Search Results (5,223)

Cytomegalovirus (CMV) is the leading infectious cause of birth defects and has been linked to increased risk of preterm birth (PTB). CMV establishes lifelong latency and is more prevalent among Black and Hispanic/Latina women, populations already at higher risk for adverse pregnancy outcomes. Vitamin D deficiency, also common in these groups, has been linked to impaired immune function and increased susceptibility to infections, including CMV. In this cross−sectional study of 63 pregnant minority women (50 CMV+, 13 CMV−), we evaluated associations among serum 25(OH)D levels, CMV serostatus, and cmvIL−10, the CMV−encoded interleukin−10 homolog that modulates host immune responses. While vitamin D insufficiency and CMV seropositivity were both highly prevalent, we found no statistically significant associations between 25(OH)D levels and CMV serostatus or cmvIL−10 levels. These findings highlight the need for further investigation into how vitamin D deficiency and CMV infection may independently or synergistically contribute to maternal and neonatal health disparities. Full article

Porcine Teschovirus (PTV) is a highly prevalent pathogen within swine populations, primarily associated with encephalitis, diarrhea, pneumonia, and reproductive disorders in pigs, thereby posing a significant threat to the sustainable development of the pig farming industry. In this study, a novel strain of PTV was isolated from the feces of a pig exhibiting symptoms of diarrhea, utilizing PK-15 cell lines. The structural integrity of the viral particles was confirmed via transmission electron microscopy, and the viral growth kinetics and characteristics were evaluated in PK-15 cells. High-throughput sequencing facilitated the acquisition of the complete viral genome, and subsequent phylogenetic analysis and full-genome alignment identified the strain as belonging to the PTV 2 genotype. Further investigation revealed that infection with the PTV-GXLZ2024 strain induces phosphorylation of the eukaryotic translation initiation factor 2α (eIF2α) in PK-15 cells, indicating activation of the unfolded protein response (UPR) through the PERK pathway, with minimal involvement of the IRE1 or ATF6 pathways. Notably, ATF4 protein expression was progressively downregulated throughout the infection, while downstream CHOP protein levels remained unchanged, indicating an incomplete UPR induced by PTV-GXLZ2024. Furthermore, PERK knockdown was found to enhance the replication of PTV-GXLZ2024. This study provides critical insights into the molecular mechanisms underlying PTV pathogenesis and establishes a foundation for future research into its evolutionary dynamics and interactions with host organisms. Full article

Penaeus vannamei aquaculture production accounts for the majority of total shrimp aquaculture output, but it has suffered a severe decline in production and economic losses due to WSSV disease. Therefore, elucidating the relationship between the host immune system and pathogens is crucial for shrimp disease prevention and control. Integrins, as receptor-related molecules, have been shown to participate in various physiological functions, including cell migration, organismal development, and the pathogenesis of multiple diseases. However, the regulatory mechanisms of integrin genes in the shrimp immune system remain unclear. This study reports that integrins may regulate the Toll, IMD, and STAT signaling pathways in P. vannamei by influencing Spätzle, TLR, and Domeless, thereby affecting the shrimp’s innate immune system against diseases. Additionally, integrins can inhibit viral entry and replication. Through RNA interference (RNAi) experiments, it was found that knocking down Pv-Integrin β increases the viral load of white spot syndrome virus (WSSV), making shrimp more susceptible to WSSV and giving rise to increasing mortality. Further research indicates that Pv-Integrin β acts as an upstream recognition receptor in the disease resistance immune pathway, influencing other signaling pathway receptors to regulate the innate immune system. Importantly, knocking down Pv-Integrin β upregulates the expression of antimicrobial peptides such as ALF1 and ALF2, but reduces the expression of Crustin1, Crustin2 and prophenoloxidase. In conclusion, this study reveals that Pv-Integrin β regulates the disease resistance immune signaling pathways by affecting the related receptors. Full article

