A STAT3 palmitoylation cycle promotes TH17 differentiation and colitis.

Cysteine palmitoylation (S-palmitoylation) is a reversible post-translational modification that is installed by the DHHC family of palmitoyltransferases and is reversed by several acyl protein thioesterases1,2. Although thousands of human proteins are known to undergo S-palmitoylation, how this modification is regulated to modulate specific biological functions is poorly understood. Here we report that the key T helper 17 (TH17) cell differentiation stimulator, STAT33,4, is subject to reversible S-palmitoylation on cysteine 108. DHHC7 palmitoylates STAT3 and promotes its membrane recruitment and phosphorylation. Acyl protein thioesterase 2 (APT2, also known as LYPLA2) depalmitoylates phosphorylated STAT3 (p-STAT3) and enables it to translocate to the nucleus. This palmitoylation-depalmitoylation cycle enhances STAT3 activation and promotes TH17 cell differentiation; perturbation of either palmitoylation or depalmitoylation negatively affects TH17 cell differentiation. Overactivation of TH17 cells is associated with several inflammatory diseases, including inflammatory bowel disease (IBD). In a mouse model, pharmacological inhibition of APT2 or knockout of Zdhhc7-which encodes DHHC7-relieves the symptoms of IBD. Our study reveals not only a potential therapeutic strategy for the treatment of IBD but also a model through which S-palmitoylation regulates cell signalling, which might be broadly applicable for understanding the signalling functions of numerous S-palmitoylation events.

The prevalence and associated factors of motoric cognitive risk syndrome in multiple ethnic middle-aged to older adults in west China: a cross-sectional study.

BACKGROUND AND PURPOSE: Motoric cognitive risk (MCR) syndrome characterized by subjective cognitive complaints and slow gait has been proposed and validated as a pre-dementia syndrome. The overall and specific ethnic prevalence of MCR and the associated factors are poorly understood in middle-aged to older community-dwelling residents in west China. METHODS: The present study included 6091 samples from the prospective cohort study, West China Health and Aging Trend (WCHAT). Multidimensional factors of demography, lifestyle, social support, anthropometrics and body components, and clinical status were investigated and analyzed by univariate and multivariate logistic regression models. Lasso regression and K-fold cross-validation were conducted to construct the most predictive model with fitted factors. RESULTS: The overall prevalence of MCR was 9.74%, and ethnically the prevalence was 14.25% in Tibetan, 11.03% in Yi, 10.72% in Han, 5.18% in Uighur and 4.55% in Qiang, respectively. In the adjusted models, the positively associated risk factors included diabetes mellitus (odds ratio [OR] = 1.51, p = 0.007), osteoarthritis (OR = 1.50, p = 0.002), depression (OR = 1.36, p = 0.005), poor sleep (OR = 1.21, p = 0.045), comorbidity (OR = 1.49, p = 0.001) and falls in the last 12 months (OR = 1.34, p = 0.031). Of note, every 1-unit increase of value in stroke was associated with an approximate 3-fold higher risk of having MCR, whilst in high-density lipoprotein with a 30% lower risk of MCR,respectively. CONCLUSIONS: Profiles of MCR from the aspects of ethnicity and the presenium stage need further exploration. It is a promising strategy to apply MCR as a primary prevention tool to prevent dementia.

Potential association between frailty and pTau in community-dwelling older adults.

