Structural and biochemical insights into the molecular mechanism of N-acetylglucosamine/N-Acetylmuramic acid kinase MurK from Clostridium acetobutylicum.

MurK is a MurNAc- and GlcNAc-specific amino sugar kinase, phosphorylates MurNAc and GlcNAc at the 6-hydroxyl group in an ATP-dependent manner, and contributes to the recovery of both amino sugars during the cell wall turnover in Clostridium acetobutylicum. Herein, we determined the crystal structures of MurK in complex with MurNAc, GlcNAc, and glucose, respectively. MurK represents the V-shaped fold, which is divided into a small N-terminal domain and a large C-terminal domain. The catalytic pocket is located within the deep cavity between the two domains of the MurK monomer. We mapped the significant enzyme-substrate interactions, identified key residues involved in the catalytic activity of MurK, and found that residues Asp77 and Arg78 from the ß4-α2-loop confer structural flexibilities to specifically accommodate GlcNAc and MurNAc, respectively. Moreover, structural comparison revealed that MurK adopts closed-active conformation induced by the N-acetyl moiety from GlcNAc/MurNAc, rather than closed-inactive conformation induced by glucose, to carry out its catalytic reaction. Taken together, our study provides structural and functional insights into the molecular mechanism of MurK for the phosphorylation of both MurNAc and GlcNAc, sugar substrate specificity, and conformational changes upon sugar substrate binding.

Successful ageing is associated with falls among older adults in India: a large population based across-sectional study based on LASI.

BACKGROUND: Falls are common in the elderly and can lead to adverse consequences, like injuries, hospitalization, disability even mortality. Successful ageing emerged in sight to assess physical, psychological and social status of older adults. This study is conducted to explore the association between them in a large Indian community-dwelling population. METHODS: Data were based on the wave 1 survey of the Longitudinal Ageing Study in India (LASI). People aged 60 and above with complete information were included. The elderly met five standards including absence of chronic diseases, freedom from disability, high cognitive ability, free from depressive symptoms and active social engagement, were classified into successful agers. The assessment of falls, fall-related injuries and multiple falls depended on interview. Multivariate logistic regression was conducted to find the associations between falls, fall-injury, multiple falls and successful ageing after adjusting both socio-demographic and biological covariates. The log-likelihood ratio test was calculated interactions in subgroups. RESULTS: 31,345 participants in LASI were finally included in our study. Of them, 20.25% reported fall, and 25% were classified into successful agers. After full adjustment, successful ageing was negatively associated with falls (OR 0.70; 95%CI 0.65-0.76) and multiple falls (OR 0.70; 95%CI 0.63-0.78). And the association did not show the significance in older adults with fall-related injuries (OR 0.86; 95%CI 0.72-1.04). CONCLUSIONS: Successful ageing was negatively associated with falls and multiple falls, but not fall-related injuries in older people in India. Future studies are demanded to explore the causal relationship and to reveal the underlying mechanism.

Causal Associations Between Gut Microbiota, Gut Microbiota-Derived Metabolites, and Alzheimer's Disease: A Multivariable Mendelian Randomization Study.

Background: Multiple studies have demonstrated that the gut microbiome is closely related to the onset of Alzheimer's disease, but the causal relationship between the gut microbiome and AD, as well as potential mediating factors, have not been fully explored. Objective: Our aim is to validate the causal relationship between the gut microbiome and the onset of AD and determine the key mechanism by which the gut microbiome mediates AD through blood metabolites using Mendelian randomization (MR) analysis methods. Methods: We first conducted bidirectional and mediating MR analyses using gut microbiota, blood amino acid metabolites, and AD-related single nucleotide polymorphisms as research data. In the analysis process, the inverse variance-weighted average method was mainly used as the primary method, with other methods serving as supplementary evidence. Results: Ultimately, we found that six types of gut bacteria and two blood amino acid metabolites have a causal effect on AD. Subsequent mediation analysis proved that decreased glutamine concentration mediates the negative causal effect of Holdemanella bacteria on AD (mediation ratio of 14.5%), and increased serum alanine concentration mediates the positive causal effect of Parabacteroide bacteria on AD (mediation ratio of 9.4%). Conclusions: Our study demonstrates the causality of Holdemanella and Parabacteroides bacteria in the onset of AD and suggests that the reduced glutamine and increased alanine serums concentration may be key nodes in mediating this effect.

