bluuebunny/crossref_metadata_2025_split huggingface dataset:
YhcB (DUF1043), a novel cell division protein conserved across gamma-proteobacteria
Authors: Mehla Jitender , Liechti George , Morgenstein Randy M. , Caufield J. Harry , Hosseinnia Ali , Gagarinova Alla , Phanse Sadhna , Brockett Mary , Sakhawalkar Neha , Babu Mohan , Xiao Rong , Montelione Gaetano T. , Vorobiev Sergey , den Blaauwen Tanneke , Hunt John F. , Uetz Peter 
Published: January 2021

AbstractYhcB, an uncharacterized protein conserved across gamma-proteobacteria, is composed predominantly of a single Domain of Unknown Function (DUF 1043) with an N-terminal transmembrane α-helix. Here, we show that E. coli YhcB is a conditionally essential protein that interacts with the proteins of the cell divisome (e.g., FtsI, FtsQ) and elongasome (e.g., RodZ, RodA). We found 7 interactions of YhcB that are conserved in Yersinia pestis and/or Vibrio cholerae. Furthermore, we identified several point mutations that abolished interactions of YhcB with FtsI and RodZ. The yhcB knock-out strain does not grow at 45°C and is hypersensitive to cell-wall acting antibiotics even in stationary phase. The deletion of yhcB leads to filamentation, abnormal FtsZ ring formation, and aberrant septa development. The 2.8 Å crystal structure for the cytosolic domain from Haemophilus ducreyi YhcB shows a unique tetrameric α-helical coiled-coil structure that combines parallel and anti-parallel coiled-coil intersubunit interactions. This structure is likely to organize interprotein oligomeric interactions on the inner surface of the cytoplasmic membrane, possibly involved in regulation of cell division and/or envelope biogenesis/integrity in proteobacteria. In summary, YhcB is a conserved and conditionally essential protein that is predicted to play a role in cell division and consequently or in addition affects envelope biogenesis.ImportanceOnly 0.8 % of the protein annotations in the UniProt are based on experimental evidence and thus, functional characterization of unknown proteins remains a rate-limiting step in molecular biology. Herein, the functional properties of YhcB (DUF1043) were investigated using an integrated approach combining X-ray crystallography with genetics and molecular biology. YhcB is a conserved protein that appears to be needed for the transition from exponential to stationary growth and is involved in cell division and/or envelope biogenesis/integrity. This study will serve as a starting point for future studies on this protein family and on how cells transit from exponential to stationary survival.
Transcriptomics data availability and reusability in the transition from microarray to next-generation sequencing
Authors: Rustici Gabriella , Williams Eleanor , Barzine Mitra , Brazma Alvis , Bumgarner Roger , Chierici Marco , Furlanello Cesare , Greger Liliana , Jurman Giuseppe , Miller Michael , Ouellette B.F. Francis , Quackenbush John , Reich Michael , Stoeckert Christian J. , Taylor Ronald C. , Trutane Stephen Chervitz , Weller Jennifer , Wilhelm Brian , Winegarden Neil 
Published: January 2021

ABSTRACTOver the last two decades, molecular biology has been changed by the introduction of high-throughput technologies. Data sharing requirements have prompted the establishment of persistent data archives. A standardized approach for recording and managing these data was first proposed in the Minimal Information About a Microarray Experiment (MIAME) guidelines. The Minimal Information about a high throughput nucleotide Sequencing Experiment (MINSEQE) proposal was introduced in 2008 as a logical extension of the guidelines to next-generation sequencing (NGS) technologies used for transcriptome analysis.We present a historical snapshot of the data-sharing situation focusing on transcriptomics data from both microarray and RNA-sequencing experiments published between 2009 and 2013, a period during which RNA-seq studies became increasingly popular for transcriptome analysis. We assess how much data from RNA-seq based experiments is actually available in persistent data archives, compared to data derived from microarray based experiments, and evaluate how these types of data differ. Based on this analysis, we provide recommendations to improve RNA-seq data availability, reusability, and reproducibility.
Genome-wide characterization and identification of synonymous codon usage patterns in Plasmodium knowlesi
Authors: Yadav Manoj Kumar , Gajbhiye Shivani 
Published: January 2021

