Clinical metabolomics characteristics of diabetic kidney disease: A meta-analysis of 1875 cases with diabetic kidney disease and 4503 controls.

AIMS: Diabetic Kidney Disease (DKD), one of the major complications of diabetes, is also a major cause of end-stage renal disease. Metabolomics can provide a unique metabolic profile of the disease and thus predict or diagnose the development of the disease. Therefore, this study summarises a more comprehensive set of clinical biomarkers related to DKD to identify functional metabolites significantly associated with the development of DKD and reveal their driving mechanisms for DKD. MATERIALS AND METHODS: We searched PubMed, Embase, the Cochrane Library and Web of Science databases through October 2022. A meta-analysis was conducted on untargeted or targeted metabolomics research data based on the strategy of standardized mean differences and the process of ratio of means as the effect size, respectively. We compared the changes in metabolite levels between the DKD patients and the controls and explored the source of heterogeneity through subgroup analyses, sensitivity analysis and meta-regression analysis. RESULTS: The 34 clinical-based metabolomics studies clarified the differential metabolites between DKD and controls, containing 4503 control subjects and 1875 patients with DKD. The results showed that a total of 60 common differential metabolites were found in both meta-analyses, of which 5 metabolites (p < 0.05) were identified as essential metabolites. Compared with the control group, metabolites glycine, aconitic acid, glycolic acid and uracil decreased significantly in DKD patients; cysteine was significantly higher. This indicates that amino acid metabolism, lipid metabolism and pyrimidine metabolism in DKD patients are disordered. CONCLUSIONS: We have identified 5 metabolites and metabolic pathways related to DKD which can serve as biomarkers or targets for disease prevention and drug therapy.

Prostaglandin Injection for Myoma Expulsion (PRIME): Case Series of a Novel Approach to Hysteroscopic Resection of FIGO Type 2 Myomas.

STUDY OBJECTIVE: To evaluate the use of dilute carboprost tromethamine injection at the endometrium/myoma junction during hysteroscopy to facilitate myoma expulsion and removal in a single procedure. DESIGN: Case series. SETTING: Single high-volume academic medical center. PATIENTS: Seven patients aged 32 to 51 years old with FIGO type 2 uterine myomas and symptoms of abnormal uterine bleeding or infertility undergoing hysteroscopic resection with a morcellation device from November 2022 to July 2023. INTERVENTION: Dilute injection of carboprost tromethamine (10 µg/mL) at time of hysteroscopic myomectomy. MEASUREMENTS AND MAIN RESULTS: The main outcome measure was ability to complete the hysteroscopic myomectomy in a single procedure using a hysteroscopic morcellator. Secondary outcomes included total operative time, fluid deficit, and postoperative pharmacologic side effects and/or surgical complications. Among our 7 patients, all had successful single procedure complete resections of myomas ranging from 0.9 to 4.6 cm in maximal diameter. Average operative time was 30 minutes, and average fluid deficit was approximately 839 mL. The carboprost dosages used ranged from 30 to 180 µg. One patient experienced prolonged postoperative nausea and vomiting that resolved with antiemetics. One patient experienced postoperative endometritis that improved with antibiotics. CONCLUSION: In this pilot study, injection of dilute carboprost intraoperatively facilitated one-step hysteroscopic myomectomy of FIGO 2 myomas, via enhanced extrusion of the intramural portion of the fibroid into the uterine cavity, with both short operative times and acceptable fluid deficits.

The role of cyanoalanine synthase and alternative oxidase in promoting salt stress tolerance in Arabidopsis thaliana.

