bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pitfalls in re-analysis of observational omics studies: a post-mortem of the human pathology atlas
Authors: Gilis Jeroen , Taelman Steff , Davey Lucas , Martens Lennart , Clement Lieven 
Published: March 2020

AbstractUhlenet al.(Reports, 18 august 2017) published an open-access resource with cancer-specific marker genes that are prognostic for patient survival in seventeen different types of cancer. However, their data analysis workflow is prone to the accumulation of false positives. A more reliable workflow with flexible Cox proportional hazards models employed on the same data highlights three distinct problems with such large-scale, publicly available omics datasets from observational studies today: (i) re-analysis results can not necessarily be taken forward by others, highlighting a need to cross-check important analyses with high impact outcomes; (ii) current methods are not necessarily optimal for the re-analysis of such data, indicating an urgent need to develop more suitable methods; and (iii) the limited availability of potential confounders in public metadata renders it very difficult (if not impossible) to adequately prioritize clinically relevant genes, which should prompt an in-depth discussion on how such information could be made more readily available while respecting privacy and ethics concerns.
Understanding the Lipidome at the Systems Level with lipidomeR
Authors: Suvitaival Tommi , Legido-Quigley Cristina 
Published: March 2020

AbstractLipidomics is one of the fastest-growing areas of molecular profiling in medicine. While increasing amounts of lipidomics data are generated, tools for analyzing and interpreting these data are not equally widely available. We present the lipidomeR -- a tool specifically designed for systematic interpretation of large lipidome-wide studies. The lipidomeR binds together statistical analysis and high-dimensional visualization, providing a reproducible pipeline for rapid interpretation of the lipidome via integrative publication-ready figures. The lipidomeR package is available through the Comprehensive R Archive (CRAN).We demonstrate the lipidomeR with three studies from the Metabolomics Workbench repository, ranging from the human plasma reference material to breast tumor tissue and to the progression of non-alcoholic liver disease (NAFLD) in the liver. In these studies, lipidomeR reveals a diversity of lipidomic patterns, both, within and between the lipid classes as well as over the stages of progression of the diseases.
The sequence of human ACE2 is suboptimal for binding the S spike protein of SARS coronavirus 2
Authors: Procko Erik 
Published: March 2020

SUMMARYThe rapid and escalating spread of SARS coronavirus 2 (SARS-CoV-2) poses an immediate public health emergency. The viral spike protein S binds ACE2 on host cells to initiate molecular events that release the viral genome intracellularly. Soluble ACE2 inhibits entry of both SARS and SARS-2 coronaviruses by acting as a decoy for S binding sites, and is a candidate for therapeutic, prophylactic and diagnostic development. Using deep mutagenesis, variants of ACE2 are identified with increased binding to the receptor binding domain of S. Mutations are found across the interface, in the N90-glycosylation motif, and at buried sites where they are predicted to enhance local folding and presentation of the interaction epitope. When single substitutions are combined, large increases in binding can be achieved. The mutational landscape offers a blueprint for engineering high affinity proteins and peptides that block receptor binding sites on S to meet this unprecedented challenge.
DrosophilaHistone Locus Body assembly and function involves multiple interactions
Authors: Koreski Kaitlin P. , Rieder Leila E. , McLain Lyndsey M. , Marzluff William F. , Duronio Robert J. 
Published: March 2020

AbstractThe histone locus body (HLB) assembles at replication-dependent (RD) histone loci and concentrates factors required for RD histone mRNA biosynthesis. TheD. melanogastergenome has a single locus comprised of ∼100 copies of a tandemly arrayed repeat unit containing one copy of each of the 5 RD histone genes. To determine sequence elements required forD. melanogasterHLB formation and histone gene expression, we used transgenic gene arrays containing 12 copies of the histone repeat unit that functionally complement loss of the ∼200 endogenous RD histone genes. A 12x histone gene array in which allH3-H4promoters were replaced withH2a-H2bpromoters does not form an HLB or express high levels of RD histone mRNA in the presence of the endogenous histone genes. In contrast, this same transgenic array is active in HLB assembly and RD histone gene expression in the absence of the endogenous RD histone genes and rescues the lethality caused by homozygous deletion of the RD histone locus. The HLB formed in the absence of endogenous RD histone genes on the mutant 12x array contains all known factors present in the wild type HLB including CLAMP, which normally binds to GAGA repeats in theH3-H4promoter. These data suggest that multiple protein-protein and/or protein-DNA interactions contribute to HLB formation, and that the large number of endogenous RD histone gene copies sequester available factor(s) from attenuated transgenic arrays, thereby preventing HLB formation and gene expression.
Clusters of bacterial RNA polymerase are biomolecular condensates that assemble through liquid-liquid phase separation
Authors: Ladouceur A-M , Parmar B , Biedzinski S , Wall J , Tope SG , Cohn D , Kim A , Soubry N , Reyes-Lamothe R , Weber SC 
Published: March 2020

