Machine and deep learning-based clinical characteristics and laboratory markers for the prediction of sarcopenia

Background:Sarcopenia is an age-related progressive skeletal muscle disorder involving the loss of muscle mass or strength and physiological function.Efficient and precise AI algorithms may play a significant role in the diagnosis of sarcopenia.In this study,we aimed to develop a machine learning model for sarcopenia diagnosis using clinical characteristics and laboratory indicators of aging cohorts.Methods:We developed models of sarcopenia using the baseline data from the West China Health and Aging Trend(WCHAT)study.For external validation,we used the Xiamen Aging Trend(XMAT)cohort.We compared the support vector machine(SVM),random forest(RF),eXtreme Gradient Boosting(XGB),and Wide and Deep(W&D)models.The area under the receiver operating curve(AUC)and accuracy(ACC)were used to evaluate the diagnostic efficiency of the models.Results:The WCHAT cohort,which included a total of 4057 participants for the training and testing datasets,and the XMAT cohort,which consisted of 553 participants for the external validation dataset,were enrolled in this study.Among the four models,W&D had the best performance(AUC=0.916±0.006,ACC=0.882±0.006),followed by SVM(AUC=0.907±0.004,ACC=0.877±0.006),XGB(AUC=0.877±0.005,ACC=0.868±0.005),and RF(AUC=0.843±0.031,ACC=0.836±0.024)in the training dataset.Meanwhile,in the testing dataset,the diagnostic efficiency of the models from large to small was W&D(AUC=0.881,ACC=0.862),XGB(AUC=0.858,ACC=0.861),RF(AUC=0.843,ACC=0.836),and SVM(AUC=0.829,ACC=0.857).In the external validation dataset,the performance of W&D(AUC=0.970,ACC=0.911)was the best among the four models,followed by RF(AUC=0.830,ACC=0.769),SVM(AUC=0.766,ACC=0.738),and XGB(AUC=0.722,ACC=0.749).Conclusions:The W&D model not only had excellent diagnostic performance for sarcopenia but also showed good economic efficiency and timeliness.It could be widely used in primary health care institutions or developing areas with an aging population.Trial Registration:Chictr.org,ChiCTR 1800018895.

Pseudomonas aeruginosa regulator PvrA binds simultaneously to multiple pseudo-palindromic sites for efficient transcription activation

Tetracycline repressor(TetR)family regulators(TFRs)are the largest group of DNA-binding transcription factors and are widely distributed in bacteria and archaea.TFRs play vital roles in controlling the expression of various genes and regulating diverse physiological processes.Recently,a TFR protein Pseudomonas virulence regulator A(PvrA),was identified from Pseudomonas aeruginosa as the transcriptional activator of genes involved in fatty acid utilization and bacterial virulence.Here,we show that PvrA can simultaneously bind to multiple pseudo-palindromic sites and upregulate the expression levels of target genes.Cryo-electron microscopy(cryo-EM)analysis indicates the simultaneous DNA recognition mechanism of PvrA and suggests that the bound DNA fragments consist of a distorted B-DNA double helix.The crystal structure and functional analysis of PvrA reveal a hinge region that secures the correct domain motion for recognition of the promiscuous promoter.Additionally,our results showed that mutations disrupting the regulatory hinge region have differential effects on biofilm formation and pyocyanin biosynthesis,resulting in attenuated bacterial virulence.Collectively,these findings will improve the understanding of the relationship between the structure and function of the TetR family and provide new insights into the mechanism of regulation of P.aeruginosa virulence.

SARS-CoV-2 impairs the disassembly of stress granules and promotes ALS-associated amyloid aggregation

The nucleocapsid(N)protein of SARS-CoV-2 has been reported to have a high ability of liquid-liquid phase separation,which enables its incorporation into stress granules(SGs)of host cells.However,whether SG invasion by N protein occurs in the scenario of SARS-CoV-2 infection is unknow,neither do we know its con-sequence.Here,we used SARS-CoV-2 to infect mam-malian cells and observed the incorporation of N protein into SGs,which resulted in markedly impaired self-dis-assembly but stimulated cell cellular clearance of SGs.NMR experiments further showed that N protein binds to the SG-related amyloid proteins via non-specific tran-sient interactions,which not only expedites the phase transition of these proteins to aberrant amyloid aggre-gation in vitro,but also promotes the aggregation of FUS with ALS-associated P525L mutation in cells.In addition,we found that ACE2 is not necessary for the infection of SARS-CoV-2 to mammalian cells.Our work indicates that SARS-CoV-2 infection can impair the dis-assembly of host SGs and promote the aggregation of SG-related amyloid proteins,which may lead to an increased risk of neurodegeneration.

