Diet and lifestyle behaviours simultaneously act on frailty: it is time to move the threshold of frailty prevention and control forward.

BACKGROUND: To analyse the association among the simultaneous effects of dietary intake, daily life behavioural factors, and frailty outcomes in older Chinese women, we predicted the probability of maintaining physical robustness under a combination of different variables. METHODS: The Fried frailty criterion was used to determine the three groups of "frailty", "pre-frailty", and "robust", and a national epidemiological survey was performed. The three-classification decision tree model was fitted, and the comprehensive performance of the model was evaluated to predict the probability of occurrence of different outcomes. RESULTS: Among the 1,044 participants, 15.9% were frailty and 50.29% were pre-frailty; the overall prevalence first increased and then decreased with age, reaching a peak at 70-74 years of age. Through univariate analysis, filtering, and embedded screening, eight significant variables were identified: staple food, spices, exercise (frequency, intensity, and time), work frequency, self-feeling, and family emotions. In the three-classification decision tree, the values of each evaluation index of Model 3 were relatively average; the accuracy, recall, specificity, precision, and F1 score range were between 75% and 84%, and the AUC was also greater than 0.800, indicating excellent performance and the best interpretability of the results. Model 3 takes exercise time as the root node and contains 6 variables and 10 types, suggesting the impact of the comprehensive effect of these variables on robust and non-robust populations (the predicted probability range is 6.67-93.33%). CONCLUSION: The combined effect of these factors (no exercise or less than 0.5 h of exercise per day, occasional exercise, exercise at low intensity, feeling more tired at work, and eating too many staple foods (> 450 g per day) are more detrimental to maintaining robustness.

Mast cell activation may contribute to adverse health transitions in COVID-19 patients with frailty.

A prominent aspect of the post-coronavirus disease-2019 (post-COVID-19) era is long-COVID. Therefore, precise patient classification and exploration of the corresponding factors affecting long-COVID are crucial for tailored treatment strategies. Frailty is a common age-related clinical syndrome characterized by deteriorated physiological functions of multiple organ systems, which increases susceptibility to stressors. Herein, we performed an inclusion and exclusion analysis (definite COVID-19 infection diagnosis, clear underlying disease information, ≥60 years old, and repeated sampling of clinical cases) of 10,613 blood samples and identified frailty cases for further investigation. RNA-Seq data were used for differential gene expression and functional and pathway analyses. The results revealed that patients with frailty were more prone to poor health conversions and more sequelae, and the blood transcriptome had obvious disturbances in pathways associated with immune regulation, metabolism, and stress response. These adverse health transitions were significantly associated with mast cell activation. Additionally, NCAPG, MCM10, and CDC25C were identified as hub genes in the peripheral blood differential gene cluster, which could be used as diagnostic markers of poor health conversion. Our results indicate that healthcare measures should be prioritized to mitigate adverse health outcomes in this vulnerable patient group, COVID-19 patients with frailty, in post-COVID era.

Collective and Individual Assessment of the Risk of Death from COVID-19 for the Elderly, 2020-2022.

Introduction: Coronavirus disease 2019 (COVID-19) has had profound disruptions worldwide. For a population or individual, it is critical to assess the risk of death for making preventative decisions. Methods: In this study, clinical data from approximately 100 million cases were statistically analyzed. A software and an online assessment tool were developed in Python to evaluate the risk of mortality. Results: Our analysis revealed that 76.51% of COVID-19-related fatalities occurred among individuals aged over 65 years, with frailty-associated deaths accounting for more than 80% of these cases. Furthermore, over 80% of the reported deaths involved unvaccinated individuals. A notable overlap was observed between aging and frailty-associated deaths, both of which were connected to underlying health conditions. For those with at least two comorbidities, the proportion of frailty and the proportion of COVID-19-related death were both close to 75 percent. Subsequently, we established a formula to calculate the number of deaths, which was validated using data from twenty countries and regions. Using this formula, we developed and verified an intelligent software designed to predict the death risk for a given population. To facilitate rapid risk screening on an individual level, we also introduced a six-question online assessment tool. Conclusions: This study examined the impact of underlying diseases, frailty, age, and vaccination history on COVID-19-related mortality, resulting in a sophisticated software and a user-friendly online scale to assess mortality risk. These tools offer valuable assistance in informed decision-making.

DNA/RNA helicase DHX36 is required for late stages of spermatogenesis.

