bluuebunny/crossref_metadata_2025_split huggingface dataset:
Coherent activity at three major lateral hypothalamic neural outputs controls the onset of motivated behavior responses
Authors: Martianova Ekaterina , Pageau Alicia , Pausic Nikola , Gentiletti Tommy Doucet , Leblanc Danahe , Proulx Christophe D. 
Published: April 2021

AbstractThe lateral hypothalamus (LH) plays an important role in motivated behavior. However, it is not known how LH neural outputs dynamically signal to major downstream targets to organize behavior. We used multi-fiber photometry to show that three major LH neural outputs projecting to the dorsal raphe nucleus (DRN), ventral tegmental area (VTA), and lateral habenula (LHb) exhibit significant coherent activity in mice engaging motivated responses, which decrease during immobility. Mice engaging active coping responses exhibit increased activity at LH axon terminals that precedes an increase in the activity of serotonin neurons and dopamine neurons, indicating that they may play a role in initiating active responses stemming from LH signal transmissions. The optogenetic activation of LH axon terminals in either the DRN, VTA, or LHb was sufficient to increase mobility but had different effects on passive avoidance and sucrose consumption, suggesting that LH outputs use complementary mechanisms to control behavioral responses. Our results support the notion that the three LH neural outputs play complementary roles in initiating motivated behaviors.
Sleep-dependent upscaled excitability, saturated neuroplasticity, and modulated cognition in the human brain
Authors: Salehinejad Mohammad Ali , Ghanavati Elham , Reinders Joerg , Hengstler Jan G. , Kuo Min-Fang , Nitsche Michael A. 
Published: April 2021

AbstractSleep strongly affects synaptic strength, making it critical for cognition, especially learning, and memory formation. Whether andhowsleep deprivation modulates human brain physiology and cognition is not well understood. Here we examined how overnight sleep deprivation vs sufficient sleep affects (a) cortical excitability, as measured by transcranial magnetic stimulation (TMS), (b) inducibility of LTP-and-LTD-like plasticity via transcranial direct current stimulation (tDCS), and (c) learning, memory and attention. The results suggest that sleep deprivation upscales cortical excitability due to enhanced glutamate-related cortical facilitation and decreased and/or reversed GABAergic cortical inhibition. Furthermore, tDCS-induced LTP-like plasticity abolishes while LTD-like plasticity converts to excitatory LTP-like plasticity under sleep deprivation. This is associated with increased EEG theta activity, which is related to sleep pressure. Finally, we show that learning and memory formation, behavioral counterparts of plasticity, and working memory and attention, which rely on cortical excitability, are impaired during sleep deprivation. Our data suggest that upscaled brain excitability, and altered plasticity, due to sleep deprivation, are associated with impaired cognitive performance.
Gut IgA Enhances Systemic IgG Responses to Pneumococcal Vaccines Through the Commensal Microbiota
Authors: Gutzeit Cindy , Grasset Emilie K. , Matthews Dean B. , Maglione Paul J. , Magri Giuliana , Britton Graham J. , Tomalin Lewis , Pybus Marc , Vaquero Sonia Tejedor , Veeramreddy Pavan K. , Tachó-Piñot Roser , Nalda Andrea Martín , Prat Marina García , Gallo Monica Martinez , Dieli-Crimi Romina , Clemente José C. , Mehandru Saurabh , Suarez-Farina Mayte , Faith Jeremiah J. , Cunningham-Rundles Charlotte , Cerutti Andrea 
Published: April 2021

