bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel two-component system-like elements reveal functional domains associated with restriction-modification systems and paraMORC ATPases in bacteria
Authors: Bellieny-Rabelo Daniel , Pretorius Willem JS , Moleleki Lucy N 
Published: August 2020

ABSTRACTBackgroundTwo-component systems (TCS) are essential machineries allowing for efficient signal recognition and transmission in bacterial cells. The majority of TCSs utilized by bacteria are composed by a sensor histidine kinase (HK) and a cognate response regulator (RR). In the present study, we report two newly predicted protein domains — Response_reg_2 (PF19192) and HEF_HK (PF19191) — in bacteria which exhibit high structural similarity, respectively, with typical domains of RRs and HKs.ResultsAdditionally, the genes encoding for the novel predicted domains exhibit a 91.6% linkage observed across 644 genomic regions recovered from 628 different bacterial strains. The remarkable adjacent co-localization between genes carrying Response_reg_2 and HEF_HK in addition to their conserved structural features, which are highly similar to those from well-known HKs and RRs, raises the possibility of Response_reg_2 and HEF_HK integrating a new TCS in bacteria. The genomic regions in which these predicted two-component systems-like are located additionally exhibit an overrepresented presence of restriction-modification (R-M) systems especially the type II R-M. Among these, there is a conspicuous presence of C-5 cytosine-specific DNA methylases which may indicate a functional association with the newly discovered domains. The solid presence of R-M systems and the presence of the GHKL family domain HATPase_c_3 across most of the HEF_HK-containing genes are also indicative that these genes are evolutionarily related to the paraMORC family of ATPases.ConclusionsThe present study uncovered two novel protein conserved domains and raised the possibility of a TCS-like system undertaking a regulatory role mechanistically linked to R-M systems in a large variety of bacterial lineages.
Fine-scale landscape genetics unveiling contemporary asymmetric movement of red panda (Ailurus fulgens) in Kangchenjunga landscape, India
Authors: Dalui Supriyo , Khatri Hiren , Singh Sujeet Kumar , Basu Shambadeb , Ghosh Avijit , Mukherjee Tanoy , Sharma Lalit Kumar , Singh Randeep , Chandra Kailash , Thakur Mukesh 
Published: August 2020

AbstractWildlife management in rapid changing landscapes requires critical planning through cross cutting networks, and understanding of landscape features, often affected by the anthropogenic activities. The present study demonstrates fine-scale spatial patterns of genetic variation and contemporary gene flow of red panda (Ailurus fulgens) populations with respect to landscape connectivity in Kangchenjunga Landscape (KL), India. The study found about 1309.54 Km2area suitable for red panda in KL-India, of which 62.21% area fell under the Protected Area network. We identified 24 unique individuals from 234 feces collected at nine microsatellite loci. The spatially explicit and non-explicit Bayesian clustering algorithms evident to exhibit population structuring and supported red panda populations to exist in meta-population frame work. In concurrence to the habitat suitability and landscape connectivity models, gene flow results supported a contemporary asymmetric movement of red panda by connecting KL- India in a crescent arc. We demonstrate the structural-operational connectivity of corridors in KL-India that facilitated red panda movement in the past. We also seek for cooperation in Nepal, Bhutan and China to aid in preparing for a comprehensive monitoring plan for the long-term conservation and management of red panda in trans-boundary landscapes.
KRSA: Network-based Prediction of Differential Kinase Activity from Kinome Array Data
Authors: DePasquale Erica A. K. , Alganem Khaled , Bentea Eduard , Nawreen Nawshaba , McGuire Jennifer L. , Naji Faris , Hilhorst Riet , Meller Jaroslaw , McCullumsmith Robert E. 
Published: August 2020

