bluuebunny/crossref_metadata_2025_split huggingface dataset:
Proteogenomic characterization of age and sex interactions in cardiac gene expression
Authors: Han Yu , Wennersten Sara A. , Wright Julianna , Ludwig R. W. , Lau Edward , Lam Maggie P. Y. 
Published: May 2022

AbstractThe risks of heart diseases are significantly modulated by biological age and sex, but how these factors influence baseline cardiac gene expression remains incompletely understood. Here we characterized young adult and early aging mouse hearts using proteogenomics to identify age and sex dependent gene expression signatures in the mouse heart. RNA sequencing from 4 months old and 20 months old female and male C57BL/6J hearts identified thousands of genes with differential transcript abundances both between sexes (male vs. female) and across age groups (20 mo. vs. 4 mo.). Sex-associated cardiac genes are broadly distributed, functioning in the TCA cycle, mitochondrial translation, autophagy, and other processes. In addition, we found over 800 genes with differential aging response between male and female, which are enriched in calmodulin signaling and cell cycle regulations. Comparison with mass spectrometry data shows a cluster of metabolism genes with up-regulated transcripts but down-regulated protein levels in aging hearts, consistent with an uncoupling of transcriptional regulations in the genetic program with protein compositions. An analysis of sex-adjusted aging cardiac transcriptomes further revealed widespread remodeling of exon usage patterns that is largely independent from differential gene expression, concomitant with upstream changes in RNA-binding protein and splice factor transcripts. To evaluate the potential impact of the splicing events on proteoform composition in the heart, we applied an RNA-guided-proteomics computational pipeline to analyze the mass spectrometry data, and putatively identified hundreds of splice events with the potential to rewire the cardiac proteome through producing detectable splice isoform specific peptides. Taken together, this study contributes to emerging evidences for considerable sexual dimorphism in the cardiac aging process involving sex-biased aging genes and regulatory networks. Aging hearts are associated with a rewiring of RNA splicing programs, including sex- and age-dependent changes in exon usages and splice patterns that have the potential to influence cardiac protein structure and function. These changes represent an under-investigated aspect of cardiac aging that should be considered in the search for disease mechanisms.
Rapidly changing speciation and extinction rates can be inferred in spite of non-identifiability
Authors: Kopperud Bjørn T. , Magee Andrew F. , Höhna Sebastian 
Published: May 2022

AbstractThe birth-death model is commonly used to infer speciation and extinction rates by fitting the model to extant phylogenetic trees. Recently, it was demonstrated that speciation and extinction rates are not identifiable if the rates are allowed to vary freely over time. The group of birth-death models that are not identifiable from each other is called a congruence class. Every model in a congruence class is equally likely, and there is no statistical evidence that can be used to favor one over the other. This issue has led researchers to question if and what patterns can reliably be inferred, and whether time-variable birth-death models should be fitted at all. We explore the congruence class in the context of several empirical phylogenies as well as hypothetical scenarios and summarize shared patterns in the congruence class. We show that strong directional trends in speciation and extinction rates are ubiquitous among most models within the congruence class, and conclude that inference of strong directional trends is therefore robust. Conversely, estimates of constant rates or gentle slopes are not robust and must be treated with caution. Additionally, most conflict in trends within the congruence class is observed near the present, implying that very recent rate changes should be treated carefully. Interestingly, the space of valid speciation rates is limited in contrast to extinction rates, which are less constrained. These results provide further evidence and insights that speciation rates can be estimated more reliably than extinction rates.
RAS and PP2A activities converge on epigenetic gene regulation
Authors: Aakula Anna , Sharma Mukund , Tabaro Francesco , Honkanen Henrik , Schapira Matthieu , Arrowsmith Cheryl , Nykter Matti , Westermarck Jukka 
Published: May 2022