SUMMARYThe gut microbiota enhances systemic immunoglobulin G (IgG) responses to vaccines. However, it is unknown whether this effect involves IgA, a mucosal antibody that coats intestinal microbes. Here we found that gut IgA increased peripheral IgG responses to pneumococcal vaccines, as these responses were profoundly impaired in mice with global or mucosa-restricted IgA deficiency. The positive effect of IgA on vaccine-induced IgG production implicated gut bacteria. Indeed, IgG responses to pneumococcal vaccines were also defective in ex-germ free mice recolonized with gut microbes from mouse or human IgA-deficient donors. IgA exerted this IgG-enhancing effect by constraining the systemic translocation of intestinal commensal antigens, which caused chronic immune activation, including T cell overexpression of programmed death-1. This immune inhibitory receptor hindered vaccine-specific IgG production by eliciting functional B cell unresponsiveness, which was reverted by anti-programmed death-1 treatment. Thus, gut IgA is functionally interconnected with systemic IgG via intestinal microbes.
Sex differences in behaviour and molecular pathology in the 5XFAD model
Authors: Sil Annesha , Erfani Arina , Lamb Nicola , Copland Rachel , Riedel Gernot , Platt Bettina 
Published: April 2021

ABSTRACTBackgroundThe prevalence of Alzheimer’s Disease (AD) is greater in women compared to men, but the reasons for this remain unknown. This sex difference has been widely neglected in experimental studies using transgenic mouse models of AD.ObjectiveHere, we studied behaviour and molecular pathology of 5-month-old 5XFAD mice, which express mutated human amyloid precursor protein and presenilin-1 on a C57BL/6J background, vs. their wild-type littermate controls, to compared both sex- and genotype-dependent differences.MethodsA novel behavioural paradigm was utilised (OF-NO-SI), comprising activity measures (Open Field, OF) arena, followed by Novel Object exploration (NO) and Social Interaction (SI) of a sex-matched conspecific. Each segment consisted of two repeated trials to assess between-trial habituation. Subsequently, brain pathology (amyloid load, stress response and inflammation markers, synaptic integrity, trophic support) was assessed using qPCR and Western blotting.ResultsFemale 5XFAD mice had higher levels of human APP and beta-amyloid (Aβ) and heightened inflammation vs males. These markers correlated with hyperactivity observed in both sexes, yet only female 5XFAD mice presented with deficits in object and social exploration. Male animals had higher expression of stress markers and neurotrophic factors irrespective of genotype, this correlated with cognitive performance.ConclusionThe impact of sex on AD-relevant phenotypes is in line with human data and emphasises the necessity of appropriate study design and reporting. Differential molecular profiles observed in male vs. female mice offer insights into possible protective mechanisms, and hence treatment strategies.
SmProt: A Reliable Repository with Comprehensive Annotation of Small Proteins Identified from Ribosome Profiling
Authors: Li Yanyan , Zhou Honghong , Chen Xiaomin , Zheng Yu , Kang Quan , Hao Di , Zhang Lili , Song Tingrui , Luo Huaxia , Hao Yajing , Chen Yiwen , Chen Runsheng , Zhang Peng , He Shunmin 
Published: April 2021

AbstractSmall proteins specifically refer to proteins consisting of less than 100 amino acids translated from small open reading frames (sORFs), which were usually missed in previous genome annotation. The significance of small proteins has been revealed in current years, along with the discovery of their diverse functions. However, systematic annotation of small proteins is still insufficient. SmProt was specially developed to provide valuable information on small proteins for scientific community. Here we present the update of SmProt, which emphasizes reliability of translated sORFs, genetic variants in translated sORFs, disease-specific sORFs translation events or sequences, and significantly increased data volume. More components such as non-AUG translation initiation, function, and new sources are also included. SmProt incorporated 638,958 unique small proteins curated from 3,165,229 primary records, which were computationally predicted from 419 ribosome profiling (Ribo-seq) datasets and collected from the literature and other sources originating from 370 cell lines or tissues in 8 species (Homo sapiens,Mus musculus,Rattus norvegicus,Drosophila melanogaster,Danio rerio,Saccharomyces cerevisiae,Caenorhabditis elegans, andEscherichia coli). In addition, small protein families identified from human microbiomes were collected. All datasets in SmProt are free to access, and available for browse, search, and bulk downloads athttp://bigdata.ibp.ac.cn/SmProt/.
Extracellular adenosine induces hypersecretion of IL-17A by T-helper 17 cells through the adenosine A2a receptor to promote neutrophilic inflammation
Authors: Tokano Mieko , Matsushita Sho , Takagi Rie , Yamamoto Toshimasa , Kawano Masaaki 
Published: April 2021

