bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bile acid-sensitive human norovirus strains are susceptible to sphingosine-1-phosphate receptor 2 inhibition
Authors: Tenge Victoria , Vijayalakshmi Ayyar B. , Ettayebi Khalil , Crawford Sue E. , Shen Yi-Ting , Neill Frederick H. , Atmar Robert L. , Estes Mary K. 
Published: January 2024

AbstractHuman noroviruses (HuNoVs) are a diverse group of RNA viruses that cause both endemic and pandemic acute viral gastroenteritis. Previously we reported that many strains of HuNoV require bile or bile acid (BA) to infect human jejunal intestinal enteroid cultures. Of note, BA was not essential for replication of a pandemic-causing GII.4 HuNoV strain. Using the BA-requiring strain GII.3, we found that the hydrophobic BA GCDCA induces multiple cellular responses that promote replication in jejunal enteroids. Further, we found that chemical inhibition of the G-protein coupled receptor, sphingosine-1- phosphate receptor 2 (S1PR2), by JTE-013 reduced both GII.3 infection in a dose- dependent manner and cellular uptake in enteroids. Herein, we sought to determine if S1PR2 is required by other BA-dependent HuNoV strains and BA-independent GII.4, and if S1PR2 is required for BA-dependent HuNoV infection in other segments of the small intestine. We found JTE-013 inhibition of S1PR2 in jejunal HIEs reduces GI.1, GII.3, and GII.17 (BA-dependent) but not the GII.4 Sydney variant (BA-independent) infection, providing additional evidence of strain-specific differences in HuNoV infection. GII.3 infection of duodenal, jejunal and ileal lines derived from the same individual was also reduced with S1PR2 inhibition, indicating a common mechanism of BA-dependent infection among multiple segments of the small intestine. Our results support a model where BA-dependent HuNoV exploit the activation of S1PR2 by BA to infect the entire small intestine.ImportanceHuman noroviruses (HuNoVs) are important viral human pathogens that cause both outbreaks and sporadic gastroenteritis. These viruses are diverse, and many strains are capable of infecting humans. Our previous studies have identified strain-specific requirements for hydrophobic bile acids (BAs) to infect intestinal epithelial cells. Moreover, we identified a BA receptor, sphingosine-1-phosphate receptor 2 (S1PR2), required for infection by a BA-dependent strain. To better understand how various HuNoV strains enter and infect the small intestine and the role of S1PR2 in HuNoV infection, we evaluated infection by additional HuNoV strains using an expanded repertoire of intestinal enteroid cell lines. We found that multiple BA-dependent strains, but not a BA- independent strain, all required S1PR2 for infection. Additionally, BA-dependent infection required S1PR2 in multiple segments of the small intestine. Together these results indicate S1PR2 has value as a potential therapeutic target for BA-dependent HuNoV infection.
Shaping the physical world to our ends: The left PF technical-cognition area
Authors: Osiurak François , Federico Giovanni , Fournel Arnaud , Gaujoux Vivien , Lamberton Franck , Ibarrola Danielle , Rossetti Yves , Lesourd Mathieu 
Published: January 2024

AbstractOur propensity to materiality, which consists in using, making, creating, and passing on technologies, has enabled us to shape the physical world according to our ends. To explain this proclivity, scientists have calibrated their lens to either low-level skills such as motor cognition or high-level skills such as language or social cognition. Yet, little has been said about the intermediate-level cognitive processes that are directly involved in mastering this materiality, that is, technical cognition. We aim to focus on this intermediate level for providing new insights into the neurocognitive bases of human materiality. Here we show that a technical-reasoning process might be specifically at work in physical problem-solving situations. We found via two distinct neuroimaging studies that the area PF (parietal F) within the left parietal lobe is central for this reasoning process in both tool-use and non-tool-use physical problem-solving and can work along with social-cognitive skills to resolve day-to-day interactions that combine social and physical constraints. Our results demonstrate the existence of a specific cognitive module in the human brain dedicated to materiality, which might be the supporting pillar allowing the accumulation of technical knowledge over generations. Intensifying research on technical cognition could nurture a comprehensive framework that has been missing in fields interested in how early and modern humans have been interacting with the physical world through technology, and how this interaction has shaped our history and culture.
Longitudinal transcriptional changes reveal genes from the natural killer cell-mediated cytotoxicity pathway as critical players underlying COVID-19 progression
Authors: Medina Matias A. , Fuentes-Villalobos Francisco , Quevedo Claudio , Aguilera Felipe , Riquelme Raul , Rioseco Maria Luisa , Barria Sebastian , Pinos Yazmin , Calvo Mario , Burbulis Ian , Kossack Camila , Alvarez Raymond A ,   COVID 19 South Chile Group, Garrido Jose Luis , Barria Maria Ines 
Published: January 2024

