species.

Conclusion

Our study shows that gains, and possibly losses, of asymmetry in genital morphology and mating position have evolved repeatedly in thenannopteragroup. Current data does not allow us to conclude whether genital asymmetry has evolved in response to changes in mating position, or vice versa.
rSeqTU – a machine-learning based R package for prediction of bacterial transcription units
Authors: Niu Sheng-Yong , Liu Binqiang , Ma Qin , Chou Wen-Chi
Published: February 2019

A transcription unit (TU) is composed of one or multiple adjacent genes on the same strand that are co-transcribed in mostly prokaryotes. Accurate identification of TUs is a crucial first step to delineate the transcriptional regulatory networks and elucidate the dynamic regulatory mechanisms encoded in various prokaryotic genomes. Many genomic features, e.g., gene intergenic distance, and transcriptomic features including continuous and stable RNA-seq reads count signals, have been collected from a large amount of experimental data and integrated into classification techniques to computationally predict genome-wide TUs. Although some tools and web servers are able to predict TUs based on bacterial RNA-seq data and genome sequences, there is a need to have an improved machine-learning prediction approach and a better comprehensive pipeline handling QC, TU prediction, and TU visualization. To enable users to efficiently perform TU identification on their local computers or high-performance clusters and provide a more accurate prediction, we develop an R package, named rSeqTU. rSeqTU uses a random forest algorithm to select essential features describing TUs and then uses support vector machine (SVM) to build TU prediction models. rSeqTU (available at https://s18692001.github.io/rSeqTU/) has six computational functionalities including read quality control, read mapping, training set generation, random-forest-based feature selection, TU prediction, and TU visualization.
Does Long-Term Selection for Development Time Result in Canalization: A Test UsingDrosophila melanogaster
Authors: Ghosh Shampa M. , Satish K. M. , Mohan J. , Joshi Amitabh
Published: February 2019

Canalization denotes the robustness of a trait against genetic or environmental perturbation. Plasticity, in contrast indicates the environmental sensitivity of a trait. Stabilizing selection is thought to increase canalization of a trait, whereas directional selection is often thought to lead to decanalization. However, the relationship between selection, canalization and plasticity remains largely unclear. Experimental evolution is a powerful approach for addressing fundamental questions in evolution. Here, we ask whether long-term directional selection for reduced pre-adult development time inDrosophila melanogasterresults in the evolution of increased canalization for development time, the trait under primary selection. We additionally investigate whether pre-adult survivorship, a trait only secondarily under selection in this experimental regime, also evolves to become canalized. We examine canalization both in terms of stability of population means and of within population variability across two environmental axes. We used four large outbred populations ofD. melanogasterselected for rapid pre-adult development and early reproduction for 295 generations, and four corresponding ancestral control populations that were not under conscious selection for development time or early reproduction. The selected populations had evolved 25% reduction in both development time and pre-adult survivorship at the time of this study. We studied development time and pre-adult survivorship of the selected populations and controls across various combinations ofrearing temperature and larval density. Development time in the selected populations had become more canalized than controls with regard to density, but not temperature. Canalization of development time across density appears to have evolved due to evolutionary changes in the lifehistory and physiology of the selected populations. Pre-adult survivorship, only a secondary correlate of fitness in the selected populations, did not show any clear trend in terms of canalization with regard to either density or temperature, and, overall variation in the trait was greater compared to development time within and across environments. Whether long-term directional selection canalizes or not, therefore, appears to be dependent in a complex way on specific interactions of trait, selection regime and environmental factor in the context of the ecology and physiology of the popualtions under study.
An Array of 60,000 Antibodies for Proteome-Scale Antibody Generation and Target Discovery
Authors: Wang Zhaohui , Li Yang , Hou Bing , Pronobis Mira I. , Wang Yuemeng , Wang Mingqiao , Cheng Guangcun , Zhang Zhe , Weng Weining , Wang Yiqiang , Tang Yanfang , Xu Xuefan , Pan Rong , Lin Fei , Wang Nan , Chen Ziqing , Wang Shiwei , Ma Luyan zulie , Li Yangrui , Huang Dongliang , Jiang Li , Wang Zhiqiang , Zeng Wenfang , Zhang Ying , Du Xuemei , Lin Ying , Li Zhiqing , Xia Qingyou , Geng Jing , Dai Huaping , Wang Chen , Yu Yuan , Zhao Xiaodong , Yuan Zheng , Yan Jian , Ren Bing , Nie Qinghua , Zhang Xiquan , Wang Kun , Chen Fuling , Zhang Qin , Zhu Yuxian , Poss Kenneth D. , Tao Shengce , Meng Xun
Published: February 2019