AbstractExtracellular adenosine, produced from ATP secreted by neuronal or immune cells, may play a role in endogenous regulation of inflammatory responses. However, the underlying molecular mechanisms are largely unknown. Here, we show that adenosine primes hypersecretion of interleukin (IL)-17A by CD4+T cells via T cell receptor activation. This hypersecretion was also induced by an adenosine A2a receptor (A2aR) agonist, PSB0777. In addition, an A2aR antagonist (Istradefylline), and inhibitors of adenyl cyclase, protein kinase A, and cAMP response element binding protein (which are signaling molecules downstream of the Gs protein coupled with the A2aR), suppressed IL-17A production, suggesting that activation of A2aR induces IL-17A production by CD4+T cells. Furthermore, immune subset studies revealed that adenosine induced hypersecretion of IL-17A by T-helper (Th)17 cells. These results indicate that adenosine is an endogenous modulator of neutrophilic inflammation. Administration of an A2aR antagonist to mice with experimental autoimmune encephalomyelitis led to marked amelioration of symptoms, suggesting that suppression of adenosine-mediated IL-17A production is an effective treatment for Th17-related autoimmune diseases.
Bacteriophages encoding human immune evasion factors adapt to livestock-associated MRSA through rounds of integration and excision
Authors: Leinweber Helena , Sieber Raphael , Larsen Jesper , Stegger Marc , Ingmer Hanne 
Published: April 2021

AbstractIn recent years there has been an increase in human infections with methicillin-resistantStaphylococcus aureus(MRSA) originating from livestock and strains carrying bacterial viruses of the Sa3int-family have disseminated into the community. Sa3int phages express immune evasion factors and are common in human staphylococcal strains. As the bacterial attachment site (attB) for Sa3int phages is mutated in livestock-associated strains, the integration frequency is low and a key question is how the phages are established. Here we show that Sa3int phages adapt to alternative bacterial integration sites by mutating the phage attachment sequence,attP, leading to enhanced integration at these sites. Using a model strain carrying the mutatedattBLAof livestock-associated strains we find that once established, the Sa3int phage, Φ13 is inducible with release of heterogenous phage populations carrying mutations inattPthat in part increase homology to alternative integration sites orattBLA. Compared to the original phage, the adaptive mutations increase phage integration in new rounds of infection. Also, Sa3int phages induced from livestock-associated outbreak strains reveal mutatedattPsequences. We suspect that promiscuity of the phage-encoded recombinase allows this adaptation and propose it may explain how phages mediate “host jumps” that are regularly observed for staphylococcal lineages.
NEU1 and NEU3 enzymes alter CD22 organization on B cells
Authors: Tran Hanh-Thuc Ton , Li Caishun , Chakraberty Radhika , Cairo Christopher W. 
Published: April 2021