AbstractCodon usage bias is a ubiquitous phenomenon occurring at both, interspecies and intraspecies level in different organisms. P. knowlesi, whose natural host is long-tailed Macaque monkeys, has recently started infecting humans as well. The genome as well as coding sequence data of P. knowlesi is used to understand their codon usage pattern in the light of other human infecting Plasmodium species: P. vivax and P. falciparum. The different codon usage indicators: GC content, relative synonymous codon usage, effective number of codon and codon adaptation index are studied to analyze codon usage in the Plasmodium species. The codon usage pattern is found to be less conserved in studied Plasmodium species, and changes species to species at the genus level. The codon usage pattern of P. knowlesi shows similarity to P. vivax as compared to P. falciparum. The ENC vs. GC3 study indicates that compositional constraints and translation selection is the decisive forces responsible for shaping their codon usage. The studies Plasmodium species shows a higher usage of A/T ending optimal codons. This favors the codon bias in P. knowlesi and P. vivax is due to high selection pressure and in P. falciparum, the compositional mutational pressure is a dominant force. In a nutshell, our finding suggests that the more or less similar codon usage pattern of P. knowlesi and P. vivax may suggest the similar host invasion and immune evasion strategies for disease establishment.
Homology between the flagellar export apparatus and ATP synthetase: evidence from synteny predating the Last Universal Common Ancestor
Authors: Matzke Nicholas J. , Lin Angela , Stone Micaella , Baker Matthew A. B. 
Published: January 2021

AbstractEvidence of homology between proteins in the ATP synthetase and the bacterial flagellar motor (BFM) has been accumulating since the 1980s. Specifically, the BFM’s Type 3 Secretion System (T3SS) export apparatus FliH, FliI, and FliJ are considered homologous to FO-b + F1-δ, F1-α/β, and F1-γ, and have similar structure and interactions. We review the discoveries that advanced the homology hypothesis and then conduct a further test by examining gene order in the two systems and their relatives. Conservation of gene order, or synteny, is often observed between closely related prokaryote species, but usually degrades with phylogenetic distance. As a result, observed conservation of synteny over vast phylogenetic distances can be evidence of shared ancestral coexpression, interaction, and function. We constructed a gene order dataset by examining the order offliH,fliI, andfliJgenes across the phylogenetic breadth of flagellar and nonflagellar T3SS. We compared this to published surveys of gene order in the F1FO-ATP synthetase, its N-ATPase relatives, and the bacterial/archaeal V- and A-type ATPases. Strikingly, thefliHIJgene order was deeply conserved, with the few exceptions appearing derived, and exactly matching the widely conserved F-ATPase gene orderatpFHAG, coding for subunitsb-δ-α-γ. The V/A-type ATPases have a similar conserved gene order shared for homologous components. Our results further strengthen the argument for homology between these systems, and suggest a rare case of synteny conserved over billions of years, dating back to well before the Last Universal Common Ancestor (LUCA).
SARS-CoV-2 infects lung epithelial cells and induces senescence and an inflammatory response in patients with severe COVID-19
Authors: Evangelou Konstantinos , Veroutis Dimitris , Foukas Periklis G. , Paschalaki Koralia , Lagopati Nefeli , Dimitriou Marios , Papaspyropoulos Angelos , Hazapis Orsalia , Polyzou Aikaterini , Havaki Sophia , Kotsinas Athanassios , Kittas Christos , Tzioufas Athanasios G. , de Leval Laurence , Vassilakos Demetris , Tsiodras Sotirios , Karakasiliotis Ioannis , Barnes Peter J , Gorgoulis Vassilis G. 
Published: January 2021