BACKGROUND: Cyanide is a toxic chemical that inhibits cellular respiration. In plants, cyanide can be produced by themselves, especially under stressful conditions. Cyanoalanine synthase (CAS) is a key enzyme involved in plant cyanide detoxification. There are three genes encoding CAS in Arabidopsis thaliana, but the roles of these genes in the plant's response to stress are less studied. In addition, it is known that alternative oxidase (AOX) mediates cyanide-resistant respiration, but the relationship between CAS and AOX in regulating the plant stress response remains largely unknown. RESULTS: Here, the effects of the overexpression or mutation of these three CAS genes on salt stress tolerance were investigated. The results showed that under normal conditions, the overexpression or mutation of the CAS genes had no significant effect on the seed germination and growth of Arabidopsis thaliana compared with wild type (WT). However, under 50, 100, and 200 mM NaCl conditions, the seeds overexpressing CAS genes showed stronger salt stress resistance, i.e., higher germination speed than WT seeds, especially those that overexpressed the CYS-C1 and CYS-D1 genes. In contrast, the seeds with CAS gene mutations exhibited salt sensitivity, and their germination ability and growth were significantly damaged by 100 and 200 mM NaCl. Importantly, this difference in salt stress resistance became more pronounced in CAS-OE, WT, and mutant seeds with increasing salt concentration. The CAS-OE seeds maintained higher respiration rates than the WT and CAS mutant seeds under salt stress conditions. The cyanide contents in CAS mutant seeds were approximately 3 times higher than those in WT seeds and more than 5 times higher than those in CAS-OE seeds. In comparison, plants overexpressing CYS-C1 had the fastest detoxification of cyanide and the best salt tolerance, followed by those overexpressing CYS-D1 and CYS-D2. Furthermore, less hydrogen sulfide (H2S) was observed in CAS-OE seedlings than in WT seedlings under long-term salt stress conditions. Nonetheless, the lack of AOX impaired CAS-OE-mediated plant salt stress resistance, suggesting that CAS and AOX interact to improve salt tolerance is essential. The results also showed that CAS and AOX contributed to the reduction in oxidative damage by helping maintain relatively high levels of antioxidant enzyme activity. CONCLUSION: In summary, the findings of the present study suggest that overexpression of Arabidopsis CAS family genes plays a positive role in salt stress tolerance and highlights the contribution of AOX to CAS-mediated plant salt resistance, mainly by reducing cyanide and H2S toxicity.

A two-stage genome-wide association study identifies novel germline genetic variations in CACNA2D3 associated with radiotherapy response in nasopharyngeal carcinoma.

BACKGROUND: Radiotherapy (RT) is the standard treatment for nasopharyngeal carcinoma (NPC). However, due to individual differences in radiosensitivity, biomarkers are needed to tailored radiotherapy to cancer patients. However, comprehensive genome-wide radiogenomic studies on them are still lacking. The aim of this study was to identify genetic variants associated with radiotherapy response in patients with NPC. METHODS: This was a large­scale genome-wide association analysis (GWAS) including a total of 981 patients. 319 individuals in the discovery stage were genotyped for 688,783 SNPs using whole genome-wide screening microarray. Significant loci were further genotyped using MassARRAY system and TaqMan SNP assays in the validation stages of 847 patients. This study used logistic regression analysis and multiple bioinformatics tools such as PLINK, LocusZoom, LDBlockShow, GTEx, Pancan-meQTL and FUMA to examine genetic variants associated with radiotherapy efficacy in NPC. RESULTS: After genome-wide level analysis, 19 SNPs entered the validation stage (P < 1 × 10- 6), and rs11130424 ultimately showed statistical significance among these SNPs. The efficacy was better in minor allele carriers of rs11130424 than in major allele carriers. Further stratified analysis showed that the association existed in patients in the EBV-positive, smoking, and late-stage (III and IV) subgroups and in patients who underwent both concurrent chemoradiotherapy and induction/adjuvant chemotherapy. CONCLUSION: Our study showed that rs11130424 in the CACNA2D3 gene was associated with sensitivity to radiotherapy in NPC patients. TRIAL REGISTRATION NUMBER: Effect of genetic polymorphism on nasopharyngeal carcinoma chemoradiotherapy reaction, ChiCTR-OPC-14005257, Registered 18 September 2014, http://www.chictr.org.cn/showproj.aspx?proj=9546 .

