Wanshan Ning

Background: Respiratory diseases are pathophysiologically diverse, but whether temporally resolved 24-hour movement behaviours (24-MB) are uniformly associated with risk across this clinical spectrum remains unclear.Methods: We analysed wrist accelerometry from 92,326 UK Biobank participants, deriving hour-level sleep, sedentary behaviour (SB), light physical activity (LPA) and moderate-to-vigorous physical activity (MVPA) across workdays and weekends. Twenty-five ICD-10 respiratory diseases were grouped into Acute, Chronic and Other strata. Associations were examined using time-resolved Cox models and restricted cubic splines. A Transformer-based Circadian Respiratory Risk (CRR) model was developed and externally validated in NHANES; Mendelian randomisation and multi-omics mediation assessed causal support and biological plausibility.Findings: Incident cases showed higher SB and lower LPA/MVPA. The CRR model revealed a prediction gradient, with stronger risk-prediction performance for chronic inflammatory/structural diseases and respiratory failure than for acute infectious outcomes. Temporal associations were diffuse in Chronic diseases, concentrated in Acute diseases and heterogeneous in Other conditions. Early-morning SB was associated with higher risk, whereas later-day LPA/MVPA was generally protective; pneumonia risk was higher with SB at 03:00 (HR 1.91) and lower with MVPA at 18:00 (HR 0.58). Protective MVPA associations began at 43–51 min/day. Females showed stronger SB-associated risk and LPA/MVPA-related protection. Multi-omics analyses implicated shared neutrophil-driven inflammation and disease-specific immune-inflammatory and tissue-remodelling pathways. Optimised 24-MB profiles lowered calibrated predicted risks, and a web platform enables individualised estimation (http://respiratory.zBiolab.cn).Interpretation: Temporally resolved 24-MB profiles revealed a pathophysiology-stratified predictive architecture of respiratory disease risk, characterised by a prediction gradient across disease strata and distinct temporal vulnerability.

Respiratory tract infections (RTIs) are a significant cause of morbidity in children, caused by a wide range of pathogens. As treatment strategies depend on the causative pathogen, early and accurate diagnosis is crucial. We developed and validated an interpretable Pathogen Diagnostic System for Pediatric Respiratory Infections (Pathog-PDx), conducting a multicenter study involving 134,500 hospitalized children across three clinical centers and two databases. The model integrated 42 clinical and laboratory features from electronic health records (EHR) to enable early pathogen identification. Prospective validation was carried out on an independent cohort of 1338 children to assess the real-world applicability of the model. Pathog-PDx accurately distinguished 22 pathogen subtypes and outperformed conventional models in identifying both single and mixed infections. The model achieved high classification performance for key pathogens, such as influenza virus (AUC = 0.95; Sn: 0.88; Sp: 0.86), with mean AUCs of 0.88 for various pathogens of RTIs. The model has been deployed as a web-based decision support system, which is freely accessible at https://pathogpdx.zzu.edu.cn. Altogether, Pathog-PDx represents a potential tool for the early identification of respiratory tract pathogens in pediatric patients, which can provide actionable predictions ahead of conventional test results to guide timely and targeted therapy.

Lysine crotonylation (Kcr) is a novel posttranslational modification that has been proven to have evolutionary conservation. However, the role of protein Kcr in the pathogenesis of endotoxic shock-induced secondary cardiomyopathy is elusive. Here a classic rat model of endotoxic shock was induced by intraperitoneal lipopolysaccharide (LPS) injection. Crotonylproteomic analysis was subsequently performed on myocardial tissues to profile the Kcr modifications that occurred during endotoxic shock, and we found that the Kcr of carnitine palmitoyltransferase 1B (CPT1B) at the K321 site was significantly upregulated in LPS-treated rats. These findings were also confirmed in rat primary cardiomyocytes and H9C2 cells exposed to LPS. Furthermore, we demonstrated that the K321cr of CPT1B impaired CPT1B activity. Moreover, we found that the mutation of K321 to R prevented the mutant CPT1B protein from being crotonylated by LPS, thus alleviating LPS-induced lipid droplet deposition and mitochondrial dysfunction, as reflected by the recovery of ATP generation and mitochondrial membrane potential. Consistently, in vivo cardiac-specific overexpression of CPT1B via an AAV9 vector with a cardiomyocyte-specific promoter (cTnT) also confirmed that the K321-R mutation of CPT1B protected against endotoxic shock-induced secondary cardiomyopathy. Further liquid chromatography–tandem mass spectrometry analysis revealed that the crotonyl-transferases P300 and CBP might be involved in the Kcr of CPT1B. Mechanistically, LPS led to the dissociation of CBP from CPT1B, which promoted the binding of P300 to CPT1B, thereby increasing the level of CPT1B K321cr in H9C2 cells. Taken together, the results of our study revealed the regulatory axis of CPT1B K321 cr/CBP/P300 in LPS-induced endotoxic shock.