ABSTRACTRAS-mediated human cell transformation requires inhibition of the tumor suppressor Protein Phosphatase 2A (PP2A). Both RAS and PP2A mediate their effects by phosphoregulation, but phosphoprotein targets and cellular processes in which RAS and PP2A activities converge in human cancers have not been systematically analyzed. Here, based on mass spectrometry phosphoproteome data we discover that phosphosites co-regulated by RAS and PP2A are enriched on proteins involved in epigenetic gene regulation. As examples, RAS and PP2A co-regulate the same phosphorylation sites on HDAC1/2, KDM1A, MTA1/2, RNF168 and TP53BP1. Mechanistically, we validate co-regulation of NuRD chromatin repressor complex by RAS and PP2A. Consistent with their known synergistic effects in cancer, RAS activation and PP2A inhibition resulted in epigenetic reporter de-repression and activation of oncogenic transcription. Notably, transcriptional de-repression by PP2A inhibition was associated with increased euchromatin and decrease in global DNA methylation. Further, targeting of RAS- and PP2A-regulated epigenetic proteins decreased viability of KRAS-mutant human lung cancer cells. Collectively the results indicate that epigenetic protein complexes involved in oncogenic gene expression constitute a significant point of convergence for RAS hyperactivity and PP2A inhibition in cancer. Further, the results provide a rich source for future understanding of phosphorylation as a previously unappreciated layer of regulation of epigenetic gene regulation in cancer, and in other RAS/PP2A-regulated cellular processes.
Antimicrobial resistance genes predict plasmid generalism and network structure in wastewater
Authors: Risely Alice , Stalder Thibault , Simmons Benno I. , Top Eva M. , Buckling Angus , Sanders Dirk 
Published: May 2022

AbstractPlasmids are mobile genetic elements that can act as mutualists or parasites to their bacterial hosts depending on their accessory genes and environment. Ecological network theory predicts that mutualists, such as plasmids with antimicrobial resistance (AMR) genes in the presence of antimicrobials, should act as generalists, while plasmids without beneficial genes are expected to be more specialised. Therefore, whether the relationship between plasmid and host is mutualistic or antagonistic is likely to have a strong impact on the formation of interaction network structures and the spread of AMR genes across microbial networks. Here we re-analyse Hi-C metagenome data from wastewater samples and identify plasmid signatures with machine learning to generate a natural host-plasmid network. We found that AMR-carrying plasmids indeed interacted with more hosts than non-AMR plasmids (on average 14 versus 3, respectively). The AMR plasmid-host subnetwork showed a much higher connectedness and nestedness than the subnetwork associated with non-AMR plasmids. The overall network was clustered around Proteobacteria and AMR-carrying plasmids giving them a crucial role in network connectivity. Therefore, by forming mutualistic networks with their hosts, beneficial AMR plasmids lead to more connected network structures that ultimately share a larger gene pool of AMR genes across the network.
Context-dependent transcriptional regulation by Drosophila Polycomb Response Elements
Authors: Coleman Rory T. , Struhl Gary 
Published: May 2022

AbstractPolycomb Response Elements (PREs) are cis-acting DNA sequences that confer heritable states of Drosophila HOX gene expression by anchoring Polycomb and Trithorax Group (PcG and TrxG) chromatin modifiers. PREs are also associated with hundreds of other Drosophila genes, most of which are regulated dynamically in response to developmental and physiological context, rather than heritably like HOX genes. Here, we assess the role(s) PREs play at these other loci by analyzing how genomic inserts of a transgenic form of the HOX gene Ultrabithorax (Ubx) can both control and respond to neighboring genes depending on the presence of a single, excisable PRE. Our results support the view that PREs and their associated PcG and TrxG modifiers act primarily to confer quantitative, rather than qualitative, influences on gene expression with the response of any given gene depending on how it integrates this information with other regulatory elements in the local genomic milieu. They also show that PREs can act on neighboring genes selectively and at remarkably long range, but that any given gene can be susceptible or impervious to PRE/PcG/TrxG input depending on context. Finally, we find that transcription and PRE/PcG-dependent silencing are not mutually exclusive: a Ubx transgene inside the intron of a continuously transcribed “host” gene is nevertheless silenced by its resident PRE. We posit that the widely accepted roles of PcG and TrxG complexes in maintaining heritable states of gene expression apply only to a limited coterie of target genes such as HOX genes that are evolutionarily selected to exclude regulatory elements that can over-ride this control.
eRNA profiling uncovers the enhancer landscape of oesophageal adenocarcinoma and reveals new deregulated pathways
Authors: Ahmed Ibrahim , Yang Shen-Hsi , Ogden Samuel , Zhang Wei , Li Yaoyong ,   the OCCAMS consortium, Sharrocks Andrew D. 
Published: May 2022