High serum uric acid is a risk factor for arterial stiffness in a Chinese hypertensive population: a cohort study.

The prospective cohort study was to explore the association between serum uric acid (SUA) and arterial stiffness in a Chinese hypertensive population. A total of 7444 participants with hypertension who completed two or more measurements of brachial-ankle pulse wave velocity (baPWV) and baseline SUA detection were followed-up in the Kailuan Study from 2010 to 2020. A restricted cubic spline curve was used to verify whether there was a linear association between baseline SUA and arterial stiffness. A Cox proportional hazard regression model was used to explore the association of between baseline SUA and the incidence of arterial stiffness. Our results showed that the restricted cubic spline curve revealed a linear relationship between baseline SUA and arterial stiffness in total participants (p < 0.001). After follow-up 4.6 ± 2.8 years, Kaplan-Meier survival curves indicated that the risk of arterial stiffness was increased in the high level of baseline SUA (Log-rank p = 0.0002). After adjusting for potential confounding factors, the HR (95% CI) for risk of stiffness was 1.33 (1.17-1.52, p < 0.001) in the highest SUA group. Hierarchical analysis showed that the HRs (95% CI) for risk of arterial stiffness were 1.45 (1.25-1.69), 1.38 (1.19-1.60), 1.41 (1.21-1.64), and 1.35 (1.15-1.58) in the highest SUA group of males, <65 years old, not taking antihypertensive drugs, and failure to achieve the control targets of blood pressure respectively (p < 0.001). These results reveal that high SUA is a risk factor for arterial stiffness in the Chinese hypertensive population.

Molecular mechanism of human ISG20L2 for the ITS1 cleavage in the processing of 18S precursor ribosomal RNA.

The exonuclease ISG20L2 has been initially characterized for its role in the mammalian 5.8S rRNA 3' end maturation, specifically in the cleavage of ITS2 of 12S precursor ribosomal RNA (pre-rRNA). Here, we show that human ISG20L2 is also involved in 18S pre-rRNA maturation through removing the ITS1 region, and contributes to ribosomal biogenesis and cell proliferation. Furthermore, we determined the crystal structure of the ISG20L2 nuclease domain at 2.9 Å resolution. It exhibits the typical αßα fold of the DEDD 3'-5' exonuclease with a catalytic pocket located in the hollow near the center. The catalytic residues Asp183, Glu185, Asp267, His322 and Asp327 constitute the DEDDh motif in ISG20L2. The active pocket represents conformational flexibility in the absence of an RNA substrate. Using structural superposition and mutagenesis assay, we mapped RNA substrate binding residues in ISG20L2. Finally, cellular assays revealed that ISG20L2 is aberrantly up-regulated in colon adenocarcinoma and promotes colon cancer cell proliferation through regulating ribosome biogenesis. Together, these results reveal that ISG20L2 is a new enzymatic member for 18S pre-rRNA maturation, provide insights into the mechanism of ISG20L2 underlying pre-rRNA processing, and suggest that ISG20L2 is a potential therapeutic target for colon adenocarcinoma.

Structural and biochemical insights into the interaction mechanism underlying HORMAD1 and its partner proteins.

The mammalian HORMA domain-containing protein 1 (HORMAD1) regulates DNA mismatch repair and homologous recombination (HR) repair in many cancers. Here, we show that the structure of human HORMAD1 adopts a self-closed conformation and displays an intra-molecular HORMA domain-closure motif interaction mode. Structural and biochemical data suggest that the interaction modes of the peptide motifs from HORMAD2 and MCM9 with HORMAD1 are highly similar to that of HORMAD1 own closure motif. The peptide motifs from diverse binding partners of HORMAD1 share a conserved Ser-Glu-Pro sequence. Additionally, structural comparison unveiled the HORMA-peptide motif interaction mode diversity among HORMA-containing proteins. Finally, cell-based assays revealed that this HORMA-closure motif interaction pattern contributes to DNA mismatch repair and is required for HORMAD1-dependent HR repair. Together, our results provide structural and biochemical insights into the common theme and functional plasticity of the HORMA domain-containing protein family, and also reveal a universal regulation mechanism for HORMAD1.