AbstractMotivationPhosphorylation by serine-threonine and tyrosine kinases is critical for determining protein function. Array-based approaches for measuring multiple kinases allow for the testing of differential phosphorylation between conditions for distinct sub-kinomes. While bioinformatics tools exist for processing and analyzing such kinome array data, current open-source tools lack the automated approach of upstream kinase prediction and network modeling. The presented tool, alongside other tools and methods designed for gene expression and protein-protein interaction network analyses, help the user better understand the complex regulation of gene and protein activities that forms biological systems and cellular signaling networks.ResultsWe present the Kinome Random Sampling Analyzer (KRSA), a web-application for kinome array analysis. While the underlying algorithm has been experimentally validated in previous publications, we tested the full KRSA application on dorsolateral prefrontal cortex (DLPFC) in male (n=3) and female (n=3) subjects to identify differential phosphorylation and upstream kinase activity. Kinase activity differences between males and females were compared to a previously published kinome dataset (11 female and 7 male subjects) which showed similar patterns to the global phosphorylation signal. Additionally, kinase hits were compared to gene expression databases forin silicovalidation at the transcript level and showed differential gene expression of kinases.Availability and implementationKRSA as a web-based application can be found athttp://bpg-n.utoledo.edu:3838/CDRL/KRSA/. The code and data are available athttps://github.com/kalganem/KRSA.Supplementary informationSupplementary data are available online.
Imaging the Transmembrane and Transendothelial Sodium Gradients in Gliomas
Authors: Khan Muhammad H. , Walsh John J. , Mihailović Jelena M. , Mishra Sandeep K. , Coman Daniel , Hyder Fahmeed 
Published: August 2020

ABSTRACTHigh sodium (Na+) in extracellular (Na+e) and blood (Na+b) compartments and low Na+in intracellular milieu (Na+i) produce strong transmembrane (ΔNa+mem) and weak transendothelial (ΔNa+end) gradients respectively, which reflect cell membrane potential (Vm) and blood-brain barrier (BBB) integrity. We developed a sodium (23Na) magnetic resonance spectroscopic imaging (MRSI) method using an intravenously-administered paramagnetic contrast agent to measure ΔNa+memand ΔNa+end.In vitro23Na-MRSI established that the23Na signal is strongly shifted by the agent compared to biological factors.In vivo23Na-MRSI showed Na+iremained unshifted and Na+bwas more shifted than Na+e, and these together created weakened ΔNa+memand enhanced ΔNa+endin rat gliomas. Specifically, RG2 and U87 tumors maintained weakened ΔNa+mem(i.e., depolarizedVm) implying an aggressive state for proliferation, and RG2 tumors displayed elevated ΔNa+endsuggesting altered BBB integrity.23Na-MRSI will allow explorations of perturbed Na+homeostasisin vivofor the tumor neurovascular unit.
Bidirectional interconversion between mutually exclusive tumorigenic and drug-tolerant melanoma cell phenotypes
Authors: Zhang Yuntian , Belote Rachel L , Urquijo Marcus A , Hansen Maike M. K. , Hejna Miroslav , Moustafa Tarek E. , Liu Tong , Lange Devin , Vand-Rajabpour Fatemeh , Chang Matthew , Lohman Brian K. , Stubben Chris , Zhang Xiaoyang , Weinberger Leor S. , VanBrocklin Matthew W , Grossman Douglas , Lex Alexander , Kulkarni Rajan , Zangle Thomas , Judson-Torres Robert L. 
Published: August 2020

AbstractHuman cancers can exhibit phenotype switching, resulting in cells that are more metastatic or that are more tolerant to treatment. However, the relationship between these aggressive states is not well understood. We investigated the dynamics of phenotypic switching in human melanoma cells by monitoring the fluorescent activity from a transgenic reporter of BRN2 promoter activation. Melanoma cells exhibit heterogeneous BRN2 expression patterns that are reestablished upon isolation and clonal outgrowth. Specifically, stable BRN2 expression was generally inherited over multiple generations while undergoing occasional bidirectional interconversion. We found that BRN2 low cells were required for tumor initiation and metastasis in animal engraftment assays but were more sensitive to targeted BRAF inhibition. In contrast, the BRN2 high state was not tumorigenic, but entry into this state was uniform and persistent among cells tolerant to targeted BRAF therapy. Single-cell RNA sequencing analyses revealed core programs exclusive to either the BRN2 high or low cells, each of which is present inex vivotumors, demonstrating the physiological relevance of these states. Our findings emphasize that one challenge of effectively targeting phenotype switching in melanoma as a therapeutic strategy could be balancing distinct aggressive phenotypes so that sensitizing tumors to BRAF inhibition does not inadvertently lead to further dissemination.TeaserUnraveling melanoma’s shape-shifting behavior: insights into how cancer cells swap between metastasis and drug evasion.
Generative modeling of single-cell population time series for inferring cell differentiation landscapes
Authors: Yeo Grace H.T. , Saksena Sachit D. , Gifford David K. 
Published: August 2020