AbstractCancer is driven by both genetic and epigenetic changes that impact on gene expression profiles and the resulting tumourigenic phenotype. Enhancers are transcriptional regulatory elements that are key to our understanding of how this rewiring of gene expression is achieved in cancer cells. Here we have harnessed the power of RNA-seq data from hundreds of patients with oesophageal adenocarcinoma (OAC) or its precursor state Barrett’s oesophagus (BO) coupled with open chromatin maps to identify potential enhancer RNAs (eRNAs) and their associated enhancer regions in this cancer. We identify ∼1000 OAC-specific enhancers and use this data to uncover new cellular pathways that are operational in OAC. Among these are enhancers for JUP, MYBL2 and CCNE1, and we show that their activity is required for cancer cell viability. We also demonstrate the clinical utility of our dataset for identifying disease stage and patient prognosis. Our data therefore identify an important set of regulatory elements that enhance our molecular understanding of OAC and point to potential new therapeutic directions.
What the book of Lambda doesn’t tell us about temperate phages and lysogeny in the real world
Authors: Berryhill Brandon A. , Garcia Rodrigo , McCall Ingrid C. , Chaudhry Waqas , Petit Marie-Agnès , Levin Bruce R. 
Published: May 2022

AbstractThe most significant difference between bacteriophages functionally and ecologically is whether they are purely lytic (virulent) or temperate. Virulent phages can only be transmitted horizontally by infection, most commonly with the death of their hosts. Temperate phages can also be transmitted horizontally, but upon infection of susceptible bacteria, their genomes can be incorporated into that of their host’s as a prophage and be transmitted vertically in the course of cell division by their lysogenic hosts. From what we know from studies with the temperate phage Lambda and other temperate phages, in laboratory culture, lysogenic bacteria are protected from killing by the phage coded for by their prophage by immunity; where upon infecting lysogens, the free temperate phage coded by their prophage are lost. Why are lysogens not also resistant as well as immune to the phage coded by their prophage since immunity does not confer protection against virulent phages? To address this question, we used a mathematical model and performed experiments with temperate and virulent mutants of the phage Lambda in laboratory culture. Our models predict and experiments confirm that selection would favor the evolution of resistant as well as immune lysogens, particularly if the environment includes virulent phage that share the same receptors as the temperate. To explore the validity and generality of this prediction, we examined ten lysogenic Escherichia coli from natural populations. All ten were capable of forming immune lysogens but their original hosts were resistant to the phage coded by their prophage.Significance StatementThis jointly theoretical and experimental study predicted that lysogenic bacteria, will be resistant as well as immune to the phage coded for by their prophage. All ten naturally occurring lysogenic Escherichia coli tested were resistant to the temperate phage coded for by their prophage.
DINAVID: A Distributed and Networked Image Analysis System for Volumetric Image Data
Authors: Han Shuo , Chen Alain , Lee Soonam , Fu Chichen , Yang Changye , Wu Liming , Winfree Seth , El-Achkar Tarek M. , Dunn Kenneth W. , Salama Paul , Delp Edward J. 
Published: May 2022