Elevated high-sensitivity C-reactive protein levels increase the risk of new-onset cardiac conduction disorders.

BACKGROUND: Previous studies have reported that inflammatory responses can promote the onset of cardiovascular diseases; however, its association with cardiac conduction disorders remains unclear. The present community-based cohort study aimed to elucidate the effects of inflammatory responses on the risk of developing cardiac conduction disorders. METHODS: After the exclusion of participants failing to meet the inclusion criteria, 86,234 eligible participants (mean age: 50.57 ± 11.88 years) were included. The participants were divided into high-sensitivity C-reactive protein (hsCRP) ≤ 3 mg/L, and hsCRP > 3 mg/L groups based on hsCRP values. Multivariate Cox proportional hazard model was used to analyze the relationship between inflammatory responses and various cardiac conduction disorders. RESULTS: After adjusting for confounding factors, we observed that compared with the hsCRP ≤ 3 mg/L group, the hsCRP > 3 mg/L group exhibited increased risks of atrioventricular block (hazard ratio [HR]:1.64, 95%confidence interval [CI] 1.44-1.87) and left (HR:1.25, 95% CI 1.07-1.45) and right bundle branch block (HR:1.31, 95% CI 1.17-1.47). Moreover, the risk of various cardiac conduction disorders increased for every 1 standard deviation increase in log (hsCRP). The restricted cubic spline function confirmed a linear relationship between log (hsCRP) and the risk of developing cardiac conduction disorders (All nonlinearity P > 0.05). CONCLUSIONS: High hsCRP levels are an independent risk factor for cardiac conduction disorders, and hsCRP levels are dose-dependently associated with the risk of conduction disorders. Our study results may provide new strategies for preventing cardiac conduction disorders.

Efficacy and Safety of Methylprednisolone for Lung Surgery: a Systematic Review and Meta-analysis of Randomized Controlled Trials.

INTRODUCTION: The administration of methylprednisolone (MP) is a component of perioperative multimodal analgesia that mitigates the potentially deleterious effects of postoperative pain and opioid consumption. However, a systematic evaluation of the efficacy and safety of MP is lacking. The present systematic review and meta-analysis was performed to quantify the potential clinical benefits and risks of perioperative MP in lung surgery. METHODS: We searched seven electronic databases for randomized controlled trials (RCTs) comparing MP with placebo. Coprimary outcomes were rest pain scores, dynamic pain scores, and cumulative morphine equivalent consumption within 24 h postoperatively. RESULTS: A total of 11 trials including 643 participants were selected for our meta-analysis. The results demonstrated that the MP group had a significant difference in coprimary outcomes (rest pain scores, dynamic pain scores, and cumulative morphine equivalent consumption) compared with the placebo group; nevertheless, the improvement was not clinically meaningful based on minimum clinically important differences (MCID). Notably, MP administration reduced serum levels of interleukin (IL)-6 at 6 h (weighted mean difference -20.49 pg/mL; 95% CI -29.94 to -11.04), and decreased the incidence rate of acute lung injury (rate ratio 0.18; 95% CI 0.03-0.98) and cognitive dysfunction (rate ratio 0.43; 95% CI 0.21-0.88) compared with the placebo group. CONCLUSIONS: Our findings suggest that the administration of MP contributed to an insignificant relief in acute postoperative pain for lung surgery in a clinical setting. Future studies should focus on exploring the role of MP in reducing pulmonary and surgical-related complications after lung surgery. CLINICAL TRIAL NUMBER: PROSPERO registration number CRD42022314224.

