bluuebunny/crossref_metadata_2025_split huggingface dataset:
NAD+Redox Imbalance in the Heart Exacerbates Diabetic Cardiomyopathy
Authors: Chiao Ying Ann , Chakraborty Akash Deep , Light Christine M. , Tian Rong , Sadoshima Junichi , Shi Xiaojian , Gu Haiwei , Lee Chi Fung 
Published: July 2020

AbstractBackgroundDiabetes is a risk factor of heart failure and promotes cardiac dysfunction. Diabetic tissues are associated with NAD+redox imbalance; however, the hypothesis that NAD+redox imbalance leads to dysfunction of diabetic hearts has not been tested. In this study, we employed mouse models with altered NAD+redox balance to test the hypothesis.Methods and ResultsDiabetes was induced in C57BL/6 mice by streptozotocin injections, and diabetic cardiomyopathy (DCM) was allowed to develop for 16 weeks. Diabetic stress led to cardiac dysfunction and lowered NAD+/NADH ratio. This diabetogenic regimen was administered to cardiac-specific knockout mice of complex I subunit Ndufs4 (cKO), a model with lowered cardiac NAD+/NADH ratio without baseline dysfunction. Cardiac NAD+redox imbalance in cKO hearts exacerbated systolic and diastolic dysfunction of diabetic mice in both sexes. Collagen levels and transcript analyses of fibrosis and extracellular matrix-dependent pathways did not show change in diabetic cKO hearts, suggesting that the exacerbated cardiac dysfunction was likely due to cardiomyocyte dysfunction. We found that cardiac NAD+redox imbalance promoted superoxide dismutase 2 (SOD2) acetylation, protein oxidation, induced troponin I S150 phosphorylation and impaired energetics in diabetic cKO hearts. Importantly, elevation of cardiac NAD+levels by nicotinamide phosphoribosyltransferase (NAMPT) normalized NAD+redox balance, over-expression alleviated cardiac dysfunction and reversed pathogenic mechanisms in diabetic mice.ConclusionOur results show that NAD+redox imbalance to regulate protein acetylation and phosphorylation is a critical mediator of the progression of DCM, and suggest the therapeutic potential of harnessing NAD+metabolism in DCM.
Primate heart regenerationviamigration and fibroblast repulsion by human heart progenitors
Authors: Schneider Christine , Foo Kylie S. , De Angelis Maria Teresa , Santamaria Gianluca , Reiter Franziska , Dorn Tatjana , Bähr Andrea , Tsoi Yat Long , Hoppmann Petra , My Ilaria , Meier Anna , Jurisch Victoria , Hornaschewitz Nadja , Schwarz Sascha , Lu Kun , Tomasi Roland , Sudhop Stefanie , Parrotta Elvira , Gaspari Marco , Cuda Giovanni , Klymiuk Nikolai , Dendorfer Andreas , Krane Markus , Kupatt Christian , Sinnecker Daniel , Moretti Alessandra , Chien Kenneth R. , Laugwitz Karl-Ludwig 
Published: July 2020

SUMMARYHuman heart regeneration is one of the most critical unmet clinical needs at a global level1. Muscular regeneration is hampered both by the limited renewing capacity of adult cardiomyocytes2-4and the onset of cardiac fibrosis5,6, resulting in reduced compliance of the tissue. Primate have proven to be ideal models for pluripotent stem cell strategies for heart regeneration, but unravelling specific approaches to drive cell migration to the site of injury and inhibition of subsequent fibrosis have been elusive. Herein, by combining human cardiac progenitor lineage tracing and single-cell transcriptomics in injured non-human primate heart bio-mimics, we uncover the coordinated muscular regeneration of the primate heartviadirected migration of human ventricular progenitors to sites of injury, subsequent fibroblast repulsion targeting fibrosis, and ultimate functional replacement of damaged cardiac muscle by differentiation and electromechanical integration. Single-cell RNAseq captured distinct modes of action, uncovering chemoattraction mediated by CXCL12/CXCR4 signalling and fibroblast repulsion regulated by SLIT2/ROBO1 guidance in organizing cytoskeletal dynamics. Moreover, transplantation of human cardiac progenitors into hypo-immunogenic CAG-LEA29Y transgenic porcine hearts following injury proved their chemotactic response and their ability to generate a remuscularized scar without the risk of arrhythmogenesisin vivo. Our study demonstrates that inherent developmental programs within cardiac progenitors are sequentially activated in the context of disease, allowing the cells to sense and counteract injury. As such, they may represent an ideal bio-therapeutic for functional heart rejuvenation.
Genomic resources and toolkits for developmental study of whip spiders (Amblypygi) provide insights into arachnid genome evolution and antenniform leg patterning
Authors: Gainett Guilherme , Sharma Prashant P. 
Published: July 2020