Mouse papillomavirus type 1 (MmuPV1) DNA is frequently integrated in benign tumors by microhomology-mediated end-joining.

MmuPV1 is a useful model for studying papillomavirus-induced tumorigenesis. We used RNA-seq to look for chimeric RNAs that map to both MmuPV1 and host genomes. In tumor tissues, a higher proportion of total viral reads were virus-host chimeric junction reads (CJRs) (1.9‰ - 7‰) than in tumor-free tissues (0.6‰ - 1.3‰): most CJRs mapped to the viral E2/E4 region. Although most of the MmuPV1 integration sites were mapped to intergenic regions and introns throughout the mouse genome, integrations were seen more than once in several genes: Malat1, Krt1, Krt10, Fabp5, Pard3, and Grip1; these data were confirmed by rapid amplification of cDNA ends (RACE)-Single Molecule Real-Time (SMRT)-seq or targeted DNA-seq. Microhomology sequences were frequently seen at host-virus DNA junctions. MmuPV1 infection and integration affected the expression of host genes. We found that factors for DNA double-stranded break repair and microhomology-mediated end-joining (MMEJ), such as H2ax, Fen1, DNA polymerase Polθ, Cdk1, and Plk1, exhibited a step-wise increase and Mdc1 a decrease in expression in MmuPV1-infected tissues and MmuPV1 tumors relative to normal tissues. Increased expression of mitotic kinases CDK1 and PLK1 appears to be correlated with CtIP phosphorylation in MmuPV1 tumors, suggesting a role for MMEJ-mediated DNA joining in the MmuPV1 integration events that are associated with MmuPV1-induced progression of tumors.

Salvianolic Acids Alleviate Chronic Mild Stress-Induced Depressive-Like Behaviors in Rats.

BACKGROUND: Salvianolic acids possess anti-inflammatory properties. This study investigated the therapeutic effect of salvianolic acids on chronic mild stress (CMS)-induced depressive-like behaviors in rats and the involvement of toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88). METHODS: Eighty male Sprague-Dawley rats were randomly subjected to CMS or non-CMS protocol for 6 weeks. Starting 3 weeks after CMS exposure, the rats in each group were administered saline, fluoxetine (positive control), salvianolic acids, or salvianolic acids + fluoxetine daily for 3 weeks. The body weight change, sucrose preference, and immobility duration in forced swimming were examined before and after drug treatment. The rats were sacrificed at 3 weeks after drug treatment. Quantitative real-time PCR was performed to measure the mRNA levels of TLR4 and MyD88 in the prefrontal cortex and hippocampus of rats. RESULTS: Compared with non-CMS rats, CMS rats had significantly reduced weight gains and sucrose preference, along with significantly increased immobility durations and elevated mRNA levels of TLR4 and MyD88 in both the prefrontal cortex and hippocampus. Treatment with fluoxetine and salvianolic acids, alone or in combination, facilitated weight gains, alleviated depressive-like behaviors, and reduced cerebral TLR4/MyD88 mRNA levels in CMS rats. Besides, fluoxetine and salvianolic acids additively suppressed TLR4/MyD88 mRNA expression in the prefrontal cortex of rats. Furthermore, TLR4 mRNA levels in both hippocampus and prefrontal cortex positively correlated with MyD88 mRNA expression, inflammatory cytokine secretion, and immobility duration but negatively correlated with sucrose preference. CONCLUSIONS: Thus, salvianolic acids alleviate depressive-like behaviors, possibly by suppressing TLR4/MyD88-mediated inflammatory signaling in the brain.

Genetic analysis of the ATP11B gene in Chinese Han population with cerebral small vessel disease.