Investigating association between gut microbiota and sarcopenia-related traits:a Mendelian randomization study

Background Observational studies have indicated a potential link between gut microbiota and sarcopenia.However,the underlying mechanisms and a causal relationship have not been established.Thus,the objective of this study is to examine the possible causal association between gut microbiota and sarcopenia-related traits,including low hand-grip strength and appendicular lean mass(ALM),to shed light on the gut–muscle axis.Methods To investigate the potential impact of gut microbiota on low hand-grip strength and ALM,we utilized a two-sample Mendelian randomization(MR)approach.Summary statistics were obtained from genome-wide association studies of gut microbiota,low hand-grip strength,and ALM.The primary MR analysis employed the random-effects inverse-variance weighted(IVW)method.To assess the robustness,we conducted sensitivity analyses using the MR pleiotropy residual sum and outlier(MR-PRESSO)test to detect and correct for horizontal pleiotropy,as well as the MR-Egger intercept test and leave-one-out analysis.Results Alcaligenaceae,Family XIII,and Paraprevotella were positively associated with the risk of low hand-grip strength(P-values<0.05).Streptococcaceae were negatively associated with low hand-grip strength(P-values<0.05).Eight bacterial taxa(Actinomycetales,Actinomycetaceae,Bacteroidaceae,Porphyromonadaceae,Prevotellaceae,Bacteroides,Marvinbryantia,and Phascolarctobacterium)were associated with a higher risk of ALM(P-values<0.05).Eubacterium fissicatena group was negatively associated with ALM(P-values<0.05).Conclusion We found several gut microbiota components causally associated with sarcopenia-related traits.Our findings provided insights into novel strategies for the prevention and treatment of sarcopenia through the regulation of the gut microbiota,contributing to a better understanding of the gut–muscle axis.

Cryo-EM structure of the nucleocapsid-like assembly of respiratory syncytial virus

Respiratory syncytial virus(RSV)is a nonsegmented,negative strand RNA virus that has caused severe lower respiratory tract infections of high mortality rates in infants and the elderly,yet no effective vaccine or antiviral therapy is available.The RSV genome encodes the nucleoprotein(N)that forms helical assembly to encapsulate and protect the RNA genome from degradation,and to serve as a template for transcription and replication.Previous crystal structure revealed a decameric ring architecture of N in complex with the cellular RNA(N-RNA)of 70 nucleotides(70-nt),whereas cryo-ET reconstruction revealed a low-resolution left-handed filament,in which the crystal monomer structure was docked with the helical symmetry applied to simulate a nucleocapsid-like assembly of RSV.However,the molecular details of RSV nucleocapsid assembly remain unknown,which continue to limit our complete understanding of the critical interactions involved in the nucleocapsid and antiviral development that may target this essential process during the viral life cycle.Here we resolve the near-atomic cryo-EM structure of RSV N-RNA that represents roughly one turn of the helical assembly that unveils critical interaction interfaces of RSV nucleocapsid and may facilitate development of RSV antiviral therapy.

Cryo-EM advances in RNA structure determination

Cryo-electron microscopy(cryo-EM)has emerged as an unprecedented tool to resolve protein structures at atomic resolution.Structural insights of biological samples not accessible by conventional X-ray crystallography and NMR can be explored with cryo-EM because measurements are carried out under near-native crystal-free conditions,and large protein complexes with conformational and compositional heterogeneity are readily resolved.RNA has remained underexplored in cryo-EM,despite its essential role in various biological processes.This review highlights current challenges and recent progress in using cryo-EM singleparticle analysis to determine protein-free RNA structures,enabled by improvement in sample preparation and integration of multiple structural and biochemical methods.