ABSTRACTPatients present a wide range of clinical severities in response SARS-CoV-2 infection, but the underlying molecular and cellular reasons why clinical outcomes vary so greatly within the population remains unknown. Here, we report that negative clinical outcomes in severely ill patients were associated with divergent RNA transcriptome profiles in peripheral immune cells compared with mild cases during the first weeks after disease onset. Protein-protein interaction analysis indicated that early-responding cytotoxic NK cells were associated with an effective clearance of the virus and a less severe outcome. This innate immune response was associated with the activation of select cytokine-cytokine receptor pathways and robust Th1/Th2 cell differentiation profiles. In contrast, severely ill patients exhibited a dysregulation between innate and adaptive responses affiliated with divergent Th1/Th2 profiles and negative outcomes. This knowledge forms the basis of clinical triage that may be used to preemptively detect high-risk patients before life-threatening outcomes ensue.Highlights- Mild COVID-19 patients displayed an early transcriptional commitment with NK cell function, whereas severe patients do so with neutrophil function.- The identified co-expressed genes give insights into a coordinated transcriptional program of NK cell cytotoxic activity being associated with mild patients.- Key checkpoints of NK cell cytotoxicity that were enriched in mild patients include:KLRD1,CD247, andIFNG.- The early innate immune response related to NK cells connects with the Th1/Th2 adaptive immune responses, supporting their relevance in COVID-19 progression.
Development of robust antiviral assays using relevant apical-out human airway organoids
Authors: Lee Ji-Hoon , LeCher Julia C. , Parigoris Eric , Shinagawa Noriyuki , Sentosa Jason , Manfredi Candela , Goh Shu Ling , De Ramyani , Tao Sijia , Zandi Keivan , Amblard Franck , Sorscher Eric J. , Spence Jason R. , Tirouvanziam Rabindra , Schinazi Raymond F. , Takayama Shuichi 
Published: January 2024

AbstractWhile breakthroughs with organoids have emerged as next-generationin vitrotools, standardization for drug discovery remains a challenge. This work introduces human airway organoids with reversed biopolarity (AORBs), cultured and analyzed in a high-throughput, single-organoid-per-well format, enabling milestones towards standardization. AORBs exhibit a spatio-temporally stable apical-out morphology, facilitating high-yield direct intact-organoid virus infection. Single-cell RNA sequencing and immunohistochemistry confirm the physiologically relevant recapitulation of differentiated human airway epithelia. The cellular tropism of five severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strains along with host response differences between Delta, Washington, and Omicron variants, as observed in transcriptomic profiles, also suggest clinical relevance. Dose-response analysis of three well-studied SARS-CoV-2 antiviral compounds (remdesivir, bemnifosbuvir, and nirmatrelvir) demonstrates that AORBs efficiently predict human efficacy, comparable to gold-standard air-liquid interface cultures, but with higher throughput (∼10-fold) and fewer cells (∼100-fold). This combination of throughput and relevance allows AORBs to robustly detect false negative results in efficacy, preventing irretrievable loss of promising lead compounds. While this work leverages the SARS-CoV-2 study as a proof-of-concept application, the standardization capacity of AORB holds broader implications in line with regulatory efforts to push alternatives to animal studies.
De Novo Atomic Protein Structure Modeling for Cryo-EM Density Maps Using 3D Transformer and Hidden Markov Model
Authors: Giri Nabin , Cheng Jianlin 
Published: January 2024