AbstractRationaleSARS-CoV-2 infection of the respiratory system can progress to a life threatening multi-systemic disease, mediated via an excess of cytokines (“cytokine storm”), but the molecular mechanisms are poorly understood.ObjectivesTo investigate whether SARS-CoV-2 may induce cellular senescence in lung epithelial cells, leading to secretion of inflammatory cytokines, known as the senescence-associated secretory phenotype (SASP).MethodsAutopsy lung tissue samples from eleven COVID-19 patients and sixty age-matched non-infected controls were analysed by immunohistochemistry for SARS-CoV-2 and markers of cellular senescence (SenTraGor, p16INK4A) and key SASP cytokines (interleukin-1β, interleukin-6). We also investigated whether SARS-CoV-2 infection of an epithelial cell line induces senescence and cytokine secretion.Measurements and Main ResultsSARS-CoV-2 was detected by immunocytochemistry and electron microscopy predominantly in alveolar type-2 (AT2) cells, which also expressed the angiotensin-converting-enzyme 2 (ACE2), a critical entry receptor for this virus. In COVID-19 samples, AT2 cells displayed increased markers of senescence [p16INK4A, SenTraGor staining positivity in 12±1.2% of cells compared to 1.7±0.13% in non-infected controls (p<0.001)], with markedly increased expression of interleukin-1β and interleukin-6 (p<0.001). Infection of epithelial cells (Vero E6) with SARS-CoV-2in-vitroinduced senescence and DNA damage (increased SenTraGor and γ-H2AX), and reduced proliferation (Ki67) compared to uninfected control cells (p<0.01).ConclusionsWe demonstrate that in severe COVID-19 patients, AT2 cells are infected with SARS-CoV-2 and show senescence and expression of proinflammatory cytokines. We also show that SARS-CoV-2 infection of epithelial cells may induce senescence and inflammation, indicating that cellular senescence may be an important molecular mechanism of severe COVID-19.
Human brain region-specific variably methylated regions (VMRs) are enriched for heritability of distinct neuropsychiatric traits
Authors: Rizzardi Lindsay F. , Hickey Peter F. , Idrizi Adrian , Tryggvadóttir Rakel , Callahan Colin M. , Stephens Kimberly E. , Taverna Sean D. , Zhang Hao , Ramazanoglu Sinan ,   GTEx Consortium, Hansen Kasper D. , Feinberg Andrew P. 
Published: January 2021

ABSTRACTBACKGROUNDDNA methylation dynamics in the brain are associated with normal development and neuropsychiatric disease and differ across functionally distinct brain regions. Previous studies of genome-wide methylation differences among human brain regions focused on limited numbers of individuals and one to two brain regions.RESULTSUsing GTEx samples, we have generated a resource of DNA methylation in purified neuronal nuclei from 8 brain regions as well as lung and thyroid tissues from 12-23 donors. We identified differentially methylated regions between brain regions (DMRs) among neuronal nuclei in both CpG (181,146) and non-CpG (264,868) contexts, few of which were unique to a single pair-wise comparison. This significantly expands the knowledge of differential methylation across the brain by 10-fold. In addition, we present the first differential methylation analysis among neuronal nuclei from basal ganglia tissues and identified 2,295 unique CpG DMRs, many associated with ion transport. Consistent with prior studies, CpG DMRs were enriched in regulatory regions while non-CpG DMRs were enriched in intergenic regions. We also identified 81,130 regions of variably CpG methylated regions (VMRs), i.e. variable methylation among individuals in the same brain region, which were enriched in regulatory regions and in CpG DMRs. Many VMRs were unique to a specific brain region, with only 202 common across all brain regions, as well as lung and thyroid. VMRs identified in the amygdala, anterior cingulate cortex, and hippocampus were enriched for heritability of schizophrenia.CONCLUSIONSThese data suggest that epigenetic variation in these particular human brain regions could be associated with the risk for this neuropsychiatric disorder.
Functional insights of two MATE transporters fromVibrio fluvialis
Authors: Mohanty Priyabrata , Shah Aneri , Bhardwaj Ashima Kushwaha 
Published: January 2021

SummaryFunctional characterization of H- and D-MATE (Multidrug and Toxin Extrusion) transporters from clinical isolates ofVibrio fluvialisrevealed H-type conferred resistance to fluoroquinolones, ethidium bromide and safranin whereas D-type exhibited marginal resistance towards ethidium bromide only. Both H-/D-type transporters were inhibited by reserpine resulting in increased intracellular norfloxacin concentration. The efflux was facilitated by both Na+/K+ions, suggesting that these efflux pumps were ion-dependent. In presence of various classes of EPIs, there was decrease in MIC exhibited by H-/D-type efflux pumps towards norfloxacin which didn’t translate into transport inhibition. But reserpine presented a conclusive pattern with decrease in MIC towards norfloxacin and increased norfloxacin accumulation inferring maximum inhibition. Substrate binding and electrostatic charge distribution of both the transporters was similar to other known MATE transporters. The H-type exhibited 10 transmembranes and D-type exhibited 11 TMs which was different from other MATE transporters known to have 12 TMs (Transmembranes). Data derived from molecular docking and ion binding studies revealed that Aspartic Acid residue in 1stTM acts as ion binding site with transport mechanism similar to NorM. Electrostatic potential map of both the transporters revealed that there is a cavity formation within the transporters surrounded by charged electronegative amino acid residues. Interestingly, surface models of both transporters revealed that 1stTM forms covalent bond with 7thTM towards extracellular space. Docking studies also revealed that reserpine covalently binds to central pocket of both transporters and serves as excellent EPI against these transporters as evidenced by MIC and drug accumulation assays.
In vivolentiviral vector gene therapy to cure hereditary tyrosinemia type 1 and prevent development of precancerous and cancerous lesions
Authors: Nicolas Clara T , VanLith Caitlin J , Allen Kari L , Hickey Raymond D , Du Zeji , Hillin Lori G , Guthman Rebekah M , Cao William J , Bhagwate Aditya , O’Brien Daniel , Kocher Jean-Pierre , Kaiser Robert A , Russell Stephen J , Lillegard Joseph B 
Published: January 2021

