Search Results (19,307)

The SARS-CoV-2 spike protein has been shown to activate Toll-like receptor 4 (TLR4), yet the precise molecular structures driving recognition and subsequent activation remain poorly defined. Here, we present in silico structural alignments and molecular docking simulations indicating potential spatial compatibility between the wild-type SARS-CoV-2 HR1HR2 fusion core and the human TLR4/MD-2 heterodimer. The computational models project candidate interfaces involving salt bridges, as well as polar and non-polar interactions, with both TLR4 and MD-2 dimerization partners, suggesting a theoretical topology compatible with the dimerization of two TLR4/MD-2 heterocomplexes. Notably, similar structural compatibility was modeled for related class I fusion proteins from other highly pathogenic viruses, including SARS-CoV, MERS-CoV, influenza viruses A, B, and C, respiratory syncytial virus (RSV), and partially Ebola virus. These findings offer an exploratory computational hypothesis regarding viral–host interactions with the host innate immune system, which can trigger immune recognition or detrimental hyperactivation. Full article

Zoonoses account for the majority of recognized mammalian viral spillover events, primarily originating from bats, rodents, and primates. Human activities have significantly accelerated these transmissions. This narrative review synthesizes the evolutionary, ecological, pathogen-related, and anthropogenic drivers of viral zoonotic spillover to identify critical leverage points for pandemic prevention. A narrative literature review was conducted. The analysis focused on factors enabling animal pathogens to transform into human pathogens, examining host species, pathogen traits, human–animal interactions, and environmental impacts. Pathogen transformation depends on host traits, contact frequency, and viral characteristics. Anthropogenic drivers—including livestock expansion, the bushmeat trade, wet markets, and the exotic pet industry—significantly elevate spillover risks. Effective pandemic prevention requires targeted interventions at the wildlife–livestock–human interfaces. A holistic, multidisciplinary collaboration between national governments and international organizations is essential to mitigate future risks. Full article

Post-COVID-19 syndrome (PCS), also referred to as post-acute sequelae of SARS-CoV-2 infection (PASC), represents a heterogeneous set of persistent clinical manifestations developing after acute infection. These conditions are associated with immune dysregulation, autonomic imbalance, impaired thymic function, and possible viral persistence. Objective: This study aims to systematically synthesise current evidence on the immunopathogenesis of PCS and to critically evaluate the application of artificial intelligence (AI) and machine learning (ML) approaches for its prediction and clinical stratification. Methods: A PRISMA 2020–informed systematic review was conducted using PubMed/MEDLINE, Scopus, Web of Science, elibrary.ru and Embase databases (January 2020–December 2025). Studies addressing immunopathological mechanisms and AI/ML applications in PCS were selected based on predefined eligibility criteria. Risk of bias in prediction studies was assessed using the PROBAST tool. Due to heterogeneity, a structured qualitative synthesis was performed. Current evidence indicates that PCS may result from sustained systemic inflammation, cytokine dysregulation, autoimmunity, and delayed restoration of T-cell homeostasis, including reduced thymic output of naïve T lymphocytes. Persistent thymic dysfunction may contribute to prolonged immune imbalance, increased susceptibility to secondary infections, and reactivation of latent viruses. AI/ML approaches—including gradient boosting, ensemble learning, deep neural networks, and natural language processing—have demonstrated promising performance across multimodal datasets. However, significant limitations were identified, including small sample sizes, overfitting, lack of external validation, and heterogeneity in outcome definitions. Conclusions: The integration of immunopathological insights with data-driven modelling highlights the potential of combined approaches for improving PCS risk stratification. However, current AI models remain insufficiently validated for clinical implementation. Future research should prioritise methodological standardisation, external validation, and incorporation of mechanistically informed biomarkers. Full article