AbstractAccurately building three-dimensional (3D) atomic structures from 3D cryo-electron microscopy (cryo-EM) density maps is a crucial step in the cryo-EM-based determination of the structures of protein complexes. Despite improvements in the resolution of 3D cryo-EM density maps, the de novo conversion of density maps into 3D atomic structures for protein complexes that do not have accurate homologous or predicted structures to be used as templates remains a significant challenge. Here, we introduce Cryo2Struct, a fully automated ab initio cryo-EM structure modeling method that utilizes a 3D transformer to identify atoms and amino acid types in cryo-EM density maps first, and then employs a novel Hidden Markov Model (HMM) to connect predicted atoms to build backbone structures of proteins. Tested on a standard test dataset of 128 cryo-EM density maps with varying resolutions (2.1 - 5.6 Å) and different numbers of residues (730 - 8,416), Cryo2Struct built substantially more accurate and complete protein structural models than the widely used ab initio method - Phenix in terms of multiple evaluation metrics. Moreover, on a new test dataset of 500 recently released density maps with varying resolutions (1.9 - 4.0 Å) and different numbers of residues (234 - 8,828), it built more accurate models than on the standard dataset. And its performance is rather robust against the change of the resolution of density maps and the size of protein structures.
Molecular detection using hybridization capture and next-generation sequencing reveals cross-species transmission of feline coronavirus type-1 between a domestic cat and a captive wild felid
Authors: Olarte-Castillo Ximena A. , Goodman Laura B. , Whittaker Gary R 
Published: January 2024

AbstractFeline coronavirus (FCoV) infection normally causes mild or subclinical signs and is common in domestic cats. However, in some cats, FCoV infection can also lead to the development of feline infectious peritonitis (FIP)—a typically lethal disease. FCoV has two serotypes or genotypes, FCoV-1 and FCoV-2, both of which can cause FIP. The main difference between the genotypes is the viral spike (S) protein that determines tropism and pathogenicity, crucial mechanisms in the development of FIP. Subclinical infection and FIP have both been reported in wild felids, including in threatened species. Due to the high genetic variability of the S gene and the technical challenges to sequencing it, detection and characterization of FCoV in wild felids have mainly centered on other more conserved genes. Therefore, the genotype causing FIP in most wild felids remains unknown. Here, we report a retrospective molecular epidemiological investigation of FCoV in a zoological institution in the United States. In 2008, a domestic cat (Felis catus) and a Pallas’ cat (Otocolobus manul) sharing the same room succumbed to FIP. Using hybridization capture and next-generation sequencing, we detected and sequenced the complete 3’-end of the viral genome (∼8.2 Kb), including the S gene, from both felids. Our data show for the first time that FCoV-1 can be transmitted between domestic and wild felids and extends the known host range of FCoV-1. Our findings highlight the importance of identifying the genotype causing FIP, to develop effective control measures.
A Neural Network for High-Precise and Well-Interpretable Electrocardiogram Classification
Authors: Liu Xiaoqiang , He Liang , Yan Jiadong , Huang Yisen , Wang Yubin , Lin Chanchan , Huang Yingxuan , Liu Xiaobo 
Published: January 2024

AbstractManual heart disease diagnosis with the electrocardiogram (ECG) is intractable due to the intertwined signal features and lengthy diagnosis procedure, especially for the 24-hour dynamic ECG signals. Consequently, even experienced cardiologists may face difficulty in producing all accurate ECG reports. In recent years, neural network-based automatic ECG diagnosis methods have exhibited promising performance, suggesting a potential alternative to the labor-intensive examination conducted by cardiologists. However, many existing approaches failed to adequately consider the temporal and channel dimensions when assembling features and ignored interpretability. And clinical theory underscores the necessity of prolonged signal observations for diagnosing certain ECG conditions such as tachycardia. Moreover, specific heart diseases manifest primarily through distinct ECG leads represented as channels. In response to these challenges, this paper introduces a novel neural network architecture for ECG classification (diagnosis). The proposed model incorporates Lead Fusing blocks, transformer-XL encoder-based Encoder modules, and hierarchical temporal attentions. Importantly, this classifier operates directly on raw ECG time-series signals rather than cardiac cycles. Signal integration begins with the Lead Fusing blocks, followed by the Encoder modules and hierarchical temporal attentions, enabling the extraction of long-dependent features. Furthermore, we argue that existing convolution-based methods compromise interpretability, while our proposed neural network offers improved clarity in this regard. Experimental evaluation on a comprehensive public dataset confirms the superiority of our classifier over state-of-the-art methods. Moreover, visualizations reveal the enhanced interpretability provided by our approach.HighlightsOur model extracts long-dependent features of ECG signals based on the Transformer-XL encoder.The proposed network offers the improved interpretability.Our classifier achieves superior performance over other state-of-the-art methods.
Enhancing radiotherapy response via intratumoral injection of the TLR9 agonist CpG to stimulate CD8 T cells in an autochthonous mouse model of sarcoma
Authors: Su Chang , Kent Collin L. , Pierpoint Matthew , Floyd Warren , Luo Lixia , Wiliams Nerissa T. , Ma Yan , Peng Brian , Lazarides Alexander L. , Subramanian Ajay , Himes Jonathan E. , Perez Vincent M. , Hernansaiz-Ballesteros Rosa D. , Roche Kimberly E. , Modliszewski Jennifer L. , Selitsky Sara R. , Shinohara Mari , Wisdom Amy J. , Moding Everett J. , Mowery Yvonne M. , Kirsch David G. 
Published: January 2024