SummaryExisting computational methods that use single-cell RNA-sequencing for cell fate prediction either summarize observations of cell states and their couplings without modeling the underlying differentiation process, or are limited in their capacity to model complex differentiation landscapes. Thus, contemporary methods cannot predict how cells evolve stochastically and in physical time from an arbitrary starting expression state, nor can they model the cell fate consequences of gene expression perturbations. We introduce PRESCIENT (Potential eneRgy undErlying Single Cell gradIENTs), a generative modeling framework that learns an underlying differentiation landscape from single-cell time-series gene expression data. Our generative model framework provides insight into the process of differentiation and can simulate differentiation trajectories for arbitrary gene expression progenitor states. We validate our method on a recently published experimental lineage tracing dataset that provides observed trajectories. We show that this model is able to predict the fate biases of progenitor cells in neutrophil/macrophage lineages when accounting for cell proliferation, improving upon the best-performing existing method. We also show how a model can predict trajectories for cells not found in the model’s training set, including cells in which genes or sets of genes have been perturbed. PRESCIENT is able to accommodate complex perturbations of multiple genes, at different time points and from different starting cell populations. PRESCIENT models are able to recover the expected effects of known modulators of cell fate in hematopoiesis and pancreatic β cell differentiation.
Process-based model of fish incubation survival for designing reservoir operations: a case study for Sacramento River winter-run Chinook salmon
Authors: Anderson James J. , Beer W. Nicholas , Israel Joshua A. , Greene Sheila 
Published: August 2020

AbstractAllocating reservoir flows to meet societal and ecosystem needs under increasing demands for water and increasing climatic variability presents challenges to resource managers. Often, regulated rivers have been operated to meet flow and temperature compliance points that mimic historical patterns. Because it is difficult to assess if this approach is efficient or equitable, new more process-based approaches to regulation are being advanced. This paper describes such an approach with a model of egg incubation survival of Sacramento River winter-run Chinook salmon (SRWRC,Oncorhynchus tshawytscha). Thermal mortality only occurs in a critical window around egg hatching when the embryo is most sensitive to temperature stress. The duration of the critical window has significant implications for Shasta Reservoir operations that are designed to control temperature during SRWRC incubation. Previous operations sought to maintain a low temperature over the entire incubation period. However, model analysis suggests that targeting cold water directly to the critical egg hatching stage provides higher survival while requiring less cold water resources. The calibrated model is publicly accessible through a web interface connected to real-time river and fish databases and a river temperature forecast model. The system is an example of the next step of river management that integrates databases with hydrological and process-based biological models for real-time analysis and for forecasting effects of river operations on the environment.
Mapping ribonucleotides embedded in genomic DNA to single-nucleotide resolution using Ribose-Map
Authors: Gombolay Alli L. , Storici Francesca 
Published: August 2020

ABSTRACTRibose-Map is a user-friendly, standardized bioinformatics toolkit for the comprehensive analysis of ribonucleotide sequencing experiments. It allows researchers to map the locations of ribonucleotides in DNA to single-nucleotide resolution and identify biological signatures of ribonucleotide incorporation. In addition, it can be applied to data generated using any currently available high-throughput ribonucleotide sequencing technique, thus standardizing the analysis of ribonucleotide sequencing experiments and allowing direct comparisons of results. This protocol describes in detail how to use Ribose-Map to analyze raw ribonucleotide sequencing data, including preparing the reads for analysis, locating the genomic coordinates of ribonucleotides, exploring the genome-wide distribution of ribonucleotides, determining the nucleotide sequence context of ribonucleotides, and identifying hotspots of ribonucleotide incorporation. Ribose-Map does not require background knowledge of ribonucleotide sequencing analysis and assumes only basic command-line skills. The protocol requires less than 3 hr of computing time for most datasets and about 30 min of hands-on time.
European agroforestry is no universal remedy for biodiversity: a time-cumulative meta-analysis
Authors: Mupepele Anne-Christine , Keller Matteo , Dormann Carsten F 
Published: August 2020