Antibodies are essential for elucidating the roles of genes decoded by genome sequencing. However, affordable technology for proteome-scale antibody generation does not exist. To address this, we developed the Proteome Epitope Tag Antibody Library (PETAL) and its array. PETAL consists of 62,208 mAbs against 15,199 peptides from diverse proteomes. PETAL harbors binders for a great multitude of proteins in nature due to antibody multispecificity, an intrinsic feature of an antibody. Distinctive combinations of 10,000-20,000 mAbs were found to target specific proteomes by array screening. Phenotype-specific mAb-target pairs were discovered for maize and zebrafish samples. Immunofluorescence and flow cytometry mAbs for human membrane proteins and ChIP-seq mAbs for transcription factors were identified from respective proteome-binding PETAL mAbs. Differential screening of cell surface proteomes of tumor and normal tissues discovered internalizing tumor antigens for antibody-drug conjugates. By discovering high affinity mAbs at a fraction of current time and cost, PETAL enables proteome-scale antibody generation and target discovery.
Optimization of graph construction can significantly increase the power of structural brain network studies
Authors: Messaritaki Eirini , Dimitriadis Stavros I. , Jones Derek K.
Published: February 2019

Structural brain networks derived from diffusion magnetic resonance imaging data have been used extensively to describe the human brain, and graph theory has allowed quantification of their network properties. Schemes used to construct the graphs that represent the structural brain networks differ in the metrics they use as edge weights and the algorithms they use to define the network topologies. In this work, twenty graph construction schemes were considered. The schemes use the number of streamlines, the fractional anisotropy, the mean diffusivity or other attributes of the tracts to define the edge weights, and either an absolute threshold or a data-driven algorithm to define the graph topology. The test-retest data of the Human Connectome Project were used to compare the reproducibility of the graphs and their various attributes (edges, topologies, graph theoretical metrics) derived through those schemes, for diffusion images acquired with three different diffusion weightings. The impact of the scheme on the statistical power of the study and on the number of participants required to detect a difference between populations or an effect of an intervention was also calculated.

The reproducibility of the graphs and their attributes depended heavily on the graph construction scheme. Graph reproducibility was higher for schemes that used thresholding to define the graph topology, while data-driven schemes performed better at topology reproducibility. Additionally, schemes that used thresholding resulted in better reproducibility for local graph theoretical metrics, while data-driven schemes performed better for global metrics. Crucially, the number of participants required to detect a difference between populations or an effect of an intervention could change by a large factor depending on the scheme used, affecting the power of studies to reveal the effects of interest.
EWAS-Galaxy: a tools suite for population epigenetics integrated into Galaxy
Authors: Murat Katarzyna , Grüning Björn , Poterlowicz Paulina Wiktoria , Westgate Gillian , Tobin Desmond J , Poterlowicz Krzysztof
Published: February 2019

Background

Epigenome-wide association studies (EWAS) analyse genome-wide activity of epigenetic marks in cohorts of different individuals to find associations between epigenetic variation and phenotype. One of the most common technique used in EWAS studies is the Infinium Methylation Assay, which quantifies the DNA methylation level of over 450k loci. Although a number of bioinformatics tools have been developed to analyse the assay they require some programming skills and experience to use them.

Results

We have developed a collection of user-friendly tools for the Galaxy platform for those without experience aimed at DNA methylation analysis using the Infinium Methylation Assay. Our tool suite is integrated into Galaxy (http://galaxyproject.org), web based platform. This allows users to analyse data from the Infinium Methylation Assay in the easiest possible way.

Conclusions

The EWAS suite provides a group of integrated tools that combine analytical methods into a range of handy analysis pipelines. Our tool suite is available from the Galaxy test toolshed, GitHub repository and also as a Docker image. The aim of this project is to make EWAS analysis more flexible and accessible to everyone.
Neural network-based alterations during repeated heat pain stimulation in major depression
Authors: Bilek Edda , Zang Zhenxiang , Wolf Isabella , Henrich Florian , Mößnang Carolin , Braun Urs , Treede Rolf-Detlef , Magerl Walter , Meyer-Lindenberg Andreas , Tost Heike
Published: February 2019