BACKGROUND: Frailty is a geriatric syndrome characterized by a decline in physiological reserves, and multiple factors contribute to the occurrence and development of frailty. Growing evidence supports a strong link and overlap between frailty and cognitive impairment, but the mechanisms involved have not yet been fully elucidated. AIM: To identify associations between 12 plasma cognition-related biomarkers and frailty in community-dwelling older adults. METHODS: A total of 375 participants (age 70.9 ± 5.8, 165 men and 210 women) were included in this study. Frailty was assessed using the modified Fried frailty phenotype. Participants were divided into not-frail group (n = 313) and frail group (n = 62). Twelve plasma cognitive biomarkers were detected by enzyme-linked immunosorbent assay (ELISA). Multinomial logistic regression was used to explore the association between different biomarkers and frailty status. RESULTS: Among the 12 biomarkers, only pTau was higher in frail individuals than in their not-frail peers (471.3 ± 58.1 pg/mL vs. 451.9 ± 61.1 pg/mL, p = 0.022). No other biomarkers had any significant association with frailty, including total-Tau (tTau), neurofilament light (NFL), amyloid-ß 40 (Aß40), amyloid-ß 40 (Aß42), S100 calcium binding protein B (S100B), visinin-like protein 1 (VLP-1), Alzheimer-associated neuronal thread protein (AD7cNTP), ß-amyloid precursor protein (ßAPP), chitinase-3-like-1 (CHI3L1), soluble complement receptor 1 (sCR1) and heart-type fatty acid binding protein (hFABP). Furthermore, pTau was compared between negative and positive subject groups for each individual criterion of frailty. Significantly higher levels of pTau were observed in those who were positive for the criteria of low grip strength (451.2 ± 61.4 pg/mL vs. 469.1 ± 57.6 pg/mL, p = 0.019), exhaustion (451.2 ± 61.6 pg/mL vs. 466.4 ± 58.4 pg/mL, p = 0.035) and low physical activity (451.1 ± 60.7 pg/mL vs. 465.7 ± 60.7 pg/mL, p = 0.034) when compared to those who were negative for each corresponding criterion. Finally, in the multivariable-adjusted analysis, the association between pTau and frailty was statistically significantly associated (OR: 1.40, 95% CI: 1.04-1.89), even after adjusting. CONCLUSIONS: The present study found a potential association between pTau and frailty. Future works should monitor the longitudinal trajectory of changes of pTau concentrations in frailty older adults. A better understanding of the molecular mechanisms behind will contribute to biomarker research in frailty.

The Comparison of Sarcopenia Diagnostic Criteria using AWGS 2019 with the Other Five Criteria in West China.

INTRODUCTION: The aim of this study was to investigate the prevalence and associated factors of sarcopenia defined by different criteria in community-dwelling adults of west China using the baseline data of West-China Health and Aging Trend (WCHAT) study. METHODS: Adults aged 50 years or older in communities of Yunnan, Guizhou, Sichuan, and Xinjiang provinces were enrolled in this study. We applied 6 -diagnostic criteria (AWGS 2019, AWGS 2014, EWGSOP1, -EWGSOP2, IWGS, and FNIH) to define sarcopenia. Muscle mass was measured based on bioimpedance analysis. Handgrip strength and walking speed were recorded, respectively. Different variables like anthropometry measures, lifestyles, chronic disease, and blood test were collected. RESULTS: We included 4,500 participants. The prevalence of sarcopenia was 22.8, 19.3, 57.1, 11.8, 24.1, and 18.1% according to the AWGS 2019, AWGS 2014, EWGSOP 1, EWGSOP 2, IWGS, and FNIH criteria, respectively. We found that serum albumin level was independently associated with sarcopenia using AWGS 2019 and IWGS. And vitamin D level was independently associated with sarcopenia using AWGS 2014, -EWGSOP2, and FNIH. While age, depressive status, BMI, hemoglobin, vitamin D, and insulin level were all significantly associated with sarcopenia using AWGS 2014, but all of these factors were not significant using AWGS 2019. CONCLUSIONS: Sarcopenia was highly prevalent in west China regardless of the diagnostic criteria. Serum albumin and vitamin D level were mostly associated with sarcopenia defined by different criteria. While most risk factors associated with the AWGS 2014-defined sarcopenia exhibited no consistent pattern with AWGS 2019, the validity of the AWGS 2019 consensus needs to be confirmed in further prospective studies.

Vitamin D status and obesity markers in older adults: results from West China Health and Aging Trends study.

