bluuebunny/crossref_metadata_2025_split huggingface dataset:
Engineered receptor binding domain immunogens elicit pan-sarbecovirus neutralizing antibodies outside the receptor binding motif
Authors: Hauser Blake M. , Sangesland Maya , Lam Evan C. , Denis Kerri J. St. , Feldman Jared , Yousif Ashraf S. , Caradonna Timothy M. , Kannegieter Ty , Balazs Alejandro B. , Lingwood Daniel , Schmidt Aaron G. 
Published: December 2020

AbstractEffective countermeasures are needed against emerging coronaviruses of pandemic potential, similar to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Designing immunogens that elicit broadly neutralizing antibodies to conserved viral epitopes on the major surface glycoprotein, spike, such as the receptor binding domain (RBD) is one potential approach. Here, we report the generation of homotrimeric RBD immunogens from different sarbecoviruses using a stabilized, immune-silent trimerization tag. In mice, we find that a cocktail of these homotrimeric sarbecovirus RBDs elicits antibodies to conserved viral epitopes outside of the ACE2 receptor binding motif (RBM). Importantly, these responses neutralize all sarbecovirus components even in context of prior SARS-CoV-2 imprinting. We further show that a substantial fraction of the neutralizing antibodies elicited after vaccination in humans also engages non-RBM epitopes on the RBD. Collectively, our results suggest a strategy for eliciting broadly neutralizing responses leading to a pan-sarbecovirus vaccine.Author summaryImmunity to SARS-CoV-2 in the human population will be widespread due to natural infection and vaccination. However, another novel coronavirus will likely emerge in the future and may cause a subsequent pandemic. Humoral responses induced by SARS-CoV-2 infection and vaccination provide limited protection against even closely related coronaviruses. We show immunization with a cocktail of trimeric coronavirus receptor binding domains induces a neutralizing antibody response that is broadened to related coronaviruses with pandemic potential. Importantly, this broadening occurs in context of an initial imprinted SARS-CoV-2 spike immunization showing that preexisting immunity can be expanded to recognize other related coronaviruses. Our immunogens focused the serum antibody response to conserved epitopes on the receptor binding domain outside of the ACE2 receptor binding motif; this contrasts with current SARS-CoV-2 therapeutic antibodies, which predominantly target the receptor binding motif.
Circular RNA profiling reveals abundant and diverse circRNAs of SARS-CoV-2, SARS-CoV and MERS-CoV origin
Authors: Yang Shaomin , Zhou Hong , Cruz-Cosme Ruth , Liu Mingde , Xu Jiayu , Niu Xiaoyu , Li Yaolan , Xiao Lizu , Wang Qiuhong , Zhu Hua , Tang Qiyi 
Published: December 2020

ABSTRACTCircular RNAs (circRNAs) encoded by DNA genomes have been identified across host and pathogen species as parts of the transcriptome. Accumulating evidences indicate that circRNAs play critical roles in autoimmune diseases and viral pathogenesis. Here we report that RNA viruses of theBetacoronavirusgenus ofCoronaviridae, SARS-CoV-2, SARS-CoV and MERS-CoV, encode a novel type of circRNAs. Throughde novocircRNA analyses of publicly available coronavirus-infection related deep RNA-Sequencing data, we identified 351, 224 and 2,764 circRNAs derived from SARS-CoV-2, SARS-CoV and MERS-CoV, respectively, and characterized two major back-splice events shared by these viruses. Coronavirus-derived circRNAs are more abundant and longer compared to host genome-derived circRNAs. Using a systematic strategy to amplify and identify back-splice junction sequences, we experimentally identified over 100 viral circRNAs from SARS-CoV-2 infected Vero E6 cells. This collection of circRNAs provided the first line of evidence for the abundance and diversity of coronavirus-derived circRNAs and suggested possible mechanisms driving circRNA biogenesis from RNA genomes. Our findings highlight circRNAs as an important component of the coronavirus transcriptome.SummaryWe report for the first time that abundant and diverse circRNAs are generated by SARS-CoV-2, SARS-CoV and MERS-CoV and represent a novel type of circRNAs that differ from circRNAs encoded by DNA genomes.
Caerulomycin and Collismycin Antibiotics Share atransFlavin-Dependent Assembly Line for 2,2’-Bipyridine Formation and Sulfur Fate Differentiation
Authors: Pang Bo , Liao Rijing , Tang Zhijun , Guo Shengjie , Wu Zhuhua , Liu Wen 
Published: December 2020