AbstractBackgroundAgroforestry is a production system combining trees with crops or livestock. It has the potential to increase biodiversity in relation to single-use systems, such as pastures or conventional agriculture, by providing a higher habitat heterogeneity. In a literature review and subsequent meta-analysis, we investigated the relationship between biodiversity and agroforestry and critically appraise the underlying evidence of the results.ResultsBiodiversity in agroforestry was higher than in conventional agriculture, but could not outcompete pastures, forests and abandoned agroforestry systems. There was no overall biodiversity benefit in agroforestry systems. Data were available for plants, birds, bats and arthropods. Arthropods and birds were the two taxonomic groups profiting from agroforestry systems. A time-cumulative meta-analysis shows that there was no general benefit of biodiversity at any point in the past besides in early 2015. Time-cumulative meta-analysis can unravel missing robustness of meta-analytical results if conclusions alternate between significant to non-significant summary effect sizes over time.ConclusionAgroforestry increases biodiversity only in silvoarable systems compared with conventional agriculture. But even this result is based on a small magnitude and single-study effect sizes were heterogeneous with sometimes opposing conclusions. The latter suggests the importance of other usually unmeasured variables, such as landscape parameters or land-use history, influencing biodiversity in agroforestry systems.
A targetable epigenetic vulnerability in PI3K/AKT inhibitor resistant cancers
Authors: Wu Di , Yan Yuqian , Wei Ting , Ye Zhenqing , Xiao Yutian , Pan Yunqian , Orme Jacob J. , Wang Dejie , Wang Liguo , Ren Shancheng , Huang Haojie 
Published: August 2020

AbstractAcquisition of resistance to PI3K/AKT-targeted monotherapy implies the existence of common resistance mechanisms independent of cancer type. Here we demonstrate that PI3K/AKT inhibitors cause glycolytic crisis, acetyl-CoA shortage and a global decrease in histone acetylation. Also, PI3K/AKT inhibitors induce drug resistance by selectively augmenting H3K27 acetylation and binding of CBP/p300 and BRD4 proteins at a subset of growth factor and receptor (GF/R) gene loci. BRD4 occupation at these loci and drug resistant cell growth are vulnerable to both bromodomain and HDAC inhibitors. Little or none occupation of HDAC proteins at the GF/R gene loci underscores the paradox that cells respond equivalently to the two classes of inhibitors with opposite modes of action. Targeting this unique epigenetic vulnerability offers two viable strategies to overcome PI3K/AKT inhibitor resistance in different cancers.
In vivoRyR1 reduction in muscle triggers a core-like myopathy
Authors: Pelletier Laurent , Petiot Anne , Brocard Julie , Giannesini Benoit , Giovannini Diane , Sanchez Colline , Travard Lauriane , Chivet Mathilde , Beaufils Mathilde , Kutchukian Candice , Bendahan David , Metzger Daniel , Armstrong Clara Franzini , Romero Norma B. , Rendu John , Jacquemond Vincent , Fauré Julien , Marty Isabelle 
Published: August 2020

AbstractSome mutations in theRYR1gene lead to congenital myopathies, through reduction in this calcium channel expression level, but the functional whole organism consequences of reduction in RyR1 amount have never been studied. We have developed and characterized a mouse model with inducible muscle specificRYR1deletion. Recombination in theRYR1gene resulted in a progressive reduction in the protein amount and was associated with a progressive muscle weakness and atrophy. Calcium fluxes in isolated muscle fibers were accordingly reduced. Alterations in the muscle structure were observed, with fibers atrophy, abnormal mitochondria distribution, membrane remodeling, associated with increase in the expression level of many proteins and inhibition of the autophagy process. This model demonstrates that RyR1 reduction is sufficient to recapitulate most features of Central Core Disease, and accordingly similar alterations were observed in muscle biopsies from Central Core Disease patients, pointing to common pathophysiological mechanisms related to RyR1 reduction.
Experimental pieces of evidence forMycobacterium ulceransdormancy
Authors: Loukil A. , Lalaoui R. , Bogreau H. , Regoui S. , Drancourt M. , Hammoudi N 
Published: August 2020