AbstractOnce described as mere “bags of enzymes”, bacterial cells are in fact highly organized, with many macromolecules exhibiting non-uniform localization patterns. Yet the physical and biochemical mechanisms that govern this spatial heterogeneity remain largely unknown. Here, we identify liquid-liquid phase separation (LLPS) as a mechanism for organizing clusters of RNA polymerase (RNAP) inE. coli. Using fluorescence imaging, we show that RNAP quickly transitions from a dispersed to clustered localization pattern as cells enter log phase in nutrient-rich media. RNAP clusters are sensitive to hexanediol, a chemical that dissolves liquid-like compartments in eukaryotic cells. In addition, we find that the transcription antitermination factor NusA forms dropletsin vitroandin vivo, suggesting that it may nucleate RNAP clusters. Finally, we use single-molecule tracking to characterize the dynamics of cluster components. Our results indicate that RNAP and NusA molecules move inside clusters, with mobilities faster than a DNA locus but slower than bulk diffusion through the nucleoid. We conclude that RNAP clusters are biomolecular condensates that assemble through LLPS. This work provides direct evidence for LLPS in bacteria and suggests that this process serves as a universal mechanism for intracellular organization across the tree of life.SignificanceBacterial cells are small and were long thought to have little to no internal structure. However, advances in microscopy have revealed that bacteria do indeed contain subcellular compartments. But how these compartments form has remained a mystery. Recent progress in larger, more complex eukaryotic cells has identified a novel mechanism for intracellular organization known as liquid-liquid phase separation. This process causes certain types of molecules to concentrate within distinct compartments inside the cell. Here, we demonstrate that the same process also occurs in bacteria. This work, together with a growing body of literature, suggests that liquid-liquid phase separation is a universal mechanism for intracellular organization that extends across the tree of life.
An easily adopted murine model of distal pancreatectomy for investigating immunotherapy efficacy in resectable pancreatic adenocarcinoma
Authors: Baxter Katherine E , de Souza Christiano Tanese , Tai Lee-Hwa , Yaghini Pasha , Daneshmand Manijeh , Bell John C , Lichty Brian D , Kennedy Michael A , Auer Rebecca C 
Published: March 2020

AbstractBackgroundAlthough surgery provides the greatest therapeutic benefit to eligible pancreatic ductal adenocarcinoma (PDAC) patients it does not significantly improve survival for the majority of patients. Unfortunately our understanding of the therapeutic benefit of combining surgery with different treatment modalities including promising immunotherapeutics is limited by the current lack of easily adopted surgical models. The purpose of this study was to develop a surgically resectable model of PDAC in immunocompetent mice for use in preclinical investigations.Materials and MethodsSurgically resectable orthotopic tumors were generated by injecting Pan02 cells into the tail of the pancreas. Fifteen days post implantation the primary tumors and tail of the pancreas were resected by laparotomy while preserving the spleen. Splenic function, tumor growth, immune phenotyping and survival were assessed following surgical resection of the primary tumor mass.ResultsAs expected orthotopic tumor implants recapitulated many of the major histological hallmarks of PDAC including disrupted lobular structure and vascular invasion. Preservation of splenic immune cell viability and function was not associated with improved survival following surgery alone. However, pre-operative vaccination with GVAX was associated with improved survival which was not impacted by surgery.ConclusionThis represents the first murine model of surgically resectable murine model of PDAC which recapitulates known pathological hallmarks of human disease in an immune competent model while allowing spleen preservation. This relatively simple and easily adopted approach provides an ideal platform to examine the efficacy of potential immunotherapy combinations for PDAC surgery patients.
RAD50 promotes DNA repair by homologous recombination and restrains antigenic variation in African trypanosomes
Authors: Mehnert Ann-Kathrin , Prorocic Marco , Dujeancourt-Henry Annick , Hutchinson Sebastian , McCulloch Richard , Glover Lucy 
Published: March 2020