BACKGROUNDS: Vitamin D deficiency and insufficiency in older adults seems to be common, but the prevalence estimates are lacking in West China. Previous studies suggested that low vitamin D status was associated with obesity. However, most of them evaluated obesity based on body mass index (BMI) and there are no studies at present exploring the association between vitamin D status and different obesity markers. The present study aims to investigate the prevalence of low vitamin D status and evaluate the association between the vitamin D status and different obesity markers among older adults in West China. METHODS: Data was based on the baseline of West China Health and Aging Trends study (WCHAT). All of the participants were older than 60 years old in the present study. Vitamin D status was based on laboratory data, and obesity markers were assessed by bioelectrical impedance analysis (BIA) using the InBody 770 analyzer. Multiple linear regression was performed to find the association between the vitamin D status and various obesity markers. RESULTS: The study included 2661 individuals (mean age: 67.7 ± 6.0 years; males: 41 %). The mean vitamin D level was 18.8 ± 6.3 ng/ml (range: 5 to 59 ng/ml); 5.2 % of participants had a sufficient level of vitamin D, 31.8 % had vitamin D insufficiency, and 63.0 % had vitamin D deficiency. Our results showed that vitamin D status was negatively associated with fat mass index (FMI), visceral fat area (VFA), and waist-hip ratio (WHR) in both sexes. Comparing to other obesity markers, WHR had the strongest correlation with vitamin D status in both sexes (ß = -6.090, P = 0.046 in males; ß = -11.253, P < 0.001 in females). No significant association was found between vitamin D status and BMI in males. CONCLUSION: The prevalence of vitamin D insufficiency and deficiency among older adults in West China was high. Among the older adults in west China, WHR showed stronger association with vitamin D status and was better for the prediction of vitamin D insufficiency or deficiency in both sexes, compared to BMI. TRIAL REGISTRATION: Chinese Clinical Trial Registry: ChiCTR1800018895 .

Long sleep duration is associated with cognitive frailty among older community-dwelling adults: results from West China Health and Aging Trend study.

OBJECTIVE: To investigate the association between sleep duration and cognitive frailty among older adults dwelling in western China. METHODS: We used the baseline data from West China Health and Aging Trend (WCHAT) study. Sleep duration was classified as short sleep duration (< 6 h), normal sleep duration (6-8 h) and long sleep duration (≥ 9 h). Fried frailty criteria and Short Portable Mental Status Questionnaire were used to measure cognitive frailty. Multinomial logistic regression was conducted to estimate odds ratio (OR) and 95% confidence interval (CI). RESULTS: A total of 4093 older adults (age = 67.8 ± 5.9 years, 1708 males and 2385 females) were included in the analysis. The prevalence of cognitive frailty was 11.8% among older adults in western China. Approximately 11.9% participants had short sleep duration (< 6 h); 22.2% had a long sleep duration (≥ 9 h). After adjusting for covariates, only long sleep duration was significantly associated with high risk of cognitive frailty (OR = 2.07, 95%CI = 1.60-2.68, P <  0.001) in western China older adults compared to normal sleep duration. CONCLUSIONS: Long sleep duration was significantly related to cognitive frailty in older adults. Intervention for long sleep duration may be helpful to prevent cognitive frailty. TRIAL REGISTRATION: Chinese Clinical Trial Registry: ChiCTR1800018895 .

Nutritional status mediates the relationship between sarcopenia and cognitive impairment: findings from the WCHAT study.

BACKGROUND: Sarcopenia is associated with cognitive impairment in older adults. However, the underlying mechanisms are not fully understood. AIM: To explore the mediating role of nutritional status in the relationship between sarcopenia and cognitive impairment. METHODS: Three thousand eight hundred and ten participants (mean age 61.94 ± 8.01 years) from the West China Health and Aging Trend (WCHAT) study were included. We defined sarcopenia using the Asian Working Group for Sarcopenia (AWGS) 2019 criteria. Cognitive status and nutritional status were measured using the Short Portable Mental Status Questionnaire (SPMSQ) and the Mini Nutritional Assessment Short Form (MNA-SF). Relationships between sarcopenia, nutritional status, and cognitive function were explored using multiple linear regression. Two mediation models were generated to examine whether nutritional status mediates the association between sarcopenia and cognitive function using PROCESS macro version 3.5. RESULTS: The study involved 3147 (82.6%) non-sarcopenic, 387 (10.2%) sarcopenic, and 276 (7.2%) severely sarcopenic individuals. In mediation model 1, sarcopenia (ß = 0.208, 95% CI 0.072 to 0.344, P = 0.0028) was significantly associated with cognitive impairment, and nutritional status mediated this association (indirect effect = 0.162, bootstrap 95% CI 0.116 to 0.212). Mediation model 2 indicated that nutritional status exhibited a full mediating effect regarding the association between sarcopenia and cognitive impairment (indirect effect = 0.131, bootstrap 95% CI: 0.08 to 0.188; direct effect = 0.046, bootstrap 95% CI - 0.115 to 0.21) and a partial mediating effect regarding the association between severe sarcopenia and cognitive impairment (indirect effect = 0.21, bootstrap 95% CI: 0.143 to 0.283; direct effect = 0.476, bootstrap 95% CI: 0.234-0.724). CONCLUSIONS: The relationship between sarcopenia and cognitive impairment was significantly mediated by nutritional status. Early nutritional interventions may prevent cognitive decline in sarcopenic older adults.