AbstractRadiation therapy is frequently used to treat cancers including soft tissue sarcomas. Prior studies established that the toll-like receptor 9 (TLR9) agonist cytosine-phosphate-guanine oligodeoxynucleotide (CpG) enhances the response to radiation therapy (RT) in transplanted tumors, but the mechanism(s) remain unclear. Here, we used CRISPR/Cas9 and the chemical carcinogen 3-methylcholanthrene (MCA) to generate autochthonous soft tissue sarcomas with high tumor mutation burden. Treatment with a single fraction of 20 Gy RT and two doses of CpG significantly enhanced tumor response, which was abrogated by genetic or immunodepletion of CD8+ T cells. To characterize the immune response to RT + CpG, we performed bulk RNA-seq, single-cell RNA-seq, and mass cytometry. Sarcomas treated with 20 Gy and CpG demonstrated increased CD8 T cells expressing markers associated with activation and proliferation, such as Granzyme B, Ki-67, and interferon-γ. CpG + RT also upregulated antigen presentation pathways on myeloid cells. Furthermore, in sarcomas treated with CpG + RT, TCR clonality analysis suggests an increase in clonal T-cell dominance. Collectively, these findings demonstrate that RT + CpG significantly delays tumor growth in a CD8 T cell-dependent manner. These results provide a strong rationale for clinical trials evaluating CpG or other TLR9 agonists with RT in patients with soft tissue sarcoma.
Full-length RNA transcript sequencing traces brain isoform diversity in house mouse natural populations
Authors: Zhang Wenyu , Guenther Anja , Gao Yuanxiao , Ullrich Kristian , Huettel Bruno , Ahmad Aftab , Duan Lei , Wei Kaizong , Tautz Diethard 
Published: January 2024

AbstractThe ability to generate multiple RNA transcript isoforms from the same gene is a general phenomenon in eukaryotes. However, the complexity and diversity of alternative isoforms in natural populations remain largely unexplored. Using a newly developed full-length transcripts enrichment protocol with 5’ CAP selection, we sequenced full-length RNA transcripts of 48 individuals from outbred populations and subspecies ofMus musculus, and from the closely related sister speciesMus spretusandMus spicilegusas outgroups. The dataset represents the most extensive full-length high-quality isoform catalog at the population level to date. In total, we reliably identified 117,728 distinct isoforms, of which only 51% were previously annotated. We show that the population-specific distribution pattern of isoforms is phylogenetically informative and reflects the segregating SNP diversity between the populations. We find that ancient housekeeping genes are a major source of the overall isoform diversity, and that the generation of alternative first exons plays a major role in generating new isoforms. Given that our data allow us to distinguish between population-specific isoforms and isoforms that are conserved across multiple populations, it is possible to refine the annotation of the reference mouse genome to a set of about 40,000 isoforms that should be most relevant for comparative functional analysis across species.
Epigenetic Modulation to perturb theSYNGAP1Intellectual Disability (ID) that ameliorates synaptic and behavioural deficits
Authors: Singh Akash Kumar , Joshi Ila , Reddy Neeharika M. N. , Purushotham Sushmitha S. , Eswaramoorthy M. , Vasudevan Madavan , Banerjee Sourav , Clement J. P , Kundu Tapas K 
Published: January 2024