Correlation between decreased plasma miR-29a and vascular endothelial injury induced by hyperlipidemia.

BACKGROUND: Hyperlipidemia is a major risk factor for vascular endothelial injury and atherosclerosis leading to cardiovascular diseases. Early diagnosis of vascular endothelial injury is important for the prevention and prognosis of cardiovascular diseases. This study aimed to investigate sensitive circulating microRNA (miRNA) as a potential diagnostic biomarker of vascular endothelial injury in a hyperlipidemic rat model. METHODS: The miRNA expression profile was detected by miRNA microarray. The hyperlipidemic rat model was established by intraperitoneal injection of vitamin D3 combined with a high-fat diet. Plasma miRNA levels were measured by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). RESULTS: No significant difference was found in the types of highly expressed miRNAs between human umbilical artery endothelial cells (HUAEC) and human umbilical vein endothelial cells (HUVEC). A total of 10 highly expressed miRNAs in endothelial cells were selected as candidate miRNAs, including miR-21, miR-126, let-7a, miR-23a, miR-221, miR-125b, miR-26a, miR-29a, miR-16, and miR-100. The plasma levels of let-7a, miR-126, miR-21, and miR-26a were significantly elevated in hyperlipidemic rats at 30 and 50 days after modeling, while the plasma level of miR-29a was significantly decreased. No significant change was found in the plasma levels of miR-125b, miR-23a, miR-221, miR-100, and miR-16. Interestingly, a significant reduction in plasma miR-29 level was detected as early as 20 days after modeling, which was earlier than for soluble intercellular adhesion molecule­1 (sICAM-1). CONCLUSION: The plasma levels of endothelial cell-enriched miRNAs were correlated with vascular endothelial injury induced by hyperlipidemia. miR-29a might serve as a potential early diagnostic biomarker of endothelial injury-related diseases.

The Choice of Anesthetic Drugs in Outpatient Hysteroscopic Surgery: A Systematic Review and Network Meta-Analysis.

Objective: Hysteroscopy is a minimally invasive gynecologic technique that is widely practiced in outpatient procedures. The choice of anesthesia is a key factor for the surgical outcome and postoperative recovery. This study was conducted to assess the effects of different anesthetic modalities based on dexmedetomidine in outpatient hysteroscopic surgery anesthesia. Methods: We did a systematic review and network meta-analysis of outpatient hysteroscopic surgery anesthesia. We searched Pubmed, Embase, and Cochrane-Library from database inception to December 31, 2021. Duplicate literature was excluded and screened separately for initial screening at three tiers: article title, abstract, and full text before deciding whether to include in this study against the above criteria. Results after analysis of categorical variables were expressed as ORR Ratio (95% CI) and continuous variables were expressed as Mean Difference (95% CI). Data collation and analyses were performed using the gemtc package in the R language. Results: Four trials were finally included with data for 301 participants, three anesthetic drugs, and five anesthetic modalities. A fixed-effects model was used for the different anesthesia modalities without significant heterogeneity (all I2<20%) in the analysis of adverse events (AEs), the incidence of respiratory depression, operative time, and time in the post-anesthesia care unit (PACU). Remimazolam tosylate was associated with a lower incidence of AEs versus dexmedetomidine, and significant differences between dexmedetomidine and propofol were absent. Propofol and various doses of remimazolam tosylate resulted in a lower incidence of respiratory depression versus dexmedetomidine, with an absence of differences between propofol and dexmedetomidine. The operative time for different anesthetic modalities was, in descending order, dexmedetomidine < remimazolam tosylate (0.60 mg/kg/h <0.48 mg/kg/h) < propofol < remimazolam tosylate (1.00 mg/kg/h), despite the absence of intergroup differences. Propofol was associated with a longer time in PACU versus dexmedetomidine and remimazolam tosylate (1.00 mg/kg/h); those of dexmedetomidine and remimazolam tosylate (1.00 mg/kg/h) were similar. The time in PACU for different anesthetic modalities, in descending order, was dexmedetomidine < remimazolam tosylate (1.00 mg/kg/h) < propofol. Propofol was associated with a longer time in PACU versus dexmedetomidine and remimazolam tosylate. Conclusion: In outpatient hysteroscopic surgery anesthesia, dexmedetomidine was associated with a higher incidence of AEs and respiratory depression and a shorter operative time and time in PACU versus remimazolam tosylate and propofol. Remimazolam tosylate showed safety benefits with a similar duration of PACU stay versus dexmedetomidine. Therefore, the choice of anesthetic drugs in outpatient surgery requires consideration of the patient's conditions and preferences.