Faecalibacterium prausnitzii produces butyrate to decrease c-Myc-related metabolism and Th17 differentiation by inhibiting histone deacetylase 3.

Decreased levels of Faecalibacterium prausnitzii (F. prausnitzii), whose supernatant plays an anti-inflammatory effect, are frequently found in inflammatory bowel disease (IBD) patients. However, the anti-inflammatory products in F. prausnitzii supernatant and the mechanism have not been fully investigated. Here we found that F. prausnitzii and F. prausnitzii-derived butyrate were decreased in the intestines of IBD patients. Supplementation with F. prausnitzii supernatant and butyrate could ameliorate colitis in an animal model. Butyrate, but not other substances produced by F. prausnitzii, exerted an anti-inflammatory effect by inhibiting the differentiation of T helper 17 (Th17) cells. The mechanism underlying the anti-inflammatory effects of the butyrate produced by F. prausnitzii involved the enhancement of the acetylation-promoted degradation of c-Myc through histone deacetylase 3 (HDAC3) inhibition. In conclusion, F. prausnitzii produced butyrate to decrease Th17 differentiation and attenuate colitis through inhibiting HDAC3 and c-Myc-related metabolism in T cells. The use of F. prausnitzii may be an effective new approach to decrease the level of Th17 cells in the treatment of inflammatory diseases.

Low levels of pyruvate induced by a positive feedback loop protects cholangiocarcinoma cells from apoptosis.

BACKGROUND: Cancer cells avidly consume glucose and convert it to lactate, resulting in a low pyruvate level. This phenomenon is known as the Warburg effect, and is important for cell proliferation. Although cMyc has often been described as an oncoprotein that preferentially contributes to the Warburg effect and tumor proliferation, mechanisms of action remain unclear. Histone deacetylase 3 (HDAC3) regulates gene expression by removing acetyl groups from lysine residues, as well as has an oncogenic role in apoptosis and contributes to the proliferation of many cancer cells including cholangiocarcinoma (CCA). HDAC inhibitors display antitumor activity in many cancer cell lines. Cancer cells maintain low levels of pyruvate to prevent inhibition of HDAC but the mechanisms remain elusive. The purpose of our study was to explore the role of cMyc in regulating pyruvate metabolism, as well as to investigate whether the inhibitory effect of pyruvate on HDAC3 could hold promise in the treatment of cancer cells. METHODS: We studied pyruvate levels in CCA cell lines using metabolite analysis, and analyzed the relationship of pyruvate levels and cell proliferation with cell viability analysis. We cultivated CCA cell lines with high or low levels of pyruvate, and then analyzed the protein levels of HDAC3 and apoptotic markers via Western Blotting. We then explored the reasons of low levels of pyruvate by using seahorse analysis and 13C6 metabolites tracing analysis, and then confirmed the results using patient tissue protein samples through Western Blotting. Bioinformatics analysis and transfection assay were used to confirm the upstream target of the low levels of pyruvate status in CCA. The regulation of cMyc by HDAC3 was studied through immunoprecipitation and Western Blotting. RESULTS: We confirmed downregulated pyruvate levels in CCA, and defined that high pyruvate levels correlated with reduced cell proliferation levels. Downregulated pyruvate levels decreased the inhibition to HDAC3 and consequently protected CCA cells from apoptosis. Synergistically upregulated LDHA, PKM2 levels resulted in low levels of pyruvate, as well as poor patient survival. We also found that low levels of pyruvate contributed to proliferation of CCA cells and confirmed that the upstream target is cMyc. Conversely, high activity of HDAC3 stabilized cMyc protein by preferential deacetylating cMyc at K323 site, which further contributed to the low pyruvate levels. Finally, this creates a positive feedback loop that maintained the low levels of pyruvate and promoted CCA proliferation. CONCLUSIONS: Collectively, our findings identify a role for promoting the low pyruvate levels regulated by c-Myc, and its dynamic acetylation in cancer cell proliferation. These targets, as markers for predicting tumor proliferation in patients undergoing clinical treatments, could pave the way towards personalized therapies.