ABSTRACTThe B cell membrane expresses sialic acid binding Immunoglobulin-like lectins, also called Siglecs, that are important for modulating immune response. Siglecs have interactions with sialoglycoproteins found on the same membrane (cis ligands) that result in homotypic and heterotypic receptor clusters. The regulation and organization of these clusters, and their effect on cell activation, is not clearly understood. We investigated the role of human neuraminidase enzymes, NEU1 and NEU3, on the clustering of CD22 on B cells using confocal microscopy. We observed that native NEU1 and NEU3 activity influence the cluster size of CD22. Using single-particle tracking, we observed that NEU3 activity increased the lateral mobility of CD22, which was in contrast to the effect of exogenous bacterial NEU enzymes. Moreover, we show that native NEU1 and NEU3 activity influenced cellular Ca2+levels, supporting a role for these enzymes in regulating B cell activation. Our results establish a role for native NEU activity in modulating CD22 organization and function on B cells.
Translational control of polyamine metabolism by CNBP is required for Drosophila locomotor function
Authors: Coni Sonia , Falconio Federica A. , Marzullo Marta , Munafò Marzia , Zuliani Benedetta , Mosti Federica , Fatica Alessandro , Ianniello Zaira , Bordone Rosa , Macone Alberto , Agostinelli Enzo , Perna Alessia , Matkovic Tanja , Sigrist Stephan , Silvestri Gabriella , Canettieri Gianluca , Ciapponi Laura 
Published: April 2021

ABSTRACTMicrosatellite expansions of CCTG repeats in the CNBP gene leads to accumulation of toxic RNA and have been associated to DM2. However, it is still unclear whether the dystrophic phenotype is also linked to CNBP decrease, a conserved CCHC-type zinc finger RNA binding protein that regulates translation and is required for mammalian development.Here we show that depletion ofDrosophilaCNBP in muscles causes age-dependent locomotor defects that are correlated with impaired polyamine metabolism. We demonstrate that the levels of ornithine decarboxylase (ODC) and polyamines are significantly reduced upon dCNBP depletion. Of note, we show a reduction of the CNBP-polyamine axis in muscle from DM2 patients. Mechanistically, we provide evidence that dCNBP controls polyamine metabolism through binding dOdc mRNA and regulating its translation. Remarkably, the locomotor defect of dCNBP-deficient flies is rescued by either polyamine supplementation or dOdc1 overexpression. We suggest that this dCNBP function is evolutionarily conserved in vertebrates with relevant implications for CNBP-related pathophysiological conditions.GRAPHICAL ABSTRACTCNBP controls muscle function by regulating the polyamine metabolismLack of dCNBP impairs locomotor function through ODC-polyamine downregulationdCNBP binds dOdc mRNA and regulates its translationPolyamine supplementation or dOdc1 reconstitution rescues locomotor defectsCNBP-ODC-polyamine levels are reduced in muscle of DM2 patients
Identification that ADAM17 mediates proteolytic maturation of calcium channel auxiliary α2δ subunits, and enables calcium current enhancement
Authors: Kadurin Ivan , Dahimene Shehrazade , Page Karen M , Ellaway Joseph I. J. , Chaggar Kanchan , Troeberg Linda , Nagase Hideaki , Dolphin Annette C. 
Published: April 2021

ABSTRACTThe auxiliary α2δ subunits of voltage-gated calcium (CaV) channels are key to augmenting expression and function of CaV1 and CaV2 channels, and are also important drug targets in several therapeutic areas, including neuropathic pain. The α2δ proteins are translated as pre-proteins encoding both α2and δ, and post-translationally proteolysed into α2and δ subunits, which remain associated as a complex. In this study we have identified ADAM17 as a key protease involved in proteolytic processing of pro-α2δ-1 and α2δ-3 subunits. We provide three lines of evidence: firstly, proteolytic cleavage is inhibited by chemical inhibitors of particular metalloproteases, including ADAM17. Secondly, proteolytic cleavage of both α2δ-1 and α2δ-3 is markedly reduced in cell lines by knockout ofADAM17but notADAM10. Thirdly, proteolytic cleavage is reduced by the N-terminal active domain of TIMP-3 (N-TIMP-3), which selectively inhibits ADAM17. We have found previously that proteolytic cleavage into mature α2δ is essential for the enhancement of CaVfunction, and in agreement, knockout of ADAM17 inhibited the ability of α2δ-1 to enhance both CaV2.2 and CaV1.2 calcium currents. Thus, our study identifies ADAM17 as a key protease required for proteolytic maturation of α2δ-1 and α2δ-3, and thus a potential drug target in neuropathic pain.
Genetic variants associated mRNA stability in lung
Authors: Li Jian-Rong , Tang Mabel , Li Yafang , Amos Christopher I , Cheng Chao 
Published: April 2021