BACKGROUND: A loss-of-function mutation in ATPase phospholipid transporting 11-B (putative) (ATP11B) gene causing cerebral small vessel disease (SVD) in vivo, and a single intronic nucleotide polymorphism in ATP11B: rs148771930 that was associated with white matter hyperintensities burden in European patients with SVD, was recently identified. Our results suggest that ATP11B may not play an essential role in SVD in the Chinese population. RESULTS: We performed target region sequencing including ATP11B gene in 182 patients with sporadic SVD, and identified five rare variants and two novel variants of ATP11B. A case-control study was then performed in 524 patients and matched 550 controls to investigate the relationship between ATP11B and sporadic SVD in the Chinese Han population. Although none of these variants were significantly associated with SVD in our samples, it is important to mention that we identified a novel variant, p. G238W, which was predicted to be pathogenic in silico. This variant was present in our cohort of patients with an extremely low frequency and was absent in the controls. CONCLUSION: Our results suggest that ATP11B may not play an essential role in SVD in the Chinese population.

A two-stage genome-wide association study to identify novel genetic loci associated with acute radiotherapy toxicity in nasopharyngeal carcinoma.

BACKGROUND: Genetic variants associated with acute side effects of radiotherapy in nasopharyngeal carcinoma (NPC) remain largely unknown. METHODS: We performed a two-stage genome-wide association analysis including a total of 1084 patients, where 319 individuals in the discovery stage were genotyped for 688,783 SNPs using whole genome-wide screening microarray. Significant variants were then validated in an independent cohort of 765 patients using the MassARRAY system. Gene mapping, linkage disequilibrium, genome-wide association analysis, and polygenic risk score were conducted or calculated using FUMA, LDBlockShow, PLINK, and PRSice software programs, respectively. RESULTS: Five SNPs (rs6711678, rs4848597, rs4848598, rs2091255, and rs584547) showed statistical significance after validation. Radiotherapy toxicity was more serious in mutant minor allele carriers of all five SNPs. Stratified analysis further indicated that rs6711678, rs4848597, rs4848598, and rs2091255 correlated with skin toxicity in patients of EBV positive, late stage (III and IV), receiving both concurrent chemoradiotherapy and induction/adjuvant chemotherapy, and with OR values ranging from 1.92 to 2.66. For rs584547, high occurrence of dysphagia was found in A allele carriers in both the discovery (P = 1.27 × 10- 6, OR = 1.55) and validation (P = 0.002, OR = 4.20) cohorts. Furthermore, prediction models integrating both genetic and clinical factors for skin reaction and dysphagia were established. The area under curve (AUC) value of receiver operating characteristic (ROC) curves were 0.657 (skin reaction) and 0.788 (dysphagia). CONCLUSIONS: Rs6711678, rs4848597, rs4848598, and rs2091255 on chromosome 2q14.2 and rs584547 were found to be novel risk loci for skin toxicity and dysphagia in NPC patients receiving radiotherapy. TRIAL REGISTRATION: Chinese Clinical Trial Register (registration number: ChiCTR-OPC-14005257 and CTXY-140007-2).

New insights into the role of cyanide in the promotion of seed germination in tomato.

BACKGROUND: Cyanide is a natural metabolite that exists widely in plants, and it is speculated to be involved in the regulation of various growth and development processes of plants in addition to being regarded as toxic waste. Previous studies have shown that exogenous cyanide treatment helps to improve seed germination, but the mechanism is still unclear. In this study, tomato (Solanum lycopersicum cv. Alisa Craig) was used as the material, and the effects of cyanide pretreatment at different concentrations on tomato seed germination were investigated. RESULTS: The results showed that exogenous application of a lower concentration of cyanide (10 µmol/L KCN) for 12 h strongly increased the tomato seed germination rate. RNA-Seq showed that compared with the control, a total of 15,418 differentially expressed genes (P<0.05) were obtained after pretreatment with KCN for 12 h, and in the next 12 h, a total of 13,425 differentially expressed genes (P<0.05) were regulated. GO and KEGG analyses demonstrated that exogenous KCN pretreatment was involved in regulating the expression (mainly downregulation) of seed storage proteins, thereby accelerating the degradation of stored proteins for seed germination. In addition, KCN pretreatment was also involved in stimulating glycolysis, the TCA cycle and oxidative phosphorylation. Notably, it is shown that KCN acted on the regulation of plant hormone biosynthesis and perception, i.e., down-regulated the gene expression of ABA biosynthesis and signal transduction, but up-regulated the expression of genes related to GA biosynthesis and response. Consistent with this, plant hormone measurements confirmed that the levels of ABA were reduced, but GA levels were induced after pretreatment with KCN. CONCLUSION: These findings provide new insights into the regulation of seed germination by cyanide, that is cyanide-mediated seed germination occurs in a time- and dose-dependent manner, and is related to the mobilization of energy metabolism and the regulation of some plant hormone signals.

