bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enhanced Behavioral Performance through Interareal Gamma and Beta Synchronization
Authors: Parto-Dezfouli Mohsen , Vezoli Julien , Bosman Conrado Arturo , Fries Pascal 
Published: March 2023

SUMMARYCognitive functioning requires coordination between brain areas. Between visual areas, feedforward gamma synchronization improves behavioral performance. Here, we investigate whether similar principles hold across brain regions and frequency bands, using simultaneous local field potential recordings from 15 areas during performance of a selective attention task. Short behavioral reaction times (RTs), an index of efficient interareal communication, occurred when occipital areas V1, V2, V4, DP showed gamma synchronization, and fronto-central areas S1, 5, F1, F2, F4 showed beta synchronization. For both area clusters and corresponding frequency bands, deviations from the typically observed phase relations increased RTs. Across clusters and frequency bands, good phase relations occurred in a correlated manner specifically when they processed the behaviorally relevant stimulus. Furthermore, the fronto- central cluster exerted a beta-band influence onto the occipital cluster whose strength predicted short RTs. These results suggest that local gamma and beta synchronization and their inter-regional coordination jointly improve behavioral performance.
The phenuivirus Toscana virus makes an atypical use of vacuolar acidity to enter host cells
Authors: Koch Jana , Xin Qilin , Obr Martin , Schäfer Alicia , Rolfs Nina , Anagho Holda , Kudulyte Aiste , Woltereck Lea , Kummer Susann , Campos Joaquin , Uckeley Zina M. , Bell-Sakyi Lesley , Kräusslich Hans-Georg , Schur Florian KM , Acuna Claudio , Lozach Pierre-Yves 
Published: March 2023

AbstractToscana virus is a major cause of arboviral disease in humans in the Mediterranean basin during summer. However, early virus-host cell interactions and entry mechanisms remain poorly characterized. Investigating iPSC-derived human neurons and cell lines, we found that virus binding to the cell surface was specific but inefficient, and 50% of bound virions were endocytosed within 10 min. Virions entered Rab5a+ early endosomes and, subsequently, Rab7a+ and LAMP-1+ late endosomal compartments. Penetration required intact late endosomes and occurred within 30 min following internalization. Virus entry relied on vacuolar acidification, with an optimal pH for viral membrane fusion at pH 5.5. The pH threshold increased to 5.8 with longer pre-exposure of virions to the slightly acidic pH in early endosomes. Strikingly, the particles remained infectious after entering late endosomes with a pH below the fusion threshold. Overall, our study establishes Toscana virus as a late-penetrating virus and reveals an atypical use of vacuolar acidity by this virus to enter host cells.
Neural activity induces strongly coupled electro-chemo-mechanical interactions and fluid flow in astrocyte networks and extracellular space – a computational study
Authors: Sætra Marte J. , Ellingsrud Ada J. , Rognes Marie E. 
Published: March 2023

ABSTRACTThe complex interplay between chemical, electrical, and mechanical factors is fundamental to the function and homeostasis of the brain, but the effect of electrochemical gradients on brain interstitial fluid flow, solute transport, and clearance remains poorly quantified. Here, via in-silico experiments based on biophysical modeling, we estimate water movement across astrocyte cell membranes, within astrocyte networks, and within the extracellular space (ECS) induced by neuronal activity, and quantify the relative role of different forces (osmotic, hydrostatic, and electrical) on transport and fluid flow under such conditions. Our results demonstrate how neuronal activity in the form of extracellular ionic input fluxes may induce complex and strongly-coupled chemical-electrical-mechanical interactions in astrocytes and ECS. Furthermore, we observe that the fluid dynamics are crucially coupled to the spatial organization of the intracellular network, with convective and electrical drift dominating ionic diffusion in astrocyte syncytia.Author SummaryOver the last decades, the neuroscience community has paid increased attention to the astrocytes – star-shaped brain cells providing structural and functional support for neurons. Astrocyte networks are likely to be a crucial pathway for fluid flow through brain tissue, which is essential for the brain’s volume homeostasis and waste clearance. However, numerous questions related to the role of osmotic pressures and astrocytic membrane properties remain unanswered. There are also substantial gaps in our understanding of the driving forces underlying fluid flow through brain tissue. Answering these questions requires a better understanding of the interplay between electrical, chemical, and mechanical forces in brain tissue. Due to the complex nature of this interplay and experimental limitations, computational modeling can be a critical tool. Here, we present a high fidelity computational model of an astrocyte network and the extracellular space. The model predicts the evolution in time and distribution in space of intra- and extracellular volumes, ion concentrations, electrical potentials, and hydrostatic pressures following neural activity. Our findings show that neural activity induces strongly coupled chemical-mechanical-electrical interactions in the tissue and suggest that chemical gradients inside astrocyte syncytia strengthen fluid flow at the microscale.
Comprehensive mutational analysis of the checkpoint signaling function of Rpa1/Ssb1 in fission yeast
Authors: Xu Yong-jie , Bhadra Sankhadip , Mahdi Alaa Taha A. , Dev Kamal , Yurtsever Ilknur , Nakamura Toru M. 
Published: March 2023