The current study aimed to identify alterations in brain activation and connectivity related to nociceptive processing and pain sensitization in major depressive disorder (MDD), using repeated heat pain stimulation during functional magnetic resonance imaging (fMRI) in 37 MDD patients and 33 healthy controls. Regional activation did not differ between groups, but functional connectivity was significantly decreased in MDD in a neural network connecting frontal, temporal and occipital areas (family-wise error (FWE)-corrected pFWE = 0.045). Supplemental analyses suggested a significant association between network connectivity and trait neuroticism (p = 0.007) but not with the clinical state or familiar risk of MDD (all p values > 0.13). Our data relate a network-based phenotype for altered pain processing and antinociceptive control to MDD and encourage future studies on the shared intermediate neural psychological risk architecture of MDD and chronic pain.
Bat-fruit networks structure resist habitat modification but species roles change in the most transformed habitats
Authors: Castaño John Harold , Andrés Carranza-Quiceno Jaime , Pérez-Torres Jairo
Published: February 2019

Species do not function as isolated entities, rather they are organized in complex networks of interactions. These networks develop the ecological processes that provide ecosystem services for human societies. Understanding the causes and consequences of changes in ecological networks due to landscape modification would allow us to understand the consequences of ecological processes. However, there is still theoretical controversy and few empirical data on the effects of network characteristics on the loss of natural environments. We investigate how bat–fruit networks respond to three landscapes representing the gradient of modification from pre-montane forest to a heterogeneous agricultural landscape in the Colombian Andes (continuous forests, forest fragments, and crops). We found that forest contained smaller bat–fruit networks than forest fragments and crops. Modified landscapes had similar ecological network structures to forest (nestedness and modularity), but crops contained less specialized networks compared to forests and fragments and the species role in these habitats change. The networks in the rural coffee landscape maintain their structure in the different transformation scenarios, indicating that seed dispersal services are maintained even in the most transformed scenarios. This could be related to the high heterogeneity present in this rural landscape. Although the number of species does not decrease due to transformations, species change their roles in the most transformed habitats. This result sheds light on the way that biodiversity responds to anthropogenic transformations, showing higher stability than theoretically predicted.
A primer on high-dimensional data analysis workflows for studying visual cortex development and plasticity
Authors: Balsor Justin L. , Jones David G. , Murphy Kathryn M.
Published: February 2019

New techniques for quantifying large numbers of proteins or genes are transforming the study of plasticity mechanisms in visual cortex (V1) into the era of big data. With those changes comes the challenge of applying new analytical methods designed for high-dimensional data. Studies of V1, however, can take advantage of the known functions that many proteins have in regulating experience-dependent plasticity to facilitate linking big data analyses with neurobiological functions. Here we discuss two workflows and provide example R code for analyzing high-dimensional changes in a group of proteins (or genes) using two data sets. The first data set includes 7 neural proteins, 9 visual conditions, and 3 regions in V1 from an animal model for amblyopia. The second data set includes 23 neural proteins and 31 ages (20d-80yrs) from human post-mortem samples of V1. Each data set presents different challenges and we describe using PCA, tSNE, and various clustering algorithms including sparse high-dimensional clustering. Also, we describe a new approach for identifying high-dimensional features and using them to construct aplasticity phenotypethat identifies neurobiological differences among clusters. We include an R package “v1hdexplorer” that aggregates the various coding packages and custom visualization scripts written in R Studio.
Transcript expression-aware annotation improves rare variant discovery and interpretation
Authors: Cummings Beryl B. , Karczewski Konrad J. , Kosmicki Jack A. , Seaby Eleanor G. , Watts Nicholas A. , Singer-Berk Moriel , Mudge Jonathan M. , Karjalainen Juha , Satterstrom F. Kyle , O’Donnell-Luria Anne , Poterba Timothy , Seed Cotton , Solomonson Matthew , Alföldi Jessica ,   The Genome Aggregation Database Production Team,   The Genome Aggregation Database Consortium, Daly Mark J. , MacArthur Daniel G.
Published: February 2019