HPV16 and HPV18 Genome Structure, Expression, and Post-Transcriptional Regulation.

Human papillomaviruses (HPV) are a group of small non-enveloped DNA viruses whose infection causes benign tumors or cancers. HPV16 and HPV18, the two most common high-risk HPVs, are responsible for ~70% of all HPV-related cervical cancers and head and neck cancers. The expression of the HPV genome is highly dependent on cell differentiation and is strictly regulated at the transcriptional and post-transcriptional levels. Both HPV early and late transcripts differentially expressed in the infected cells are intron-containing bicistronic or polycistronic RNAs bearing more than one open reading frame (ORF), because of usage of alternative viral promoters and two alternative viral RNA polyadenylation signals. Papillomaviruses proficiently engage alternative RNA splicing to express individual ORFs from the bicistronic or polycistronic RNA transcripts. In this review, we discuss the genome structures and the updated transcription maps of HPV16 and HPV18, and the latest research advances in understanding RNA cis-elements, intron branch point sequences, and RNA-binding proteins in the regulation of viral RNA processing. Moreover, we briefly discuss the epigenetic modifications, including DNA methylation and possible APOBEC-mediated genome editing in HPV infections and carcinogenesis.

Correction: Yu et al. HPV16 and HPV18 Genome Structure, Expression, and Post-Transcriptional Regulation. Int. J. Mol. Sci. 2022, 23, 4943.

In the published review [...].

Preclinical Pharmacokinetics and Bioavailability of Oxypeucedanin in Rats after Single Intravenous and Oral Administration.

Oxypeucedanin, a furanocoumarin extracted from many traditional Chinese herbal medicines, has a variety of pharmacological effects. However, the independent pharmacokinetic characteristics and bioavailability of this compound remains elusive. In this study, a rapid, sensitive, and selective method using ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC/MS/MS) was developed for evaluating the intravenous and oral pharmacokinetics of oxypeucedanin. After intravenous administration of oxypeucedanin (2.5, 5, and 10 mg/kg), and intragastric administration of oxypeucedanin (20 mg/kg), blood samples were collected periodically from the tail vein. The plasma concentration-time curves were plotted, and the pharmacokinetic parameters were calculated using a non-compartmental model analysis. After intravenous administration of oxypeucedanin (single dosing at 2.5, 5, and 10 mg/kg) to rats, the pharmacokinetics fit the linear kinetics characteristics, which showed that some parameters including average elimination half-life (T1/2Z of 0.61~0.66 h), mean residence time (MRT of 0.62~0.80 h), apparent volume of distribution (VZ of 4.98~7.50 L/kg), and systemic clearance (CLZ of 5.64~8.55 L/kg/h) are dose-independent and the area under concentration-time curve (AUC) increased in a dose-proportional manner. Single oral administration of oxypeucedanin (20 mg/kg) showed poor and slow absorption with the mean time to reach the peak concentration (Tmax) of 3.38 h, MRT of 5.86 h, T1/2Z of 2.94 h, and a mean absolute bioavailability of 10.26% in rats. These results provide critical information for a better understanding of the pharmacological effect of oxypeucedanin, which will facilitate its research and development.

Development of models for cervical cancer screening: construction in a cross-sectional population and validation in two screening cohorts in China.