Background: Respiratory diseases are pathophysiologically diverse, but whether temporally resolved 24-hour movement behaviours (24-MB) are uniformly associated with risk across this clinical spectrum remains unclear.Methods: We analysed wrist accelerometry from 92,326 UK Biobank participants, deriving hour-level sleep, sedentary behaviour (SB), light physical activity (LPA) and moderate-to-vigorous physical activity (MVPA) across workdays and weekends. Twenty-five ICD-10 respiratory diseases were grouped into Acute, Chronic and Other strata. Associations were examined using time-resolved Cox models and restricted cubic splines. A Transformer-based Circadian Respiratory Risk (CRR) model was developed and externally validated in NHANES; Mendelian randomisation and multi-omics mediation assessed causal support and biological plausibility.Findings: Incident cases showed higher SB and lower LPA/MVPA. The CRR model revealed a prediction gradient, with stronger risk-prediction performance for chronic inflammatory/structural diseases and respiratory failure than for acute infectious outcomes. Temporal associations were diffuse in Chronic diseases, concentrated in Acute diseases and heterogeneous in Other conditions. Early-morning SB was associated with higher risk, whereas later-day LPA/MVPA was generally protective; pneumonia risk was higher with SB at 03:00 (HR 1.91) and lower with MVPA at 18:00 (HR 0.58). Protective MVPA associations began at 43–51 min/day. Females showed stronger SB-associated risk and LPA/MVPA-related protection. Multi-omics analyses implicated shared neutrophil-driven inflammation and disease-specific immune-inflammatory and tissue-remodelling pathways. Optimised 24-MB profiles lowered calibrated predicted risks, and a web platform enables individualised estimation (http://respiratory.zBiolab.cn).Interpretation: Temporally resolved 24-MB profiles revealed a pathophysiology-stratified predictive architecture of respiratory disease risk, characterised by a prediction gradient across disease strata and distinct temporal vulnerability.

COVID-19 is associated with increased risks of neurological and psychiatric sequelae. Alternative polyadenylation (APA) is ubiquitous in human genes, resulting in mRNA diversity, and has been validated to play a pivotal regulatory role in the onset and progression of a variety of diseases, including viral infections. Here, we analyzed the APA usage across different cell types in frontal cortex cells from non-viral control group and COVID-19 patients, and identified functionally related APA events in COVID-19. According to our study, the poly(A) site (PAS) usage is different among cell types and following SARS-COV-2 infection. Moreover, we found the genes with significant PAS level changes affected pathways related to RNA splicing, and neuronal development and function, suggesting that survivors of COVID-19 will have a high risk of these diseases and that alternative splicing functions cause these changes. Additionally, APA usage and its correlation with gene expression levels varied across genes, some prefer short isoform that is more stable to produce more proteins, while others may be regulated by different mechanisms. A total of 267 risk genes targeted by microRNAs for common neurological and psychiatric disorders were found to undergo significant changes in APA following infection. In conclusion, our comprehensive analysis of APA in neural cells from COVID-19 patients at the single-cell level elucidated changes in APA levels in the brains of SARS-COV-2-infected patients and confirmed that these changes impair the function of the nervous system, providing important insights for COVID-19-associated sequelae.

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social communication and interaction, alongside restricted, and repetitive behaviors. Emerging evidence suggests that gut microbiota alterations may contribute to ASD pathogenesis via the gut-brain axis. However, many previous studies have not adequately controlled for confounding genetic and environmental variables. In this study, we examined the gut microbiota profiles of 19 children with ASD, 8 siblings with non-ASD, and 36 parents from 17 families, providing a unique design that minimized biases related to shared genetic and familial environments. Metagenomic sequencing revealed significant differences in gut microbiota diversity and composition between groups. Specifically, children with ASD had lower abundances of Bifidobacterium and higher abundances of both Bacteroides and Clostridium species compared to their siblings, with notable dysbiosis correlated to ASD-specific symptoms. These findings highlight the potential role of microbiota alterations in ASD pathogenesis and suggest familial microbiota traits influenced by both genetic and environmental factors. Further exploration of gut microbial therapies could offer promising avenues for ASD intervention.

BACKGROUND: Serum lactate levels are used to evaluate tissue hypoxia and predict outcomes in cases of sepsis and septic shock. Lactate can participate in a posttranslational modification known as lactylation. Myocardial depression during sepsis and septic shock is common. Here, we investigated the role of lactate in sepsis-induced myocardial depression. METHODS: Septic myocardial depression in rats was induced by lipopolysaccharide administration or cecal ligation and puncture. Lactylation and protein profiles of heart tissues from the control and lipopolysaccharide groups were analyzed using proteomic analysis. Lactylation of the HADHA (trifunctional enzyme subunit alpha) at K166 and K728 was detected in septic heart tissues and lipopolysaccharide-induced cultured cells. Mutation of K166 and K728 HADHA were used to clarify the effects of HADHA lactylation on mitochondrial function, ATP production, energy metabolism, and heart function. Transcriptomic and metabolomic analyses were used to identify differentially expressed genes and differential metabolites in H9c2 (rat cardiomyoblast cell line) cells. RESULTS: We identified 1127 lysine lactylation sites, with 83 differentially lactylated lysine sites. By integrating multifeature hybrid learning and protein language models, we identified lactylation at K166 and K728 of the HADHA as functionally important. We confirmed that lactylation at these sites was influenced by lactate levels and inhibited the HADHA activity, which disturbed mitochondrial function, ATP production, and energy metabolism. This reduction in the contraction force of cardiomyocytes can influence heart function in vitro and in vivo. Furthermore, this study revealed that sirtuin 1 and sirtuin 3 regulated the lactylation of HADHA at K166 and K728. CONCLUSIONS: This study reveals the significant impact of lactylation on cardiomyocyte metabolism. Lactate-induced HADHA lactylation disturbs cardiomyocyte mitochondrial function and metabolism and promotes sepsis-induced cardiac dysfunction. These findings inform the development of new therapeutic targets for sepsis-induced myocardial depression.