Background: Chronic obstructive pulmonary disease (COPD) is prevalent in China. The role of body mass index (BMI) in COPD progression and prognosis is unclear. We analyzed the association between BMI and pulmonary function, inflammation levels and exacerbation in Chinese COPD patients. Methods: Our retrospective real world research included 744 patients with COPD diagnosed by spirometry and hospitalized from January 1st, 2014 to December 31st, 2016. The indicators were gathered from hospital records database and frequency of exacerbation in the three years were followed up. All 744 patients were divided into four groups by BMI grades. We analyzed the association between BMI and pulmonary function, inflammation levels and exacerbation by Spearman bivariate correlations, Kruskal-Wallis test, Mann-Whitney U test and logistic regression. Results: The singly proportion (median of BMI) of these patients in underweight, normal weight, overweight and obesity was 7.80% (17.54), 45.97% (22.12), 27.96% (27.00) and 18.28% (31.25) respectively. With increasing of BMI grades, the values of forced expiratory volume in 1 second (FEV₁), peak expiratory flow (PEF), forced expiratory flow (FEF25/50/75) and diffusing capacity of carbon monoxide (DLCO) were correspondingly increasing; the percentage of neutrophils and C-reactive protein (CRP) presented significant declining trend while the trend of the percentage of eosinophils was negative; the dose of systemic corticosteroid and length of stay present decreasing tendency; the frequency of exacerbation and hospitalization were decreasing. These were similar results in gender, smoking status COPD subgroups. Conclusions: In our study, BMI was moderately correlated with pulmonary function positively and exacerbations negatively. To some extent, BMI might be a useful indicator to predict the prognosis of COPD patients and for long-term management.

Background: Mitochondrial dysfunction is an important pathogenic event in acute kidney injury (AKI). GCN5L1 is a specific acetyltransferase in mitochondria, which regulates glucose and fatty acid metabolism. However, the role of GCN5L1 in mitochondrial dysfunction and the pathogenesis of ischemic AKI are not fully understood. Methods: The protein level of GCN5L1 was detected by western blot assay. Acetylated proteomics was used to explore the level of acetylated TFAM. Duolink proximity ligation assay and co-immunoprecipitation were used to detect the interaction of TFAM and translocase of outer membrane 70 (TOM70). mtDNA copy number, the expression of mitochondrial electron transport chain complexes, the number and morphology of mitochondria were measured. The renal injury of AKI mice was reflected by the levels of creatinine and urea nitrogen and the pathological changes of renal tissue. Results: We showed that GCN5L1 was highly expressed in vivo and in vitro and renal tubules specific knockdown of GCN5L1 could effectively attenuate AKI-induced mitochondrial impairment. Besides, acetylated proteomics revealed that acetylated TFAM was significantly upregulated in AKI mice kidney, which reminded us that TFAM might be an acetylating substrate of GCN5L1. Mechanistically, we evidenced that GCN5L1 could acetylate TFAM at its K76 site and subsequently inhibited its binding to TOM70, thereby reducing TFAM import into mitochondria and mitochondrial biogenesis. Clinically, GCN5L1 and acetylated TFAM were positively correlated with disease severity (all p < 0.05). Conclusions: In sum, these data demonstrated an unrecognized regulating mechanism of GCN5L1 on TFAM acetylation and its intracellular trafficking, and a potential intervening target for AKI associated mitochondrial disorders as well.

In response to the escalating antibiotic resistance in multidrug-resistant pathogens, we propose an innovative phagemid-based capsid system to generate CRISPR-Cas13a-loaded antibacterial capsids (AB-capsids) for targeted therapy against multidrug-resistant Staphylococcus aureus. Our optimized phagemid system maximizes AB-capsid yield and purity, showing a positive correlation with phagemid copy number. Notably, an 8.65-fold increase in copy number results in a 2.54-fold rise in AB-capsid generation. Phagemids carrying terL-terS-rinA-rinB (prophage-encoded packaging site genes) consistently exhibit high packaging efficiency, and the generation of AB-capsids using lysogenized hosts with terL-terS deletion resulted in comparatively lower level of wild-type phage contamination, with minimal compromise on AB-capsid yield. These generated AB-capsids selectively eliminate S. aureus strains carrying the target gene while sparing non-target strains. In conclusion, our phagemid-based capsid system stands as a promising avenue for developing sequence-specific bactericidal agents, offering a streamlined approach to combat antibiotic-resistant pathogens within the constraints of efficient production and targeted efficacy.