AbstractBackgroundThe advancement of high content optical microscopy has enabled the acquisition of very large 3D image datasets. Image analysis tools and three dimensional visualization are critical for analyzing and interpreting 3D image volumes. The analysis of these volumes require more computational resources than a biologist may have access to in typical desktop or laptop computers. This is especially true if machine learning tools are being used for image analysis. With the increased amount of data analysis and computational complexity, there is a need for a more accessible, easy-to-use, and efficient network-based/cloud-based 3D image processing system.ResultsThe Distributed and Networked Analysis of Volumetric Image Data (DINAVID) system was developed to enable remote analysis of 3D microscopy images for biologists. DINAVID is a server/cloud-based system with a simple web interface that allows biologists to upload 3D volumes for analysis and visualization. DINAVID is designed using open source tools and has two main sub-systems, a computational system for 3D microscopy image processing and analysis as well as a 3D visualization system.ConclusionsIn this paper, we will present an overview of the DINAVID system and compare it to other tools currently available for microscopy image analysis.
Inhibition of DNMT1 methyltransferase activity via glucose-regulatedO-GlcNAcylation alters the epigenome
Authors: Shin Heon , Leung Amy , Costello Kevin R. , Senapati Parijat , Kato Hiroyuki , Lee Michael , Lin Dimitri , Tang Xiaofang , Chen Zhen Bouman , Schones Dustin E. 
Published: May 2022

AbstractThe DNA methyltransferase activity of DNMT1 is vital for genomic maintenance of DNA methylation. We report here that DNMT1 function is regulated byO-GlcNAcylation, a protein modification that is sensitive to glucose levels, and that elevatedO-GlcNAcylation of DNMT1 from high glucose environment leads to alterations to the epigenome. Using mass spectrometry and complementary alanine mutation experiments, we identified S878 as the major residue that isO-GlcNAcylated on DNMT1. Functional studies further revealed thatO-GlcNAcylation of DNMT1-S878 results in an inhibition of methyltransferase activity, resulting in a general loss of DNA methylation that is preferentially at partially methylated domains (PMDs). This loss of methylation corresponds with an increase in DNA damage and apoptosis. These results establishO-GlcNAcylation of DNMT1 as a mechanism through which the epigenome is regulated by glucose metabolism and implicates a role for glycosylation of DNMT1 in metabolic diseases characterized by hyperglycemia.
AtlasXbrowser enables spatial multi-omics data analysis through the precise determination of the region of interest
Authors: Barnett Joshua , Silverman Jonah , Wetzel Molly , Rao Poorvi , Sotudeh Noori , Wang Liya 
Published: May 2022

AbstractRecent developments in novel spatial sequencing technologies allow for the incorporation of spatial information into high-throughput sequencing assays. One such method, Deterministic Barcoding in Tissue for spatial omics sequencing (DBiT-seq, abbreviated herein as DBiT), utilizes perpendicular microfluidic channels to deliver DNA barcodes across the tissue in a spatially-encoded manner, allowing for sequenced reads to be mapped back onto the 2-D coordinates of the tissue to provide spatial coordinates to cells. DBiT has been the first spatial sequencing technology developed for epigenomic assays beyond transcriptome and proteome. However, despite existing of many open-source software packages for downstream bioinformatics analysis, there is no software available for processing DBiT image data with evenly spaced channels. To facilitate the integration of DBiT spatial and sequenced data, here we proposed a new method to precisely capture the spatial information and further developed AtlasXbrowser based on the new method to extract spatial data from the image data.AtlasXbrowser is a python-based tool with GUI that requires no technical expertise to operate and enables researchers to incorporate brightfield and epifluorescence images of processed tissue samples into downstream bioinformatics analysis tools.Availability and implementationFreely available at https://github.com/atlasxomics/AtlasXbrowser.
High throughput peptidomics elucidates immunoregulatory functions of plant thimet oligopeptidase-directed proteostasis
Authors: Iannetta Anthony A. , Berg Philip , Nejat Najmeh , Smythers Amanda L. , Setu Rezwana R. , Wesser Uyen , Purvis Ashleigh L. , Brown Zoe A. , Wommack Andrew J. , Popescu Sorina C. , Hicks Leslie M. , Popescu George V. 
Published: May 2022

