bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nasal tissue-resident memory CD4+T cells persist after influenza A virus infection and provide heterosubtypic protection
Authors: Mathew Nimitha R. , Gailleton Romain , Scharf Lydia , Schön Karin , Strömberg Anneli , Lycke Nils , Bemark Mats , Tang Ka-Wei , Angeletti Davide 
Published: July 2024

AbstractCD4 tissue-resident memory T (CD4 TRM) cells are crucial adaptive immune components involved in preventing influenza A virus (IAV) infection. Despite their importance, their physiological role in the upper respiratory tract, the first site of contact with IAV, remains unclear. Here, we find that, after IAV infection, antigen-specific CD4 TRM persist in the nasal tissue (NT) compartment and play a prime role in local viral clearance. Single cell RNA sequencing analysis reveals that NT CD4 TRM are heterogeneous and transcriptionally distinct as compared to their lung counterparts. Mechanistically, we demonstrate that the CXCR6- CXCL16 axis is involved in CD4 TRM residency in the NT. Furthermore, we show that the NT of mice and humans contains a high frequency of IL-17-producing CD4 TRM that aid in local viral clearance and in reducing tissue damage. Collectively, our results support a robust physiological role for nasal tissue CD4 TRM in preventing IAV infection.
Basement membrane patterning by spatial deployment of a secretion-regulating protease
Authors: Ku Hui-Yu , Bilder David 
Published: July 2024

ABSTRACTWhile paradigms for patterning of cell fates in development are well-established, paradigms for patterning morphogenesis, particularly when organ shape is influenced by the extracellular matrix (ECM), are less so. Morphogenesis of the Drosophila egg chamber (follicle) depends on anterior-posterior distribution of basement membrane (BM) components such as Collagen IV (Col4), whose symmetric gradient creates tissue mechanical properties that specify the degree of elongation. Here we show that the gradient is not regulated by Col4 transcription but instead relies on post-transcriptional mechanisms. The metalloprotease ADAMTS-A, expressed in a gradient inverse to that of Col4, limits Col4 deposition in the follicle center and manipulation of its levels can cause either organ hyper- or hypo-elongation. We present evidence that ADAMTS-A acts within the secretory pathway, rather than extracellularly, to limit Col4 incorporation into the BM. High levels of ADAMTS-A in follicle termini are normally dispensable but suppress Col4 incorporation when transcription is elevated. Our data show how an organ can employ patterned expression of ECM proteases with intracellular as well as extracellular activity to specify BM properties that control shape.
Integrated functional genomic analysis identifies the regulatory variants underlying a major QTL for disease resistance in European sea bass
Authors: Mukiibi Robert , Ferraresso Serena , Franch Rafaella , Peruzza Luca , Rovere Giulia Dalla , Babbucci Massimiliano , Bertotto Daniela , Toffan Anna , Pascoli Francesco , Faggion Sara , Peñaloza Carolina , Tsigenopoulos Costas S. , Houston Ross D. , Bargelloni Luca , Robledo Diego 
Published: July 2024

ABSTRACTBackgroundViral nervous necrosis (VNN) is a viral disease threatening the sustainability of global aquaculture, and affecting over 50 of farmed and ecologically important species. A major QTL for resistance to VNN has been previously described in European sea bass, but the underlying causal gene(s) and mutation(s) are unknown. To identify the mechanisms and genetic factors underpinning resistance to VNN, we integrated farmed and wild genetic data with multiple functional genomics assays in a farmed European sea bass population.ResultsA high heritability (h2 ∼ 0.40) was estimated for VNN resistance. A major QTL for this trait was confirmed on chromosome 3, and whole-genome resequencing narrowed its location to a small region containing 4 copies of interferon alpha inducible protein 27-like 2A (IFI27L2A) genes, and one copy of the interferon alpha inducible protein 27-like 2 (IFI27L2) gene. RNA sequencing revealed a clear association between the QTL genotype and the expression of two of theIFI27L2Agenes, and theIFI27L2gene. Integration with chromatin accessibility and histone modification data pinpointed two SNPs in active regulatory regions of two of these genes (IFI27L2AandIFI27L2), and transcription factor binding site gains for the resistant alleles were predicted. These alleles, particularly the SNP variant CHR3:10077301, exhibited higher frequency in Eastern Mediterranean sea bass populations, which show considerably higher levels of resistance to VNN.ConclusionsThe SNP variant CHR3:10077301, through modulation ofIFI27L2andIFI27L2Agenes, is likely the causative mutation underlying resistance to VNN in European sea bass. This is one of the first causative mutations discovered for disease resistance traits, and paves the way for marker-assisted selection as well as biotechnological approaches to enhance resistance to VNN in European sea bass and other susceptible species.
Mouse parasubthalamicCrhneurons drive alcohol drinking escalation and behavioral disinhibition
Authors: Kreifeldt Max , Okhuarobo Agbonlahor , Dunning Jeffery L , Lopez Catherine , Macedo Giovana , Sidhu Harpreet , Contet Candice 
Published: July 2024