AbstractBackgroundThe resurgence of interest in the comparative developmental study of chelicerates has led to important insights, such as the discovery of a genome duplication shared by spiders and scorpions, inferred to have occurred at the most recent common ancestor of Arachnopulmonata (a clade comprised of the five book lung-bearing arachnid orders). Nonetheless, several arachnid groups remain understudied in the context of development and genomics, such as the order Amblypygi (whip spiders). The phylogenetic position of Amblypygi in Arachnopulmonata posits them as an interesting group to test the incidence of the proposed genome duplication in the common ancestor of Arachnopulmonata, as well as the degree of retention of duplicates over 450 Myr. Moreover, whip spiders have their first pair of walking legs elongated and modified into sensory appendages (a convergence with the antenna of mandibulates), but the genetic patterning of these antenniform legs has never been investigated.ResultsWe established genomic resources and protocols for cultivation of embryos and gene expression assays by in situ hybridization to study the development of the whip spiderPhrynus marginemaculatus. Using embryonic transcriptomes from three species of Amblypygi, we show that the ancestral whip spider exhibited duplications of all ten Hox genes. We deploy these resources to show that paralogs of the leg gap genesdachshundandhomothoraxretain arachnopulmonate-specific expression patterns inP. marginemaculatus. We characterize the expression of leg gap genesDistal-less, dachshund-1/2andhomothorax-1/2in the embryonic antenniform leg and other appendages, and provide evidence that allometry, and by extension the antenniform leg fate, is specified early in embryogenesis.ConclusionThis study is the first step in establishingP. marginemaculatusas a model for modern chelicerate evolutionary developmental study, and provides the first resources sampling whip spiders for comparative genomics. Our results suggest that Amblypygi share a genome duplication with spiders and scorpions, and set up a framework to study the genetic specification of antenniform legs. Future efforts to study whip spider development must emphasize the development of tools for functional experiments inP. marginemaculatus.
A CRISPR-based SARS-CoV-2 diagnostic assay that is robust against viral evolution and RNA editing
Authors: Ooi Kean Hean , Tay Jie Wen Douglas , Teo Seok Yee , Liu Mengying Mandy , Kaewsapsak Pornchai , Jin Shengyang , Gao Yong-Gui , Tan Meng How 
Published: July 2020

AbstractExtensive testing is essential to break the transmission of the new coronavirus SARS-CoV-2, which causes the ongoing COVID-19 pandemic. Recently, CRISPR-based diagnostics have emerged as attractive alternatives to quantitative real-time PCR due to their faster turnaround time and their potential to be used in point-of-care testing scenarios. However, existing CRISPR-based assays for COVID-19 have not considered viral genome mutations and RNA editing in human cells. Here, we present the VaNGuard (Variant Nucleotide Guard) test that is not only specific and sensitive for SARS-CoV-2, but can also detect the virus when its genome or transcriptome has evolved or has been edited by deaminases in infected human cells. We show that an engineered AsCas12a enzyme is more tolerant of mismatches than wildtype LbCas12a and that multiplexed Cas12a targeting can overcome the presence of single nucleotide variations. Our assay can be completed in 30 minutes with a dipstick for a rapid point-of-care test.
Viability and mitochondrial bioenergetic functions in human colon cancer cells are not affected by treatment with peptides mtCPP1, UPF25, mtgCPP, and mtCPP1gHO
Authors: Timohhina Natalja , Cerrato Carmine Pasquale , Kurrikoff Kaido , Chekulayev Vladimir , Aid-Vanakova Jekaterina , Puurand Marju , Tepp Kersti , Shevchuk Igor , Langel Ulo , Kaambre Tuuli 
Published: July 2020

