bluuebunny/crossref_metadata_2025_split huggingface dataset:
Whole-brain connectivity atlas of glutamatergic and GABAergic neurons in mouse dorsal and median raphe nucleus
Authors: Xu Zhengchao , Feng Zhao , Zhao Mengting , Sun Qingtao , Deng Lei , Jia Xueyan , Jiang Tao , Luo Pan , Chen Wu , Yuan Jing , Li Xiangning , Gong Hui , Luo Qingming , Li Anan 
Published: December 2020

AbstractThe dorsal raphe nucleus (DR) and median raphe nucleus (MR) contain populations of glutamatergic and GABAergic neurons regulating diverse behavioral functions. Their whole-brain input-output circuits remain incompletely understood. We used viral tracing combined with fluorescence micro-optical sectioning tomography to generate a comprehensive whole-brain atlas of inputs and outputs of glutamatergic and GABAergic neurons in the DR and MR. We discovered that these neurons receive inputs from similar upstream brain regions. The glutamatergic and GABAergic neurons in the same raphe nucleus have divergent projection patterns with differences in critical brain regions. Specifically, MR glutamatergic neurons project to the lateral habenula via multiple pathways. Correlation and cluster analysis indicated that glutamatergic and GABAergic neurons in the same raphe nucleus receive inputs from heterogeneous neurons in upstream brain regions and send different collateral projections. This connectivity atlas provides insights into the cell heterogeneity, anatomical connectivity and behavioral functions of the raphe nucleus.
DnaJC7 binds natively folded structural elements in tau to inhibit amyloid formation
Authors: Hou Zhiqiang , Wydorski Pawel M. , Perez Valerie A. , Mendoza-Oliva Aydé , Ryder Bryan D. , Mirbaha Hilda , Kashmer Omar , Joachimiak Lukasz A. 
Published: December 2020

ABSTRACTMolecular chaperones, including Hsp70/Hsp40 families, play central roles in binding substrates to prevent their aggregation. How Hsp40s select different conformations of substrates remains poorly understood. Here, we report a novel interaction between the Hsp40 DnaJC7 and tau that efficiently suppresses tau aggregationin vitroand in cells. DnaJC7 binds preferentially to natively folded wild-type tau, but disease-associated mutants in tau reduce chaperone binding affinity. We identify that DnaJC7 uses a single TPR domain to recognize a β-turn element in tau that contains the275VQIINK280amyloid motif. Wild-type tau β-turn fragments, but not mutant fragments, can block full-length tau binding to DnaJC7. These data suggest DnaJC7 preferentially binds and stabilizes natively folded conformations of tau to prevent tau conversion into amyloids. This identifies a novel mechanism of tau aggregation regulation that can be exploited as both a diagnostic and a therapeutic intervention.
HISAT-3N: a rapid and accurate three-nucleotide sequence aligner
Authors: Zhang Yun , Park Chanhee , Bennett Christopher , Thornton Micah , Kim Daehwan 
Published: December 2020

AbstractNucleotide conversion sequencing technologies such as bisulfite-seq and SLAM-seq are powerful tools to explore the intricacies of cellular processes. In this paper, we describe HISAT-3N (hierarchical indexing for spliced alignment of transcripts - 3 nucleotides), which rapidly and accurately aligns sequences consisting of nucleotide conversions by leveraging powerful hierarchical index and repeat index algorithms originally developed for the HISAT software. Tests on real and simulated data sets demonstrate that HISAT-3N is over 7 times faster, has greater alignment accuracy, and has smaller memory requirements than other modern systems. Taken together HISAT-3N is the ideal aligner for use with converted sequence technologies.
RORα enforces stability of the T-helper-17 cell effector program
Authors: Lee June-Yong , Hall Jason A. , Pokrovskii Maria , Kroehling Lina , Wu Lin , Littman Dan R. 
Published: December 2020