AbstractCorticotropin-releasing factor (CRF, encoded byCrh) signaling is thought to play a critical role in the development of excessive alcohol drinking and the emotional and physical pain associated with alcohol withdrawal. Here, we investigated the parasubthalamic nucleus (PSTN) as a potential source of CRF relevant to the control of alcohol consumption, affect, and nociception in mice. We identified PSTNCrhneurons as a neuronal subpopulation that exerts a potent and unique influence on behavior by promoting not only alcohol but also saccharin drinking, while PSTN neurons are otherwise known to suppress consummatory behaviors. Furthermore, PSTNCrhneurons are causally implicated in the escalation of alcohol and saccharin intake produced by chronic intermittent ethanol (CIE) vapor inhalation, a mouse model of alcohol use disorder. In contrast to our predictions, the ability of PSTNCrhneurons to increase alcohol drinking is not mediated by CRF1signaling. Moreover, the pattern of behavioral disinhibition and reduced nociception driven by their activation does not support a role of negative reinforcement as a motivational basis for the concomitant increase in alcohol drinking. Finally, silencingCrhexpression in the PSTN slowed down the escalation of alcohol intake in mice exposed to CIE and accelerated their recovery from withdrawal-induced mechanical hyperalgesia. Altogether, our results suggest that PSTNCrhneurons may represent an important node in the brain circuitry linking alcohol use disorder with sweet liking and novelty seeking.
Genome assembly of a diversity panel ofChenopodium quinoa
Authors: Rey Elodie , Abrouk Michael , Dufau Isabelle , Rodde Nathalie , Saber Noha , Cizkova Jana , Fiene Gabriele , Stanschewski Clara , Jarvis David E , Jellen Eric N , Maughan Peter J , von Baer Ingrid , Troukhan Maxim , Kravchuk Maksym , Hribova Eva , Cauet Stephane , Krattinger Simon G. , Tester Mark 
Published: July 2024

AbstractQuinoa (Chenopodium quinoa) is an important crop for the future challenges of food and nutrient security. Deep characterization of quinoa diversity is needed to support the agronomic improvement and adaptation of quinoa as its worldwide cultivation expands. In this study, we report the construction of chromosome-scale genome assemblies of eight quinoa accessions covering the range of phenotypic and genetic diversity of both lowland and highland quinoas. The assemblies were produced from a combination of PacBio HiFi reads and Bionano Saphyr optical maps, with total assembly sizes averaging 1.28 Gb with a mean N50 of 71.1 Mb. Between 43,733 and 48,564 gene models were predicted for the eight new quinoa genomes, and on average, 66% of each quinoa genome was classified as repetitive sequences. Alignment between the eight genome assemblies allowed the identification of structural rearrangements including inversions, translocations, and duplications. These eight novel quinoa genome assemblies provide a resource for association genetics, comparative genomics, and pan-genome analyses for the discovery of genetic components and variations underlying agriculturally important traits.
Extracellular vesicle-derived miRNA-mediated cell-cell communication inference for single-cell transcriptomic data with miRTalk
Authors: Shao Xin , Li Chengyu , Qian Jingyang , Yang Haihong , Yang Xinyu , Liao Jie , Xu Xiao , Fan Xiaohui 
Published: July 2024