Correction to: Low levels of pyruvate induced by a positive feedback loop protects cholangiocarcinoma cells from apoptosis.

Following publication of the original article [1], the authors reported an error in.

Bifidobacterium longum affects the methylation level of forkhead box P3 promoter in 2, 4, 6-trinitrobenzenesulphonic acid induced colitis in rats.

Bifidobacterium longum (B. Longum) is a common probiotic colonized in the human gut and against the development of chronic inflammation including inflammatory bowel disease (IBD). But the underlying mechanism remains unknown. The aim of this study was to evaluate the affection of B. longum on the methylation levels of forkhead box P3 (Foxp3) promoter. 2, 4, 6-trinitrobenzenesulphonic acid (TNBS)-induced colitis rat models were treated with B. longum or medium, respectively. The genomic DNA of spleen peripheral blood mononuclear cells (PBMC) cells was extracted. After bisulphite treatment and pyrosequencing, the methylation levels of each CpG sites in the promoter of forkhead box protein P3 (Foxp3) were analyzed. B. Longum treatment changes the methylation level in Foxp3 promoter in TNBS-treated colitis rats, and significantly demethylates several CpG sites in Foxp3 promoter. The demethylation of Foxp3 promoter might be involved in the effectiveness of B. Longum treatment for IBD. Further research remains necessary to investigate the role of B. Longum in Foxp3 demethylation. Using B. Longum or its metabolic products is an option for further investigations on potential treatments for IBD.

Transient temperature measurement of silicon carbide Schottky barrier diode based on thermal reflection.

In this article, we present a transient temperature detection device for silicon carbide (SiC) Schottky barrier diodes (SBDs) based on thermal reflection theory. We constructed a thermal reflection temperature measurement device based on a 530-nm green laser. This device is more suitable for transient temperature measurement of SiC SBDs than previous thermal reflection equipment. The accuracy of temperature measurement by our device was confirmed by comparison with the results of infrared thermal imaging. The high temporal resolution characteristics of the thermal reflection technology allowed the detection of millisecond-level transient temperature changes in SiC SBDs. In addition, we investigated the complementarity of transient temperature change curves during heating and cooling processes, as well as the reasons for the differences between these curves. Finally, we used the structural function method combined with the Bayesian deconvolution algorithm to obtain the thermal resistance along the heat flow path of the device and validated the results using an established thermal resistance testing method.

The associations of daytime napping and motoric cognitive risk syndrome: Findings from the China Health and Retirement Longitudinal Study.

INTRODUCTION: Motoric cognitive risk syndrome (MCR), characterized by subjective cognitive complaints and slow gait in older populations, is associated with sleep duration. However, the association between MCR and daytime nap duration has not been thoroughly explored. METHODS: Baseline data from the China Health and Retirement Longitudinal Study (CHARLS) were used in this study. MCR was defined as the coexistence of subjective cognitive complaints and objective slow gait speed without a history of dementia or mobility disability. Daytime nap duration was categorized into four groups: no napping, short napping (<30 min), moderate napping (30-89 min) and extended napping (≥90 min). Multivariable logistic regression models were used to explore the association of daytime napping duration and MCR. RESULTS: A total of 4230 individuals aged ≥60 were included in the current analysis, of which 463 were diagnosed with MCR. Moderate napping of 30-89 min per day was found to be significantly associated with lower odds of MCR compared with the reference group of no napping. In subgroup analysis, individuals with sleep durations of <7 h per night had lower odds of MCR in the model that adjusted for all potential confounders with ≥30 min daytime nap duration compared with no napping. Interestingly, for people with a night sleep duration of 7-8 h, only those with a moderate nap of 30-89 min had lower odds of MCR than non-nappers after adjustment for potential confounders. CONCLUSION: A moderate nap of 30-89 min could lower the odds of MCR, especially for older adults with a night sleep duration of ≤8 h.

Associations of parity and cognitive decline, depression, and chronic comorbidity in West China: Results from WCHAT study.