Background: Monoclonal antibodies (mAbs) initially played a major role in outpatient COVID-19 management by providing rapid passive immunity and reducing progression to severe disease. However, continuous SARS-CoV-2 evolution progressively compromised the effectiveness of several anti-spike products. This narrative review summarizes the trajectory of COVID-19 mAbs across three phases: early clinical efficacy, loss of efficacy due to immune escape, and future directions. Methods: We conducted a narrative review focusing on mechanisms of action, pivotal clinical trials, and real-world effectiveness of neutralizing anti-spike mAbs and host-directed immunomodulatory mAbs. Emphasis was placed on the impact of variants—especially Omicron—on susceptibility and clinical use, as well as on emerging next-generation platforms. Results: First-generation neutralizing mAbs substantially reduced the hospitalization rates during the Alpha and Delta waves, while immunomodulatory mAbs became standard options for the hyperinflammatory phase in hospitalized patients. With the emergence of Omicron and its sub-lineages, extensive immune escape led to marked reductions in neutralization for many earlier anti-spike agents and consequent restrictions in use. Later-generation approaches targeting more conserved epitopes provided temporary solutions but were also challenged by ongoing antigenic drift. Host-directed immunomodulators retained clinical relevance because their mechanism is independent of viral spike mutations. Conclusions: The clinical role of monoclonal antibodies in COVID-19 has been dynamic and increasingly constrained by viral evolution. Future strategies should prioritize broadly neutralizing antibodies targeting conserved epitopes, innovative delivery platforms, and integration with real-time surveillance to preserve clinical utility in the endemic phase and improve preparedness for future outbreaks. Full article

Background: Although prolonged inflammatory symptoms are an infrequent and problematic adverse effect of vaccination that can occur in some people, the transient activation of acute phase reactants (APRs) is expected with adjuvanted vaccines and helps to potentiate immune responses. Methods: This experiment examined the association between vaccine reactogenicity and immunogenicity in monkeys immunized with an adjuvanted recombinant protein including a receptor binding domain–human IgG1-Fc fusion protein (RBD-Fc) sequenced from the ancestral Wuhan strain of SARS-CoV-2. The acute inflammatory reaction to immunization was assessed by determining the decline in serum iron levels at 24 h and the increase in the neutrophil-to-lymphocyte ratio (NLR) as the adherent neutrophil pool trafficked into circulation. Results: Robust primary and secondary antibody responses were elicited. Larger decreases in serum iron and higher NLRs were associated with a stronger inhibition of RBD binding with angiotensin-converting enzyme (ACE2) when five early viral variants of SARS-CoV-2 were tested, including Wuhan, Alpha, Beta, Gamma and Delta. Inhibition of ACE2-RBD binding was less evident when the Omicron variant was tested. Individual variation in the APR was also predictive of the persistence of cell-mediated immunity based on the number of interferon-expressing mononuclear cells activated by viral antigen in ELISpot assays. Conclusions: Rapid antibody responses to primary immunization and large secondary responses to booster immunizations were elicited by this adjuvanted recombinant RBD-Fc vaccine, and our analysis affirmed the view that a transient APR can enhance antibody binding with antigen proteins. Full article

Positive-strand RNA viruses represented by SARS-CoV-2 and DENV spread globally with high infectivity and frequent mutations, posing a severe threat to human health. However, specific and effective antiviral drugs remain limited. RNA-dependent RNA polymerase (RdRp) plays a critical role in the genome replication of RNA viruses and shows high structural conservation. No homologous protein exists in human cells, making RdRp an effective, safe, and broad-spectrum antiviral target. Therefore, establishing an RdRp activity assay for drug development based on its mechanism is of great significance. This paper summarizes the structural characteristics of RdRp and the methods for constructing RdRp activity assay, especially for cell-free activity assay. In addition, several reported RdRp inhibitors and their pharmaceutical progress are also reviewed, aiming to provide a reference for the development of novel antiviral drugs targeting RdRp. Full article

This work presents a spatially explicit 19-variable reaction–diffusion model for within-host SARS-CoV-2 dynamics that integrates viral kinetics, innate and adaptive immune responses, cytokine regulation, antibody production, and tissue-level thermoregulatory dynamics. Adaptive immune recruitment is described through smooth sigmoidal activation functions, whereas pro-inflammatory cytokines are controlled by Michaelis–Menten-type saturation with IL-10 feedback. The thermoregulatory component is formulated as a downstream tissue-level inflammatory readout driven by bounded virus-dependent pyrogenic forcing, homeostatic relaxation, and effective thermal diffusion. The system is solved using a meshless multiquadric radial basis function collocation method based on Kansa’s formulation. Numerical simulations reproduce the qualitative progression of acute infection, including early viral expansion, innate immune activation, delayed adaptive recruitment, and immune-mediated clearance. Spatial analysis reveals heterogeneous tissue-level patterns, such as localized viral foci, antibody depletion near the infection center, delayed cytotoxic effector coverage, and transient thermal gradients. The proposed framework provides a biologically interpretable and computationally flexible approach for investigating the spatiotemporal organization of within-host SARS-CoV-2 immune dynamics, while remaining a mechanistic modeling study rather than a patient-specific clinical predictor. Full article