ABSTRACTHomologous recombination dominates as the major form of DNA repair inTrypanosoma brucei, and is especially important for recombination of the subtelomeric variant surface glycoprotein during antigenic variation. RAD50, a component of the MRN complex (MRE11, RAD50, NBS1), is central to homologous recombination through facilitating resection and governing the DNA damage response. The function of RAD50 in trypanosomes is untested. Here we report that RAD50 is required for RAD51-dependent homologous recombination, phosphorylation of histone H2A and controlled resection following a DNA double strand break (DSB). Perhaps surprisingly, DSB resection in therad50nulls was not impaired and appeared to peak earlier than in the parental strains. Finally, we show that RAD50 suppresses DNA repair using donors with short stretches of homology at a subtelomeric locus, with null strains producing a greater diversity of expressed VSG variants following DSB repair. We conclude that RAD50 promotes stringent homologous recombination at subtelomeric loci and restrains antigenic variation.
Stability and detection of nucleic acid from viruses and hosts in mosquito blood meals
Authors: Drummond Coyne , Gebhardt Mary E. , Sáenz Robles Maria Teresa , Carpi Giovanna , Hoyer Isaiah , Pastusiak Andrzej , Reddy Michael R. , Norris Douglas E. , Pipas James M. , Jackson Ethan K. 
Published: March 2020

AbstractMonitoring the presence and spread of pathogens in the environment is of critical importance. Rapid detection of infectious disease outbreaks and prediction of their spread can facilitate early responses of health agencies and reduce the severity of outbreaks. Current sampling methods are sorely limited by available personnel and throughput. For instance, xenosurveillance utilizes captured arthropod vectors, such as mosquitoes, as sampling tools to access blood from a wide variety of vertebrate hosts. Next generation sequencing (NGS) of nucleic acid from individual blooded mosquitoes can be used to identify mosquito and host species, and microorganisms including pathogens circulating within either host. However, there are practical challenges to collecting and processing mosquitoes for xenosurveillance, such as the rapid metabolization or decay of microorganisms within the mosquito midgut. This particularly affects pathogens that do not replicate in mosquitoes, preventing their detection by NGS or other methods. Accordingly, we performed a series of experiments to establish the windows of detection for DNA or RNA from human blood and/or viruses present in mosquito blood meals. Our results will contribute to trap design for mosquito-based xenosurveillance, including sample stabilization and ideal time spent from collection to NGS processing.
Mitochondrial dysfunction underlying sporadic inclusion body myositis is ameliorated by the mitochondrial homing drug MA-5
Authors: Oikawa Yoshitsugu , Izumi Rumiko , Koide Masashi , Hagiwara Yoshihiro , Kanzaki Makoto , Suzuki Naoki , Kikuchi Koichi , Matsuhashi Tetsuro , Akiyama Yukako , Ichijo Mariko , Toyohara Takafumi , Suzuki Takehiro , Mishima Eikan , Akiyama Yasutoshi , Ogata Yoshiaki , Suzuki Chitose , Aoki Masashi , Itoi Eiji , Kure Shigeo , Hayashi Ken-ichiro , Abe Takaaki 
Published: March 2020

AbstractSporadic inclusion body myositis (sIBM) is the most common idiopathic inflammatory myopathy, and several reports have suggested that mitochondrial abnormalities are involved in its etiology.We recruited 9 sIBM patients and found significant histological changes and an elevation of growth differential factor 15 (GDF15), a marker of mitochondrial disease, strongly suggesting the involvement of mitochondrial dysfunction. Bioenergetic analysis of sIBM patient myoblasts revealed impaired mitochondrial function.Decreased ATP production, reduced mitochondrial size and reduced mitochondrial dynamics were also observed in sIBM myoblasts. Cell vulnerability to oxidative stress also suggested the existence of mitochondrial dysfunction.Mitochonic acid-5 (MA-5) increased the cellular ATP level, reduced mitochondrial ROS, and provided protection against sIBM myoblast death.MA-5 also improved the survival of sIBM skin fibroblasts as well as mitochondrial morphology and dynamics in these cells. The reduction in the gene expression levels of Opa1 and Drp1 was also reversed by MA-5, suggesting the modification of the fusion/fission process. These data suggest that MA-5 may provide an alternative therapeutic strategy for treating not only mitochondrial diseases but also sIBM.
Pan-genome analysis ofMycobacterium africanum: insights to dynamics and evolution
Authors: Olawoye Idowu B. , Frost Simon D.W. , Happi Christian T. 
Published: March 2020