AbstractConventional therapy for hereditary tyrosinemia type-1 (HT1) with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) delays and in some cases fails to prevent disease progression to liver fibrosis, liver failure, and activation of tumorigenic pathways. Here we demonstrate for the first time a cure of HT1 by direct,in vivoadministration of a therapeutic lentiviral vector targeting the expression of a human fumarylacetoacetate hydrolase (FAH) transgene in the porcine model of HT1. This therapy was well tolerated and provided stable long-term expression of FAH in pigs with HT1. Genomic integration displayed a benign profile, with subsequent fibrosis and tumorigenicity gene expression patterns similar to wild-type animals as compared to NTBC-treated or diseased untreated animals. Indeed, the phenotypic and genomic data followingin vivolentiviral vector administration demonstrate comparative superiority over other therapies includingex vivocell therapy and therefore support clinical application of this approach.
Loss of mutually protective effects between osteoclasts and chondrocytes in damaged joints drives osteoclast-mediated cartilage degradation via matrix metalloproteinases
Authors: Larrouture Quitterie C , Cribbs Adam P , Snelling Sarah J , Knowles Helen J 
Published: January 2021

AbstractOsteoclasts are large multinucleated cells that resorb bone to regulate bone remodelling during skeletal maintenance and development. It is overlooked that osteoclasts also digest cartilage during this process, as well as in degradative conditions including osteoarthritis, rheumatoid arthritis and primary bone sarcomas such as giant cell tumour of bone. This study explores the poorly understood mechanisms behind the interaction between osteoclasts and cartilage. Morphologically, osteoclasts differentiated on acellular human cartilage formed multinucleated cells expressing characteristic osteoclast marker genes (e.g.CTSK, MMP9) and proteins (TRAP, VNR) that visibly damaged the cartilage surface by SEM, but without the formation of resorption pits. Osteoclasts caused increased glycosaminoglycan (GAG) release from acellular and cellular human cartilage that was dependent on direct contact with the substrate. Direct co-culture with chondrocytes during osteoclast differentiation increased the number of large osteoclasts formed. When osteoclasts were cultured on dentine, direct co-culture with chondrocytes inhibited osteoclast formation and reduced basal degradation of cartilage. This suggests a mutually protective effect on their ‘native’ tissue between bone-resident osteoclasts and chondrocytes, that is reversed when the joint structure breaks down and osteoclasts are in contact with non-native substrates. Mechanistically, osteoclast-mediated cartilage degradation was inhibited by the pan-MMP inhibitor GM6001 and by TIMP1, indicative of a role for soluble MMPs. RNA sequencing and RT-qPCR analysis identifiedMMP8as overexpressed in osteoclasts differentiated on cartilage versus dentine, whileMMP9was the most highly expressed MMP on both substrates. Inhibition of eitherMMP8orMMP9by siRNA in mature osteoclasts reduced GAG release, confirming their involvement in cartilage degradation. Immunohistochemical expression of MMP8 and MMP9 was evident in osteoclasts in osteosarcoma tissue sections. Understanding and controlling the activity of osteoclasts might represent a new therapeutic approach for pathologies characterized by cartilage degeneration and presents an attractive target for further research.
LiquidCNA: tracking subclonal evolution from longitudinal liquid biopsies using somatic copy number alterations
Authors: Lakatos Eszter , Hockings Helen , Mossner Maximilian , Huang Weini , Lockley Michelle , Graham Trevor A. 
Published: January 2021