Chinese expert consensus on assessment of cognitive impairment in the elderly.

Cognitive impairment is a term that refers to the impairment of one or more cognitive domains to varying degrees caused by a variety of reasons. It is under a high prevalence, many risk factors, complex etiology, and great harm to the elderly population. Early screening, diagnosis, and intervention for cognitive impairment in the elderly are of great importance. However, at present, the recognition rate of cognitive impairment for the elderly in China is low, the rate of missed diagnosis is high, and the evaluation is not standardized. This consensus integrates the commonly used cognitive function assessment scales in China and abroad, and aims to popularize the screening of cognitive impairment, standardize the evaluation methods and procedures of cognitive impairment in the elderly, and establish clinical diagnoses, interventions, and follow-up plans in a timely manner.

Association between Perceived Salt Intake and Arterial Stiffness.

To explore the association of perceived salt intake (SI) level with arterial stiffness in the community population in northern China. We enrolled participants who completed the health questionnaire, physical examination, and brachial-ankle pulse wave velocity (baPWV) test during 2010-2019 and divided them into <6 g (low SI), 6-10 g (medium SI), and >10 g (high SI) groups based on their daily SI. The influence of SI on baPWV was analyzed using the multivariate logistic regression model. A total of 36324 subjects, aged (49.10 ± 12.57) years with a male to female ratio of 25934 : 10390, met the inclusion criteria and were enrolled. The average baPWV was (1527.73 ± 355.61) cm/s. Logistic regression analysis showed that after adjusting for other confounders, daily SI>10 g (high SI) was a risk factor for arterial stiffness (baPWV ≥1400 cm/s), with the odds ratio (95% confidence interval [CI]) of 1.17 (1.04-1.31). High SI is independently associated with arterial stiffness.

Comprehensive analysis of an autophagy-related prognostic model for predicting survival based on TCGA and ICGC database in hepatocellular carcinoma patients.

Background: There is accumulating evidence that autophagic activity is crucial to the development of hepatocellular carcinoma (HCC). Thus, we sought to develop a predictive model based on autophagy-related genes (ARGs) to forecast the prognosis of HCC patients. Methods: Based on expression data from The Cancer Genome Atlas (TCGA) and ARGs from Human Autophagy Database (HADb), the differentially expressed ARGs were screened. The prognosis-related ARGs were identified using a univariate Cox regression analysis. Using multivariate Cox regression analysis, a prognostic model was developed. To assess the predictive value of the model, receiver operating characteristic (ROC) curve, Kaplan-Meier curve, and multivariable Cox regression analyses were conducted. A data cohort gathered independently from the International Cancer Genome Consortium (ICGC) database further verified the model's predictive accuracy. The immune landscape was generated using the TIMER and CIBERSORT algorithms. Finally, the correlation between the prognostic signature and gene mutation status was analyzed by employing "maftools" package. Results: We identified a novel prediction model based on the ARGs of PLD1 and SLC36A1 with significant prognostic values for HCC in both univariate and multivariate Cox regression analysis, and patients were classified into high- or low-risk groups based on their risk scores. High-risk patients had significantly shorter overall survival (OS) times than low-risk patients (P=5e-4). According to the ROC curve analysis, the risk score had a higher predictive value than the other clinical characteristics. Prognostic nomograms were also performed to visualize the relationship between individual predictors and survival rates in patients with HCC. Further, an external independent cohort of ICGC patients provided additional confirmation of the predictive efficacy of the model. We subsequently analyzed the differential immune densities of the two groups and discovered that various immune cells, including naïve B cells, resting memory cluster of differentiation (CD)4 T cells, regulatory T cells, M2 macrophages, and neutrophils, had considerably larger infiltrating densities in the high-risk group than the low-risk group. Conclusions: We established a robust autophagy-related risk model having a certain prediction accuracy for predicting the prognosis of HCC patients. Our findings will contribute to the definition of prognosis and establishment of personalized treatment interventions for HCC patients.