ABSTRACTReplication protein A (RPA) is a heterotrimeric complex and the major single-strand DNA (ssDNA) binding protein in eukaryotes. It plays important roles in DNA replication, repair, recombination, telomere maintenance, and checkpoint signaling. Because RPA is essential for cell survival, understanding its checkpoint signaling function in cells has been challenging. Several RPA mutants have been reported previously in fission yeast. None of them, however, has a defined checkpoint defect. A separation-of-function mutant of RPA, if identified, would provide significant insights into the checkpoint initiation mechanisms. We have explored this possibility and carried out an extensive genetic screening for Rpa1/Ssb1, the large subunit of RPA in fission yeast, looking for mutants with defects in checkpoint signaling. This screen has identified twenty-five primary mutants that are sensitive to genotoxins. Among these mutants, two have been confirmed partially defective in checkpoint signaling primarily at the replication fork, not the DNA damage site. The remaining mutants are likely defective in other functions such as DNA repair or telomere maintenance. Our screened mutants, therefore, provide a valuable tool for future dissection of the multiple functions of RPA in fission yeast.AUTHOR SUMMARYOriginally discovered as a protein required for replication of simian virus SV40 DNA, replication protein A is now known to function in DNA replication, repair, recombination, telomere maintenance, and checkpoint signaling in all eukaryotes. The protein is a complex of three subunits and the two larger ones are essential for cell growth. This essential function however complicates the studies in living cells, and for this reason, its checkpoint function remains to be fully understood. We have carried out an genetic screening of the largest subunit of this protein in fission yeast, aiming to find a non-lethal mutant that lacks the checkpoint function. This extensive screen has uncovered two mutants with a partial defect in checkpoint signaling when DNA replication is arrested. Surprisingly, although the two mutants also have a defect in DNA repair, their checkpoint signaling remains largely functional in the presence of DNA damage. We have also uncovered twenty-three mutants with defects in DNA repair or telomere maintenance, but not checkpoint signaling. Therefore, the non-lethal mutants uncovered by this study provide a valuable tool for dissecting the multiple functions of this biologically important protein in fission yeast.
The EDC4-XRN1 axis controls P-body dynamics to link mRNA decapping with decay
Authors: Brothers William R. , Ali Farah , Kajjo Sam , Fabian Marc R. 
Published: March 2023