Myocardial infarction-induced cardiovascular diseases remain a leading cause of mortality worldwide. Excessive post-infarct fibrosis contributes to adverse cardiac remodeling and the progression to heart failure. In vivo reprogramming strategies offer a promising avenue for heart regeneration by directly converting resident fibroblasts into cardiomyocytes through enforced expression of cardiogenic genes. This approach circumvents the need for invasive biopsies, cell expansion, induction of pluripotency, or autologous transplantation. Despite these advantages, key challenges persist, including low reprogramming efficiency and limited cellular targeting specificity. A critical factor for effective anti-fibrotic therapy is the precise and efficient delivery of reprogramming effectors specifically to fibrotic fibroblasts, while minimizing off-target effects on non-fibroblast cardiac cells and fibroblasts in non-cardiac tissues. In this review, we discuss the cellular and molecular mechanisms underlying in vivo cardiac reprogramming, with a focus on fibroblast heterogeneity, key transcriptional drivers, and relevant intercellular interactions. We also examine current advances in fibroblast-specific delivery systems employing both viral and non-viral vectors for the administration of lineage-reprogramming factors such as cDNA overexpressions or microRNAs. Finally, we underscore innovative strategies that hold promise for enhancing the precision and efficacy of cellular reprogramming, ultimately fostering translational development and paving the way for rigorous preclinical assessment. Full article

Cathepsin L (CatL) is a critical protease involved in cleaving the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), facilitating viral entry into host cells. Inhibition of CatL is essential for preventing SARS-CoV-2 cell entry, making it a potential therapeutic target for drug development. Six QSAR models were established to predict the inhibitory activity (expressed as IC₅₀ values) of candidate compounds against CatL. These models were developed using statistical method heuristic methods (HMs), the evolutionary algorithm gene expression programming (GEP), and the ensemble method random forest (RF), along with the kernel-based machine learning algorithm support vector regression (SVR) configured with various kernels: radial basis function (RBF), linear-RBF hybrid (LMIX2-SVR), and linear-RBF-polynomial hybrid (LMIX3-SVR). The particle swarm optimization algorithm was applied to optimize multi-parameter SVM models, ensuring low complexity and fast convergence. The properties of novel CatL inhibitors were explored through molecular docking analysis. The LMIX3-SVR model exhibited the best performance, with an $R^2$ of 0.9676 and 0.9632 for the training set and test set and RMSE values of 0.0834 and 0.0322. Five-fold cross-validation $R_{5-fold}^2$ = 0.9043 and leave-one-out cross-validation $R_{loo}^2$ = 0.9525 demonstrated the strong prediction ability and robustness of the model, which fully proved the correctness of the five selected descriptors. Based on these results, the IC₅₀ values of 578 newly designed compounds were predicted using the HM model, and the top five candidate compounds with the best physicochemical properties were further verified by Property Explorer Applet (PEA). The LMIX3-SVR model significantly advances QSAR modeling for drug discovery, providing a robust tool for designing and screening new drug molecules. This study contributes to the identification of novel CatL inhibitors, which aids in the development of effective therapeutics for SARS-CoV-2. Full article

The aggregation of α-synuclein (αSyn) is a central feature of Parkinson’s disease (PD) and other synucleinopathies. The efficient clearance of αSyn depends largely on the autophagy–lysosomal pathway. Emerging genetic evidence highlights the role of pleckstrin homology and RUN domain-containing M1 protein (PLEKHM1), a critical regulator of autophagosome–lysosome fusion, in the pathogenesis of multiple neurodegenerative diseases. This study investigates the possible effects of increased PLEKHM1 expression on αSyn pathology and neurodegeneration in mice. We utilized a mouse model of PD that is based on A53T-αSyn overexpression, achieved by the stereotactic injection of recombinant adeno-associated viral vectors (rAAV) into the substantia nigra. Additionally, this study explores the effect of PLEKHM1 overexpression on the autophagy–lysosomal pathway under physiological conditions, using transgenic autophagy reporter mice. PLEKHM1 overexpression facilitated the αSyn-induced degeneration of dopaminergic somata in the substantia nigra and degeneration of dopaminergic axon terminals in the striatum. In concert with αSyn expression, PLEKHM1 also potentiated microglial activation. The extent of αSyn pathology, as reported by staining for phosphorylated αSyn, was not affected by PLEKHM1. Using RFP-EGFP-LC3 autophagy reporter mice, rAAV-mediated PLEKHM1 overexpression reduced lysosomal and autolysosomal area, increased LAMP1-LC3 colocalization, and decreased the autolysosome-to-autophagosome ratio. Concurrently, PLEKHM1 overexpression in both genotypes caused p62 accumulation, accompanied by reduced overlap with lysosomal and autophagosomal markers but increased colocalization with autolysosomal markers, indicating impaired cargo degradation during late-stage autophagy. Taken together, elevated PLEKHM1 levels exacerbate neurodegeneration in αSyn-overexpressing mice, possibly by impairing autophagic flux. Now, with in vivo evidence complementing genetic data, alterations in PLEKHM1 expression appear to compromise autophagy, potentially enhancing neuronal vulnerability to secondary insults like αSyn pathology. Full article