AbstractCell-free DNA (cfDNA) measured via liquid biopsies provides a way for minimally-invasive monitoring of tumour evolutionary dynamics during therapy. Here we present liquidCNA, a method to track subclonal evolution from longitudinally collected cfDNA samples based on somatic copy number alterations (SCNAs). LiquidCNA utilises SCNA profiles derived through cost-effective low-pass whole genome sequencing to automatically and simultaneously genotype and quantify the size of the dominant subclone without requiring prior knowledge of the genetic identity of the emerging clone. We demonstrate the accuracy of liquidCNA in synthetically generated sample sets andin vitroandin silicomixtures of cancer cell lines. Applicationin vivoin patients with metastatic lung cancer reveals the progressive emergence of a novel tumour sub-population. LiquidCNA is straightforward to use, computationally inexpensive and enables continuous monitoring of subclonal evolution to understand and control therapy-induced resistance.
Fast and Accurate Influenza Forecasting in the United States with Inferno
Authors: Osthus Dave 
Published: January 2021

AbstractInfectious disease forecasting is an emerging field and has the potential to improve public health through anticipatory resource allocation, situational awareness, and mitigation planning. By way of exploring and operationalizing disease forecasting, the U.S. Centers for Disease Control and Prevention (CDC) has hosted FluSight since the 2013/14 flu season, an annual flu forecasting challenge. Since FluSight’s onset, forecasters have developed and improved forecasting models in an effort to provide more timely, reliable, and accurate information about the likely progression of the outbreak. While improving the predictive performance of these forecasting models is often the primary objective, it is also important for a forecasting model to run quickly, facilitating further model development, improvement, and scalability. In this vein I introduce Inferno, a fast and accurate flu forecasting model inspired by Dante, the top performing model in the 2018/19 FluSight challenge. When compared to all models that participated in FluSight 2018/19, Inferno would have placed 2nd in both the national and state challenges, behind only Dante. Inferno, however, runs in minutes and is trivially parallelizable, while Dante takes hours to run, representing a significant operational improvement with minimal impact to performance. A future consideration for forecasting competitions like FluSight will be how to encourage improvements to secondarily important properties of forecasting models, such as runtime, generalizability, and interpretability.
Psoriasis: Recent progress in molecular‐targeted therapies
Authors: Honma Masaru , Hayashi Kei 
Published: January 2021

AbstractPsoriasis is a multifactorial recalcitrant inflammatory skin disease characterized by bothersome scaly reddish plaques especially on frequently chafed body parts, such as the extensor sites of the extremities and scalp. Nonetheless, through recent advance in molecular‐targeted therapies including biologics and small‐molecule inhibitors, even the severest symptoms of psoriasis and its comorbidities, such as psoriatic arthritis, can be excellently treated. The superb clinical effects lead to not only remarkable alleviation of symptoms but also a deep understanding of patients’ impaired “quality of life” caused by this disease. Along with the development of novel treatment options targeting various specific molecules, such as proinflammatory cytokines and signal transduction‐associated molecules, clinicians have thoroughly understood the molecular mechanism of psoriasis, and discovered that the IL‐23/IL‐17 axis mainly depending on Th17 cell function is a crucial pathogenesis of this disease. Accumulation of knowledge about the working mechanism and clinical effect of molecular‐targeted therapies is indispensable for clinicians to establish a more refined therapeutic strategy for treating psoriasis.
Specific cutaneous infiltrates in patients with haematological neoplasms: a retrospective study with 49 patients
Authors: Calado Rebeca , Relvas Maria , Morgado Francisca , Cardoso José Carlos , Tellechea Oscar 
Published: January 2021

AbstractBackgroundHaematological neoplasms account for around 9% of all cancers, and they are recognised as an important cause of skin infiltration. However, studies analysing cutaneous metastasis of haematological neoplasms are scarce. We describe the clinical spectrum and outcomes of specific cutaneous manifestations of leukaemias, lymphomas, multiple myeloma (MM), and blastic plasmacytoid dendritic cell neoplasm (BPDN) and make a review of the literature.MethodsData from 49 patients diagnosed with secondary cutaneous infiltration of systemic haematological neoplasms over the last 10 years in a tertiary dermatology centre were retrospectively collected, and clinical‐evolutive features were analysed.ResultsMost cases were lymphoma (44.9%, n = 22), followed by leukaemia cutis (38.8%, n = 19), secondary plasmacytoma (10.2%, n = 5) and BPDN (6.1%, n = 3). Nodules were the predominant type of lesion, and most patients presented with multiple (≥3) lesions. In 51% (n = 25) of cases, cutaneous infiltration was detected before the diagnosis of the underlying malignancy. The patients in diverse nosological groups did not differ in terms of survival (P = 0.052).ConclusionsWe recognise the clinical heterogeneity of specific cutaneous infiltrates. The high proportion of cases in which skin involvement was key to the diagnosis of systemic malignancy emphasises the role of the dermatologist in recognising and correctly managing these patients.