BACKGROUND: Current methods for cervical cancer screening result in an increased number of referrals and unnecessary diagnostic procedures. This study aimed to develop and evaluate a more accurate model for cervical cancer screening. METHODS: Multiple predictors including age, cytology, high-risk human papillomavirus (hrHPV) DNA/mRNA, E6 oncoprotein, HPV genotyping, and p16/Ki-67 were used for model construction in a cross-sectional population including women with normal cervix (N = 1085), cervical intraepithelial neoplasia (CIN, N = 279), and cervical cancer (N = 551) to predict CIN2+ or CIN3+. A base model using age, cytology, and hrHPV was calculated, and extended versions with additional biomarkers were considered. External validations in two screening cohorts with 3-year follow-up were further conducted (NCohort-I = 3179, NCohort-II = 3082). RESULTS: The base model increased the area under the curve (AUC, 0.91, 95% confidence interval [CI] = 0.88-0.93) and reduced colposcopy referral rates (42.76%, 95% CI = 38.67-46.92) compared to hrHPV and cytology co-testing in the cross-sectional population (AUC 0.80, 95% CI = 0.79-0.82, referrals rates 61.62, 95% CI = 59.4-63.8) to predict CIN2+. The AUC further improved when HPV genotyping and/or E6 oncoprotein were included in the base model. External validation in two screening cohorts further demonstrated that our models had better clinical performances than routine screening methods, yielded AUCs of 0.92 (95% CI = 0.91-0.93) and 0.94 (95% CI = 0.91-0.97) to predict CIN2+ and referrals rates of 17.55% (95% CI = 16.24-18.92) and 7.40% (95% CI = 6.50-8.38) in screening cohort I and II, respectively. Similar results were observed for CIN3+ prediction. CONCLUSIONS: Compared to routine screening methods, our model using current cervical screening indicators can improve the clinical performance and reduce referral rates.

Oncogenic splicing factor SRSF3 regulates ILF3 alternative splicing to promote cancer cell proliferation and transformation.

Alternative RNA splicing is an important focus in molecular and clinical oncology. We report here that SRSF3 regulates alternative RNA splicing of interleukin enhancer binding factor 3 (ILF3) and production of this double-strand RNA-binding protein. An increased coexpression of ILF3 isoforms and SRSF3 was found in various types of cancers. ILF3 isoform-1 and isoform-2 promote cell proliferation and transformation. Tumor cells with reduced SRSF3 expression produce aberrant isoform-5 and -7 of ILF3. By binding to RNA sequence motifs, SRSF3 regulates the production of various ILF3 isoforms by exclusion/inclusion of ILF3 exon 18 or by selection of an alternative 3' splice site within exon 18. ILF3 isoform-5 and isoform-7 suppress tumor cell proliferation and the isoform-7 induces cell apoptosis. Our data indicate that ILF3 isoform-1 and isoform-2 are two critical factors for cell proliferation and transformation. The increased SRSF3 expression in cancer cells plays an important role in maintaining the steady status of ILF3 isoform-1 and isoform-2.

Succinate induces skeletal muscle fiber remodeling via SUNCR1 signaling.

The conversion of skeletal muscle fiber from fast twitch to slow-twitch is important for sustained and tonic contractile events, maintenance of energy homeostasis, and the alleviation of fatigue. Skeletal muscle remodeling is effectively induced by endurance or aerobic exercise, which also generates several tricarboxylic acid (TCA) cycle intermediates, including succinate. However, whether succinate regulates muscle fiber-type transitions remains unclear. Here, we found that dietary succinate supplementation increased endurance exercise ability, myosin heavy chain I expression, aerobic enzyme activity, oxygen consumption, and mitochondrial biogenesis in mouse skeletal muscle. By contrast, succinate decreased lactate dehydrogenase activity, lactate production, and myosin heavy chain IIb expression. Further, by using pharmacological or genetic loss-of-function models generated by phospholipase Cß antagonists, SUNCR1 global knockout, or SUNCR1 gastrocnemius-specific knockdown, we found that the effects of succinate on skeletal muscle fiber-type remodeling are mediated by SUNCR1 and its downstream calcium/NFAT signaling pathway. In summary, our results demonstrate succinate induces transition of skeletal muscle fiber via SUNCR1 signaling pathway. These findings suggest the potential beneficial use of succinate-based compounds in both athletic and sedentary populations.