Spermatogenesis is a highly complex developmental process that typically consists of mitosis, meiosis, and spermiogenesis. DNA/RNA helicase DHX36, a unique guanine-quadruplex (G4) resolvase, plays crucial roles in a variety of biological processes. We previously showed that DHX36 is highly expressed in male germ cells with the highest level in zygotene spermatocytes. Here, we deleted Dhx36 in advanced germ cells with Stra8-GFPCre and found that a Dhx36 deficiency in the differentiated spermatogonia leads to meiotic defects and abnormal spermiogenesis. These defects in late stages of spermatogenesis arise from dysregulated transcription of G4-harboring genes, which are required for meiosis. Thus, this study reveals that Dhx36 plays crucial roles in late stages of spermatogenesis.

Exploring the causal relationship between inflammatory bowel disease and sarcopenia-related traits: a two-sample Mendelian randomization analysis.

Previous observational studies have shown an association between inflammatory bowel disease (IBD) and sarcopenia. However, the causal relationship between IBD (including ulcerative colitis and Crohn's disease) and sarcopenia remains unclear. Thus, this study investigated whether genetically predicted IBD play a function in the occurrence of sarcopenia using Mendelian randomization (MR) analysis. This study used independent single nucleotide polymorphisms (SNPs) significantly associated with IBD as instrument variables (IVs). Sarcopenia-related components (hand grip strength, walking space, and appendicular lean mass (ALM)) were investigated as outcome factors, with summary-level data regarding these components of sarcopenia obtained from the UK Biobank. The IVW-MR analysis revealed that there were significant negative associations between IBD and hand grip strength (both left and right) as well as ALM. Besides, the results of IVW-MR analysis provided strong evidence of a causal relationship between genetically predicted Crohn's disease and hand grip strength and ALM. However, there were no significant associations found between ulcerative colitis and sarcopenia-related traits. Sensitivity tests confirmed the accuracy and robustness of the above MR analysis. Conclusions: Our MR analysis showed the causal effect of Crohn's disease on hand grip strength and ALM. This suggests that Crohn's disease may be a potential risk factor for sarcopenia.

Asymptomatic Transmissibility Calls for Implementing a Zero-COVID Strategy to End the Current Global Crisis.

The coronavirus disease 2019 (COVID-19) pandemic has led to unprecedented global challenges. A zero-COVID strategy is needed to end the crisis, but there is a lack of biological evidence. In the present study, we collected available data on SARS, MERS, and COVID-19 to perform a comprehensive comparative analysis and visualization. The study results revealed that the fatality rate of COVID-19 is low, whereas its death toll is high compared to SARS and MERS. Moreover, COVID-19 had a higher asymptomatic rate. In particular, COVID-19 exhibited unique asymptomatic transmissibility. Further, we developed a foolproof operating software in Python language to simulate COVID-19 spread in Wuhan, showing that the cumulative cases of existing asymptomatic spread would be over 100 times higher than that of only symptomatic spread. This confirmed the essential role of asymptomatic transmissibility in the uncontrolled global spread of COVID-19, which enables the necessity of implementing the zero-COVID policy. In conclusion, we revealed the triggering role of the asymptomatic transmissibility of COVID-19 in this unprecedented global crisis, which offers support to the zero-COVID strategy against the recurring COVID-19 spread.

Development and validation of a novel diagnostic model for musculoskeletal aging (sarcopenia) based on cuproptosis-related genes associated with immunity.

OBJECTIVE: Sarcopenia is a geriatric disease characterized by accelerated skeletal muscle mass and function loss due to aging. Cell death plays a pivotal role in the onset and progress of sarcopenia. The purpose of this study was to investigate the role of cuproptosis-related genes (CRGs) and immune infiltration in sarcopenia development. METHODS: Three microarray expression datasets from the Gene Expression Omnibus (GEO) database were merged and batch-corrected by R software to identify differentially expressed genes (DEGs) between old and young skeletal muscles. Subsequently, DEGs were subjected to functional enrichment and gene set enrichment analysis (GSEA) to investigate the roles of DEGs and immune infiltration in the pathogenesis of musculoskeletal aging. Then, ssGSEA was performed to calculate the proportion of immune cells and functions within each muscle sample to analyze the differences between the older and young healthy muscle groups. In order to select candidate CRGs, the correlation between CRGs and immune infiltration was analyzed. Finally, a novel nomogram model of musculoskeletal aging was constructed based on candidate CRGs associated with immunity. Additionally, the diagnostic model based on key CRGs was tested using a validation dataset, and its diagnostic performance was evaluated by the area under curve (AUC) value. RESULTS: 141 DEGs were identified between 45 older samples and 50 young healthy samples. Compared to young healthy muscle tissues, significantly lower infiltration levels of T-regulatory cells were identified in older muscle tissues, while dendritic cells (DCs) and mast cells were relatively higher. Based on the CRGs from seven candidates, a novel model with high prediction efficiency (AUC = 0.856) was established to diagnose and screen for sarcopenia. CONCLUSION: The CRGs associated with immunity may play a vital role in the development of musculoskeletal aging, providing a novel avenue for early diagnosis. Furthermore, immune cell infiltration is essential for the progression of musculoskeletal aging.

