The lung is the primary organ targeted by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), making respiratory failure a leading coronavirus disease 2019 (COVID-19)-related mortality. However, our cellular and molecular understanding of how SARS-CoV-2 infection drives lung pathology is limited. Here we constructed multi-omics and single-nucleus transcriptomic atlases of the lungs of patients with COVID-19, which integrate histological, transcriptomic and proteomic analyses. Our work reveals the molecular basis of pathological hallmarks associated with SARS-CoV-2 infection in different lung and infiltrating immune cell populations. We report molecular fingerprints of hyperinflammation, alveolar epithelial cell exhaustion, vascular changes and fibrosis, and identify parenchymal lung senescence as a molecular state of COVID-19 pathology. Moreover, our data suggest that FOXO3A suppression is a potential mechanism underlying the fibroblast-to-myofibroblast transition associated with COVID-19 pulmonary fibrosis. Our work depicts a comprehensive cellular and molecular atlas of the lungs of patients with COVID-19 and provides insights into SARS-CoV-2-related pulmonary injury, facilitating the identification of biomarkers and development of symptomatic treatments.

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Our group recently reported the identification of novel coumestan derivatives as Mycobacterium tuberculosis (Mtb) Pks13-thioesterase (TE) domain inhibitors, with mutations observed (D1644G and N1640K) in the generated coumestan-resistant Mtb colonies. Herein, we report a further structure−activity relationships exploration exploiting the available Pks13-TE X-ray co-crystal structure that resulted in the discovery of extremely potent coumestan analogues 48 and 50. These molecules possess excellent anti-tuberculosis activity against both the drug-susceptible (MIC = 0.0039 μg/mL) and drug-resistant Mtb strains (MIC = 0.0078 μg/mL). Moreover, the excellent in vitro activity is translated to the in vivo mouse serum inhibitory titration assay, with administration of coumestan 48 at 100 mg/kg showing an 8-fold higher activity than that of isoniazid or TAM16 given at 10 or 100 mg/kg, respectively. Preliminary ADME-Tox data for the coumestans were promising and, coupled with the practicality of synthesis, warrant further in vivo efficacy assessments of the coumestan derivatives.

A complete diagnostic autopsy is the gold-standard to gain insight into Coronavirus disease 2019 (COVID-19) pathogenesis. To delineate the in situ immune responses to SARS-CoV-2 viral infection, here we perform comprehensive high-dimensional transcriptional and spatial immune profiling in 22 COVID-19 decedents from Wuhan, China. We find TIM-3-mediated and PD-1-mediated immunosuppression as a hallmark of severe COVID-19, particularly in men, with PD-1+ cells being proximal rather than distal to TIM-3+ cells. Concurrently, lymphocytes are distal, while activated myeloid cells are proximal, to SARS-CoV-2 viral antigens, consistent with prevalent SARS-CoV-2 infection of myeloid cells in multiple organs. Finally, viral load positively correlates with specific immunosuppression and dendritic cell markers. In summary, our data show that SARS-CoV-2 viral infection induces lymphocyte suppression yet myeloid activation in severe COVID-19, so these two cell types likely have distinct functions in severe COVID-19 disease progression, and should be targeted differently for therapy.

Polyketide synthase 13 (Pks13) is an important enzyme found in Mycobacterium tuberculosis (M. tuberculosis) that condenses two fatty acyl chains to produce α-alkyl β-ketoesters, which in turn serve as the precursors for the synthesis of mycolic acids that are essential building blocks for maintaining the cell wall integrity of M. tuberculosis. Coumestan derivatives have recently been identified in our group as a new chemotype that exert their antitubercular effects via targeting of Pks13. These compounds were active on both drug-susceptible and drug-resistant strains of M. tuberculosis as well as showing low cytotoxicity to healthy cells and a promising selectivity profile. No cross-resistance was found between the coumestan derivatives and first-line TB drugs. Here we report that treatment of M. tuberculosis bacilli with 15 times the MIC of compound 1, an optimized lead coumestan compound, resulted in a colony forming unit (CFU) reduction from 6.0 log10 units to below the limit of detection (1.0 log10 units) per mL culture, demonstrating a bactericidal mechanism of action. Single dose (10 mg/kg) pharmacokinetic studies revealed favorable parameters with a relative bioavailability of 19.4%. In a mouse infection and chemotherapy model, treatment with 1 showed dose-dependent mono-therapeutic activity, whereas treatment with 1 in combination with rifampin showed clear synergistic effects. Together these data suggest that coumestan derivatives are promising agents for further TB drug development.

Aim To explore the sleep quality among Chinese nurses and identify the association between night shift and sleep quality and health. Background Chinese nurses have many night shifts; the effect of it regarding nurses' sleep quality and health is still not being explored. Methods This was a cross‐sectional study. There were 3,206 nurse participants. The participants self‐completed a sociodemographic questionnaire, the Pittsburgh Sleep Quality Index (PSQI) and the Cornell Medical Index (CMI). Results Night shift nurses demonstrated relatively worse sleep quality (55.1%) and more health problems (20.7%). Night shift work was significantly associated with poor sleep quality (β = 0.96, confidence interval [CI] = 0.67–1.26) and poor health (β = 2.01, CI = 0.15–3.88). Except for sleep medication (β = 0.02, CI = −0.01, 0.05) and psychological health (β = 0.38, CI = −0.27, 1.03), night shift work was significantly associated with other PSQI domains and physical health. Conclusion Night shift work was a risk factor for nurses' sleep quality and health. Night shift nurses have more sleep disorders and physical health problems. Implications for Nursing Management Nurse managers should pay attention to the impact of shift work on nurses’ sleep quality and health and reform the rotating shift work system to improve nurses’ occupational health.

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Aim: To test the effectiveness of discharge guidance based on the theoretical framework of the Omaha System on Mainland Chinese patients with angina without interventional treatment. Methods: A randomized controlled trial was conducted on 150 Mainland Chinese patients with angina without interventional treatment between December, 2015 and September, 2016. The participants were randomly allocated to discharge guidance based on the Omaha System or usual care. The participants were assessed with the self-designed Problem Rating Survey Scale, including three dimensions and seven items. The Cronbach's alpha coefficient was 0.81. The 7-item-level content validity index was 0.80-1.00 and the scale-level content validity index was 0.94. Results: The scores of the outcome measures differed significantly between the two groups at all three time points (admission day; 3 days before discharge; discharge day) and increased gradually. Improvements in knowledge, behavior , and the total score of the intervention group were significantly higher than those of the control group. An improvement in status did not differ significantly. Conclusion: The Omaha System-based discharge guidance is effective at enhancing knowledge and behavior in patients from Mainland China with angina without interventional treatment.