AbstractMycobacterium tuberculosiscomplex (MTBC) consists of seven major lineages with three of them reported to circulate within West Africa: lineage 5 (West African 1) and lineage 6 (West African 2) which are geographically restricted to West Africa and lineage 4 (Euro-American lineage) which is found globally. It is unclear why the West African lineages are not found elsewhere; some hypotheses suggest that it could either be harboured by an animal reservoir which is restricted to West Africa, or strain preference for hosts of West African ethnicity, or inability to compete with other lineages in other locations.We tested the hypothesis thatM. africanum(MAF) might have emigrated out of West Africa but was outcompeted by more virulent strains ofM. tuberculosis(MTB).Whole genome sequences of MTB from Nigeria (n=21), China (n=21) and MAF from Mali (n=24) were retrieved, and a pan-genome analysis was performed after fully annotating these genomes. The outcome of this analysis shows that Lineages 4, 5 and 6 have relatively close pan-genomes whilst lineage 2 has an open pan-genome. We also see a correlation in numbers of some multiple copy core genes and amino acid substitution with lineage specificity that may have contributed to geographical distribution of these lineages.The findings in this study provides a perspective to one of the hypotheses thatM. africanummight find it difficult to compete against the more modern lineages outside West Africa hence its localization to the geographical region.
Catch composition and life history characteristics of sharks and rays (Elasmobranchii) landed in the Andaman and Nicobar Islands, India
Authors: Tyabji Zoya , Wagh Tanmay , Patankar Vardhan , Jabado Rima W. , Sutaria Dipani 
Published: March 2020

ABSTRACTThe scientific literature on the diversity and biological characteristics of sharks and rays from the Andaman and Nicobar Archipelago fishing grounds is scarce and compromised by species misidentifications. We carried out systematic fish landing surveys in South Andamans from January 2017 to May 2018, a comprehensive and cost-effective way to fill this data gap. We sampled 5,742 individuals representing 57 shark and ray species. Of the 36 species of sharks and 21 species of rays landed, six species of sharks -Loxodon macrorhinus, Carcharhinus amblyrhynchos, Sphyrna lewini, Carcharhinus albimarginatus,Carcharhinus brevipinna,andParagaelus randallidominated landings and comprised 83.35 % of shark landings, while three species of rays were most abundant –Pateobatis jenkinsii,Himantura leopardaandH. tutul, and comprised 48.82 % of ray landings. We report size extensions for seven shark species as well as three previously unreported ray species, increasing the known diversity for the islands and for India. For sharks, mature individuals of small-bodied species (63.48 % males of total landings of species less than 1.5 m total length) and immature individuals of larger species (84.79 % males of total landings of species larger than 1.5 m total length) were mostly landed; whereas for rays, mature individuals were predominantly landed (80.71 % males of total landings) likely reflecting differences in fishing patterns as well as habitat preferences and life history stages across species. Further, juvenile sharks and gravid females were landed in large quantities which might be unsustainable in the long-term. Landings were female-biased inC. amblyrhynchos, S. lewiniandP. jenkinsii,and male-biased inL. macrorhinusandH. leoparda, indicating either spatio-temporal or gear specific sexual segregation in these species. Understanding these nuances - the composition and biology of sharks and rays landed in different fisheries seasonally will inform future conservation and fishery management measures for these species in the Andaman and Nicobar Islands.
Inhibitory effect of the TSG-6 on the BMP-4/Smad signaling pathway and odonto/osteogenic differentiation of dental pulp stem cells
Authors: Wang Ying , Yuan Shuai , Sun Jingjing , Gong Yuping , Liu Sirui , Guo Runying , He Wei , Liu Yiming , Kang Peng , Li Rui 
Published: March 2020

