Human coronaviruses (CoV) cause respiratory infections that range from mild to severe. CoVs are a large family of viruses with considerable genetic heterogeneity and a multitude of viral types, making preventing and treating these viruses difficult. Comprehensive treatments that inhibit CoV infections fulfill a pressing medical need and may be immensely valuable in managing emerging and endemic CoV infections. As the main protease (Mpro) is highly conserved across many CoVs, this protease has been identified as a route for broad CoV inhibition. We utilize the advanced generative chemistry platform Chemistry42 for de novo molecular design and obtained novel small-molecule, non-peptide-like inhibitors targeting the SARS-CoV-2 Mpro. ISM3312 is identified as an irreversible, covalent Mpro inhibitor from extensive virtual screening and structure-based optimization efforts. ISM3312 exhibits low off-target risk and outstanding antiviral activity against multiple human coronaviruses, including SARS-CoV-2, MERS-CoV, 229E, OC43, NL63, and HKU1 independent of P-glycoprotein (P-gp) inhibition. Furthermore, ISM3312 shows significant inhibitory effects against Nirmatrelvir-resistant Mpro mutants, suggesting ISM3312 may contribute to reduced viral escape in these settings. Incorporating ISM3312 and Nirmatrelvir into antiviral strategy could improve preparedness and reinforce defenses against future coronavirus threats.

Background Particular matter 2.5 (PM2.5) is one of the most important air pollutant, and it is positively associated with the development of chronic obstructive pulmonary disease (COPD). However, the precise underlying mechanisms through which PM2.5 promotes the development of COPD remains largely unknown. Methods Mouse alveolar destruction were determined by histological analysis of lung tissues and lung function test. Alveolar type II cells (AT2) to alveolar type I cells (AT1) transition in PM2.5-induced COPD mouse model was confirmed via immunofluorescence staining and qPCR analysis. The differentially expressed genes in PM2.5-induced COPD mouse model were identified by RNA-sequencing of alveolar epithelial organoids and generated by bioinformatics analysis. Results In this study, we found that 6 months exposure of PM2.5 induced a significantly decreased pulmonary compliance and resulted in pulmonary emphysema in mice. We showed that PM2.5 exposure significantly reduced the AT2 to AT1 cell transition in vitro and in vivo. In addition, we found a reduced expression of the intermediate AT2-AT1 cell process marker claudin 4 (CLDN4) at day 4 of differentiation in mouse alveolar organoids treated with PM2.5, suggesting that PM2.5 exposure inhibited AT2 cells from entering the transdifferentiation process. RNA-sequencing of mouse alveolar organoids showed that several key signaling pathways that involved in the AT2 to AT1 cell transition were significantly altered including the Wnt signaling, MAPK signaling and signaling pathways regulating pluripotency of stem cells following PM2.5 exposure. Conclusions In summary, these data demonstrate a critical role of AT2 to AT1 cell transition in PM2.5-induced COPD mouse model and reveal the signaling pathways that potentially regulate AT2 to AT1 cell transition during this process. Our findings therefore advance the current knowledge of PM2.5-induced COPD and may lead to a novel therapeutic strategy to treat this disease.

Additional file 2. Alveolar differentiation phase RNA-seq, include RNA sequencing data of alveolar organoids in differentiation phase.

In this paper, we establish two mathematical models to study H1N1 influenza transmission dynamics. One model is for the case of concurrent treatment, in which we assume that untreated individuals are detected at random and moved to the treatment compartment at any time of their infected phase, and the other model deals with the case of early diagnosis, in which we assume that with some probability sigma is an element of[0; 1], individuals are diagnosed at the moment of infection and immediately moved to the treatment compartment. Both models are analyzed including the derivation of the basic and control reproduction numbers, the proof of global stability of disease-free equilibrium points, and demonstrating how the acquired reproduction number can be used to explain the adverse effects associated with antiviral treatment. This effect is also explained using a quantity termed the total control reproduction number. We also compare the differences between the two models in evaluating outcomes of influenza. Numerical simulations are conducted to verify the theoretical analysis results.

In this paper, we describe an SIR model with age-structured and media coverage for the spread of influenza, which transmits within a population in a short time, and the population is divided into two parts including the adolescent and the adult, respectively. The numerical simulations show that media coverage plays an important role in controlling the prevalence of influenza, moreover, the duration of media coverage should not last long when influenza epidemic appears, otherwise it may cause negative effects. And we also should consider the heterogeneity of the population when some interventions are proposed, if not, we may misestimate the size of the disease.

BACKGROUND: Peak expiratory flow (PEF) measurement is less expensive and requires fewer skills than spirometry testing. It is thus expected to be a reasonable substitute for spirometry in airflow obstruction screening when spirometry is unavailable.OBJECTIVES: To evaluate the validation of PEF measurement in the detection of airflow obstruction using newly established regression equations.METHODS: The PEFs of 553 'normal' participants aged 40-85 years were measured using mechanical devices. Based on these data, regression equations were generated to predict normal PEF values. Data were then collected from 3379 subjects. The specificity and sensitivity of the different predicted PEF cut-off points for detecting airflow obstruction were evaluated by spirometry, based on previously generated regression equations.RESULTS: Using newly established reference values for PEF, PEF had higher sensitivity and specificity than the questionnaire in detection of airflow obstruction. That PEF < 80% of predicted was more effective in the detection of airflow obstruction was confirmed by the lower limit of normal of forced expiratory volume in 1 second/forced vital capacity, Global Initiative for Chronic Obstructive Lung Disease (GOLD), and GOLD plus symptom, with a sensitivity of 78.7%, 76.8%, 85.3% and a specificity of 81.9%, 83.8%, 81.4%, respectively.CONCLUSIONS: Mechanical PEF may be a reasonable method of screening for airflow obstruction in settings where spirometry is unavailable.

Little is known about chronic obstructive pulmonary disease (COPD) in Chinese nonsmokers. The present study aimed to investigate the profiles of COPD among nonsmokers based on the Chinese Epidemiological Survey of COPD (CESCOPD).In the CESCOPD, 20,245 subjects aged 40 yrs or older were interviewed with questionnaires and spirometry tests. Subjects with a post-bronchodilator forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) ratio of <0.70 were identified as having COPD. Data of 12,471 nonsmokers and 1,024 smoking COPD patients were analysed in the current study.The overall prevalence of COPD among nonsmokers was 5.2% (95% confidence interval 4.8-5.6). Being male, of advanced age, lower body mass index (BMI) and lower educational level, having exposure to environmental tobacco smoke, coal and/or biomass smoke, poor ventilation in the kitchen, a family history of respiratory disease and recurrent childhood cough were all independently associated with a higher risk of having COPD among nonsmokers. Nonsmokers with respiratory symptoms without airflow limitation showed a somewhat different pattern of risk factors. Nonsmokers with COPD were less likely to present with chronic productive coughs and lower BMI, while more likely to have received a physician diagnosis of asthma and respiratory diseases in childhood, than smokers with COPD.Chronic obstructive pulmonary disease is prevalent among Chinese nonsmokers, and nonsmoking chronic obstructive pulmonary disease may have different profiles from smoking chronic obstructive pulmonary disease.