Background/Objectives: In the first months of their life, infants rely on maternal antibodies for immune protection. Breastmilk is a major source of these defenses, supplying secretory IgA, IgG, and IgM that help guard mucosal surfaces against pathogens such as SARS-CoV-2. Most studies on breastmilk immunity in the context of COVID-19 have emphasized circulating monomeric IgA, rather than the multimeric secretory IgA (sIgA) that is active at mucosal barriers. This study assessed in-depth the contribution of breastmilk antibody subtypes to SARS-CoV-2 neutralization capacity and how these profiles differ following maternal COVID-19 infection versus vaccination during pregnancy or postpartum. Methods: In this prospective cohort study, breastmilk samples were collected longitudinally from individuals who had COVID-19 during pregnancy or received COVID-19 mRNA vaccination during pregnancy or postpartum. Serological assays measured IgG, IgM, systemic IgA, and secretory IgA against SARS-CoV-2 spike and nucleocapsid antigens. Results: COVID-19 infection during pregnancy resulted in significantly higher systemic and secretory IgA levels compared to vaccination. Secretory IgA demonstrated a strong correlation with neutralization capacity. Principal component analysis revealed distinct antibody profiles in COVID-19-exposed individuals versus vaccinated cohorts, with significant overlap between pregnancy and postpartum vaccination groups. Conclusions: Although both COVID-19 vaccination and disease elicit sustained COVID-19-related antibodies in breastmilk, COVID-19 infection elicits a broader and more diverse antibody response in breastmilk, specifically with a greater secretory IgA generation. These findings support the value of maternal vaccination to safely confer mucosal immunity to neonates and the need for optimized vaccine formulations for mucosal immunity. Full article

This study analyses the pharmacological profiles of medications administered to critically ill COVID-19 patients to evaluate their efficacy regarding recovery rates and duration of hospitalization. The results demonstrate a significant difference in clinical outcomes. While the administration of Ceftazidime, Ceftriaxone, and Oseltamivir was associated with negative survival trends, Dexamethasone and Favipiravir were associated with a fourfold higher probability of survival in severe cases. Notably, no pharmacological intervention significantly reduced the length of hospital stay; instead, recovery duration was primarily influenced by comorbidities such as obesity, cardiovascular disease, and diabetes. Furthermore, age and preexisting physiological conditions remained primary predictors of mortality. Observational analysis in our study for drug repurposing identified Amikacin, Remdesivir, and Rivaroxaban as potential therapeutic candidates. However, Dexamethasone was identified as the most effective treatment for recovery, likely due to a molecular structure with high potential binding affinity to the SARS-CoV-2 virus. These findings suggest that while specific repurposed drugs offer measurable benefits, patient history remains a critical determinant of outcomes, highlighting the necessity for further research to refine therapies against emerging viral pathogens. Full article

Background: SARS-CoV-2 reinfections increased substantially after the emergence of Omicron variants. Methods: We conducted a cross-sectional study of 2095 individuals with prior Omicron BA.2 infection in Shanghai, China, during the early post-zero-COVID period. Data on demographics, infection history, and lifestyle factors were collected via questionnaire, and blood samples were obtained for ancestral RBD-blocking antibody measurement. Results: Meeting WHO physical activity recommendations (≥600 MET-min/week) was associated with lower reinfection odds (OR = 0.59, 95% CI: 0.46–0.74, p < 0.001). The overall median ancestral RBD-blocking antibody level was 263.93 U/mL (IQR: 36.41–331.87). Older age was associated with lower ancestral RBD-blocking antibody levels (β = –0.0038 per year, 95% bootstrap CI: –0.0057 to –0.0019, p < 0.001). All vaccinated groups had significantly higher ancestral RBD-blocking antibody levels than unvaccinated individuals: partially vaccinated (β = 0.4440, 95% CI: 0.1569 to 0.6830, p < 0.001), fully vaccinated (β = 0.8516, 95% CI: 0.7464 to 0.9595, p < 0.001), homologous booster (β = 1.0297, 95% CI: 0.9408 to 1.1223, p < 0.001), and heterologous booster (β = 1.0838, 95% CI: 0.9387 to 1.2226, p < 0.001). Time since last immune event was inversely associated with ancestral RBD-blocking antibody levels (β = –0.0232 per month, 95% CI: –0.0385 to –0.0077, p = 0.0031). Conclusions: In this cross-sectional study, meeting WHO physical activity recommendations was associated with 41% lower odds of SARS-CoV-2 reinfection, although reverse causality cannot be ruled out. All vaccinated groups had higher ancestral RBD-blocking antibody levels than unvaccinated individuals. Older age and longer time since last immune event were associated with lower ancestral RBD-blocking antibody levels. These associations need confirmation in prospective, well-powered studies. Full article