ABSTRACTDeadenylation-dependent mRNA decapping and decay is the major cytoplasmic mRNA turnover pathway in eukaryotes. Many mRNA decapping and decay factors associate with each other via protein-protein interaction motifs. For example, the decapping enzyme DCP2 and the 5’-3’ exoribonuclease XRN1 interact with enhancer of mRNA decapping protein 4 (EDC4), a large scaffold that has been reported to stimulate mRNA decapping. mRNA decapping and decay factors are also found in processing bodies (P-bodies), evolutionarily conserved ribonucleoprotein (RNP) granules that are often enriched with mRNAs targeted for decay, such as microRNA (miRNA)-targeted mRNAs, yet paradoxically are not required for mRNA decay to occur. In this study, we show that disrupting the interaction between XRN1 and EDC4 or altering their stoichiometry leads to an inhibition of mRNA decapping, with miRNA-targeted mRNAs being stabilized in a translationally repressed state. Importantly, we demonstrate that this concomitantly leads to larger P-bodies that are directly responsible for preventing mRNA decapping under these conditions. Finally, we demonstrate that P-bodies act to support cell viability and prevent stress granule formation under conditions when XRN1 is limiting. Taken together, these data demonstrate that the interaction between XRN1 and EDC4 regulates P-body dynamics to properly coordinate mRNA decapping with 5’-3’ decay in human cells.HIGHLIGHTSXRN1-EDC4 interaction couples mRNA decapping with mRNA decay.Disrupting XRN1-EDC4 contact generates larger P-bodies that, in turn, inhibit decapping.P-bodies support cellular fitness in the absence of XRN1.
Thiol reductive stress activates the hypoxia response pathway
Authors: Ravi  , Kumar Ajay , Bhattacharyya Shalmoli , Singh Jogender 
Published: March 2023

AbstractOwing to their capability to disrupt the oxidative protein folding environment in the endoplasmic reticulum (ER), thiol antioxidants such as dithiothreitol (DTT) are used as ER-specific stressors. We recently showed that thiol antioxidants modulate the methionine-homocysteine cycle by upregulating an S-adenosylmethionine-dependent methyltransferase,rips-1, inCaenorhabditis elegans. However, the changes in cellular physiology induced by thiol stress that modulate the methionine-homocysteine cycle remain uncharacterized. Here, using forward genetic screens inC. elegans, we discover that thiol stress enhancesrips-1expression via the hypoxia response pathway. We demonstrate that thiol stress activates the hypoxia response pathway. The activation of the hypoxia response pathway by thiol stress is conserved in human cells. The hypoxia response pathway enhances thiol toxicity viarips-1expression and confers protection against thiol toxicity viarips-1-independent mechanisms. Finally, we show that DTT might activate the hypoxia response pathway by producing hydrogen sulfide. Our studies reveal an intriguing interaction between thiol-mediated reductive stress and the hypoxia response pathway and challenge the current model that thiol antioxidant DTT disrupts only the ER milieu in the cell.
Genus-Wide Genomic Characterization ofMacrococcus: Insights into Evolution, Population Structure, and Functional Potential
Authors: Carroll Laura M. , Pierneef Rian , Mafuna Thendo , Magwedere Kudakwashe , Matle Itumeleng 
Published: March 2023

AbstractMacrococcusspecies have been isolated from a range of mammals and mammal-derived food products. While they are largely considered to be animal commensals,Macrococcusspp. can be opportunistic pathogens in both veterinary and human clinical settings. This study aimed to provide insight into the evolution, population structure, and functional potential of theMacrococcusgenus, with an emphasis on antimicrobial resistance (AMR) and virulence potential. All high-quality, publicly availableMacrococcusgenomes (n= 104, accessed 27 August 2022), plus six South African genomes sequenced here (two strains from bovine clinical mastitis cases and four strains from beef products), underwent taxonomic assignment (using four different approaches), AMR determinant detection (via AMRFinderPlus), and virulence factor detection (using DIAMOND and the core Virulence Factor Database). Overall, the 110Macrococcusgenomes were of animal commensal, veterinary clinical, food-associated (including food spoilage), and environmental origins; five genomes (4.5%) originated from human clinical cases. Notably, none of the taxonomic assignment methods produced identical results, highlighting the potential forMacrococcusspecies misidentifications. The most common predicted antimicrobial classes associated with AMR determinants identified acrossMacrococcusincluded macrolides, beta-lactams, and aminoglycosides (n= 81, 61, and 44 of 110 genomes; 73.6, 55.5, and 40.0%, respectively). Genes showing homology toStaphylococcus aureusexoenzyme aureolysin were detected across multiple species (using 90% coverage,n= 40 and 77 genomes harboring aureolysin-like genes at 60% and 40% amino acid [AA] identity, respectively).Staphylococcus aureusPanton-Valentine leucocidin toxin-associatedlukF-PVandlukS-PVhomologs were identified in eightM. canisgenomes (≥40% AA identity, >85% coverage). Using a method that delineates populations using recent gene flow (PopCOGenT), two species (M. caseolyticusandM. armenti) were composed of multiple within-species populations. Notably,M. armentiwas partitioned into two populations, which differed in functional potential (e.g., one harbored beta-lactamase family, type II toxin-antitoxin system, and stress response proteins, while the other possessed a Type VII secretion system; PopCOGenTP< 0.05). Overall, this study leverages all publicly availableMacrococcusgenomes in addition to newly sequenced genomes from South Africa to identify genomic elements associated with AMR or virulence potential, which can be queried in future experiments.
Structural and functional properties of the transporter SLC26A6 reveal mechanism of coupled anion exchange
Authors: Tippett David N. , Breen Colum , Butler Stephen J. , Sawicka Marta , Dutzler Raimund 
Published: March 2023