ABSTRACTLinear nonribosomal peptide synthetases (NRPSs) and polyketide synthases (PKSs) template the modular biosynthesis of numerous nonribosomal peptides, polyketides and their hybrids though assembly line chemistry. This chemistry can be complex and highly varied, and thus challenges the understanding in the diverse polymerization processes of amino acid and carboxylate monomers programmed by various NRPSs and PKSs in nature. Here, we report that caerulomycin and collismycin peptide-polyketide hybrid antibiotics share an unusual assembly line that involves NRPS activity to recruit a flavoprotein actingin transand catalyze C-C bond formation and heterocyclization during 2,2’-bipyridine formation. Simultaneously, this assembly line provides dethiolated and thiolated 2,2’-bipyridine intermediates through differential treatment of the sulfhydryl group arising from L-cysteine incorporation. Subsequent L-leucine extension, which does not contribute any atoms to either caerulomycins or collismycins, plays a key role in sulfur fate determination by selectively advancing one of the two 2,2’-bipyridine intermediates down a path to the final products with or without sulfur decoration. These findings further the appreciation of assembly line chemistry and will facilitate the development of related molecules using synthetic biology approaches.
Environmental conditions and diffusion-limited microbial transfer drive specific microbial communities detected at different sections in oil-production reservoir with water-flooding
Authors: Gao Peike , Tian Huimei , Li Guoqiang , Zhao Feng , Xia Wenjie , Gu Ji-Dong , Le Jianjun , Ma Ting 
Published: December 2020

ABSTRACTThis study investigated the distribution of microbial communities in the oilfield production facilities of a water-flooding petroleum reservoir and the roles of environmental variation, microorganisms in injected water, and diffusion-limited microbial transfer in structuring the microbial communities. Similar bacterial communities were observed in surface water-injection facilities dominated by aerobic or facultative anaerobic Betaproteobacteria, Alphaproteobacteria, and Flavobacteria. Distinct bacterial communities were observed in downhole of the water-injection wells dominated by Clostridia, Deltaproteobacteria, Anaerolineae, and Synergistia, and in the oil-production wells dominated by Gammaproteobacteria, Betaproteobacteria, and Epsilonproteobacteria.Methanosaeta, Methanobacterium, andMethanolineawere dominant archaeal taxa in the water-injection facilities, while the oil-production wells were predominated byMethanosaeta,Methanomethylovorans, andMethanocalculus. Energy, nucleotide, translation, and glycan biosynthesis metabolisms were more active in the downhole of the water-injection wells, while bacterial chemotaxis, biofilm formation, two-component system, and xenobiotic biodegradation was associated with the oil-production wells. The number of shared OTUs and its positive correlation with formation permeability revealed differential diffusion-limited microbial transfer in oil-production facilities. The overall results indicate that environmental variation and microorganisms in injected water are the determinants that structure microbial communities in water-injection facilities, and the determinants in oil-bearing strata are environmental variation and diffusion-limited microbial transfer.IMPORTANCEWater-flooding continually inoculates petroleum reservoirs with exogenous microorganisms, nutrients, and oxygen. However, how this process influences the subsurface microbial community of the whole production process remains unclear. In this study, we investigated the spatial distribution of microbial communities in the oilfield production facilities of a water-flooding petroleum reservoir, and comprehensively illustrate the roles of environmental variation, microorganisms in injected water, and diffusion-limited microbial transfer in structuring the microbial communities. The results advance fundamental understanding on petroleum reservoir ecosystems that subjected to anthropogenic perturbations during oil production processes.
Dissociation of the intramolecularly cleaved N- and C-terminal fragments of the adhesion G protein-coupled receptor GPR133 (ADGRD1) increases canonical signaling
Authors: Frenster Joshua D. , Stephan Gabriele , Ravn-Boess Niklas , Bready Devin , Wilcox Jordan , Kieslich Bjoern , Wilde Caroline , Sträter Norbert , Wiggin Giselle R. , Liebscher Ines , Schöneberg Torsten , Placantonakis Dimitris G. 
Published: December 2020