SummaryT helper 17 (Th17) cells regulate mucosal barrier defenses, but also promote multiple autoinflammatory diseases. Although many molecular determinants of Th17 cell differentiation have been described, the transcriptional programs that sustain Th17 cellsin vivoremain obscure. The transcription factor RORγt is critical for Th17 cell differentiation, but a distinct role of the closely-related RORα, which is co-expressed in Th17 cells, is not known. Here we demonstrate that, although dispensable for Th17 cell differentiation, RORα governs optimal Th17 responses in peripheral tissues. Thus, the absence of RORα in T cells led to significant reductions in both RORγt expression and effector function amongst Th17 cells, due to need for cooperative RORα and RORγt binding to a newly-identifiedRorcenhancer element that is essential for Th17 lineage maintenancein vivo. Altogether, these data point to a non-redundant role of RORα in Th17 lineage maintenance via reinforcement of the RORγt transcriptional program.
Detection of PD-L1-expressing myeloid cell clusters in the hyaluronan-enriched stroma in tumor tissue and tumor-draining lymph nodes
Authors: Dominguez-Gutierrez Paul R. , Kwenda Elizabeth , Donelan William , O’Malley Padraic , Crispen Paul L. , Kusmartsev Sergei 
Published: December 2020

AbstractExpression of the transmembrane protein PD-L1 is frequently up-regulated in cancer. Since PD-L1-expressing cells can induce apoptosis or anergy of T lymphocytes through binding to PD1 receptor, the PD-L1-mediated inhibition of activated PD1+T cells considered as a major pathway for tumor immune escape. However, the mechanisms that regulate the expression of PD-L1 in the tumor microenvironment not fully understood. Analysis of organotypic tumor tissue slice cultures, obtained from tumor-bearing mice as well as from cancer patients, revealed that tumor-associated hyaluronan (HA) supports the development of the immunosuppressive PD-L1+macrophages. Using genetically modified tumor cells, we identified both epithelial tumor cells and cancer-associated fibroblasts (CAFs) as the major source of HA in the tumor microenvironment. HA-producing tumor cells and, in particular CAFs of bone marrow origin, directly interact with tumor-recruited Hyal2+myeloid cells forming the large stromal congregates/clusters that are highly enriched for both HA and PD-L1. Furthermore, similar cell clusters comprising of HA-producing fibroblasts and PD-L1+macrophages were detected in the tumor-draining lymph nodes. Collectively, our findings indicate that the formation of multiple large HA-enriched stromal clusters that support the development of PD-L1-expressing antigen-presenting cells in the tumor microenvironment and draining lymph nodes could contribute to the immune escape and resistance to immunotherapy in cancer.
Transcriptome-wide investigation of stop codon readthrough in Saccharomyces cerevisiae
Authors: Mangkalaphiban Kotchaphorn , He Feng , Ganesan Robin , Wu Chan , Baker Richard , Jacobson Allan 
Published: December 2020

ABSTRACTTranslation of mRNA into a polypeptide is terminated when the release factor eRF1 recognizes a UAA, UAG, or UGA stop codon in the ribosomal A site and stimulates nascent peptide release. However, stop codon readthrough can occur when a near-cognate tRNA outcompetes eRF1 in decoding the stop codon, resulting in the continuation of the elongation phase of protein synthesis. At the end of a conventional mRNA coding region, readthrough allows translation into the mRNA 3’-UTR. Previous studies with reporter systems have shown that the efficiency of termination or readthrough is modulated by cis-acting elements other than stop codon identity, including two nucleotides 5’ of the stop codon, six nucleotides 3’ of the stop codon in the ribosomal mRNA channel, and stem-loop structures in the mRNA 3’-UTR. It is unknown whether these elements are important at a genome-wide level and whether other mRNA features proximal to the stop codon significantly affect termination and readthrough efficiencies in vivo. Accordingly, we carried out ribosome profiling analyses of yeast cells expressing wild-type or temperature-sensitive eRF1 and developed bioinformatics strategies to calculate readthrough efficiency, and to identify mRNA and peptide features which influence that efficiency. We found that the stop codon (nt +1 to +3), the nucleotide after it (nt +4), the codon in the P site (nt -3 to -1), and 3’-UTR length are the most influential features in the control of readthrough efficiency, while nts +5 to +9 and mRNA secondary structure in the 3’-UTR had milder effects. Additionally, we found low readthrough genes to have shorter 3’-UTRs compared to high readthrough genes in cells with thermally inactivated eRF1, while this trend was reversed in wild-type cells. Together, our results demonstrated the general roles of known regulatory elements in genome-wide regulation and identified several new mRNA or peptide features affecting the efficiency of translation termination and readthrough.AUTHOR SUMMARYOf the 64 codons that exist for translation of the genetic code into a polypeptide chain, only UAA, UAG, and UGA signify termination of continued protein synthesis. However, the efficiency of termination is not the same for different mRNAs and is likely influenced by mRNA sequences proximal to these “stop” codons. Here, we sought to expand current understanding of termination efficiency to a genome-wide scale. Our analysis identifies novel mRNA features that may regulate the efficiency of translation termination, including the identities of the stop codon, the penultimate codon, the proximal nucleotides, and the length of mRNA 3’-untranslated region. As ∼11% of human diseases are caused by mutations that introduce premature stop codons, resulting in both accelerated mRNA decay and truncated protein product, our findings are valuable for understanding and developing therapeutics targeting the termination step of mRNA translation.
Trait Evolution in Microbial Communities
Authors: Zhao Lihong , Ridenhour Benjamin J , Remien Christopher H 
Published: December 2020