Background/Objectives: The African swine fever virus (ASFV) multi-gene family (MGF) 360 proteins play critical roles in immune evasion, replication regulation, and virulence determination. Despite substantial advances in this field, the functional roles of many members within this gene family remain to be fully characterized. Methods: In this study, Transcriptional kinetics analysis indicated that the expression profile of MGF 360-2L was consistent with that of the late marker gene B646L (p72). Transcriptomic profiling identified 13 and 171 differentially expressed genes (DEGs) at 12 and 24 h post-infection (hpi) with ΔMGF 360-2L, respectively. Results: Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses indicated that these DEGs were predominantly enriched in Type I interferon (IFN-I) signaling pathways. It is noteworthy that transcriptome analysis further demonstrates that the absence of MGF 360-2L specifically results in the dysregulation of expression of the replication-essential genes E199L and E301R. These findings indicate that MG F360-2L is essential for maintaining the stable expression of these proteins. Conclusions:MGF 360-2L is a late gene that contributes to the precise regulation of viral protein expression and modulates the host immune response during infection. Full article

The emergence of the SARS-CoV-2 JN.1 lineage in late 2023 marked a major shift in viral evolution. By January 2024, it had displaced XBB variants to become the dominant strain worldwide. JN.1 and its descendants are antigenically distinct from earlier Omicron subvariants, with approximately 30 additional spike mutations compared to XBB-derived viruses. The combination of these features alongside growing evidence of considerable immune evasion prompted the FDA to recommend that vaccine formulations be updated to target JN.1 rather than XBB.1.5. The continued dominance of JN.1-derived variants necessitates the characterization of viral infection in established animal models to inform vaccine efficacy and elucidate host–pathogen interactions driving disease outcomes. In this study, transgenic mice expressing human ACE2 were infected with SARS-CoV-2 subvariants JN.1, KP.2, and EG.5.1 to compare the pathogenicity of JN.1-lineage and XBB-lineage SARS-CoV-2 viruses. Infection with JN.1 and KP.2 resulted in attenuated disease, with animals exhibiting minimal clinical symptoms and no significant weight loss. In contrast, EG.5.1-infected mice exhibited rapid progression to severe clinical disease, substantial weight loss, and 100% mortality within 7 days of infection. All variants replicated effectively within the upper and lower respiratory tracts and caused significant lung pathology. Notably, EG.5.1 resulted in neuroinvasive infection with a significantly high viral burden in the brain. Additionally, EG.5.1 infection resulted in a significant increase in CD8⁺ T cell and CD11b⁺ CD11c⁺ dendritic cell populations in infected lungs. Full article

Pain is a multifactorial phenomenon involving neuronal, immune, and glial components. Annexin A1 (AnxA1), a glucocorticoid-regulated protein with pro-resolving properties, has emerged as a critical modulator of pain. Present in both peripheral and central compartments, AnxA1 acts through the formyl peptide receptor FPR2/ALX to regulate immune responses, modulate nociceptive signaling, and promote tissue homeostasis. Its mimetic peptide, Ac_2–26, has demonstrated robust antinociceptive effects in various pain models, including those induced by inflammation, tissue injury, viral infection, and opioid exposure. AnxA1 modulates cytokine expression, inhibits pro-nociceptive pathways such as TRPV1 and CXCL12/CXCR4, and reprograms macrophages. In the central nervous system, it attenuates neuroinflammation and central sensitization. Notably, AnxA1 can exhibit context-dependent effects, contributing to either the resolution or exacerbation of inflammation. This review examines the molecular mechanisms by which AnxA1 bridges the immune and nervous system pathways, highlighting its therapeutic potential in pain management. Full article