AbstractMembers of the SLC26 family constitute a conserved class of anion transport proteins, which encompasses uncoupled transporters with channel-like properties, coupled exchangers and motor proteins. Among the ten functional paralogs in humans, several participate in the secretion of bicarbonate in exchange with chloride and thus play an important role in maintaining pH homeostasis. Previously, we have elucidated the structure of murine SLC26A9 and defined its function as an uncoupled chloride transporter (Walter, Sawicka, & Dutzler, 2019). Here we have determined the structure of the closely related human transporter SLC26A6 and characterized it as a coupled exchanger of chloride with bicarbonate and presumably also oxalate. The structure defines an inward-facing conformation of the protein that generally resembles known structures of SLC26A9. The altered anion selectivity between both paralogs is a consequence of a remodeled ion binding site located in the center of a mobile unit of the membrane-inserted domain, which also accounts for differences in the coupling mechanism.
Identification of a carbohydrate-recognition motif of purinergic receptors
Authors: Zhao Lifen , Wei Fangyu , He Xinheng , Jiang Hualiang , Wen Liuqing , Cheng Xi 
Published: March 2023

AbstractAs a major class of biomolecules, carbohydrates play indispensable roles in various biological processes. However, it remains largely unknown how carbohydrates directly modulate important drug targets, such as G-protein coupled receptors (GPCRs). Here, we employed P2Y purinoceptor 14 (P2Y14), a drug target for inflammation and immune responses, to uncover the sugar nucleotide activation of GPCRs. Integrating molecular dynamics simulation with functional study, we identified the uridine diphosphate (UDP)-sugar-binding site on P2Y14, and revealed that a UDP-glucose might activate the receptor by bridging the transmembrane helices (TM) 2 and 7. Between TM2 and TM7 of P2Y14, a conserved salt bridging chain (K2.60-D2.64-K7.35-E7.36, KDKE) was identified to distinguish different UDP-sugars, including UDP-glucose, UDP-galactose, UDP-glucuronic acid and UDP-N-acetylglucosamine. We identified the KDKE chain as a conserved functional motif of sugar binding for both P2Y14 and P2Y purinoceptor 12 (P2Y12), and then designed three sugar nucleotides as agonists of P2Y12. These results not only expand our understanding for activation of purinergic receptors but also provide insights for the carbohydrate drug development for GPCRs.
Comparative genomics analysis of three conserved plasmid families in the Western Hemisphere soft tick-borne relapsing fever borreliae provides insight into variation in genome structure and antigenic variation systems
Authors: Kneubehl Alexander R. , Lopez Job E. 
Published: March 2023