AbstractThe popularity of the specially synthesized cell-penetrating peptides (CPPs) in cancer treatment has grown recently. The main aim of this study was to investigate the effects of four mitochondrially targeted antioxidant CPPs on the viability and bioenergetic function of mitochondria in human adenocarcinoma Caco-2 cells. The number of viable cells was measured by MTT and trypan blue assays. Respirometry and the permeabilized cell technique were applied to measure the mitochondrial function in this cell line. We did not observe any significant effect of CPPs on the mitochondrial reserve respiratory capacity, the function of respiratory chain complexes, and the inclination of these cancer cells to aerobic glycolysis. mtgCPP peptide with the highest antioxidant activity demonstrated improved mitochondrial coupling efficiency. CPPs do not affect mitochondrial function directly but can be considered in therapeutics as a drug-delivery molecule
Rhizobium desertarenaesp. nov., isolated from the Saline Desert Soil from the Rann of Kachchh, India
Authors: Khairnar Mitesh , Hagir Ashwini , Narayan Avinash , Jain Kunal , Madamwar Datta , Shouche Yogesh , Rahi Praveen 
Published: July 2020

AbstractA novel bacterial strain designated ADMK78Twas isolated from the saline desert soil. The cells were rod-shaped, Gram-negative, and non-motile. The strain ADMK78Tgrows best at 28°C and pH 7.0 and can tolerate up to 2% (w/v) NaCl. Based on 16S rRNA gene phylogeny, the strain ADMK78Tbelongs to the genusRhizobium, with the highest similarity toRhizobium wuzhouenseW44T(98.7%) andRhizobium ipomoeaeshin9-1T(97.9%). Core-genes based phylogenetic analysis revealed that the strain ADMK78Tforms a distinct branch in betweenRhizobium ipomoeaeshin9-1TandRhizobium selenitireducensBAA-1503T. The average nucleotide identity of ADMK78Twas less than 82%, to members of the familyRhizobiaceae. The genomic DNA G+C content of strain ADMK78Tis 58.6 mol%. The major fatty acids of strain ADMK78Twere C18:0and C18:1 ω7c. The strain ADMK78Tshowed differences in physiological, phenotypic, and protein profiles estimated by MALDI-TOF MS to its closest relatives. Based on the phenotypic, chemotaxonomic properties, and phylogenetic analyses, the strain ADMK78Tcould be distinguished from the recognized species of the genusRhizobium. It is suggested to represent a novel species of this genus, for which the nameRhizobium desertarenaesp. nov. is proposed. The type strain is ADMK78T(=MCC 3400T; KACC 21383T; JCM 33657T).
Dissimilar conservation pattern in hepatitis C virus mutant spectra, consensus sequences, and data banks
Authors: García-Crespo Carlos , Soria María Eugenia , Gallego Isabel , de Ávila Ana Isabel , Martínez-González Brenda , Vázquez-Sirvent Lucía , Gómez Jordi , Briones Carlos , Gregori Josep , Quer Josep , Perales Celia , Domingo Esteban 
Published: July 2020

AbstractThe influence of quasispecies dynamics on long-term virus diversification in nature is a largely unexplored question. Specifically, whether intra-host nucleotide and amino acid variation in quasispecies fits variation observed in consensus sequences or data bank alignments is unknown. Genome conservation and dynamics simulations are used for the computational design of universal vaccines, therapeutic antibodies and pan-genomic antiviral agents. The expectation is that selection of escape mutants will be limited when mutations at conserved residues are required. This strategy assumes long-term (epidemiologically relevant) conservation but, critically, does not consider short-term (quasispecies-dictated) residue conservation. We have calculated mutant frequencies of individual loci from mutant spectra of hepatitis C virus (HCV) populations passaged in cell culture and from infected patients. Nucleotide or amino acid conservation in consensus sequences of the same populations, or in the Los Alamos HCV data bank did not match residue conservation in mutant spectra. The results relativize the concept of sequence conservation in viral genetics, and suggest that residue invariance in data banks is an insufficient basis for the design of universal viral ligands for clinical purposes. Our calculations suggest relaxed mutational restrictions during quasispecies dynamics, which may contribute to higher calculated short-term than long-term viral evolutionary rates.
IPANEMAP: Integrative Probing Analysis of Nucleic Acids Empowered by Multiple Accessibility Profiles
Authors: Saaidi Afaf , Allouche Delphine , Regnier Mireille , Sargueil Bruno , Ponty Yann 
Published: July 2020