ABSTRACTBackgroundWhetherMycobacterium ulcerans, the etiological agent of the neglected Buruli ulcer in numerous tropical countries, would exist in a dormant state as reported for closely relatedMycobacteriumspecies, is not established.MethodologySixM. ulceransstrains were exposed to a progressive depletion in oxygen for two months, using a previously described Wayne model of dormancy; and further examined by microscopy using DDD staining, microcalorimetry and subculture in the presence of dead and replicativeM. ulceransas controls.Principal Findings/ConclusionsM. ulceransCU001 strain died during the progressive oxygen depletion and four of five remaining strains exhibited Nile Red-stained intracellular lipid droplets after DDD staining and a 14-20-day regrowth when exposed to ambient air, diagnosing dormancy. A fifthM. ulcerans19423 strain stained negative in DDD and slowly regrew in 27 days. Three testedM. ulceransstrains yielded microcalorimetric pattern similar to that of the negative (dead) homologous controls, differing from that of the homologous positive (replicative) controls. The relevance of these experimental observations, suggesting a previously unreported dormancy state ofM. ulcerans, needs to be investigated in the natural ecological niches whereM. ulceransthrive and in Buruli ulcer lesions.Author summaryMycobacterium ulceransis an environmental opportunistic pathogen of mammals and humans, causing a subcutaneous necrotizing infection named Buruli ulcer. Molecular detection ofM. ulceransDNA revealed different ecological niches whereM. ulceransmay thrive, but the molecular biology approach does not catch the physiological state ofM. ulceransin these different ecological niches. Thus, the reservoir and the mode of transmission ofM. ulceransremain elusive. Here, we investigated experimental dormancy ofM. ulceransby using a previously described Wayne model of dormancy coupled with microscopy using DDD staining, microcalorimetry and subculture. Our findings demonstrate for the first time that someM. ulceransstrains exhibit a physiological state of dormancy; potentially limiting isolation and culture ofM. ulceransfrom environmental niches.
A Validated Functional Analysis of PALB2 Missense Variants for Use in Clinical Variant Interpretation
Authors: Brnich Sarah E. , Arteaga Eyla Cristina , Wang Yueting , Tan Xianming , Berg Jonathan S. 
Published: August 2020

AbstractClinical genetic testing readily detects germline genetic variants. Yet, the evidence available for variant classification as benign or pathogenic is often limited by the rarity of individual variants, leading to many “variant of uncertain significance” (VUS) classifications. VUS cannot guide clinical decisions, complicating counseling and management. Laboratory assays can potentially aid reclassification, but require benchmarking against variants with definitive interpretations to have sufficient predictive power for clinical use. Of all clinically identified germline variants in hereditary breast cancer genePALB2(Partner and Localizer of BRCA2), ~50% are VUS and ~90% of VUS are missense. Truncating PALB2 variants have homologous recombination (HR) defects and instead rely on error-prone non-homologous end-joining (NHEJ) for DNA damage repair (DDR). Recent reports show some missense PALB2 variants may also be damaging, but thus far functional studies have lacked benchmarking controls. Using the Traffic Light Reporter (TLR) to quantify cellular HR and NHEJ using fluorescent markers, we assessed variant-level DDR capacity in hereditary breast cancer genes. We first determined the TLR’s dynamic range usingBRCA2missense variants of known significance as benchmarks for normal/abnormal HR function. We then tested 37PALB2variants, generating functional data for germlinePALB2variants at a moderate level of evidence for a pathogenic interpretation (PS3_moderate) for 8 variants, or a supporting level of evidence in favor of a benign interpretation (BS3_supporting) for 13 variants, based on the ability of the assay to correctly classifyPALB2validation controls. This new data can be applied in subsequent variant interpretations for direct clinical benefit.