Population-attributable fractions of risk factors for all-cause dementia in China rural and urban areas: a cross-sectional study.

BACKGROUND: The prevalence of dementia in China, particularly in rural areas, is consistently increasing; however, research on population-attributable fractions (PAFs) of risk factors for dementia is scarce. METHODS: We conducted a cross-sectional survey, namely, the China Multicentre Dementia Survey (CMDS) in selected rural and urban areas from 2018 to 2020. We performed face-to-face interviews and neuropsychological and clinical assessments to reach a consensus on dementia diagnosis. Prevalence and weighted PAFs of eight modifiable risk factors (six classical: less childhood education, hearing impairment, depression, physical inactivity, diabetes, and social isolation, and two novels: olfactory decline and being unmarried) for all-cause dementia were estimated. RESULTS: Overall, CMDS included 17,589 respondents aged ≥ 65 years, 55.6% of whom were rural residents. The age- and sex-adjusted prevalence for all-cause dementia was 9.11% (95% CI 8.96-9.26), 5.19% (5.07-5.31), and 11.98% (11.8-12.15) in the whole, urban, and rural areas of China, respectively. Further, the overall weighted PAFs of the eight potentially modifiable risk factors were 53.72% (95% CI 52.73-54.71), 50.64% (49.4-51.89), and 56.54% (55.62-57.46) in the whole, urban, and rural areas of China, respectively. The eight risk factors' prevalence differed between rural and urban areas. Lower childhood education (PAF: 13.92%) and physical inactivity (16.99%) were primary risk factors in rural and urban areas, respectively. CONCLUSIONS: The substantial urban-rural disparities in the prevalence of dementia and its risk factors exist, suggesting the requirement of resident-specific dementia-prevention strategies.

The Hubei Memory and Aging Cohort Study: Study Design, Baseline Characteristics, and Prevalence of Cognitive Impairments.

BACKGROUND: Despite the improved access to health services in China, inadequate diagnosis and management of dementia are common issues, especially in rural regions. OBJECTIVE: The Hubei Memory & Aging Cohort Study was designed as a prospective study in Central China to determine the prevalence, incidence, and risk factors for dementia and mild cognitive impairment (MCI) among urban and rural older adults. METHODS: From 2018-2020, participants aged ≥65 years were screened, and data regarding their life behaviors, families, socio-economic status, physical and mental health, social and psychological factors, and cognition were collected. Diagnoses of MCI and dementia were made via consensus diagnosis using the Diagnostic and Statistical Manual of Mental Disorders fourth edition criteria. RESULTS: Of 8,221 individuals who completed their baseline clinical evaluation, 4,449 (54.1%) were women and 3,164 (38.4%) were from remote rural areas (average age: 71.96 years; mean education period: 7.58 years). At baseline, 25.98%(95%confidence interval [CI]: 24.99-26.96) and 7.24%(95%CI: 6.68-7.80) of the participants were diagnosed with MCI and dementia, respectively. Prevalence showed a strong relationship with age. The substantial disparities between rural and urban regions in MCI and dementia prevalence and multiple dementia-related risk factors were revealed. Especially for dementia, the prevalence rate in rural areas was 2.65 times higher than that in urban regions. CONCLUSION: Our results suggested that public health interventions are urgently needed to achieve equitable diagnosis and management for people living with dementia in the communities across urban and rural areas.

Urban-rural disparities in mild cognitive impairment and its functional subtypes among community-dwelling older residents in central China.