AbstractTargeted proteolysis activities activated during the plant immune response catalyze the synthesis of stable endogenous peptides. Little is known about their biogenesis and biological roles. Herein, we characterize an Arabidopsis thaliana mutant top1top2 in which targeted proteolysis of immune-active peptides is drastically impaired during effector-triggered immunity (ETI). For effective ETI, the redox-sensitive thimet oligopeptidases TOP1 and TOP2 are required. Quantitative mass spectrometry-based peptidomics allowed differential peptidome profiling of wild type (WT) and top1top2 mutant at the early ETI stages. Biological processes of energy-producing and redox homeostasis were enriched, and TOPs were necessary to maintain the dynamics of ATP and NADP(H) accumulation in the plant during ETI. Subsequently, a set of novel TOPs substrates validated in vitro enabled the definition of the TOP-specific cleavage motif and informed an in-silico model of TOP proteolysis to generate bioactive peptide candidates. Several candidates, including those derived from proteins associated with redox metabolism, were confirmed in planta. The top1top2 background rescued WT’s ETI deficiency caused by treatment with peptides derived from targeted proteolysis of the negative immune regulator FBR12, the reductive enzyme APX1, the isoprenoid pathway enzyme DXR, and ATP-subunit β. These results demonstrate TOPs role in orchestrating the production and degradation of phytocytokines.
Mapping odorant sensitivities reveals a sparse but structured representation of olfactory chemical space by sensory input to the mouse olfactory bulb
Authors: Burton Shawn D. , Brown Audrey , Eiting Thomas P. , Youngstrom Isaac A. , Rust Thomas C. , Schmuker Michael , Wachowiak Matt 
Published: May 2022

SUMMARYIn olfactory systems, convergence of sensory neurons onto glomeruli generates a map of odorant receptor identity. How glomerular maps relate to sensory space remains unclear. We sought to better characterize this relationship in the mouse olfactory system by defining glomeruli in terms of the odorants to which they are most sensitive. Using high-throughput odorant delivery and ultrasensitive imaging of sensory inputs, we imaged responses to 185 odorants presented at concentrations determined to activate only one or a few glomeruli across the dorsal olfactory bulb. The resulting datasets defined the tuning properties of glomeruli - and, by inference, their cognate odorant receptors - in a low-concentration regime, and yielded consensus maps of glomerular sensitivity across a wide range of chemical space. Glomeruli were extremely narrowly tuned, with ~25% responding to only one odorant, and extremely sensitive, responding to their effective odorants at sub-picomolar to nanomolar concentrations. Such narrow tuning in this concentration regime allowed for reliable functional identification of many glomeruli based on a single diagnostic odorant. At the same time, the response spectra of glomeruli responding to multiple odorants was best predicted by straightforward odorant structural features, and glomeruli sensitive to distinct odorants with common structural features were spatially clustered. These results define an underlying structure to the primary representation of sensory space by the mouse olfactory system.
HumanMine: advanced data searching, analysis and cross-species comparison
Authors: Lyne Rachel , Bazaga Adrián , Butano Daniela , Contrino Sergio , Heimbach Joshua , Hu Fengyuan , Kalderimis Alexis , Lyne Mike , Reierskog Kevin , Stepan Radek , Sullivan Julie , Wise Archie , Yehudi Yo , Micklem Gos 
Published: May 2022

AbstractHumanMine (www.humanmine.org) is an integrated database of human genomics and proteomics data that provides a powerful interface to support sophisticated exploration and analysis of data compiled from experimental, computational and curated data sources. Built using the InterMine data integration platform, HumanMine includes genes, proteins, pathways, expression levels, SNPs, diseases and more, integrated into a single searchable database. HumanMine promotes integrative analysis, a powerful approach in modern biology that allows many sources of evidence to be analysed together. The data can be accessed through a user-friendly web interface as well as a powerful, scriptable web service API to allow programmatic access to data. The web interface includes a useful identifier resolution system, sophisticated query options and interactive results tables that enable powerful exploration of data, including data summaries, filtering, browsing and export. A set of graphical analysis tools provide a rich environment for data exploration including statistical enrichment of sets of genes or other biological entities. HumanMine can be used for integrative multi-staged analysis that can lead to new insights and uncover previously unknown relationships.Database URL: https://www.humanmine.org