SUMMARYGPR133 (ADGRD1), an adhesion G protein-coupled receptor (GPCR), is necessary for growth of glioblastoma (GBM), a brain malignancy. The extracellular N-terminus of GPR133 is thought to be autoproteolytically cleaved into an N-terminal and a C-terminal fragment (NTF and CTF). Nevertheless, the role of this cleavage in receptor activation remains unclear. Here, we show that the wild-type (WT) receptor is cleaved after protein synthesis and generates significantly more canonical signaling than an uncleavable point mutant (H543R) in patient-derived GBM cultures and HEK293T cells. However, the resulting NTF and CTF remain non-covalently bound until the receptor is trafficked to the plasma membrane, where we find NTF-CTF dissociation. Using a fusion of the hPAR1 receptor N-terminus and the CTF of GPR133, we demonstrate that thrombin-induced cleavage and shedding of the hPAR1 NTF increases receptor signaling. This study supports a model where dissociation of the NTF at the plasma membrane promotes GPR133 activation.Highlights-GPR133 is intramolecularly cleaved in patient-derived GBM cultures-Cleaved GPR133 signals at higher efficacy than the uncleavable GPR133 H543R mutant-The N- and C-terminal fragments (NTF and CTF) of GPR133 dissociate at the plasma membrane-Acute thrombin-induced cleavage of the human PAR1 NTF from the GPR133 CTF increases signalingeTOC BlurbFrenster et al. demonstrate intramolecular cleavage of the adhesion GPCR GPR133 in glioblastoma and HEK293T cells. The resulting N- and C-terminal fragments dissociate at the plasma membrane to increase canonical signaling. The findings suggest dissociation of GPR133’s N-terminus at the plasma membrane represents a major mechanism of receptor activation.
Astroglial calcium transfer from endoplasmic reticulum to mitochondria determines synaptic integration
Authors: Serrat Roman , Covelo Ana , Kouskoff Vladimir , Delcasso Sebastien , Ruiz Andrea , Chenouard Nicolas , Stella Carol , Blancard Corinne , Salin Benedicte , Julio-Kalajzić Francisca , Cannich Astrid , Massa Federico , Varilh Marjorie , Deforges Severine , Robin Laurie M. , De Stefani Diego , Busquets-Garcia Arnau , Gambino Frederic , Beyeler Anna , Pouvreau Sandrine , Marsicano Giovanni 
Published: December 2020

SummaryIntracellular calcium signaling underlies the astroglial control of synaptic transmission and plasticity. Mitochondria-endoplasmic reticulum contacts (MERCs) are key determinants of calcium dynamics, but their functional impact on astroglial regulation of brain information processing is currently unexplored. We found that the activation of astrocyte mitochondrial-associated CB1 receptors (mtCB1) determines MERCs-dependent intracellular calcium signaling and synaptic integration. The stimulation of mtCB1 receptors promotes calcium transfer from the endoplasmic reticulum to mitochondria through specific mechanisms regulating the activity of the mitochondrial calcium uniporter (MCU) channel. Physiologically, mtCB1-dependent mitochondrial calcium uptake determines the precise dynamics of cytosolic calcium events in astrocytes upon endocannabinoid mobilization. Accordingly, electrophysiological recordings in hippocampal slices showed that genetic exclusion of mtCB1 receptors or specific astroglial MCU inhibition blocks lateral synaptic potentiation, a key example of astrocyte-dependent integration of distant synapses activity. Altogether, these data reveal an unforeseen link between astroglial MERCs and the regulation of brain network functions.
Coordinated post-transcriptional control of oncogene-induced senescence by UNR/CSDE1
Authors: Avolio Rosario , Inglés-Ferrandiz Marta , Ciocia Annagiulia , Bonnin Sarah , Ribó Anna , Gebauer Fátima 
Published: December 2020

SUMMARYOncogene-induced senescence (OIS) is a form of stable cell cycle arrest elicited in cells as a response to oncogenic stimulation. OIS must be bypassed for transformation, but the mechanisms of OIS establishment and bypass remain poorly understood, especially at the post-transcriptional level. Here we show that the RNA binding protein UNR/CSDE1, previously involved in melanoma metastasis, unexpectedly enables OIS in primary mouse keratinocytes that have been challenged by over-expression of oncogenic H-Ras. Depletion of CSDE1 leads to senescence bypass, cell immortalization and tumor formation in vivo, indicating that CSDE1 behaves as a tumor suppressor. Using iCLIP-Seq, RNA-Seq and polysome profiling we have uncovered two independent molecular branches by which CSDE1 contributes to OIS. On one hand, CSDE1 enhances the senescence-associated secretory phenotype (SASP) by promoting the stability of SASP factor mRNAs. On the other hand, CSDE1 represses the synthesis of the pro-oncogenic RNA binding protein YBX1. Importantly, depletion of YBX1 from immortal keratinocytes rescues senescence and uncouples proliferation arrest from the SASP, revealing multilayered post-transcriptional mechanisms exerted by CSDE1 to control senescence. Our data uncover a novel function of CSDE1, and highlight the relevance of post-transcriptional control in the regulation of senescence.
Small-angle neutron scattering solution structures of NADPH-dependent sulfite reductase
Authors: Murray Daniel T. , Weiss Kevin L. , Stanley Christopher B. , Nagy Gergely , Stroupe M. Elizabeth 
Published: December 2020