Sindbis virus (SINV), a prototype of the Alphavirus genus (family Togaviridae), is a globally distributed arbovirus causing febrile rash and debilitating arthritis in humans. Viral structural proteins—capsid (C), E1, and E2—are fundamental to the virion’s architecture, mediating all stages from assembly to host cell entry and pathogenesis, thus representing critical targets for study. This review consolidates the historical and current understanding of SINV structural biology, tracing progress from early microscopy to recent high-resolution cryo-electron microscopy (cryo-EM) and X-ray crystallography. We detail the virion’s precise T = 4 icosahedral architecture, composed of a nucleocapsid core and an outer glycoprotein shell. Key functional roles tied to protein structure are examined: the capsid’s dual capacity as a serine protease and an RNA-packaging scaffold that interacts with the E2 cytoplasmic tail; the E1 glycoprotein’s function as a class II fusion protein driving membrane fusion; and the E2 glycoprotein’s primary role in receptor binding, which dictates cellular tropism and serves as the main antigenic target. Furthermore, we connect these molecular structures to viral evolution and disease, analyzing how genetic variation among SINV genotypes, particularly in the E2 gene, influences host adaptation, immune evasion, and the clinical expression of arthritogenic and neurovirulent disease. In conclusion, the wealth of structural data on SINV offers a powerful paradigm for understanding alphavirus biology. However, critical gaps persist, including the high-resolution visualization of dynamic conformational states during viral entry and the specific molecular determinants of chronic disease. Addressing these challenges through integrative structural and functional studies is paramount. Such knowledge will be indispensable for the rational design of next-generation antiviral therapies and broadly protective vaccines against the ongoing threat posed by SINV and related pathogenic alphaviruses. Full article

The IQSEC2 protein is a guanine nucleotide exchange factor for Arf6. Pathogenic variants in the X-linked IQSEC2 gene are associated with drug-resistant epilepsy, severe intellectual disability, and autism. The vast majority of disease-causing variants introduce premature termination codons into the IQSEC2 gene, resulting in little or no IQSEC2 protein being produced. Approximately 20% of cases are missense variants in the seven functional domains of the IQSEC2 protein. We sought to determine whether an adeno-associated virus (AAV) containing the IQSEC2 gene could rescue abnormal phenotypes in mice in two different Iqsec2 mouse models with premature Iqsec2 termination codons resulting in a knockout of the Iqsec2 gene expression and in mice with an A350V Iqsec2 missense mutation. In the Iqsec2 knockout mice, the AAV significantly improved growth, corrected behavioral abnormalities, and normalized the seizure threshold. Behavioral abnormalities were partially rescued in A350V mice, which expression studies suggest may have been due to the feedback inhibition of the endogenous Iqsec2 allele by viral IQSEC2. We propose that the success in the Iqsec2 knockout mice warrants a proof-of-concept study for gene replacement therapy in boys with IQSEC2 premature termination variants. Full article

Schmallenberg virus (SBV) is a negative-sense RNA virus transmitted by insect vectors, causing arthrogryposis-hydranencephaly syndrome in newborn ruminants. Since its discovery in Germany and the Netherlands in 2011, SBV has rapidly spread across multiple European countries, resulting in significant economic losses in the livestock industry. With the increasing global animal trade and the expanded range of insect transmission, the risk of SBV introduction into non-endemic regions is also rising. As the gold standard for serological testing, the virus neutralization test (VNT) is crucial for tracking the spread of SBV and evaluating the efficacy of vaccines. However, in non-endemic regions, the lack of local viral strains and the biosafety risks associated with introducing foreign strains pose challenges to the implementation of VNT. In this study, we employed reverse genetics techniques using vesicular stomatitis virus (VSV) to substitute the VSV G protein with the envelope glycoproteins of SBV, thereby successfully generating and rescuing the recombinant virus rVSVΔG-eGFP-SBVGPC. The recombinant virus was then thoroughly characterized in terms of SBV Gc protein expression, viral morphology, and growth kinetics. Importantly, rVSVΔG-eGFP-SBVGPC exhibited SBV-specific cell tropism and was capable of reacting with SBV-positive serum, enabling the measurement of neutralizing antibody titers. The results suggest that this recombinant virus can serve as a feasible alternative for SBV neutralization tests, with promising potential for application in serological screening and vaccine evaluation. Full article