AbstractThe manual production of reliable RNA structure models from chemical probing experiments benefits from the integration of information derived from multiple protocols and reagents. However, the interpretation of multiple probing profiles remains a complex task, hindering the quality and reproducibility of modeling efforts.We introduceIPANEMAP, the first automated method for the modeling of RNA structure from multiple probing reactivity profiles. Input profiles can result from experiments based on diverse protocols, reagents, or collection of variants, and are jointly analyzed to predict the dominant conformations of an RNA.IPANEMAPcombines sampling, clustering, and multi-optimization, to produce secondary structure models that are both stable and well-supported by experimental evidences. The analysis of multiple reactivity profiles, both publicly available and produced in our study, demonstrates the good performances ofIPANEMAP, even in a mono probing setting. It confirms the potential of integrating multiple sources of probing data, informing the design of informative probing assays.AvailabilityIPANEMAPis freely downloadable athttps://github.com/afafbioinfo/IPANEMAPContactyann.ponty@lix.polytechnique.frSupplementary information available at NAR online.
A calcineurin-mediated scaling mechanism that controls a K+-leak channel to regulate morphogen and growth factor transcription
Authors: Yi Chao , Spitters Tim WGM , Al-Far Ezz Al-Din Ahmed , Wang Sen , Xiong Tian Long , Cai Simian , Yan Xin , Guan Kaomei , Wagner Michael , El-Armouche Ali , Antos Christopher L. 
Published: July 2020

AbstractThe increase in activity of the two-pore potassium-leak channel Kcnk5b maintains allometric juvenile growth of adult zebrafish appendages. However, it remains unknown how this channel maintains allometric growth and how its bioelectric activity is regulated to scale these anatomical structures. We show the activation of Kcnk5b is sufficient to activate several genes that are part of important development programs. We providein vivotransplantation evidence that the activation of gene transcription is cell autonomous. We also show that Kcnk5b will induce the expression of different subsets of the tested developmental genes in different cultured mammalian cell lines, which may explain how one electrophysiological stimulus can coordinately regulate the allometric growth of diverse populations of cells in the fin that use different developmental signals. We also provide evidence that the post-translational modification of serine 345 in Kcnk5b by calcineurin regulates channel activity to scale the fin. Thus, we show how an endogenous bioelectric mechanism can be regulated to promote coordinated developmental signaling to generate and scale a vertebrate appendage.
Replication dynamics of recombination-dependent replication forks
Authors: Naiman Karel , Campillo-Funollet Eduard , Watson Adam T. , Budden Alice , Miyabe Izumi , Carr Antony M. 
Published: July 2020

AbstractDNA replication fidelity is essential for maintaining genetic stability. Forks arrested at replication fork barriers can be stabilised by the intra-S phase checkpoint, subsequently being rescued by a converging fork, or resuming when the barrier is removed. However, some arrested forks cannot be stabilised and fork convergence cannot rescue in all situations. Thus, cells have developed homologous recombination-dependent mechanisms to restart persistently inactive forks. To understand HR-restart we use polymerase usage sequencing to visualizein vivoreplication dynamics at anS. pombereplication barrier,RTS1, and model replication by Monte Carlo simulation. We show that HR-restarted forks synthesise both strands with Pol δ for up to 30 kb without maturing to a δ/ε configuration and that Pol α is not used significantly on either strand, suggesting the lagging strand template remains as a gap that is filled in by Pol δ later. We further demonstrate that HR-restarted forks progress uninterrupted through a fork barrier that arrests canonical forks. Finally, by manipulating lagging strand resection during HR-restart by deletingpku70, we show that the leading strand initiates replication at the same position, signifying the stability of the 3’ single strand in the context of increased resection.
Genome reduction is associated with bacterial pathogenicity across different scales of temporal and ecological divergence
Authors: Murray Gemma G. R. , Charlesworth Jane , Miller Eric L. , Casey Michael J. , Lloyd Catrin T. , Gottschalk Marcelo , Tucker A. W. (Dan) , Welch John J. , Weinert Lucy A. 
Published: July 2020