ABSTRACTSulfite reductase (SiR), a dodecameric complex of flavoprotein reductase subunits (SiRFP) and hemoprotein oxidase subunits (SiRHP), reduces sulfur reduction for biomass incorporation. Electron transfer within SiR requires intra- and inter-subunit interactions that are mediated by the relative position of each protein, governed by flexible domain movements. Using small-angle neutron scattering, we report the first solution structures of SiR heterodimers containing a single copy of each subunit. These structures show how the subunits bind and how both subunit binding and oxidation state impact SiRFP’s conformation. Neutron contrast matching experiments on selectively deuterated heterodimers allow us to define the contribution of each subunit to the solution scattering. SiRHP binding induces a change in the position of SiRFP’s flavodoxin-like domain relative to its ferredoxin-NADP+reductase domain while compacting SiRHP’s N-terminus. Reduction of SiRFP leads to a more open structure relative to its oxidized state, re-positioning SiRFP’s N-terminal flavodoxin-like domain towards the SiRHP binding position. These structures show, for the first time, how both SiRHP binding to, and reduction of, SiRFP positions SiRFP for electron transfer between the subunits.
The convergence and divergence of episodic and semantic functions across lateral parietal cortex
Authors: Humphreys Gina F. , Jung JeYoung , Lambon Ralph Matthew A. 
Published: December 2020

AbstractSeveral decades of neuropsychological and neuroimaging research have highlighted the importance of lateral parietal cortex (LPC) across a myriad of cognitive domains. Yet, despite the prominence of this region the underlying function of LPC remains unclear. Two domains that have placed particular emphasis on LPC involvement are semantic memory and episodic memory retrieval. From each domain, sophisticated models have been proposed as to the underlying function, as well as the more domain-general assumption that LPC is engaged by any form of internally-directed cognition (episodic and semantic retrieval both being examples if this process). Here we directly address these alternatives using a combination of fMRI, functional connectivity and DTI white-matter connectivity data. The results show that ventral LPC (angular gyrus) was positively engaged during episodic retrieval but disengaged during semantic memory retrieval. In addition, the level of activity negatively varied with task difficulty in the semantic task whereas episodic activation was independent of difficulty. In contrast, dorsal LPC (intraparietal sulcus) showed domain general activation that was positively correlated with task difficulty. In terms of functional and structural connectivity, a dorsal-ventral and anterior-posterior gradient of connectivity was found to different processing networks (e.g., mid-angular gyrus (AG) connected with episodic retrieval). We propose a unifying model in which LPC as a whole might share a common underlying neurocomputation (e.g., multimodal buffering) with variations in the emergent, expressed cognitive functions across subregions arising from differences in the underlying white matter connectivity.
CAZymes inMaribacter dokdonensis62-1 from the Patagonian shelf: Genomics and physiology compared to related flavobacteria and a co-occurringAlteromonasstrain
Authors: Wolter Laura A. , Mitulla Maximilian , Kalem Jovan , Daniel Rolf , Simon Meinhard , Wietz Matthias 
Published: December 2020