Background: Metabolic reprogramming plays a pivotal role in tumorigenesis and development of lung adenocarcinoma (LUAD). However, the precise mechanisms and potential targets for metabolic reprogramming in LUAD remain elusive. Our prior investigations revealed that the mitochondrial ribosomal protein MRPL12, identified as a novel mitochondrial transcriptional regulatory gene, exerts a critical influence on mitochondrial metabolism. Despite this, the role and regulatory mechanisms underlying MRPL12’s transcriptional activity in cancers remain unexplored. Methods: Human LUAD tissues, Tp53^fl/fl;Kras^G12D-driven LUAD mouse models, LUAD patient-derived organoids (PDO), and LUAD cell lines were used to explored the expression and function of MRPL12. The posttranslational modification of MRPL12 was analyzed by mass spectrometry, and the oncogenic role of key phosphorylation sites of MRPL12 in LUAD development was verified in vivo and in vitro. Results: MRPL12 was upregulated in human LUAD tissues, Tp53^fl/fl;Kras^G12D-driven LUAD tissues in mice, LUAD PDO, and LUAD cell lines, correlating with poor patient survival. Overexpression of MRPL12 significantly promoted LUAD tumorigenesis, metastasis, and PDO formation, while MRPL12 knockdown elicited the opposite phenotype. Additionally, MRPL12 deletion in a Tp53^fl/fl;Kras^G12D-driven mouse LUAD model conferred a notable survival advantage, delaying tumor onset and reducing malignant progression. Mechanistically, we discovered that MRPL12 promotes tumor progression by upregulating mitochondrial oxidative phosphorylation. Furthermore, we identified UBASH3B as a specific binder of MRPL12, dephosphorylating tyrosine 60 in MRPL12 (MRPL12 Y60) and inhibiting its oncogenic functions. The decrease in MRPL12 Y60 phosphorylation impeded the binding of MRPL12 to POLRMT, downregulating mitochondrial metabolism in LUAD cells. In-depth in vivo, in vitro, and organoid models validated the inhibitory effect of MRPL12 Y60 mutation on LUAD. Conclusion: This study establishes MRPL12 as a novel oncogene in LUAD, contributing to LUAD pathogenesis by orchestrating mitochondrial metabolism reprogramming towards oxidative phosphorylation (OXPHOS). Furthermore, it confirms Y60 as a specific phosphorylation modification site regulating MRPL12’s oncogenic functions, offering insights for the development of LUAD-specific targeted drugs and clinical interventions. Graphical

Acute kidney injury (AKI) is a serious disease with no effective treatment. Abnormal opening of mitochondrial permeability transition pore (MPTP) is an important pathological process in ischemia reperfusion injury (IRI), the key factor of AKI. It is essential to elucidate MPTP regulation mechanism. Here, we identified mitochondrial ribosomal protein L7/L12 (MRPL12) specifically binds to adenosine nucleotide translocase 3 (ANT3) under normal physiological conditions, stabilizes MPTP and maintains mitochondrial membrane homeostasis in renal tubular epithelial cells (TECs). During AKI, MRPL12 expression was significantly decreased in TECs, and MRPL12-ANT3 interaction was reduced, leading to ANT3 conformation change, MPTP abnormal opening, and cell apoptosis. Importantly, MRPL12 overexpression protected TECs from MPTP abnormal opening and apoptosis during hypoxia/reoxygenation (H/R). Our results suggest MRPL12-ANT3 axis involves in AKI by regulating MPTP, and MRPL12 could be potential intervention target for treatment of AKI.