Plant viruses have been traditionally considered pathogens restricted to plant hosts. However, recent studies have shown that some plant viruses can infect and replicate in filamentous fungi and oomycetes, suggesting that their host range is broader than previously thought, and that their ecological interactions are more complex. In this study, we investigated the ability of the well-characterized positive-sense RNA plant virus Tobacco mosaic virus (TMV) to replicate in four major phytopathogenic fungi from different taxonomic groups: Botrytis cinerea, Fusarium oxysporum f. sp. lycopersici, Verticillium dahliae, and Monilinia fructicola. Using a recombinant TMV-based vector expressing a green fluorescent protein (TMV-GFP-1056) as reporter, we demonstrated that TMV can enter, replicate, and persist within the mycelia of B. cinerea and V. dahliae—at least through the first subculture. However, it cannot replicate in F. oxysporum f. sp. lycopersici and M. fructicola. RNA interference (RNAi) is a conserved eukaryotic epigenetic mechanism that provides an efficient defence against viruses. We explored the role of RNAi in the interaction between TMV and the mycelia of V. dahliae and B. cinerea. Our results revealed a strong induction of the Dicer-like 1 and Argonaute 1 genes, which are key compounds of the RNA silencing pathway. This RNAi-based response impaired TMV-GFP replication in both fungi. Notably, despite viral replication and RNAi activation, the virulence of V. dahliae and B. cinerea on their respective host plants remained unaffected. These findings reinforce the emerging recognition of cross-kingdom virus transmission and interactions, which likely play a crucial role in pathogen ecology and viral evolution. Understanding these virus–fungus interactions not only sheds light on RNAi interference silencing mechanisms but also suggests that plant viruses like TMV could serve as simple and effective tools for functional genomic studies in fungi, such as in V. dahliae and B. cinerea. Full article

Despite medical advances having made HIV a survivable condition, HIV persists as the 11th leading cause of death among young Black women. Enhancing the quality of care engagement through beneficial patient–provider relationships can close gaps in retention and adherence, enabling long, healthy lives. Using constructivist grounded theory informed by an established framework for patient-centered care in complex cancer settings and insight from local HIV advocates, this work identifies what provider actions retain women in care and why. Through focus groups and interviews, eleven Black women in the Southwestern United States, an understudied population, express that providers who engage them as co-creators in maintaining good health are more likely to retain them. Concurrently, when women are attuned to their own health care and interpersonal needs, they discern which providers are equally committed to their health based upon observed provider actions. These actions, such as listening attentively, taking time, and paying attention to the whole person, in conjunction with women’s motivation and active involvement, create a reciprocal dynamic that increases the likelihood these women will remain virally suppressed. The ideal relationship is one in which the provider empowers and champions women as drivers of their own care. Full article

Influenza A virus pandemics pose a persistent global health threat, and emerging antiviral resistance underscores the critical importance of developing novel broad-spectrum therapeutic agents. Building on licorice’s (Glycyrrhiza spp.) historical use in traditional Chinese medicine for respiratory infections—as documented in the Chinese Guidelines for Diagnosis and Treatment of Influenza—and its demonstrated anti-SARS-CoV-2 activity, we identified licoflavone B as a potent anti-influenza agent, bridging ethnopharmacological knowledge with mechanistic validation. In this study, we identified licoflavone B, a natural flavonoid derived from licorice (Glycyrrhiza spp.), as a potent inhibitor of diverse influenza viruses, including multiple influenza A subtypes and type B virus. Mechanistic studies revealed that licoflavone B selectively targets the viral RNA-dependent RNA polymerase (RdRp), effectively suppressing viral replication. The compound exhibits a favorable selectivity index (SI = 14.9–29.9), indicating a promising therapeutic window. Molecular docking simulations identified potential binding interactions between licoflavone B and regions of the RdRp complex, which were further validated by dose-dependent inhibition of viral nucleoprotein (NP) and polymerase subunit PB2 expression in Western blot and immunofluorescence assays. In addition, licoflavone B maintained broad-spectrum antiviral activity against multiple influenza strains, including H1N1 (A/Puerto Rico/8/34), H3N2 (A/Darwin/9/2021), and a clinical influenza B isolate (B/Beijing/ZYY-B18/2018). These findings position licoflavone B as a promising lead compound for developing next-generation, broad-spectrum antiviral therapies against influenza and potentially other viruses. Full article