AbstractSporadic heterozygous mutations inSYNGAP1affects social and emotional behaviour that are often observed in intellectual disability (ID) and autism spectrum disorder (ASD). Although neurophysiological deficits have been extensively studied, the epigenetic landscape ofSYNGAP1mutation-mediated intellectual disability is unexplored. Here, we have surprisingly found that the p300/CBP specific acetylation marks of histones are significantly repressed in the adolescent hippocampus ofSyngap1+/-mouse. To establish the causal relationship ofSyngap1+/-phenotype and the altered histone acetylation signature we have treated 2-4 months oldSyngap1+/-mouse with glucose-derived carbon nanosphere (CSP) conjugated potent small molecule activator (TTK21) of p300/CBP lysine acetyltransferase (CSP-TTK21). The enhancement of the p300/CBP specific acetylation marks of histones by CSP-TTK21 restored deficits in spine density, synaptic function, and social preferences ofSyngap1+/-mouse that is very closely comparable to wild type littermates. The hippocampal RNA-Seq analysis of the treated mice revealed that the expression of many critical genes related to the ID/ASD reversed due to the treatment of the specific small molecule activator. This study could be the first demonstration of the reversal of autistic behaviour and neural wiring upon the modulation of altered epigenetic modification (s).
A Bag-Of-Motif Model Captures Cell States at Distal Regulatory Sequences
Authors: Cornejo-Páramo Paola , Zhang Xuan , Louis Lithin , Yang Yi-Hua , Li Zelun , Humphreys David , Wong Emily S. 
Published: January 2024

AbstractDeciphering the intricate regulatory code governing cell-type-specific gene expression is a fundamental goal in genetics. Current methods struggle to capture the complex interplay between gene distal regulatory sequences and cell context. We developed a computational approach, BOM (Bag-of-Motifs), which represents cis-regulatory sequences by the type and number of TF binding motifs it contains, irrespective of motif order, orientation, and spacing. This simple yet powerful representation allows BOM to efficiently capture the complexity of cell-type-specific information encoded within these sequences. We apply BOM to mouse, human, and zebrafish distal regulatory regions, demonstrating remarkable accuracy. Notably, the method outperforms more complex deep learning models at the same task using fewer parameters. BOM can also uncover cross-species sequence similarities unrecognized by genome alignments. We experimentally validate ourin silicopredictions using enhancer reporter assay, showing that motifs with the most significant explanatory power are sequence determinants of cell-type specific enhancer activity. BOM offers a novel systematic framework for studying cell-type or condition-specific cis-regulatory sequences. Using BOM, we demonstrate the existence of a highly predictive sequence code at distal regulatory regions in mammals driven by TF binding motifs.
Prototype mRNA vaccines imprint broadly neutralizing human serum antibodies after Omicron variant-matched boosting
Authors: Liang Chieh-Yu , Raju Saravanan , Liu Zhuoming , Li Yuhao , Arunkumar Guha A. , Case James Brett , Zost Seth J. , Acreman Cory M. , Carvalho dos Anjos Deborah Carolina , McLellan Jason S. , Crowe James E. , Whelan Sean P.J. , Elbashir Sayda M. , Edwards Darin K. , Diamond Michael S. 
Published: January 2024

ABSTRACTImmune imprinting is a phenomenon in which an individual’s prior antigenic experiences influence responses to subsequent infection or vaccination. Here, using antibody depletion and multiplexed spike-binding assays, we characterized the type-specificity and cross-reactivity of serum antibody responses after mRNA vaccination in mice and human clinical trial participants. In mice, a single priming dose of a preclinical version of mRNA-1273 vaccine encoding Wuhan-1 spike minimally imprinted serum responses elicited by Omicron boosters, enabling a robust generation of type-specific antibodies. However, substantial imprinting was observed in mice receiving an Omicron booster after two priming doses of mRNA-1273, an effect that was mitigated by a second booster dose of Omicron mRNA vaccine. In humans who received two BA.5 or XBB.1.5 Omicron-matched boosters after two or more doses of the prototype mRNA-1273 vaccine, spike-binding and neutralizing serum antibodies cross-reacted with circulating Omicron variants as well as more distantly related sarbecoviruses. Because the serum neutralizing response against Omicron strains and other sarbecoviruses was completely abrogated after pre-clearing with the Wuhan-1 spike protein, antibodies induced by XBB.1.5 boosting in humans focus on conserved epitopes shaped and shared by the antecedent mRNA-1273 primary series. Our depletion analysis also identified cross-reactive neutralizing antibodies that recognize distinct epitopes in the receptor binding domain (RBD) and S2 proteins with differential inhibitory effects on members of the sarbecovirus subgenus. Thus, although the serum antibody response to Omicron-based boosters in humans is dominantly imprinted by prior immunizations with prototype mRNA-1273 vaccines, this outcome can be beneficial as it drives expansion of multiple classes of cross-neutralizing antibodies that inhibit infection of emerging SARS-CoV-2 variants and extend activity to distantly related sarbecoviruses.