Background and Objectives: The SARS-CoV-2 pandemic disrupted oral and maxillofacial surgery (OMS) services worldwide because of the high aerosol-generating nature of head-and-neck procedures, restricted access to elective dental care, and systemic reallocation of hospital resources. Continuous longitudinal multi-year data covering both the pandemic and the post-pandemic phases from regional Romanian (and more broadly central and southeastern European) emergency centers remain scarce. We aimed to quantify the impact of the pandemic on OMS activity in a large Romanian regional referral center and to evaluate post-pandemic resilience. Materials and Methods: We conducted a retrospective single-center study of all inpatient admissions to the OMS Clinic of a tertiary emergency hospital in western Romania between 1 January 2018 and 31 December 2024. Three periods were pre-specified: pre-pandemic (2018–2019), pandemic (2020–2022) and post-pandemic (2023–2024). A Newey–West segmented interrupted-time-series (ITS) regression and a negative-binomial monthly count model with Fourier seasonality were fitted; length of hospital stay was further analyzed with a multivariable gamma-log generalized linear model adjusted for age, sex, county, primary ICD-10 chapter and total ICD-10 codes. Variables analyzed included case volume, demographics, primary and secondary ICD-10 diagnoses, length of hospital stay (LOS), case complexity (total ICD-10 codes per admission) and in-hospital mortality. Results: A total of 11,628 inpatient admissions corresponding to 8084 unique patients (56.5% male; mean age 52.2 ± 19.2 years) were analyzed. Compared with the pre-pandemic baseline (mean 2037 admissions/year), annual volume dropped by 45.1% in 2020, 44.0% in 2021 and 32.3% in 2022, with a nadir of −76% during the first state of emergency (April 2020; n = 34 admissions). Recovery was rapid; 2024 exceeded the pre-pandemic baseline by +10.1% on raw counts and by +16.2% on admissions per 100,000 catchment population using year-specific INS denominators. The segmented ITS regression confirmed an immediate level drop of −114.2 admissions/month in March 2020 (95% CI −133.1 to −95.3; p < 0.001) and a positive post-intervention slope of +2.06 admissions/month (95% CI 1.23–2.88; p < 0.001), with observed monthly volume returning to the counterfactual projection by October 2023. The case mix shifted significantly (χ² = 406.9, p < 0.0001); elective benign neoplasm admissions were reduced from 7.2% to 2.0%, while neoplasms of uncertain behavior nearly doubled from 15.7% to 27.5%. Case complexity increased during the pandemic (mean ICD codes 4.08 ± 2.42 vs. 3.44 ± 2.30; p < 0.001); after exclusion of administrative codes (whole Z chapter and U07.x), the difference attenuated to 3.34 vs. 3.17 codes (still p < 0.001 by Kruskal–Wallis), indicating that the largest portion of the unadjusted increase was driven by the new mandatory pre-admission SARS-CoV-2 screening code Z11.5 rather than true clinical complexity. Notably, the clinically interpretable proxy R63.3 (feeding difficulty) independently rose from 41.5% to 53.1%. The crude median LOS did not differ between the pre-pandemic and pandemic periods (3.07 vs. 3.06 d; p = 0.19) and dropped significantly post-pandemic (2.22 d; p < 0.001); however, after multivariable adjustment for case mix, age, sex, county and code count, the LOS was 15.7% shorter during the pandemic (adjusted ratio 0.84, 95% CI 0.82–0.87; p < 0.001) and 22.8% shorter post-pandemic (adjusted ratio 0.77, 95% CI 0.75–0.80; p < 0.001) relative to baseline. Conclusions: The pandemic caused a severe but transient contraction of OMS activity accompanied by increased case complexity and a marked shift away from elective surgery. Inpatient volume returned to and exceeded the pre-pandemic baseline by 2024. These results support the value of standing pandemic-preparedness protocols, sustained access to preventive dental care, and integrated tele-triage pathways for future public-health crises. Full article