OBJECTIVE: To investigate the associations between parity (the number of offspring a female has borne) and cognitive function, depression, and chronic comorbidity in Western China. METHODS: A total of 846 women aged 50-55 years were included in the current analysis. Cognitive status was measured using a 10-item short portable mental status questionnaire (SPMSQ). Depressive symptoms were assessed using the 15-item geriatric depression scale (GDS-15). Other characteristics were self-reported. The associations between parity and cognitive decline, depression, and chronic comorbidity were analyzed using univariable and multivariable models. Multivariable models were adjusted for age, ethnic group, occupation, marital status, educational level, lifestyle factors, and sleeping time. RESULTS: Among the enrolled women, 26.71% were either childless or had one child, 47.40% had two children, 18.32% had three children, and 7.57% had ≥4 children. Compared to women with low parity, women with two or more children exhibited a higher risk of cognitive decline. Moreover, having four or more children was significantly associated with depression and chronic comorbidity. After adjusting covariates, women with three or more children exhibited a higher risk of cognitive decline than those with low parity. However, high parity was not significantly associated with depression or chronic comorbidity after adjustment for covariates. CONCLUSION: Our study showed that ≥3 children was associated with cognitive decline in women. Longitudinal studies are needed to evaluate this conclusion and to investigate the mechanisms involved. More importantly, families and societies should pay more attention to women's long-term health outcomes related to fertility.

Identification and Validation of Co-Expressed Immune-Related Gene Signature Affecting the Pattern of Immune Infiltrating in Esophageal Cancer.

OBJECTIVE: Esophageal squamous cell carcinoma (ESCC) is a common malignant tumor of the digestive tract, and its molecular mechanisms have not been fully clarified. This study aimed to evaluate the immune infiltration pattern of esophageal cancer through a gene co-expression network, and to provide biomarkers for immunotherapy of esophageal cancer. METHODS: We downloaded RNA-seq data of ESCC samples from GSE53625 and GSE66258 datasets, then assessed the immune score and tumor purity through the ESTIMATE algorithm. Next, a co-expression network was constructed by the weighted gene co-expression network analysis, and the key co-expressed immune- related genes were identified on the basis of existing human immune-related genes. Afterward, we utilized bioinformatics algorithms including GSVA, CIBERSORT, and ssGSEA to clarify the relationship between hub genes and immune infiltration patterns. Finally, these hub genes were used to evaluate the sensitivity to immunotherapy by the subclass mapping algorithm, which were further validated by digital pathology through the Hover- Net algorithm. RESULTS: Sixteen immune-related genes with robust expression characteristics were identified and used to build gene signatures. The expression of gene signature was significantly related to the immune infiltration pattern and immunotherapy sensitivity prediction in patients with esophageal cancer. Consistent with previous studies, genetic changes at the level of somatic mutations such as NFE2L2 were revealed. CONCLUSION: A total of 16 immune-related genes with the total expression gene signature can be used as biomarkers for immunotherapy of esophageal squamous cell carcinoma. Its molecular mechanisms deserve further study to guide clinical treatment in the future.

Association of Handgrip Strength Weakness and Asymmetry With Incidence of Motoric Cognitive Risk Syndrome in the China Health and Retirement Longitudinal Study.

BACKGROUND AND OBJECTIVES: Motoric cognitive risk (MCR) syndrome is a type of pre-dementia. It is defined as the co-occurrence of subjective cognitive complaints and a slow gait speed. A recent study found that handgrip strength (HGS) asymmetry is associated with an increased risk of neurodegenerative disorders. We aimed to investigate the associations of HGS weakness and asymmetry separately and together with MCR incidence among older Chinese adults. METHODS: Data from the 2011 and 2015 waves of the China Health and Retirement Longitudinal Study were used. HGS values <28 kg for male participants and <18 kg for female participants were considered HGS weaknesses. HGS asymmetry was assessed by the ratio of nondominant to dominant HGS. We used 3 different cutoff values of HGS ratio to define asymmetry, including 10%, 20%, and 30%. Specifically, HGS ratios <0.90 or >1.10 (10%), <0.80 or >1.20 (20%), and <0.70 or >1.30 (30%) were classified as asymmetry. The participants were classified into 4 groups: neither weakness nor asymmetry (neither), asymmetry only, weakness only, and weakness and asymmetry (both). The association between baseline HGS status and 4-year incidence of MCR was examined using logistic regression analyses. RESULTS: A total of 3,777 participants 60 years and older were included in the baseline analysis. The prevalence of MCR at the baseline was 12.8%. Participants with asymmetry only, weakness only, and both showed significantly increased risk of MCR. After excluding participants with MCR at baseline, 2,328 participants were included in the longitudinal analysis. There were 111 MCR cases (4.77%) over the 4-year follow-up period. Participants with HGS weakness and asymmetry together at baseline had increased odds of incident MCR (HGS ratio at 10%: odds ratio [OR] 4.48, p < 0.001; HGS ratio at 20%: OR 5.43, p < 0.001; HGS ratio at 30%: OR 6.02, p < 0.001). DISCUSSION: These results show that the presence of both HGS asymmetry and weakness is associated with MCR incidence. The early recognition of HGS asymmetry and weakness may be helpful in the prevention and treatment of cognitive dysfunction.