ABSTRACTCarbohydrate-active enzymes (CAZymes) are an important feature of bacteria in productive marine systems such as continental shelves, where phytoplankton and macroalgae produce diverse polysaccharides. We herein describeMaribacter dokdonensis62-1, a novel strain of this flavobacterial species, isolated from alginate-supplemented seawater collected at the Patagonian continental shelf.M. dokdonensis62-1 harbors a diverse array of CAZymes in multiple polysaccharide utilization loci (PUL). Two PUL encoding polysaccharide lyases from families 6, 7, 12 and 17 allow substantial growth with alginate as sole carbon source, with simultaneous utilization of mannuronate and guluronate as demonstrated by HPLC. Furthermore, strain 62-1 harbors a mixed-feature PUL encoding both ulvan- and fucoidan-targeting CAZymes. Core-genome phylogeny and pangenome analysis revealed variable occurrence of these PUL in relatedMaribacterandZobelliastrains, indicating specialization to certain “polysaccharide niches”. Furthermore, lineage- and strain-specific genomic signatures for exopolysaccharide synthesis possibly mediate distinct strategies for surface attachment and host interaction. The wide detection of CAZyme homologs in algae-derived metagenomes suggests global occurrence in algal holobionts, supported by sharing multiple adaptive features with the hydrolytic model flavobacteriumZobellia galactanivorans. Comparison withAlteromonassp. 76-1 isolated from the same seawater sample revealed that these co-occurring strains target similar polysaccharides but with different genomic repertoires, coincident with differing growth behavior on alginate that might mediate ecological specialization. Altogether, our study contributes to the perception ofMaribacteras versatile flavobacterial polysaccharide degrader, with implications for biogeochemical cycles, niche specialization and bacteria-algae interactions in the oceans.
Computational prediction of MHC anchor locations guide neoantigen identification and prioritization
Authors: Xia Huiming , McMichael Joshua , Becker-Hapak Michelle , Onyeador Onyinyechi C. , Buchli Rico , McClain Ethan , Pence Patrick , Supabphol Suangson , Richters Megan M. , Basu Anamika , Ramirez Cody A. , Puig-Saus Cristina , Cotto Kelsy C. , Freshour Sharon L. , Hundal Jasreet , Kiwala Susanna , Goedegebuure S. Peter , Johanns Tanner M. , Dunn Gavin P. , Ribas Antoni , Miller Christopher A. , Gillanders William E. , Fehniger Todd A. , Griffith Obi L. , Griffith Malachi 
Published: December 2020

AbstractNeoantigens are novel peptide sequences resulting from sources such as somatic mutations in tumors. Upon loading onto major histocompatibility complex (MHC) molecules, they can trigger recognition by T cells. Accurate neoantigen identification is thus critical for both designing cancer vaccines and predicting response to immunotherapies. Neoantigen identification and prioritization relies on correctly predicting whether the presenting peptide sequence can successfully induce an immune response. As the majority of somatic mutations are single nucleotide variants, changes between wildtype and mutated peptides are typically subtle and require cautious interpretation. A potentially underappreciated variable in neoantigen-prediction pipelines is the mutation position within the peptide relative to its anchor positions for the patient’s specific MHC molecules. While a subset of peptide positions are presented to the T-cell receptor for recognition, others are responsible for anchoring to the MHC, making these positional considerations critical for predicting T-cell responses. We computationally predicted high probability anchor positions for different peptide lengths for 328 common HLA alleles and identified unique anchoring patterns among them. Analysis of 923 tumor samples shows that 6-38% of neoantigen candidates are potentially misclassified and can be rescued using allelespecific knowledge of anchor positions. A subset of anchor results were orthogonally validated using protein crystallography structures. Representative anchor trends were experimentally validated using peptide-MHC stability assays and competition binding assays. By incorporating our anchor prediction results into neoantigen prediction pipelines, we hope to formalize, streamline and improve the identification process for relevant clinical studies.One Sentence SummaryNeoantigen prediction accuracy is significantly influenced by the mutation position within the neoantigen and its relative position to the patient’s allele-specific MHC anchor locations.
Natural SARS-CoV-2 infections, including virus isolation, among serially tested cats and dogs in households with confirmed human COVID-19 cases in Texas, USA
Authors: Hamer Sarah A. , Pauvolid-Corrêa Alex , Zecca Italo B. , Davila Edward , Auckland Lisa D. , Roundy Christopher M. , Tang Wendy , Torchetti Mia , Killian Mary Lea , Jenkins-Moore Melinda , Mozingo Katie , Akpalu Yao , Ghai Ria R. , Spengler Jessica R. , Behravesh Casey Barton , Fischer Rebecca S. B. , Hamer Gabriel L. 
Published: December 2020

AbstractThe natural infections and epidemiological roles of household pets in SARS-CoV-2 transmission are not understood. We conducted a longitudinal study of dogs and cats living with at least one SARS-CoV-2 infected human in Texas and found 47.1% of 17 cats and 15.3% of 59 dogs from 25.6% of 39 households were positive for SARS-CoV-2 via RT-PCR and genome sequencing or neutralizing antibodies. Virus was isolated from one cat. The majority (82.4%) of infected pets were asymptomatic. Re-sampling of one infected cat showed persistence of viral RNA at least 32 d-post human diagnosis (25 d-post initial test). Across 15 antibody-positive animals, titers increased (33.3%), decreased (33.3%) or were stable (33.3%) over time. A One Health approach is informative for prevention and control of SARS-CoV-2 transmission.