Magnetically induced self-assembly DNAzyme electrochemical biosensor based on gold-modifiedα-Fe2O3/Fe3O4heterogeneous nanoparticles for sensitive detection of Ni2.

A magnetically induced self-assembly DNAzyme electrochemical biosensor based on gold-modifiedα-Fe2O3/Fe3O4heterogeneous nanoparticles was successfully fabricated to detect Nickel(II) (Ni2+). The phase composition and magnetic properties ofα-Fe2O3/Fe3O4heterogeneous nanoparticles controllably prepared by the citric acid (CA) sol-gel method were investigated in detail. Theα-Fe2O3/Fe3O4heterogeneous nanoparticles were modified by using trisodium citrate as reducing agent, and the magnetically induced self-assemblyα-Fe2O3/Fe3O4-Au nanocomposites were obtained. The designed Ni2+-dependent DNAzyme consisted of the catalytic chain modified with the thiol group (S1-SH) and the substrate chain modified with methylene blue (S2-MB). The MGCE/α-Fe2O3/Fe3O4-Au/S1/BSA/S2 electrochemical sensing platform was constructed and differential pulse voltammetry was applied for electrochemical detection. Under the optimum experimental parameters, the detection range of the biosensor was 100 pM-10µM (R2 = 0.9978) with the limit of detection of 55 pM. The biosensor had high selectivity, acceptable stability, and reproducibility (RSD = 4.03%).

Prevalence and risks of mild cognitive impairment of Chinese community-dwelling women aged above 60 years: A cross-sectional study.

Evidence has shown that risks of cognitive impairment differ between genders. This cross-sectional study sought to determine the prevalence of mild cognitive impairment (MCI) in Chinese community-dwelling women aged above 60 years and identify risks of MCI by multivariate logistic regression analysis. Totally, 1760 Chinese community-dwelling women entered the study. Cognitive function was assessed with Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA). MCI was diagnosed by Petersen's criteria. Sociodemographic information, past medical conditions, and age at menopause were screened. The primary study outcome was prevalence of MCI. MCI was diagnosed in 378 (21.5%) women. Older age was a significant risk of MCI (OR 1.621, 95%CI 1.386-1.894; P < 0.001). Low education was associated a 4-fold increase in the risk of MCI (OR 4.036, 95%CI 3.168-5.142). Furthermore, current depression was associated with 2.6-fold increase in the risk of MCI (OR 2.618, 95%CI 1.499-4.587, P = 0.001). Moreover, frequent physical exercise and more leisure and social time activities were associated with significantly reduced risks of MCI, while poor financial status was associated with a significantly increased risk of MCI. Slightly more than 20% of Chinese women aged above 60 years had MCI, and independent risks included older age, low education status, and current depression, highlighting the importance of screening for and removing or minimizing risks of MCI in this specific population.

KSHV RNA-binding protein ORF57 inhibits P-body formation to promote viral multiplication by interaction with Ago2 and GW182.

Cellular non-membranous RNA-granules, P-bodies (RNA processing bodies, PB) and stress granules (SG), are important components of the innate immune response to virus invasion. Mechanisms governing how a virus modulates PB formation remain elusive. Here, we report the important roles of GW182 and DDX6, but not Dicer, Ago2 and DCP1A, in PB formation, and that Kaposi's sarcoma-associated herpesvirus (KSHV) lytic infection reduces PB formation through several specific interactions with viral RNA-binding protein ORF57. The wild-type ORF57, but not its N-terminal dysfunctional mutant, inhibits PB formation by interacting with the N-terminal GW-domain of GW182 and the N-terminal domain of Ago2, two major components of PB. KSHV ORF57 also induces nuclear Ago2 speckles. Homologous HSV-1 ICP27, but not EBV EB2, shares this conserved inhibitory function with KSHV ORF57. By using time-lapse confocal microscopy of HeLa cells co-expressing GFP-tagged GW182, we demonstrated that viral ORF57 inhibits primarily the scaffolding of GW182 at the initial stage of PB formation. Consistently, KSHV-infected iSLK/Bac16 cells with reduced GW182 expression produced far fewer PB and SG, but 100-fold higher titer of infectious KSHV virions when compared to cells with normal GW182 expression. Altogether, our data provide the first evidence that a DNA virus evades host innate immunity by encoding an RNA-binding protein that promotes its replication by blocking PB formation.