Aerosol-generating procedures (AGPs) expose healthcare personnel to airborne pathogens and require portable engineering controls that can be integrated into routine clinical workflows. We developed a portable, foldable negative-pressure aerosol-containment system (FNPACS) combining adaptive fan control, an H14 high-efficiency particulate air (HEPA) filter, and a disposable metal-oxide prefilter in a mobile filtration module. Bench performance was evaluated using pressure-flow testing in accordance with National Environmental Balancing Bureau (NEBB) procedures and International Organization for Standardization (ISO) 14644-3, polyalphaolefin aerosol challenge testing, and smoke visualization, while an exploratory clinical study assessed environmental contamination via real-time reverse-transcription PCR (rRT-PCR) in 11 patients (31 assay analyses). Bench testing demonstrated HEPA filtration efficiencies of 99.994–99.997%, stable negative-pressure generation across fan duty cycles, no detectable downstream breakthrough beyond the HEPA filter under the tested conditions, and effective inward airflow on smoke testing. A Lagrangian discrete phase model (DPM) particle-tracking simulation further characterized size-dependent aerosol-surrogate transport. Under HEPA-ON active-extraction conditions, 73.0–86.1% of simulated 0.3–10 µm water-equivalent particles were transported to the HEPA suction pathway, while 13.9–27.0% were deposited on internal wall surfaces. In the clinical evaluation, SARS-CoV-2 RNA detection on environmental swabs was limited and predominantly low level. The clearest reproducible signal occurred on the top interior surface under HEPA-OFF conditions, whereas HEPA-ON detections were isolated or presumptive high-Ct signals without reproducible confirmation. These findings provide preliminary engineering and usability support for FNPACS as a feasible near-source aerosol-control platform for AGPs. The patient swab component should be interpreted as an exploratory, proof-of-concept assessment rather than confirmatory evidence of clinical containment efficiency because several clinical cases had non-supportive patient-related controls and were therefore not used in the primary containment interpretation. Full article

Accurate viral protein function annotation is essential for genomic surveillance, yet conventional retrieval-augmented generation (RAG) pipelines often fragment biological evidence into fixed-length text chunks, disrupting relationships among ORFs, annotations, structural domains, sequence motifs, residue mappings, and model-derived attention evidence. We propose ViroBioTree, a tree-structured biological evidence retrieval framework for downstream viral protein evidence review rather than a new primary annotation classifier. Built as an evidence organization layer on ViralMultiNet-derived ORF-level predictions and annotations, ViroBioTree converts sequence, annotation, structure, and attention evidence into typed biological nodes and traceable edges, then performs deterministic multi-channel recall, evidence-aware reranking, balanced TopK selection, rule-based verification, and node-cited report generation. In a demo benchmark, ViroBioTree achieved its strongest deterministic proxy performance on structure-explanation tasks, with Precision@K = 1.0, Recall@K = 1.0, and diversity = 0.52; these values reflect expected node-type and tag agreement rather than independent biological correctness. A bounded full-scale SARS-CoV-2 index contained 39,800 ORF rows, 80,000 attention records, 199,418 nodes, and 495,886 edges. In a stratified full20k diagnostic evaluation, ViroBioTree showed task-dependent advantages over LlamaIndex vector retrieval for conflict detection, evidence retrieval, and structure explanation, while LlamaIndex remained competitive or stronger for annotation-rich function annotation. A cross-family Influenza A Virus (IAV) diagnostic audit showed that the schema can represent IAV evidence namespaces while explicitly exposing missing formal ORF inputs, missing attention evidence, and unavailable residue/PDB assertions. Supplementary robustness, external sanity-check, diversity-risk, expert-evaluation, domain-tool positioning, and cross-family audit analyses supported traceability, report quality, and conservative evidence handling, but also showed that stable Precision@K under query perturbation does not necessarily imply stable retrieved evidence sets. ViroBioTree operates offline and deterministically, but does not address raw-read assembly, base calling, primary ORF prediction, or wet-lab validation. Its results should be interpreted as proxy and expert-reviewed evidence for traceable viral protein evidence retrieval and report generation rather than as direct validation of biological function annotation. Full article