The acceleration of DNA sequencing in patients and population samples has resulted in unprecedented catalogues of human genetic variation, but the interpretation of rare genetic variants discovered using such technologies remains extremely challenging. A striking example of this challenge is the existence of disruptive variants in dosage-sensitive disease genes, even in apparently healthy individuals. Through manual curation of putative loss of function (pLoF) variants in haploinsufficient disease genes in the Genome Aggregation Database (gnomAD)(1), we show that one explanation for this paradox involves alternative mRNA splicing, which allows exons of a gene to be expressed at varying levels across cell types. Currently, no existing annotation tool systematically incorporates this exon expression information into variant interpretation. Here, we develop a transcript-level annotation metric, the proportion expressed across transcripts (pext), which summarizes isoform quantifications for variants. We calculate this metric using 11,706 tissue samples from the Genotype Tissue Expression project(2) (GTEx) and show that it clearly differentiates between weakly and highly evolutionarily conserved exons, a proxy for functional importance. We demonstrate that expression-based annotation selectively filters 22.8% of falsely annotated pLoF variants found in haploinsufficient disease genes in gnomAD, while removing less than 4% of high-confidence pathogenic variants in the same genes. Finally, we apply our expression filter to the analysis of de novo variants in patients with autism spectrum disorder (ASD) and developmental disorders and intellectual disability (DD/ID) to show that pLoF variants in weakly expressed regions have effect sizes similar to those of synonymous variants, while pLoF variants in highly expressed exons are most strongly enriched among cases versus controls. Our annotation is fast, flexible, and generalizable, making it possible for any variant file to be annotated with any isoform expression dataset, and will be valuable for rare disease diagnosis, rare variant burden analyses in complex disorders, and curation and prioritization of variants in recall-by-genotype studies.
Control of Hematopoietic Stem and Progenitor Cell Function Through Epigenetic Regulation of Energy Metabolism and Genome Integrity
Authors: Yang Zhenhua , Shah Kushani , Khodadadi-Jamayran Alireza , Jiang Hao
Published: February 2019

It remains largely unclear how stem cells regulate bioenergetics and genome integrity to ensure tissue homeostasis. Here, our integrative gene analyses suggest metabolic and genotoxic stresses may underlie the common functional defects of both fetal and adult hematopoietic stem and progenitor cells (HSPCs) upon loss of DPY30, an epigenetic modulator that facilitates H3K4 methylation. DPY30 directly regulates expression of several key glycolytic genes, and its loss in HSPCs critically impaired energy metabolism, including both glycolytic and mitochondrial pathways. We also found significant increase in DNA breaks as a result of impaired DNA repair upon DPY30 loss, and inhibition of DNA damage response partially rescued clonogenicity of the DPY30-deficient HSPCs. Moreover, CDK inhibitor p21 was upregulated in DPY30-deficient HSPCs, and p21 deletion alleviated their functional defect. These results demonstrate that epigenetic mechanisms by H3K4 methylation play a crucial role in HSPC function through control of energy metabolism and protecting genome integrity.
Spatial heterogeneity and organization of tumor mutation burden and immune infiltrates within tumors based on whole slide images correlated with patient survival in bladder cancer
Authors: Xu Hongming , Park Sunho , Clemenceau Jean René , Choi Jinhwan , Radakovich Nathan , Lee Sung Hak , Hwang Tae Hyun
Published: February 2019

High-TMB (TMB-H) could result in an increased number of neoepitopes from somatic mutations expressed by a patient’s own tumor cell which can be recognized and targeted by neighboring tumor-infiltrating lymphocytes (TILs). Deeper understanding of spatial heterogeneity and organization of tumor cells and their neighboring immune infiltrates within tumors could provide new insights into tumor progression and treatment response. Here we developed and applied computational approaches using digital whole slide images (WSIs) to investigate spatial heterogeneity and organization of regions harboring TMB-H tumor cells and TILs within tumors, and its prognostic utility. In experiments using WSIs from The Cancer Genome Atlas bladder cancer (BLCA), our findings show that WSI-based approaches can reliably predict patient-level TMB status and delineate spatial TMB heterogeneity and co-organization with TILs. TMB-H patients with low spatial heterogeneity enriched with high TILs show improved overall survival indicating a prognostic role of spatial TMB and TILs information in BLCA.
A chromatin modulator sustains self-renewal and enables differentiation of postnatal neural stem and progenitor cells
Authors: Shah Kushani , King Gwendalyn D. , Jiang Hao
Published: February 2019

It remains unknown whether H3K4 methylation, an epigenetic modification associated with gene activation, regulates fate determination of the postnatal neural stem and progenitor cells (NSCs and NPCs, or NSPCs). Here we show that the Dpy30 subunit of the major H3K4 methyltransferase complexes is preferentially expressed at a high level in NSCs and NPCs. By genetically inactivating Dpy30 in specific regions of mouse brain, we demonstrate a crucial role of efficient H3K4 methylation in maintaining both the self-renewal and differentiation capacity of postnatal NSPCs. Dpy30 inactivation results in deficiency in global H3K4 methylation, and disrupts development of hippocampus and especially the dentate gyrus and subventricular zone, the major regions for postnatal NSC activities. By in vitro assays on neurospheres from mouse brains as well as human and mouse NPCs, we show that Dpy30 is indispensable for sustaining the self-renewal and proliferation of NSPCs in a cell-intrinsic manner, and also enables the differentiation of mouse and human NPCs to neuronal and glial lineages. Dpy30 directly regulates H3K4 methylation and the induction of several genes critical in neurogenesis. These findings link a prominent epigenetic mechanism of gene expression to the fundamental properties of NSPCs, and may have implications in neurodevelopmental disorders.