AbstractMicroRNAs are released from cells in extracellular vesicles (EVs), representing an essential mode of cell-cell communication (CCC) via an inhibitory effect on gene expression. The advent of single-cell RNA-sequencing (scRNA-seq) technologies has ushered in an era of elucidating EV-derived miRNA-mediated CCC. However, the lack of computational methods to infer such CCC poses an outstanding challenge. Herein, we present miRTalk (https://github.com/multitalk/miRTalk), a pioneering framework for inferring EV-derived miRNA-mediated CCC with a probabilistic model and a curated database, miRTalkDB, which includes EV-derived miRNA-target associations. The benchmarking against simulated and real-world datasets demonstrated the remarkable accuracy and robustness of miRTalk. Subsequently, we employed miRTalk to uncover the in-depth CCC mechanisms underlying three disease scenarios. In summary, miRTalk represents the first approach for inferring EV-derived miRNA-mediated CCC with scRNA-seq data, providing invaluable insights into the CCC dynamics underpinning biological processes.
Single-Platelet Mapping of Jugular, Puncture-Wound Thrombi Reveals the Spatial Evolution of Platelet Activation
Authors: Rhee Sung , Pokrovskaya Irina D. , Ball Kelly , Webb Michael W. , Kamykowski Jeffrey A. , Zhao Oliver , Driehaus Elizabeth R. , Aronova Maria A. , Whiteheart Sidney W. , Leapman Richard D. , Storrie Brian 
Published: July 2024

AbstractBackgroundThe contributions of platelet activation to thrombus formation during hemostatic bleeding cessation likely involve multiple activation states. However, the spatial and temporal distribution of platelets in these states has not been defined in a clot.ObjectivesTo use single-platelet mapping of activation states within jugular vein puncture thrombi to determine how the spatial distribution of platelet state evolves during hemostasis.MethodsMontaged, wide-area electron micrographs (EM) were taken at various time points, post-puncture, and annotated for platelet activation state. These classifications were mapped onto the images to identify regions of platelet activation and calculate neighbor associations. The importance of α-granule secretion was tested using VAMP8-/-mice.Resultsmapping of platelet activation states at 1 min post-puncture showed extensive spatial intermixing of most platelet activation classes. No high-activation-state, platelet-rich core was observed in 5-min post-puncture thrombi, rather such platelets tended to be localized on the interior surfaces of thrombus vaults open to the circulation. Only at a later stage, 20 min post-puncture, was distinct clustering of high activation, degranulated, cytosol-rich platelets observed. These clusters localized to the central portion of the intravascular platelet-rich crown, and they were now inaccessible to the circulation. Counterintuitively, deletion of the primary platelet v-SNARE, VAMP8, increased the frequency and spatial clustering of highly activated, degranulated platelets in association with intra-thrombus vault surfaces at 5 min post puncture.ConclusionsWe conclude recent multi-activation state models can provide a realistic thrombus formation framework if linked together to encompass the dynamics of puncture wound formation.
SMCHD1 maintains heterochromatin and genome compartments in human myoblasts
Authors: Huang Zhijun , Cui Wei , Ratnayake Ishara , Tawil Rabi , Pfeifer Gerd P. 
Published: July 2024

ABSTRACTMammalian genomes are subdivided into euchromatic A compartments that contain mostly active chromatin, and inactive, heterochromatic B compartments. However, it is unknown how A and B genome compartments are established and maintained. Here we studied SMCHD1, an SMC-like protein in human male myoblasts. SMCHD1 colocalizes with Lamin B1 and the heterochromatin mark H3K9me3. Loss of SMCHD1 leads to extensive heterochromatin depletion at the nuclear lamina and acquisition of active chromatin states along all chromosomes. In absence of SMCHD1, long range intra-chromosomal and inter-chromosomal contacts between B compartments are lost while many new TADs and loops are formed. Inactivation of SMCHD1 promotes numerous B to A compartment transitions accompanied by activation of silenced genes. SMCHD1 functions as an anchor for heterochromatin domains ensuring that these domains are inaccessible to epigenome modification enzymes that typically operate in active chromatin. Therefore, A compartments are formed by default when not prevented by SMCHD1.
Molecular dynamics investigation of the influenza hemagglutinin conformational changes in acidic pH
Authors: Badiee Shadi A , Kumar Vivek Govind , Moradi Mahmoud 
Published: July 2024

AbstractThe surface protein hemagglutinin (HA) of the influenza virus plays a pivotal role in facilitating viral infection by binding to sialic acid receptors on host cells. Its conformational state is pH-sensitive, impacting its receptor-binding ability and evasion of the host immune response. In this study, we conducted extensive equilibrium microsecond-level all-atom molecular dynamics (MD) simulations of the HA protein to explore the influence of low pH on its conformational dynamics. Specifically, we investigated the impact of protonation on conserved histidine residues (His1062) located in the hinge region of HA2. Our analysis encompassed comparisons between non-protonated (NP), partially protonated (1P, 2P), and fully-protonated (3P) conditions. Our findings reveal substantial pH-dependent conformational alterations in the HA protein, affecting its receptor-binding capability and immune evasion potential. Notably, the non-protonated form exhibits greater stability compared to protonated states. Conformational shifts in the central helices of HA2 involve outward movement, counterclockwise rotation of protonated helices, and fusion peptide release in protonated systems. Disruption of hydrogen bonds between the fusion peptide and central helices of HA2 drives this release. Moreover, HA1 separation is more likely in the fully-protonated system (3P) compared to non-protonated systems (NP), underscoring the influence of protonation. These insights shed light on influenza virus infection mechanisms and may inform the development of novel antiviral drugs targeting HA protein and pH-responsive drug delivery systems for influenza.
Predicting Enzyme Functions Using Contrastive Learning with Hierarchical Enzyme Structure Information
Authors: Duan Hongyu , Li Ziyan , Wu Yixuan , Chen Wen , Xia Li C 
Published: July 2024