AbstractExpression quantitative trait loci (eQTLs) analyses have been widely used to identify genetic variants associated with gene expression levels to understand what molecular mechanisms underlie genetic traits. The resultant eQTLs might affect the expression of associated genes through transcriptional or post-transcriptional regulation. In this study, we attempt to distinguish these two types of regulation by identifying genetic variants associated with mRNA stability of genes (stQTLs). Specifically, we computationally inferred mRNA stability of genes based on RNA-seq data and performed association analysis to identify stQTLs. Using the Genotype-Tissue Expression (GTEx) lung RNA-Seq data, we identified a total of 142,801 stQTLs for 3,942 genes and 186,132 eQTLs for 4,751 genes from 15,122,700 genetic variants for 13,476 genes, respectively. Interesting, our results indicated that stQTLs were enriched in the CDS and 3’UTR regions, while eQTLs are enriched in the CDS, 3’UTR, 5’UTR, and upstream regions. We also found that stQTLs are more likely than eQTLs to overlap with RNA binding protein (RBP) and microRNA (miRNA) binding sites. Our analyses demonstrate that simultaneous identification of stQTLs and eQTLs can provide more mechanistic insight on the association between genetic variants and gene expression levels.Author SummaryIn the past decade, many studies have identified genetic variants associated with gene expression level (eQTLs) in different phenotypes, including tissues and diseases. Gene expression is the result of cooperation between transcriptional regulation, such as transcriptional activity, and post-transcriptional regulation, such as mRNA stability. Here, we present a computational framework that take advantage of recently developed methods to estimate mRNA stability from RNA-Seq, which is widely used to estimate gene expression, and then to identify genetic variants associated with mRNA stability (stQTLs) in lung tissue. Compared to eQTLs, we found that genetic variants that affects mRNA stability are more significantly located in the CDS and 3’UTR regions, which are known to interact with RNA-binding proteins (RBPs) or microRNAs to regulate stability. In addition, stQTLs are significantly more likely to overlap the binding sites of RBPs. We show that the six RBPs that most significantly bind to stQTLs are all known to regulate mRNA stability. This pipeline of simultaneously identifying eQTLs and stQTLs using only RNA-Seq data can provide higher resolution than traditional eQTLs study to better understand the molecular mechanisms of genetic variants on the regulation of gene expression.
Reactive astrocytes promote proteostasis in Huntington’s disease through the JAK2-STAT3 pathway
Authors: Abjean Laurene , Haim Lucile Ben , Riquelme-Perez Miriam , Gipchtein Pauline , Derbois Céline , Palomares Marie-Ange , Petit Fanny , Hérard Anne-Sophie , Gaillard Marie-Claude , Guillermier Martine , Gaudin-Guérif Mylène , Aurégan Gwenaelle , Sagar Nisrine , Héry Cameron , Dufour Noëlle , Robil Noémie , Kabani Mehdi , Melki Ronald , De la Grange Pierre , Bemelmans Alexis P. , Bonvento Gilles , Deleuze Jean-François , Hantraye Philippe , Flament Julien , Bonnet Eric , Brohard Solène , Olaso Robert , Brouillet Emmanuel , Sauvage Maria-Angeles Carrillo-de , Escartin Carole 
Published: April 2021