AbstractEmerging bacterial pathogens threaten global health and food security, and so it is important to ask whether these transitions to pathogenicity have any common features. We present a systematic study of the claim that pathogenicity is associated with genome reduction and gene loss. We compare broad-scale patterns across all bacteria, with detailed analyses ofStreptococcus suis,a zoonotic pathogen of pigs, which has undergone multiple transitions between disease and carriage forms. We find that pathogenicity is consistently associated with reduced genome size across three scales of divergence (between species within genera, and between and within genetic clusters ofS. suis). While genome reduction is most often associated with bacterial endosymbionts, other correlates of symbiosis (reduced metabolic capacity, GC content, and the expansion of non-coding elements) are not found consistently in pathogens, and genome reduction in pathogens cannot be attributed to changes in intracellularity or host restriction. Together, our results indicate that genome reduction is a predictive marker of pathogenicity in bacteria, and that the causes and consequences of genome reduction in pathogens are sometimes distinct from those in endosymbionts.
AE-LGBM: Sequence-Based Novel Approach To Detect Interacting Protein PairsviaEnsemble of Autoencoder and LightGBM
Authors: Sharma Abhibhav , Singh Buddha 
Published: July 2020

1.AbstractProtein-protein interactions (PPIs) are a vital phenomenon for every biological process. Prediction of PPI can be very helpful in the probing of protein functions which can further help in the development of new and powerful therapy designs for disease prevention. A lot of experimental studies have been done previously to study PPIs. However, lab-based experimental studies of PPI prediction are resource-extensive and time-consuming. In recent years, several high throughput, computational approaches to predict PPI have been developed but they could be fallible in terms of accuracy and false-positive rate. To overcome these shortcomings, we propose a novel approach AE-LGBM to predict the PPI more accurately. This method is based on the LightGBM classifier and utilizes the Autoencoder, which is an artificial neural network, to efficiently produce lower-dimensional, discriminative, and noise-free features. We incorporate conjoint triad (CT) features along with Composition-Transition-Distribution (CTD) features into the model and obtained promising results. The ten-fold cross-validation results indicate that the prediction accuracies obtained for Human and Yeast datasets are 98.7% and 95.4% respectively. This method was further evaluated on other datasets and has achieved excellent accuracies of 100%, 100%, 99.9%, 99.2% on E.coli, M.musculus, C.elegans, and H.sapiens respectively. We also executed AE-LGBM over three important PPI networks namely, single-core network (CD9), the multiple-core network (The Ras/Raf/MEK/ERK pathway), and the cross-connection network (Wnt Network). The method was successful in predicting the pathway with an impressive accuracy of 100%, 100%, and 98.9% respectively. These figures are significantly higher than previous methods that are based on state-of-the-art models and models including LightGBM or Autoencoder, proving AE-LGBM to be highly versatile, efficient, and robust.
Large-scale Characterization of Drug Responses of Clinically Relevant Proteins in Cancer Cell Lines
Authors: Zhao Wei , Li Jun , Chen Mei-Ju , Ju Zhenlin , Nesser Nicole K. , Johnson-Camacho Katie , Boniface Christopher T. , Lawrence Yancey , Pande Nupur T. , Davies Michael A. , Herlyn Meenhard , Muranen Taru , Zervantonakis Ioannis , Von Euw Erika , Schultz Andre , Kumar Shwetha V. , Korkut Anil , Spellman Paul T. , Akbani Rehan , Slamon Dennis J. , Gray Joe W. , Brugge Joan S. , Lu Yiling , Mills Gordon B. , Liang Han 
Published: July 2020

SummaryPerturbation biology is a powerful approach to developing quantitative models of cellular behaviors and gaining mechanistic insights into disease development. In recent years, large-scale resources for phenotypic and mRNA responses of cancer cell lines to perturbations have been generated. However, similar large-scale protein response resources are not available, resulting in a critical knowledge gap for elucidating oncogenic mechanisms and developing effective cancer therapies. Here we generated and compiled perturbed expression profiles of ~210 clinically relevant proteins in >12,000 cancer cell-line samples in response to >150 drug compounds using reverse-phase protein arrays. We show that integrating protein response signals substantially increases the predictive power for drug sensitivity and aids in gaining insights into mechanisms of drug resistance. We build a systematic map of protein-drug connectivity and develop an open-access, user-friendly data portal for community use. Our study provides a valuable information resource for a broad range of quantitative modeling and biomedical applications.HighlightsA large collection of cancer cell line protein responses to drug perturbationsPerturbed protein responses greatly increase predictive power for drug sensitivityBuild a systematic map of protein-drug connectivity based on response profilesDevelop a user-friendly, interactive data portal for community use