AbstractEnzyme functional annotation is a fundamental challenge in biology, and many computational tools have been developed. Accurate function prediction of enzymes relies heavily on sequence and structural information, providing critical insights into enzyme activity and specificity. However, for less studied proteins or proteins with previously uncharacterized functions or multiple activities, most of these tools cannot accurately predict functional annotations, such as enzyme commission (EC) numbers. At the same time, functional hierarchical information between enzyme species categorized based on EC numbers has not been sufficiently investigated. To address these challenges, we propose a machine learning algorithm named EnzHier, which assigns EC numbers to enzymes with better accuracy and reliability compared to state-of-the-art tools. EnzHier cleverly learns the functional hierarchy of enzymes by optimizing triplet loss, enabling it to annotate understudied enzymes confidently and identify confounding enzymes with two or more EC numbers. By incorporating both sequence and structural information, EnzHier enhances its predictive capabilities. We experimentally demonstrate its excellent performance. We anticipate that this tool will be widely used to predict the function of uncharacterized enzymes, thereby advancing many fields such as drug design and discovery and medical diagnostics.
A high affinity monoclonal antibody against HLA-E-VL9 enhances natural killer cell anti-tumor killing
Authors: Hwang Joyce K. , Marston Daniel J. , Wrapp Daniel , Li Dapeng , Tuyishime Marina , Brackenridge Simon , Rhodes Brianna , Quastel Max , Kapingidza A. Brenda , Gater Jacob , Harner Austin , Wang Yunfei , Rountree Wes , Ferrari Guido , Borrow Persephone , McMichael Andrew J. , Gillespie Geraldine M. , Haynes Barton F. , Azoitei Mihai L. 
Published: July 2024

AbstractNatural killer (NK) cells kill target cells following triggering via germline-encoded receptors interacting with target cell-expressed ligands (direct killing), or via antibody-dependent cellular cytotoxicity (ADCC) mediated by FcγRIIIa. NK cytotoxicity is modulated by signaling through activating or inhibitory receptors. A major checkpoint is mediated by the NK inhibitory receptor NKG2A/CD94 and its target cell ligand, HLA-E, which is complexed with HLA signal sequence-derived peptides termed VL9 (HLA-E-VL9). We have previously reported the isolation of a murine HLA-E-VL9-specific IgM antibody 3H4 and the generation of a higher affinity IgG version (3H4v3). Here we have used phage display library selection to generate a high affinity version of 3H4v3, called 3H4v31, with an ∼700 fold increase in binding affinity. We show using an HLA-E-VL9+ K562 tumor model that, in vitro, the addition of 3H4v31 to target cells increased direct killing of targets by CD16-negative NK cell line NK-92 and also mediated ADCC by NK-92 cells transfected with CD16. Moreover, ADCC by primary NK cells was also enhanced in vitro by 3H4v31. 3H4v31 was also able to bind and enhance target cell lysis of endogenously expressed HLA-E-VL9 on human cervical cancer and human pancreatic cancer cell lines. In vivo, 3H4v31 slowed the growth rate of HLA-E-VL9+ K562 tumors implanted into NOD/SCID/IL2rγnullmice compared to isotype control when injected with NK-92 cells intratumorally. Together, these data demonstrate that mAb 3H4v31 can enhance NK cell killing of HLA-E-VL9-expressing tumor cells in vitro by both direct killing activity and by ADCC. Moreover, mAb 3H4v31 can enhance NK cell control of tumor growth in vivo. We thus identify HLA-E-VL9 monoclonal antibodies as a promising novel anti-tumor immunotherapy.One Sentence SummaryA high affinity monoclonal antibody against HLA-E-VL9 enhances natural killer cell anti-tumor killing by checkpoint inhibition and antibody dependent cellular cytotoxicity.
Elucidating the Type 2 Diabetes Regulatory Network: Identification of EGFR as a Key Hub and Novel Drug Candidates
Authors: Ochoa Ricardo Romero , Rojas Celic Abigail Cohen 
Published: July 2024