AbstractHuntington’s disease is a fatal neurodegenerative disease characterized by striatal neurodegeneration, aggregation of mutant Huntingtin and the presence of reactive astrocytes. Astrocytes are important partners for neurons and engage in a specific reactive response in Huntington’s disease that involves morphological, molecular and functional changes. How reactive astrocytes contribute to Huntington’s disease is still an open question, especially because their reactive state is poorly reproduced in experimental mouse models.Here, we show that the JAK2-STAT3 pathway, a central cascade controlling astrocyte reactive response, is activated in the putamen of Huntington’s disease patients. Selective activation of this cascade in astrocytes through viral gene transfer reduces the number and size of mutant Huntingtin aggregates in neurons and improves neuronal defects in two complementary mouse models of Huntington’s disease. It also reduces striatal atrophy and increases glutamate levels, two central clinical outcomes measured by non-invasive magnetic resonance imaging. Moreover, astrocyte-specific transcriptomic analysis shows that activation of the JAK2-STAT3 pathway in astrocytes coordinates a transcriptional program that increases their intrinsic proteolytic capacity, through the lysosomal and ubiquitin-proteasome degradation systems. This pathway also enhances their production and exosomal release of the co-chaperone DNAJB1, which contributes to mutant Huntingtin clearance in neurons.Together, our results show that the JAK2-STAT3 pathway controls a beneficial proteostasis response in reactive astrocytes in Huntington’s disease, which involves bi-directional signalling with neurons to reduce mutant Huntingtin aggregation, eventually improving disease outcomes.
Effects of BCG vaccination on donor unrestricted T cells in humans
Authors: Gela Anele , Murphy Melissa , Hadley Kate , Hanekom Willem A. , Henry Boom W. , Johnson John L. , Hoft Daniel F. , Joosten Simone A. , Ottenhoff Tom H.M. , Suliman Sara , Branch Moody D. , Lewinsohn David M. , Hatherill Mark , Seshadri Chetan , Nemes Elisa , Scriba Thomas J. ,   The Delayed BCG Study Team
Published: April 2021

SummaryAntigen classes other than proteins can be presented to T cells by near-monomorphic antigen-presenting molecules such as CD1, MR1, and butyrophilin 3A1. We sought to define the roles of donor unrestricted T (DURT) cells, including MR1-reactive MAIT cells, CD1b-reactive glucose monomycolate (GMM)-specific T cells, CD1d-reactive NKT cells, and γδ T cells, in vaccination againstMycobacterium tuberculosis. We characterized DURT cells following primary bacille Calmette-Guerin (BCG) vaccination in infants or BCG-revaccination in adults. BCG (re)vaccination did not modulate peripheral blood frequencies, T cell activation or memory profiles of MAIT cells, CD1b-restricted GMM-specific and germline-encoded mycolyl-reactive (GEM) cells or CD1d- restricted NKT cells. By contrast, BCG vaccination was associated with increased frequencies of γδ T cells as well as a novel subset of IFN-γ-expressing CD4+T cells with a CD26+CD161+TRAV1-2−phenotype in infants. More studies are required to understand the full potential of DURT cells in new TB vaccine strategies.
Enhancing and inhibitory motifs have coevolved to regulate CD4 activity
Authors: Lee Mark S. , Tuohy Peter J. , Kim Caleb , Lichauco Katrina , Parrish Heather L. , Doorslaer Koenraad Van , Kuhns Michael S. 
Published: April 2021

SUMMARYCD4+T cells use T cell receptor (TCR)-CD3 complexes, and CD4, to respond to peptide antigens within MHCII molecules (pMHCII). We report here that, through ∼435 million years of evolution in jawed vertebrates, purifying selection has shaped motifs in the extracellular, transmembrane, and intracellular domains of eutherian CD4 that both enhance pMHCII responses and are coevolving with residues in an intracellular motif that inhibits pMHCII responses. Importantly, while CD4 interactions with the Src kinase, Lck, are classically viewed as the key determinant of CD4’s contribution to pMHCII responses, we found that without the inhibitory motif CD4-Lck interactions are not necessary for robust responses to pMHCII. In summary, motifs that mediate events on the outside and inside of CD4+T cells coevolved to finetune the relay of pMHCII-specific information across the membrane. These results have implications for the evolution and function of complex transmembrane receptors and for biomimetic engineering.