BACKGROUND: Substantial variations in the prevalence of mild cognitive impairment (MCI) and its subtypes have been reported, although mostly in geographically defined developed countries and regions. Less is known about MCI and its subtypes in rural areas of less developed central China. AIMS: The study aimed to compare the prevalence of MCI and its subtypes in residents aged 65 years or older in urban and rural areas of Hubei Province, China. METHODS: Participants aged 65 years or older were recruited between 2018 and 2019. Inperson structured interviews and clinical and neuropsychological assessments were performed at city health community centres and township hospitals. RESULTS: Among 2644 participants without dementia, 735 had MCI, resulting in a prevalence of 27.8% for total MCI, 20.9% for amnestic MCI (aMCI) and 6.9% for non-amnestic MCI (naMCI). The prevalence of MCI in urban and rural areas was 20.2% and 44.1%, respectively. After adjusting for demographic factors, the prevalence of total MCI, aMCI and naMCI differed significantly between rural and urban areas (adjusted odds ratio (OR) 2.10, 1.44 and 3.76, respectively). Subgroup analysis revealed an association between rural socioeconomic and lifestyle disadvantage and MCI and its subtypes. CONCLUSIONS: Our findings suggest that the prevalence of MCI among urban residents in central China is consistent with that in other metropolis areas, such as Shanghai, but the prevalence in rural areas is twice that in urban areas. Prospective studies and dementia prevention in China should focus on rural areas.

Comprehensive Analysis to Identify the Epithelial-Mesenchymal Transition-Related Immune Signatures as a Prognostic and Therapeutic Biomarkers in Hepatocellular Carcinoma.

Background: Hepatocellular carcinoma (HCC) is a highly heterogeneous disease with the high rates of the morbidity and mortality due to the lack of the effective prognostic model for prediction. Aim: To construct a risk model composed of the epithelial-mesenchymal transition (EMT)-related immune genes for the assessment of the prognosis, immune infiltration status, and chemosensitivity. Methods: We obtained the transcriptome and clinical data of the HCC samples from The Cancer Genome Atlas (TCGA) and The International Cancer Genome Consortium (ICGC) databases. The Pearson correlation analysis was applied to identify the differentially expressed EMT-related immune genes (DE-EMTri-genes). Subsequently, the univariate Cox regression was introduced to screen out the prognostic gene sets and a risk model was constructed based on the least absolute shrinkage and selection operator-penalized Cox regression. Additionally, the receiver operating characteristic (ROC) curves were plotted to compare the prognostic value of the newly established model compared with the previous model. Furthermore, the correlation between the risk model and survival probability, immune characteristic, and efficacy of the chemotherapeutics were analyzed by the bioinformatics methods. Results: Six DE-EMTri-genes were ultimately selected to construct the prognostic model. The area under the curve (AUC) values for 1-, 2-, and 3- year were 0.773, 0.721, and 0.673, respectively. Stratified survival analysis suggested that the prognosis of the low-score group was superior to the high-score group. Moreover, the univariate and multivariate analysis indicated that risk score [hazard ratio (HR) 5.071, 95% CI 3.050, 8.432; HR 4.396, 95% CI 2.624, 7.366; p < 0.001] and stage (HR 2.500, 95% CI 1.721, 3.632; HR 2.111, 95% CI 1.443, 3.089; p < 0.001) served as an independent predictive factors in HCC. In addition, the macrophages, natural killer (NK) cells, and regulatory T (Treg) cells were significantly enriched in the high-risk group. Finally, the patients with the high-risk score might be more sensitive to cisplatin, doxorubicin, etoposide, gemcitabine, and mitomycin C. Conclusion: We established a reliable EMTri-genes-based prognostic signature, which may hold promise for the clinical prediction.

Urban-Rural Disparities in the Association Between Body Mass Index and Cognitive Impairment in Older Adults: A Cross-Sectional Study in Central China.