Functional deficit of sense organs as a risk factor for cognitive functional disorder in Chinese community elderly people.

OBJECTIVE: To explore the relationship between mild cognitive impairment (MCI) and sense organs functional deficit in community elderly people. METHODS: A total of 3095 community elderly people above 60 years in Hebei Province were selected by cross-sectional random cluster sampling method, who were evaluated face-to-face for general demographic data, the condition of sense organs functional deficit (vision, hearing, gustation, olfactory sensation, taste) and cognitive function by Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). RESULTS: A total of 3075 valid questionnaires were obtained. (a) 1368 old people (44.49%) were defined with sense organs functional deficit (defined as one or more of glaucoma, fundus disease, hearing impairment, olfactory disorder and taste disorder) in 3095 elderly people. According to questionnaires, MCI was diagnosed in 689 of 3075 participants (22.41%). The hearing disorder and glaucoma of MCI group were higher than that of the normal control group (X2 were 5.998 and 7.430, respectively, P were .014 and .006, respectively). (b) The MMSE score of the hearing disorder were significantly lower than those of non-hearing disorder group (t = 2.046, P = .041). (c) Multinomial logistics regression analysis was applied by MCI as the dependent variable and the various sensory organs defects as independent variables. The hearing impairment (Wald = 8.582, P = .003, OR = 1.485, 95% CI: 1.140-1.934) and glaucoma (Wald = 8.020, P = .005, OR = 1.847, 95% CI: 1.208-2.824) were associated with MCI. CONCLUSION: The sensory organs functional defects is associated with the mild cognitive impartment in Chinese elderly, especially in vision and hearing disorder.

Experiencing earthquake in the first trimester of the fetal life increases subsequent diabetes risk in the adulthood: a cross-sectional study.

OBJECTIVE: To investigate the long-term effect of prenatal exposure to earthquake stress on diabetes risk in the adulthood. METHODS: This study included employees of Tangshan Kailuan Mining Group between July 29, 1976 and April 28, 1977. The exposure group included subjects who experienced the Tangshan Earthquake during their prenatal period and who had lived in Tangshan since birth. The non-exposure group included subjects who were born 1-1.9 years after the earthquake and who had lived in Tangshan since birth. A questionnaire was designed that included sociodemographic information, conditions during pregnancy, and earthquake experience. Anthropometric measurements including height and weight, body mass index (BMI), waist circumference were made. Fasting plasma glucose (FPG) and lipid profiles were also determined. RESULTS: Totally 947 subjects were included with 397 subjects in the exposed group and 550 subjects in the non-exposed group. The diabetes rate is significant different in these four groups(χ2 =8.045, P = 0.045). Moreover, 11.8, 7.5 and 8.0% of the subjects who were exposed to earthquake in the 1st, 2nd, and 3rd trimester of pregnancy had diabetes. 5.1% of the subjects had diabetes in non-exposure group. Our multivariate analysis showed that 1st trimester (OR 2.481, 95%CI 1.02, 6.034; P = 0.045) and loss of family members during earthquake (OR 2.452, 95%CI 1.293, 4.653; P = 0.006) were associated with significantly increased risk of diabetes. CONCLUSIONS: Exposure to earthquake during the first trimester of pregnancy and experience of family member loss in the earthquake significantly increased the subsequent risk of diabetes in the middle age (36-39 years of age). Our data suggest that earthquake experience in the early pregnancy has a longer-term effect on diabetes risk during adulthood.