Objective: Long COVID (LC) has been defined as a chronic condition that occurs after SARS-CoV-2 infection and persists for more than 3 months. Dyspnea is the most common and disabling symptom with several mechanisms identified. The pathophysiology of post-COVID dyspnea is unknown. The aim of this study is to analyze the clinical profile of patients presenting with dyspnea in the context of LC and to assess its possible relation with complementary diagnostic tests. Material and Methods: This is a retrospective cohort study including adult patients diagnosed with LC attending a post-COVID outpatient clinic. Dyspnea was assessed using mMRC and Borg scales. Complementary tests included chest imaging, pulmonary function tests (PFTs) and a six-minute walk test (6MWT). These assessments were performed at several time points throughout follow-up (3, 6, and 12 months). Results: Eighty patients diagnosed with LC were included, the mean age was 60.0 ± 14.4 and 43 (54.8%) were female. Most patients were hospitalized during acute infection (97.5%) and 25 patients experienced respiratory failure. During the follow-up, chest X-rays showed persistent abnormalities in 67.5% of patients, and 6MWT was pathological in 61.3% at 277 days (IQR 176–326) after acute infection. No significant differences were observed in the prevalence of ventilatory failure across dyspnea severity categories. Reduced DLCO was observed in 20% of patients, while obstructive or restrictive patterns were infrequent. Through three follow-up visits, pulmonary function and exercise capacity remained stable, with modest improvements in DLCO and exercise-induced desaturation (p = 0.005). In multivariable analysis, obesity (adjusted OR 7.88; p = 0.023) and lower DLCO (p = 0.049) were independent predictors of more severe dyspnea, highlighting the role of non-pulmonary factors in Long COVID. Conclusions: This study describes the clinical and functional profile of a cohort of patients with LC. Although abnormal findings were frequent, only impaired DLCO and obesity were independently associated with dyspnea severity, while imaging and six-minute walk test abnormalities showed no consistent association with symptom intensity, supporting a multifactorial origin of post-COVID dyspnea. Full article

Vitex rotundifolia is a medicinal plant rich in terpenoids and flavonoids, whereas the liverwort Ptychanthus striatus represents an underexplored bryophyte source of specialized metabolites. In this study, a bioassay-guided phytochemical investigation of Vietnamese V. rotundifolia leaves and P. striatus was conducted to identify natural inhibitors of SARS-CoV-2 main protease (Mpro). The crude methanol extracts and selected fractions showed inhibitory activity against SARS-CoV-2 Mpro, thereby guiding subsequent chromatographic separation. Thirteen compounds, including diterpenoids, lupane-type triterpenoids, and flavonoids, were isolated from V. rotundifolia, while ten terpenoid, phenolic, bibenzyl, and bisbibenzyl-type metabolites were obtained from P. striatus. Most isolated compounds are reported from these species for the first time, and compound P8 from P. striatus is described as a new natural product. All isolated compounds were evaluated for their inhibitory activity against SARS-CoV-2 Mpro. Among them, chrysoplenol D was the most potent inhibitor, with an IC₅₀ value of 0.08 ± 0.01 µM, followed by selected phenolic/bibenzyl-type metabolites from P. striatus and other flavonoid derivatives from V. rotundifolia. Most diterpenoids showed weak or negligible inhibition. Molecular docking studies supported the experimental results by showing that representative active compounds could bind within the catalytic pocket of SARS-CoV-2 Mpro and interact with key residues, including His41, Gly143, and Cys145. These findings expand the phytochemical knowledge of Vietnamese V. rotundifolia and P. striatus and highlight chrysoplenol D and related flavonoid or bibenzyl-type natural products as promising scaffolds for further development of SARS-CoV-2 Mpro inhibitors. Full article