AbstractBorreliaspirochetes, causative agents of Lyme disease and relapsing fever (RF), have a uniquely complex genome consisting of a linear chromosome and circular and linear plasmids. The plasmids harbor genes important for the vector-host life cycle of these tick-borne bacteria. The role of Lyme disease causingBorreliaplasmids is more refined compared to RF spirochetes because of limited plasmid-resolved genomes for RF spirochetes. We recently addressed this limitation and found that three linear plasmid families (F6, F27, and F28) were syntenic across all species. Given this conservation, we further investigated the three plasmid families. The F6 family, also known as the megaplasmid, contained regions of repetitive DNA. The F27 was the smallest, encoding genes with unknown function. The F28 family encoded the expression locus for antigenic variation in all species exceptBorrelia hermsiiandBorrelia anserina.Taken together, this work provides a foundation for future investigations to identify essential plasmid-localized genes that drive the vector-host life cycle of RFBorrelia.IMPORTANCEBorreliaspp. spirochetes are arthropod-borne bacteria found globally and infect humans and other vertebrates. RF borreliae are understudied and misdiagnosed pathogens because of the vague clinical presentation of disease and the elusive feeding behavior of argasid ticks. Consequently, genomics resources for RF spirochetes have been limited. Analyses ofBorreliaplasmids have been challenging because they are often highly fragmented and unassembled. By utilizing Oxford Nanopore Technologies, we recently generated plasmid-resolved genomes for sevenBorreliaspp. found in the Western Hemisphere. This current study is a more in-depth investigation into the linear plasmids that were conserved and syntenic across species. This analysis determined differences in genome structure and, importantly, in antigenic variation systems between species. This work is an important step in identifying crucial plasmid-borne genetic elements essential for the life cycle of RF spirochetes.
Glycans modulate lipid binding in Lili-Mip lipocalin protein
Authors: SureshKumar Harini , Appadurai Rajeswari , Srivastava Anand 
Published: March 2023

AbstractThe unique viviparous Pacific Beetle cockroaches provide nutrition to their embryo by secreting milk proteins Lili-Mip, which is a lipid-binding glycoprotein that crystallizes in vivo. The resolved in vivo crystal structure of variably glycosylated Lili-Mip shows a classical Lipocalin fold with an eight-stranded antiparallel beta-barrel enclosing a fatty acid. The availability of physiologically unaltered glycoprotein structure makes Lili-Mip a very attractive model system to investigate the role of glycans on protein structure, dynamics, and function. Towards that end, we have employed all-atom molecular dynamics simulations on various glycosylated stages of a bound and free Lili-Mip protein and characterized the impact of glycans and the bound lipid on the dynamics of this glycoconjugate. Our work provides important molecular-level mechanistic insights into the role of glycans in the nutrient storage function of the Lili-Mip protein. Our analyses show that the glycans locally stabilize spatially proximal residues and regulate the low amplitude opening motions of the residues at the entrance of the binding pocket. Glycans, which are located at the portal end of the barrel, also restrict the distal barrel depth and allosterically modulate the lipid dynamics in the barrel. A simple but effective distance-based network analysis of the protein also reveals the role of glycans in the subtle rewiring of residues crucial for determining the barrel depth and lipid orientation.
Excess Mortality in the Vaccination Era in the United States, By State and 6-Month Period
Authors: Faust Jeremy Samuel , Renton Benjamin , Du Chengan , Chen Alexander Junxiang , Li Shu-Xia , Lin Zhenqiu , Krumholz Harlan M. 
Published: March 2023

AbstractIntroductionThe US continued to record all-cause excess mortality after the rollout of vaccines. We sought to quantify excess mortality by state and compare these rates to primary series vaccination completion levels.MethodsObservational cohort, US and state-level data. Expected monthly deaths were modeled using pre-pandemic US and state-level data (2015-2020). Mortality data was accessed from CDC public reporting.ResultsWe find that in a two-year period since the rollout of vaccines, the US recorded >874,000 excess deaths. Vaccination rates and excess mortality were most strongly correlated in first two periods before the Omicron variant.ConclusionThe association between vaccination and lower excess mortality rates was strongest in 2021 and early 2022, prior to high population rates of infection-acquired immunity. The findings underscore the benefits of the rapid vaccination rollout campaign and the continued need to boost at-risk populations.