K-SEIR-Sim: A simple customized software for simulating the spread of infectious diseases.

Infectious disease is a great enemy of humankind. The ravages of COVID-19 are leading to profound crises across the world. There is an urgent requirement for analyzing the current pandemic situation, predicting trends over time, and assessing the effectiveness of containment measures. Thus, numerous statistical models, primarily based on the susceptible-exposed-infected-recovered or removed (SEIR) model, have been established. However, these models are highly technical, which are difficult for the public and governing bodies to understand and use. To address this issue, we developed a simple operating software based on our improved K-SEIR model termed as the kernelkernel SEIR simulator (K-SEIR-Sim). This software includes natural propagation parameters, containment measure parameters, and certain characteristic parameters that can deduce the effects of natural propagation and containment measures. Further, the applicability of the proposed software was demonstrated using the example of the COVID-19 outbreak in the United States and the city of Wuhan, China. Operating results verified the potency of the proposed software in evaluating the epidemic situation and human intervention during COVID-19. Importantly, the software can perform real-time, backward-looking, and forward-looking analysis by functioning in data-driven and model-driven ways. All of them have considerable practical values in their applications according to the actual needs of personal use. Conclusively, K-SEIR-Sim is the first simple customized operating software that is highly valuable for the global fight against COVID-19 and other infectious diseases.

Rediscovery of Caffeine: An Excellent Drug for Improving Patient Outcomes while Fighting WARS.

The COVID-19 (here specifically called Worldwide Acute Respiratory Syndrome, WARS) pandemic is surging worldwide. Unfortunately, no specific drug meets the urgent need to fight this pandemic, leading to thousands of deaths. The theory of host-directed therapies (HDTs) is viewed as the ideal means to rephrase the treatment of infectious diseases. However, related drugs based on this theory have not been identified. Previously, we realized that caffeine is the ligand of type 2 taste receptors (TAS2Rs), which play a critical role in host defense. Here, we gathered data on caffeine acting as an immunomodulator. Unexpectedly, we found that caffeine can fight WARS by acting on multiple organs, which may prevent the virus from entering the cell, stimulate the phagocytosis of macrophages, enhance breathing, and inhibit the cytokine storm. Thus, the immunoprotective effects of caffeine can improve the therapeutic outcomes in patients infected with coronavirus. Collectively, we report that caffeine, an FDA-approved, highly safe, inexpensive, and widely available drug, could be an excellent HDT for battling WARS.

Existing bitter medicines for fighting 2019-nCoV-associated infectious diseases.

The sudden outbreak of COVID-19 has led to more than seven thousand deaths. Unfortunately, there are no specific drugs available to cure this disease. Type 2 taste receptors (TAS2Rs) may play an important role in host defense mechanisms. Based on the idea of host-directed therapy (HDT), we performed a negative co-expression analysis using big data of 60 000 Affymetrix expression arrays and 5000 TCGA data sets to determine the functions of TAS2R10, which can be activated by numerous bitter substances. Excitingly, we found that the main functions of TAS2R10 involved controlling infectious diseases caused by bacteria, viruses, and parasites, suggesting that TAS2R10 is a key trigger of host defense pathways. To quickly guide the clinical treatment of 2019-nCoV, we searched currently available drugs that are agonists of TAS2Rs. We identified many cheap, available, and safe medicines, such as diphenidol, quinine, chloroquine, artemisinin, chlorpheniramine, yohimbine, and dextromethorphan, which may target the most common symptoms caused by 2019-nCoV. We suggest that a cocktail-like recipe of existing bitter drugs may help doctors to fight this catastrophic disease and that the general public may drink or eat bitter substances, such as coffee, tea, or bitter vegetables, to reduce the risk of infection.

Systematic prediction of the biological functions of TAS2R10 using positive co-expression analysis.