AbstractIntroductionType 2 diabetes (T2D) is a complex metabolic disorder with incompletely understood molecular mechanisms. This study aimed to elucidate the T2D regulatory network and identify potential drug targets and candidates.MethodsWe performed differential gene expression analysis on multiple T2D datasets, constructed protein-protein interaction networks, and conducted a meta-analysis to identify key hub genes. Functional enrichment analysis was performed on the resulting network. Structure-based virtual screening targeting EGFR, followed by molecular dynamics simulations, was used to identify potential drug candidates.ResultsEGFR emerged as a consistently top-ranked hub gene across studies. The regulatory network comprised hub genes, transcription factors, and miRNAs involved in processes such as apoptosis regulation, cellular response to organic substances, and reactive oxygen species metabolism. Virtual screening identified three compounds with favorable ADMET properties and strong binding affinities to EGFR, outperforming control drugs. These compounds demonstrated stable interactions in molecular dynamics simulations.ConclusionsOur integrative analysis provides new insights into the T2D regulatory network, highlighting EGFR as a potential therapeutic target. The identified drug candidates offer promising avenues for T2D treatment and related disorders involving EGFR signaling, bridging systems biology and drug discovery approaches in metabolic disease research.
Molecular bases and specificity behind the activation of the immune system OAS/RNAse L pathway by viral RNA
Authors: Jung-Rodriguez Emma , Barbault Florent , Bignon Emmanuelle , Monari Antonio 
Published: July 2024

AbstractThe first line of defense against invading pathogens usually relies on the innate immune systems. In this context the recognition of exogenous RNA structure is primordial to fight, notably, against RNA viruses. One of the most efficient immune response pathways is based on the sensing of RNA double helical motifs by the oligoadenylate synthase (OAS) proteins, which in turns triggers the activity of RNase L and, thus, cleaving cellular and viral RNA. In this contribution by using long range molecular dynamics simulation, complemented with enhanced sampling techniques, we elu-cidate the structural features leading to the activation of OAS by interaction with a model double strand RNA oligomer mimicking a viral RNA. We characterize the allosteric regulation induced by the nucleic acid leading to the population of the active form of the protein. Furthermore, we also identify the free energy profile connected to the active vs. inactive conformational transitions in presence and absence of RNA. Finally, the role of two RNA mutations, identified as able to down-regulate OAS activation, in shaping the protein/nucleic acid interface and the conformational land-scape of OAS are also analyzed.
Post-transcriptional cross- and auto-regulation buffer expression of the human RNA helicasesDDX3XandDDX3Y
Authors: Rengarajan Shruthi , Derks Jason , Bellott Daniel W. , Slavov Nikolai , Page David C. 
Published: July 2024

AbstractThe Y-linked geneDDX3Yand its X-linked homologDDX3Xsurvived the evolution of the human sex chromosomes from ordinary autosomes.DDX3Xencodes a multi-functional RNA helicase, with mutations causing developmental disorders and cancers. We find that, among X-linked genes with surviving Y homologs,DDX3Xis extraordinarily dosage-sensitive. Studying cells of individuals with sex chromosome aneuploidy, we observe that when the number of Y chromosomes increases,DDX3Xtranscript levels fall; conversely, when the number of X chromosomes increases,DDX3Ytranscript levels fall. In 46,XY cells, CRISPRi knockdown of eitherDDX3XorDDX3Ycauses transcript levels of the homologous gene to rise. In 46,XX cells, chemical inhibition of DDX3X protein activity elicits an increase inDDX3Xtranscript levels. Thus, perturbation of eitherDDX3XorDDX3Yexpression is buffered – by negative cross-regulation ofDDX3XandDDX3Yin 46,XY cells, and by negative auto-regulation ofDDX3Xin 46,XX cells.DDX3X-DDX3Ycross-regulation is mediated through mRNA destabilization – as shown by metabolic labeling of newly transcribed RNA – and buffers total levels of DDX3X and DDX3Y protein in human cells. We infer that post-transcriptional auto-regulation of the ancestral (autosomal)DDX3gene transmuted into auto- and cross-regulation ofDDX3XandDDX3Yas these sex-linked genes evolved from ordinary alleles of their autosomal precursor.