BACKGROUND: Some studies have demonstrated an association between low and high body mass index (BMI) and an increased risk of dementia. However, only a few of these studies were performed in rural areas. OBJECTIVE: This cross-sectional study investigated the associations between BMI and cognitive impairment among community-dwelling older adults from rural and urban areas. METHODS: 8,221 older persons enrolled in the Hubei Memory & Ageing Cohort Study (HMACS) were recruited. Sociodemographic and lifestyle data, comorbidities, physical measurements, and clinical diagnoses of cognitive impairment were analyzed. Logistic regression was performed to assess the associations of BMI categories with cognitive impairment. A series of sensitivity analyses were conducted to test whether reverse causality could influence our results. RESULTS: Being underweight in the rural-dwelling participants increased the risk of cognitive impairment. Being overweight was a protective factor in rural-dwelling participants aged 65-69 years and 75-79 years, whereas being underweight was significantly associated with cognitive impairment (OR, 1.37; 95% CI: 1.03-1.83; p < 0.05). Sensitivity analyses support that underweight had an additive effect on the odds of cognitive impairment and was related to risk of dementia. Interaction test revealed that the differences between urban/rural in the relationship between BMI and cognitive impairment are statistically significant. CONCLUSION: Associations between BMI and cognitive impairment differ among urban/rural groups. Older people with low BMI living in rural China are at a higher risk for dementia than those living in urban areas.

High serum uric acid is associated with increased arterial stiffness in hypertension.

Serum uric acid level has been found to be associated with cerebrovascular diseases. However, whether serum uric acid level is a risk factor for arterial stiffness in the hypertension population is unclear. This study was designed to determine the relationship between serum uric acid level and arterial stiffness in the hypertension population. A total of 10450 participants were evaluated for the risk of arterial stiffness. Brachial-ankle pulse wave velocity (baPWV) was assessed, and high baPWV was determined as the highest quartile of baPWV values in a sex-specific manner. We evaluated the association between serum uric acid level and baPWV through multivariate-adjusted linear and logistic regression analyses. There was a significant difference on high baPWV between patients with quartiles of serum uric acid level in females and males (p<0.01), respectively. The odds ratios (95% CI) of the highest baPWV quartile across the sex-specific serum uric acid level were 1.0, 1.71 (1.35, 2.17), 1.75 (1.38, 2.23), and 1.95 (1.51, 2.51) in female, and 1.0, 1.33 (1.09, 1.64), 1.36 (1.11, 1.67), and 1.67 (1.36, 2.04) in male after adjusting for potential confounders. In conclusion, serum uric acid level could be considered as an important risk factor for arterial stiffness in Chinese hypertension population.

GRIN2B Gene Polymorphism in Chronic Ketamine Users.

BACKGROUND AND OBJECTIVES: We examined the allelic variants of N-methyl- d-aspartate receptor 2B (GRIN2B) and analyzed the associations between GRIN2B gene polymorphism with ketamine use conditions and psychopathological symptoms in chronic ketamine users. METHODS: A total of 231 subjects were recruited. Four single nucleotide polymorphisms of GRIN2B, rs1805502, rs7301328, rs890, and rs1806201 were examined in 151 male chronic ketamine users and 80 controls. Psychopathological symptoms in chronic ketamine users were evaluated using the Positive and Negative Syndrome Scale, the Beck Depression Inventory, and the Beck Anxiety Inventory. RESULTS: The genotype CC of rs1806201 had a lower frequency in ketamine users than that in control subjects (χ2 = 8.167, P = .004) and the T allele frequency of rs1806201 in ketamine users was higher than that in the control subjects (P = .009, odds ratio = 2.019 [1.196-3.410]). Ketamine users of genotype TT and CC of rs1806201 had an earlier onset of ketamine use than subjects of genotype TC (P = .038, P = .049, respectively). The dose of ketamine consumption per day of use was higher in genotype GG of rs7301328 than that in those with CG in ketamine users (P = .026). There were no significant differences of the severity of psychopathologic symptoms among different genotypes tested. CONCLUSION AND SCIENTIFIC SIGNIFICANCE: GRIN2B gene polymorphism may play a role in ketamine abuse. (Am J Addict 2020;29:105-110).