SIGNIFICANCE STATEMENT

As a highly prominent epigenetic mark that is associated with gene activation and a number of neurodevelopmental disorders in human, the role of histone H3K4 methylation in the fate determination of neural stem cells is unclear. Result of this study uncover a profound role of this epigenetic modification in the fundamental properties of postnatal neural stem cells, including self-renewal and differentiation, and may have implications for a better understanding and treatment of a broad spectrum of neurodevelopmental disorders associated with H3K4 methylation modulators.
TheDrosophila melanogasterPIF1 helicase promotes survival during replication stress and processive DNA synthesis during double-strand gap repair
Authors: Kocak Ece , Dykstra Sarah , Nemeth Alexandra , Coughlin Catherine G. , Rodgers Kasey , McVey Mitch
Published: February 2019

PIF1 is a 5’ to 3’ DNA helicase that can unwind double-stranded DNA and disrupt nucleic acid-protein complexes. InSaccharomyces cerevisiae, Pif1 plays important roles in mitochondrial and nuclear genome maintenance, telomere length regulation, unwinding of G-quadruplex structures, and DNA synthesis during break-induced replication. Some, but not all, of these functions are shared with other eukaryotes. To gain insight into the evolutionarily conserved functions of PIF1, we createdpif1null mutants inDrosophila melanogasterand assessed their phenotypes throughout development. We found thatpif1mutant larvae exposed to high concentrations of hydroxyurea, but not other DNA damaging agents, experience reduced survival to adulthood. Embryos lacking PIF1 fail to segregate their chromosomes efficiently during early nuclear divisions, consistent with a defect in DNA replication. Furthermore, loss of the BRCA2 protein, which is required for stabilization of stalled replication forks in metazoans, causes synthetic lethality in third instar larvae lacking either PIF1 or the polymerase delta subunit POL32. Interestingly,pif1mutants have a reduced ability to synthesize DNA during repair of a double-stranded gap, but only in the absence of POL32. Together, these results support a model in which Drosophila PIF1 functions with POL32 during times of replication stress but acts independently of POL32 to promote synthesis during double-strand gap repair.
Varying crosslinking motifs drive the mesoscale mechanics of actin-microtubule composites
Authors: Ricketts Shea N. , Francis Madison L. , Farhadi Leila , Rust Michael J. , Das Moumita , Ross Jennifer L. , Robertson-Anderson Rae M.
Published: February 2019

The cytoskeleton dynamically tunes its mechanical properties by altering the interactions between semiflexible actin filaments, rigid microtubules, and crosslinking proteins. Here, we use optical tweezers microrheology and confocal microscopy to characterize how varying crosslinking motifs impact the microscopic and mesoscale mechanics and mobility of actin-microtubule composites. We show that, upon subtle changes in the crosslinking pattern, composites separate into two distinct classes of force response – primarily elastic versus more viscous behavior. For example, a composite in which actin and microtubules are crosslinked to each other is markedly more elastic than one in which both filaments are crosslinked but cannot link together. Notably, this distinction only emerges at mesoscopic scales in response to nonlinear forcing, whereas varying crosslinking motifs have little impact on the microscale mechanics and steady-state mobility of composites. Our unexpected scale-dependent results not only inform the physics underlying key cytoskeleton processes and structures, but, more generally, provide valuable perspective to materials engineering endeavors focused on polymer composites.
Temperature-dependent changes to host-parasite interactions alter the thermal performance of a bacterial host
Authors: Padfield Daniel , Castledine Meaghan , Buckling Angus
Published: February 2019

Thermal performance curves (TPCs) are used to predict changes in species interactions, and hence range shifts, disease dynamics and community composition, under forecasted climate change. Species interactions might in turn affect TPCs. Here, we investigate whether temperature-dependent changes in a microbial host-parasite interaction (the bacteriumPseudomonas fluorescens, and its bacteriophage, SBWФ2) changes the host TPC. The bacteriophage had a narrower infectivity range, with their critical thermal maximum ∼6°C lower than those at which the bacteria still had high growth. Consequently, in the presence of phage, the host TPC had a higher optimum temperature and a lower maximum growth rate. These changes were driven by a temperature-dependent evolution, and cost, of resistance; the largest cost of resistance occurring where bacteria grew best in the absence of phage. Our work highlights how ecological and evolutionary mechanisms can alter the effect of a parasite on host thermal performance, even over very short timescales.

Data accessibility statement

All data and R code used in the analysis will be made available on GitHub and archived on Zenodo.