SIRT3 Activator Honokiol Inhibits Th17 Cell Differentiation and Alleviates Colitis.

BACKGROUND: Honokiol (HKL), a natural extract of the bark of the magnolia tree and an activator of the mitochondrial protein sirtuin-3 (SIRT3), has been proposed to possess anti-inflammatory effects. This study investigated the inhibitory effects of HKL on T helper (Th) 17 cell differentiation in colitis. METHODS: Serum and biopsies from 20 participants with ulcerative colitis (UC) and 18 healthy volunteers were collected for the test of serum cytokines, flow cytometry analysis (FACS), and relative messenger RNA (mRNA) levels of T cell subsets, as well as the expression of SIRT3 and phosphorylated signal transducer and activator of transcription/retinoic acid-related orphan nuclear receptor γt (p-STAT3/RORγt) signal pathway in colon tissues. In vitro, naïve clusters of differentiation (CD) 4 + T cells isolated from the mouse spleen differentiated to subsets including Th1, Th2, Th17, and regulatory T (Treg) cells. Peripheral blood monocytes (PBMCs) from healthy volunteers were induced to the polarization of Th17 cells. After HKL treatment, changes in T cell subsets, related cytokines, and transcription factors were measured. The dextran sulfate sodium (DSS)-induced colitis and interleukin (IL)-10-deficient mice were intraperitoneally injected with HKL. These experiments were conducted to study the effect of HKL on the development, cytokines, and expression of signaling pathway proteins in colitis. RESULTS: Patients with UC had higher serum IL-17 and a higher proportion of Th17 differentiation in blood compared with healthy participants; while IL-10 level and the proportion of Treg cells were lower. Higher relative mRNA levels of RORγt and a lower SIRT3 expression in colon tissues were observed. In vitro, HKL had little effect on the differentiation of naïve CD4+ T cells to Th1, Th2, or Treg cells, but it downregulated IL-17 levels and the Th17 cell ratio in CD4+ T cells from the mouse spleen and human PBMCs under Th17 polarization. Even with a STAT3 activator, HKL still significantly inhibited IL-17 levels. In DSS-induced colitis mice and IL-10 deficient mice treated with HKL, the length of the colon, weight loss, disease activity index, and histopathological scores were improved, IL-17 and IL-21 levels, and the proportion of Th17 cells were decreased. Sirtuin-3 expression was increased, whereas STAT3 phosphorylation and RORγt expression were inhibited in the colon tissue of mice after HKL treatment. CONCLUSIONS: Our study demonstrated that HKL could partially protect against colitis by regulating Th17 differentiation through activating SIRT3, leading to inhibition of the STAT3/RORγt signaling pathway. These results provide new insights into the protective effects of HKL against colitis and may facilitate the research of new drugs for inflammatory bowel disease.

Prognostic value of temporal muscle thickness, a novel radiographic marker of sarcopenia, in patients with brain tumor: A systematic review and meta-analysis.

Sarcopenia has been identified as a prognostic factor among certain types of cancer. However, it is unclear whether there is prognostic value of temporalis muscle thickness (TMT), a potential surrogate for sarcopenia, in adults patients with brain tumors. Therefore, we searched the Medline, Embase, and PubMed to systematically review and meta-analyze the relationship between TMT and overall survival, progression-free survival, and complications in patients with brain tumors and the hazard ratio (HR) or odds ratios (OR), and 95% confidence interval (CI) were evaluated. The quality in prognostic studies (QUIPS) instrument was employed to evaluate study quality. Nineteen studies involving 4570 patients with brain tumors were included for qualitative and quantitative analysis. Meta-analysis revealed thinner TMT was associated with poor overall survival (HR, 1.72; 95% CI, 1.45-2.04; P < 0.01) in patients with brain tumors. Sub-analyses showed that the association existed for both primary brain tumors (HR, 2.02; 95% CI, 1.55-2.63) and brain metastases (HR, 1.39; 95% CI, 1.30-1.49). Moreover, thinner TMT also was the independent predictor of progression-free survival in patients with primary brain tumors (HR, 2.88; 95% CI, 1.85-4.46; P < 0.01). Therefore, to improve clinical decision making it is important to integrate TMT assessment into routine clinical settings in patients with brain tumors.