AbstractThis study aimed to observe the molecular mechanism underlying the effect of tumor necrosis factor–inducible protein 6 (TSG-6) on the bone morphogenetic protein-4 (BMP-4)/drosophila mothers against decapentaplegic protein(Smad) signaling pathway and mineralization of dental pulp stem cells (DPSCs) in inflammatory environment. Normal and TSG-6 gene–modified DPSCs were cultured in a mineralization-inducing fluid containing 0 and 50 ng/mL TNF-α separately. The real-time polymerase chain reaction was used to measure the expression of TSG-6 and odonto/osteogenic differentiation makers at the mRNA level. Western blot analysis and cellular immunofluorescence were used to observe the odonto/osteogenic differentiation of DPSCs and the variation of BMP-4/Smad signaling pathway at the protein level. Moreover, normal and modified DPSCs combined with hydrogel were used for subcutaneous implantation in nude mice. The expression of odonto/osteogenic markers and BMP-4/Smad-related proteins was lower in Ad-TSG-6 DPSCs than in normal DPSCs after mineralization induction, and was higher in TSG-6-RNAi DPSCs than in normal DPSCs after culturing with mineralization-inducing fluid containing 50 ng/mL TNF-α. The subcutaneous transplantation of normal and modified DPSCs combined with hydrogel in nude mice demonstrated that normal DPSCs were formed in the tissue containing collagen. The tissue formed by Ad-TSG-6 DPSCs was highly variable, and the cells were very dense. The expression of odonto/osteogenic markers of Ad-TSG-6 DPSCs were lower in Ad-TSG-6 DPSCs than in normal DPSCs. We can know that TNF-α regulates the expression of TSG-6, thereby inhibiting the BMP-4/Smad signaling pathway and the odonto/osteogenic differentiation ability of DPSCs.
CHOmics: a web-based tool for multi-omics data analysis and interactive visualization in CHO cell lines
Authors: Lin Dongdong , Yalamanchili Hima , Zhang Xinmin , Lewis Nathan E. , Alves Christina S. , Groot Joost , Arnsdorf Johnny , Bjørn Sara Peterson , Wulff Tune , Voldborg Bjørn Gunnar Rude , Zhou Yizhou , Zhang Baohong 
Published: March 2020

ABSTRACTChinese hamster ovary (CHO) cell lines are widely used in industry for biological drug production. During cell culture development, considerable effort is invested to understand the factors that greatly impact cell growth, specific productivity and product qualities of the biotherapeutics. High-throughput omics approaches have been increasingly utilized to reveal cellular mechanisms associated with cell line phenotypes and guide process optimization, comprehensive omics data analysis and management have been a challenge. Here we developed CHOmics, a web-based tool for integrative analysis of CHO cell line omics data that provides an interactive visualization of omics analysis outputs and efficient data management. CHOmics has a built-in comprehensive pipeline for RNA sequencing data processing and multilayer statistical modules to explore relevant genes or pathways. Moreover, advanced functionalities were provided to enable users to customize their analysis and visualize the output systematically and interactively. The tool was also designed with the flexibility to allow other omics data input and thereby enabling multi-omics comparison and visualization at both gene and pathway levels. Collectively, CHOmics is an integrative platform for data analysis, visualization and management with expectations to promote the broader use of omics in CHO cell research. The open-source tool is freely available athttp://www.chomics.org.
Comparative Pathogenesis Of COVID-19, MERS And SARS In A Non-Human Primate Model
Authors: Rockx Barry , Kuiken Thijs , Herfst Sander , Bestebroer Theo , Lamers Mart M. , de Meulder Dennis , van Amerongen Geert , van den Brand Judith , Okba Nisreen M.A. , Schipper Debby , van Run Peter , Leijten Lonneke , Verschoor Ernst , Verstrepen Babs , Langermans Jan , Drosten Christian , van Vlissingen Martje Fentener , Fouchier Ron , de Swart Rik , Koopmans Marion , Haagmans Bart L. 
Published: March 2020

AbstractA novel coronavirus, SARS-CoV-2, was recently identified in patients with an acute respiratory syndrome, COVID-19. To compare its pathogenesis with that of previously emerging coronaviruses, we inoculated cynomolgus macaques with SARS-CoV-2 or MERS-CoV and compared with historical SARS-CoV infections. In SARS-CoV-2-infected macaques, virus was excreted from nose and throat in absence of clinical signs, and detected in type I and II pneumocytes in foci of diffuse alveolar damage and mucous glands of the nasal cavity. In SARS-CoV-infection, lung lesions were typically more severe, while they were milder in MERS-CoV infection, where virus was detected mainly in type II pneumocytes. These data show that SARS-CoV-2 can cause a COVID-19-like disease, and suggest that the severity of SARS-CoV-2 infection is intermediate between that of SARS-CoV and MERS-CoV.One Sentence SummarySARS-CoV-2 infection in macaques results in COVID-19-like disease with prolonged virus excretion from nose and throat in absence of clinical signs.