AbstractUnderstanding the evolutionary dynamics of microbial communities is a key step towards the goal of predicting and manipulating microbiomes to promote beneficial states. While interactions within microbiomes and between microbes and their environment collectively determine the community composition and population dynamics, we are often concerned with traits or functions of a microbiome that link more directly to host health. To study how traits of a microbiome are impacted by eco-evolutionary dynamics, we recast a classic resource-mediated population dynamic model into a population genetic framework which incorporates traits. The relative fitness of each group of microbes can be explicitly written in terms of population dynamic parameters, and corresponding evolutionary dynamics emerge. Using several example systems, we demonstrate how natural selection, mutation, and shifts in the environment work together to produce changes in traits over time.
Pitfalls in Post Hoc Analyses of Population Receptive Field Data
Authors: Stoll Susanne , Infanti Elisa , de Haas Benjamin , Schwarzkopf D. Samuel 
Published: December 2020

AbstractData binning involves grouping observations into bins and calculating bin-wise summary statistics. It can cope with overplotting and noise, making it a versatile tool for comparing many observations. However, data binning goes awry if the same observations are used for binning (selection) and contrasting (selective analysis). This creates circularity, biasing noise components and resulting in artifactual changes in the form of regression towards the mean. Importantly, these artifactual changes are a statistical necessity. Here, we use (null) simulations and empirical repeat data to expose this flaw in the scope of post hoc analyses of population receptive field data. In doing so, we reveal that the type of data analysis, data properties, and circular data cleaning are factors shaping the appearance of such artifactual changes. We furthermore highlight that circular data cleaning and circular sorting of change scores are selection practices that result in artifactual changes even without circular data binning. These pitfalls might have led to erroneous claims about changes in population receptive fields in previous work and can be mitigated by using independent data for selection purposes. Our evaluations highlight the urgency for us researchers to make the validation of analysis pipelines standard practice.Graphical abstractHighlightsCircular data binning produces artifactual changes in the form of regression towards the meanAnalysis type, data properties, and circular data cleaning shape these artifactual changesCircular data cleaning and sorting produce artifactual changes even without circular data binning
Minnesota peat viromes reveal terrestrial and aquatic niche partitioning for local and global viral populations
Authors: ter Horst Anneliek M. , Santos-Medellín Christian , Sorensen Jackson W. , Zinke Laura A. , Wilson Rachel M. , Johnston Eric R. , Trubl Gareth G. , Pett-Ridge Jennifer , Blazewicz Steven J. , Hanson Paul J. , Chanton Jeffrey P. , Schadt Christopher W. , Kostka Joel E. , Emerson Joanne B. 
Published: December 2020