Type 2 taste receptor 10 (TAS2R10), belonging to the TAS2R family of bitter receptors, is widely expressed in extra-oral tissues. However, its biological roles beyond bitterness sensing in the tongue have remained largely elusive. The present study aimed to perform a positive co-expression analysis using 60,000 Affymetrix expression arrays and 5,000 The Cancer Genome Atlas datasets to uncover such roles. Based on the functional enrichment analysis, it was indicated that in the Gene Ontology (GO) category biological process, TAS2R10 was mostly involved in 'cellular protein metabolic process', 'protein modification process', 'cellular protein modification process' and 'cellular component assembly'. In the GO category cellular component, the co-expressed genes were accumulated in 'Spt-Ada-Gcn5 acetyltransferase (SAGA)-type complex' and 'SAGA complex', and in the category molecular function, they were concentrated in 'hexosaminidase activity', 'cytoskeletal adaptor activity', 'cyclin binding' and 'ß-N-acetylhexosaminidase activity'. Of note, it was indicated that TAS2R10 may be involved in 'ubiquitin-mediated proteolysis', which may provide a starting point to fully investigate the detailed functions of TAS2R10 in the future. TAS2R10 was also indicated to be associated with human diseases, i.e. 'Salmonella infection'. Overall, the present study was the first to perform a comprehensive bioinformatics analysis of the functions of TAS2R10 and provide insight regarding the notion that this gene may have crucial roles beyond bitterness sensing.

DICER1 regulates antibacterial function of epididymis by modulating transcription of ß-defensins.

DICER1 is a key enzyme responsible for the maturation of microRNAs. Recent evidences suggested that DICER1 and microRNAs expressed in epididymis were involved in the control of male fertility. However, the exact mechanism remains to be elucidated. Here, we created a mouse line by targeted disruption of Dicer1 gene in the principal cells of distal caput epididymis. Our data indicated that a set of ß-defensin genes were downregulated by DICER1 rather than by microRNAs. Moreover, DICER1 was significantly enriched in the promoter of ß-defensin gene and controlled transcription. Besides, the antibacterial ability of the adult epididymis significantly declined upon Dicer1 deletion both in vitro and in vivo. And a higher incidence of reproductive defect was observed in middle-aged Dicer1-/- males. These results suggest that DICER1 plays an important role in transcription of ß-defensin genes, which are associated with the natural antibacterial properties in a microRNA-independent manner, and further impacts the male fertility.

CRISPR/Cas9-mediated genome editing reveals the synergistic effects of ß-defensin family members on sperm maturation in rat epididymis.

The epididymis is a male reproductive organ involved in posttesticular sperm maturation and storage, but the mechanism underlying sperm maturation remains unclear. ß-Defensins (Defbs) belong to a family of small, cysteine-rich, cationic peptides that are antimicrobial and modulate the immune response. A large number of Defb genes are expressed abundantly in the male reproductive tract, especially in the epididymis. We and other groups have shown the involvement of several Defb genes in regulation of sperm function. In this study, we found that Defb23, Defb26, and Defb42 were highly expressed in specific regions of the epididymis. Rats with CRISPR/Cas9-mediated single-gene disruption of Defb23, Defb26, or Defb42 had no obvious fertility phenotypes. Those with the deletion of Defb23/ 26 or Defb23/ 26/ 42 became subfertile, and sperm isolated from the epididymal cauda of multiple-mutant rats were demonstrated decreased motility. Meanwhile, the sperm showed precocious capacitation and increased spontaneous acrosome reaction. Consistent with premature capacitation and acrosome reaction, sperm from multiple-gene-knockout rats had significantly increased intracellular calcium. These results suggest that Defb family members affect sperm maturation by a synergistic pattern in the epididymis.-Zhang, C., Zhou, Y., Xie, S., Yin, Q., Tang, C., Ni, Z., Fei, J., Zhang, Y. CRISPR/Cas9-mediated genome editing reveals the synergistic effects of ß-defensin family members on sperm maturation in rat epididymis.

Emerging roles for PIWI proteins in cancer.

It is generally accepted that PIWI proteins are predominately expressed in the germline but absent in somatic tissues. Their best-characterized role is to suppress transposon expression, which ensures genomic stability in the germline. However, increasing evidence has suggested that PIWI proteins are linked to the hallmarks of cancer defined by Weinberg and Hanahan, such as cell proliferation, anti-apoptosis, genomic instability, invasion and metastasis. This provides new possibilities for anticancer therapies through the targeting of PIWI proteins, which may have fewer side effects due to their potential classification as a CTA (cancer/testis antigen). Furthermore, PIWI has been proposed to act as a diagnostic and prognostic marker for many types of cancer, and even to differentiate early- and late-stage cancers. We herein summarize the latest progress in this exciting field, hoping to encourage new investigations of PIWIs in cancer biology that will help to develop new therapeutics for clinical application.