STAT3 palmitoylation initiates a positive feedback loop that promotes the malignancy of hepatocellular carcinoma cells in mice.

Constitutive activation of the transcription factor STAT3 (signal transducer and activator of transcription 3) contributes to the malignancy of many cancers such as hepatocellular carcinoma (HCC) and is associated with poor prognosis. STAT3 activity is increased by the reversible palmitoylation of Cys108 by the palmitoyltransferase DHHC7 (encoded by ZDHHC7). Here, we investigated the consequences of S-palmitoylation of STAT3 in HCC. Increased ZDHHC7 abundance in HCC cases was associated with poor prognosis, as revealed by bioinformatics analysis of patient data. In HepG2 cells in vitro, DHHC7-mediated palmitoylation enhanced the expression of STAT3 target genes, including HIF1A, which encodes the hypoxia-inducible transcription factor HIF1α. Inhibiting DHHC7 decreased the S-palmitoylation of STAT3 and decreased HIF1α abundance. Furthermore, stabilization of HIF1α by cyclin-dependent kinase 5 (CDK5) enabled it to promote the expression of ZDHHC7, which generated a positive feedback loop between DHHC7, STAT3, and HIF1α. Perturbing this loop reduced the growth of HCC cells in vivo. Moreover, DHHC7, STAT3, and HIF1α were all abundant in human HCC tissues. Our study identifies a pathway connecting these proteins that is initiated by S-palmitoylation, which may be broadly applicable to understanding the role of this modification in cancer.

Association between daytime nap duration and risks of frailty: Findings from the China Health and Retirement Longitudinal Study.

Introduction: Night sleep duration and total sleep duration are associated with frailty. However, the association between daytime nap duration and the risks of frailty has not been explored thoroughly. Methods: This study used data from the China Health and Retirement Longitudinal Study (CHARLS). Participants aged 60 years and older at baseline were included in this study. Individuals with daytime nap duration were categorized into four groups: no napping, short napping (< 30 min), moderate napping (30-89 min), and extended napping (≥90 min). Frailty was assessed using a modified Physical Frailty Phenotype (PFP) scale. Non-frail participants at baseline were followed up for 4 years. The association between nap duration and risks of frailty at baseline and incident frailty was evaluated by logistic regression and discrete-time Cox regression analyses, respectively. Results: In total, 5,126 participants were included in this study. For individuals with night sleep duration of ≥9 h, short nappers showed higher odds [odds ratio (OR) = 4.08, 95% confidence interval (CI): 1.30-12.78] for frailty compared with non-habitual nappers at baseline, while moderate nappers were less likely to be frail (OR = 0.18, 95% CI: 0.04-0.73). In the follow-up study, short nappers showed higher risks for frailty compared with participants of the no napping group with night sleep duration of < 6 h [hazard ratio (HR) = 1.91, 95% CI: 1.07-3.43] or 6-9 h (HR = 1.97, 95% CI: 1.18-3.30). Compared with short nappers, older adults with extended napping (HR = 0.41, 95% CI: 0.22-0.77) showed lower risks for frailty in those with night sleep duration of 6-9 h. For individuals with night sleep duration of ≥9 h, moderate napping (HR = 0.20, 95% CI: 0.05-0.77) decreased the risks for frailty compared with short napping. Conclusion: Among older adults with night sleep duration of < 9 h, short nappers posed higher risks for frailty compared with non-habitual nappers. Extended naps for those with a night sleep duration of 6-9 h or moderate naps for those with night sleep duration of ≥9 h could lower the risk of frailty compared with short naps. Future studies on the timing, purpose, frequency, and quality of daytime napping and objectively measured nap duration are needed to explore the association between daytime napping and risks of frailty.