AbstractBackgroundPeatlands are expected to experience sustained yet fluctuating higher temperatures due to climate change, leading to increased microbial activity and greenhouse gas emissions. Despite mounting evidence for viral contributions to these processes in peatlands underlain with permafrost, little is known about viruses in other peatlands. More generally, soil viral biogeography and its potential drivers are poorly understood at both local and global scales. Here, 87 metagenomes and five viral size-fraction metagenomes (viromes) from a boreal peatland in northern Minnesota (the SPRUCE whole-ecosystem warming experiment and surrounding bog) were analyzed for dsDNA viral community ecological patterns, and the recovered viral populations (vOTUs) were compared to our curated PIGEON database of 266,805 vOTUs from diverse ecosystems.ResultsWithin the SPRUCE experiment, viral community composition was significantly correlated with peat depth, water content, and carbon chemistry, including CH4and CO2concentrations, but not with temperature during the first two years of warming treatments. Peat vOTUs with aquatic-like signatures (shared predicted protein content with marine and/or freshwater vOTUs) were significantly enriched in more waterlogged surface peat depths. Predicted host ranges for SPRUCE vOTUs were relatively narrow, generally within a single bacterial genus. Of the 4,326 SPRUCE vOTUs, 164 were previously detected in other soils, mostly peatlands. None of the previously identified 202,372 marine and freshwater vOTUs in our PIGEON database were detected in SPRUCE peat, but 1.9% of 78,203 genus-level viral clusters (VCs) were shared between soil and aquatic environments. On a per-sample basis, vOTU recovery was 32 times higher from viromes compared to total metagenomes.ConclusionsResults suggest strong viral “species” boundaries between terrestrial and aquatic ecosystems and to some extent between peat and other soils, with differences less pronounced at the “genus” level. The significant enrichment of aquatic-like vOTUs in more waterlogged peat suggests that viruses may also exhibit niche partitioning on more local scales. These patterns are presumably driven in part by host ecology, consistent with the predicted narrow host ranges. Although more samples and increased sequencing depth improved vOTU recovery from total metagenomes, the substantially higher per-sample vOTU recovery after viral particle enrichment highlights the utility of soil viromics.
Microbiome and Metabolome driven differentiation of TGF-β producing Tregs leads to Senescence and HIV latency
Authors: Ghneim Khader , Sharma Ashish Arunkumar , Ribeiro Susan Pereira , Fourati Slim , Ahlers Jeffrey , Kulpa Deanna , Xu Xuan , Brehm Jessica , Talla Aarthi , Arumugam Sahaana , Darko Samuel , Rodriguez Benigno , Shive Carey , Cristescu Razvan , Loboda Andrey , Balderas Robert , Wang I-Ming , Hunt Peter , Lamarre Daniel , Douek Daniel , Hazuda Daria , Lederman Michael M. , Deeks Steven , Sekaly Rafick-Pierre 
Published: December 2020

SummaryCurrent therapeutic interventions to eradicate latent HIV (“reservoir”) and restore immune function in ART-treated HIV infection have yet to show efficacy. To explore mechanisms of HIV persistence, we apply an integrated systems biology approach and identify a distinct group of individuals with poor CD4 T-cell reconstitution (Immunologic non-responders, “INRs”) and high frequencies of cells with inducible HIV. Contrary to the prevailing notion that immune activation drives HIV persistence and immune dysfunction, peripheral blood leukocytes from these subjects have enhanced expression of a network of genes regulated by cellular senescence driving transcription factors (TFs) FOXO3, SMAD2 and IRF3. In these subjects, increased frequencies of regulatory T cells and expression of the TGF-β signaling cascade are complimented by the downregulation of cell cycle, metabolic and pro-inflammatory pathways. Lactobacillaceae family and metabolites (members of the butyrate family – i.e. α-ketobutyrate) were correlated with Treg frequencies in “Senescent-INRs”ex vivo,triggered the differentiation of TGF-β producing Tregs and promoted HIV latency establishmentin vitro.These cascades, downstream of PD-1/TGF-β, prevent memory T cell differentiation and are associated with an increase in frequencies of cells with inducible HIVex vivo.Our findings identify cellular senescence responses that can be targeted by PD-1 or TGF-β specific interventions that have shown safety and efficacy in cancer, and may prove to be crucial for HIV eradication.
Dectin-1 mediated DC-SIGN Recruitment toCandida albicansContact Sites
Authors: Choraghe Rohan P. , Neumann Aaron K. 
Published: December 2020

AbstractAt host-pathogen contact sites withCandida albicans, Dectin-1 activates pro-inflammatory signaling, while DC-SIGN promotes adhesion to the fungal surface. We observed that Dectin-1 and DC-SIGN collaborate to enhance capture/retention ofC. albicansunder fluid shear culture conditions. Therefore, we devised a cellular model system wherein we could investigate the interaction between these two receptors during the earliest stages of host-pathogen interaction. In cells expressing both receptors, DC-SIGN was quickly recruited to contact sites (103.15% increase) but Dectin-1 did not similarly accumulate. Once inside the contact site, FRAP studies revealed a strong reduction in lateral mobility of DC-SIGN (but not Dectin-1), consistent with DC-SIGN engaging in multivalent adhesive binding interactions with cell wall mannoprotein ligands. Interestingly, in the absence of Dectin-1 co-expression, DC-SIGN recruitment to the contact was much poorer—only 35.04%. These data suggested that Dectin-1 promotes the active recruitment of DC-SIGN to the contact site. We proposed that Dectin-1 signaling activates the RHOA pathway, leading to actomyosin contractility that promotes DC-SIGN recruitment, perhaps via the formation of a centripetal ActoMyosin Flow (AMF) directed into the contact site. Indeed, RHOA pathway inhibitors significantly reduced Dectin-1 associated DC-SIGN recruitment to the contact site. We used agent based modeling to predict DC-SIGN transport kinetics with (“Directed+Brownian”) and without (“Brownian”) the hypothesized actomyosin flow-mediated transport. The Directed+Brownian transport model predicted a DC-SIGN contact site recruitment (108.72%), similar to that we observed experimentally under receptor co-expression. Brownian diffusive transport alone predicted contact site DC-SIGN recruitment of only 54.02%. However, this value was similar to experimentally observed recruitment in cells without Dectin-1 or treated with RHOA inhibitor, suggesting that it accurately predicted DC-SIGN recruitment when a contact site AMF would not be generated. TIRF microscopy of nascent cell contacts on glucan-coated glass revealed Dectin-1 dependent DC-SIGN and F-actin (LifeAct) recruitment kinetics to early-stage contact site membranes. DC-SIGN entry followed F-actin with a temporal lag of 8.35 ± 4.57 seconds, but this correlation was disrupted by treatment with RHOA inhibitor. Thus, computational and experimental evidence provides support for the existence of a Dectin-1/RHOA-dependent AMF that produces a force to drive DC-SIGN recruitment to pathogen contact sites, resulting in improved pathogen capture and retention by immunocytes. These data suggest that the rapid collaborative response of Dectin-1 and DC-SIGN in early contact sties might be important for the efficient acquisition of yeast under flow conditions, such as those that prevail in circulation or mucocutaneous sites of infection.
The perceptions on the recent COVID-19 pandemic: a study on health-care students in Malaysia
Authors: Mohd Zain Norhayati , Che Mut Nur Anis Izzati 
Published: December 2020

PurposeThe purpose of this paper is to study the perception of health-care students on the recent COVID-19 pandemic in Malaysia. There was one study by Caliskhan et al. (2020) conducted among Turkish final-year medical students showed that the students were knowledgeable about and aware of the COVID-19 pandemic. To the authors’ knowledge, there are limited number of studies conducted among health-care students in Malaysia.Design/methodology/approachThe online questionnaire was randomly distributed to the health-care students in Malaysia. The questionnaire consists of socio-demographic data and perceptions on COVID-19. Descriptive analysis was used to analyse the perceptions of the health-care students on COVID-19.FindingsHealth-care students in Malaysia have positive perceptions on COVID-19, and it did not give huge impact of their interest in this health-care field. Thus, it is important that this issue is investigated, and the perceptions of health-care students on COVID-19 can be highlighted.Research limitations/implicationsThe strength of this study was the participation from the health-care students from various institutions, which have different experience and backgrounds. The study was limited on the items of question utilised. Due to the limited time and urgency of the survey, the authors were unable to study their knowledge, attitudes and way they are going to cope with this kind of pandemic as the students and as future health-care workers.Originality/valueThe paper points out the effect on the recent COVID-19 pandemic on health-care students in Malaysia. It also points out the perceptions of health-care students in Malaysia on the current pandemic. It is expected that the results of this research would serve as baseline data for health-care institutions in Malaysia to continue equip the future front liners that can adapt future challenges.