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Although the correlation between cognition and physical function has been well studied in the general population, the genetic and environmental nature of the correlation has been rarely investigated. We conducted a classical twin analysis on cognitive and physical function, including forced expiratory volume in one second (FEV1), forced vital capacity (FVC), handgrip strength, five-times-sit-to-stand test (FTSST), near visual acuity, and number of teeth lost in 379 complete twin pairs. Bivariate twin models were fitted to estimate the genetic and environmental correlation between physical and cognitive function. Bivariate analysis showed mildly positively genetic correlations between cognition and FEV1, rG = 0.23 [95% CI: 0.03, 0.62], as well as FVC, rG = 0.35 [95% CI: 0.06, 1.00]. We found that FTSST and cognition presented very high common environmental correlation, rC = -1.00 [95% CI: -1.00, -0.57], and low but significant unique environmental correlation, rE = -0.11 [95% CI: -0.22, -0.01], all in the negative direction. Meanwhile, near visual acuity and cognition also showed unique environmental correlation, rE = 0.16 [95% CI: 0.03, 0.27]. We found no significantly genetic correlation for cognition with handgrip strength, FTSST, near visual acuity, and number of teeth lost. Cognitive function was genetically related to pulmonary function. The FTSST and cognition shared almost the same common environmental factors but only part of the unique environmental factors, both with negative correlation. In contrast, near visual acuity and cognition may positively share part of the unique environmental factors.

The hub genes found by the criterion of BMI based GS > 0.2 and MM > 0.8 with a threshold of P-value

Summary of the sequencing reads and the mapped results for the 7 monozygotic twin pairs (DOCX 17Â kb)

Existing pressure sensitive adhesives (PSA) are mostly based on petrochemical-based polymers. This study reveals a new class of bio-based polymers that can be used as PSA. The polymers are hydroxyl-containing polyesters from the step-growth polymerization of epoxidized oleic acid (EOA), an AB-type monomer containing both a carboxylic acid group (A) and an epoxy group (B). The monomer is derived from epoxidation of renewable methyl oleate followed by selective hydrolysis of the ester group. The polymers (PEOA) of EOA were characterized for their chemical structure and molecular weight. The PEOA after being cured with a very small amount of a crosslinking agent could serve as a PSA with high peel strength, high tack force, superior shear resistance, excellent aging resistance, and excellent thermal stability. The PSA contains 99 wt% of green renewable materials. The PSA were also characterized for their viscoelastic properties and thermal properties.

Aims We carried out a meta-analysis to summarize the evidence from published studies on macronutrients intake and risk of Parkinson's disease (PD). Methods Pertinent studies were identified by a search of PubMed and Embase. Study-specific effect was combined with the random-effect model. The dose–response relationship was assessed by the restricted cubic spline. Results For highest versus lowest level of intake, the relative risk (RR) of PD was 1.13 (95% CI 0.88–1.44) for protein (7 articles including 1570 PD cases among 357 827 subjects), RR 1.24 (95% CI 1.05–1.48) for carbohydrate (8 articles including 1482 PD cases among 232 869 subjects), RR 0.88 (95% CI 0.74–1.06) for fat (12 articles including 2936 PD cases among 374 124 subjects), RR 0.97 (95% CI 0.75–1.26) for cholesterol (6 articles including 1713 PD cases among 170 058 subjects) and 1.39 (95% CI 1.01–1.92) for energy (8 articles including 1553 PD cases among 170 317 subjects), respectively. Among prospective studies adjusting for smoking and coffee/caffeine, no associations were found between PD risk and intake of protein (RR 1.02, 95% CI 0.80–1.30), carbohydrate (RR 1.11, 95% CI 0.86–1.43), fat (RR 0.90, 95% CI 0.70–1.16), cholesterol (RR 0.89, 95% CI 0.74–1.09) and energy (RR 0.97, 95% CI 0.93–1.02); however, polyunsaturated fatty acid (RR 0.78, 95% CI 0.64–0.96) was inversely associated with PD risk. Limited data showed a linear dose–response relationship between the aforementioned macronutrients and PD risk. Conclusions Dietary intake of protein, carbohydrate, cholesterol and energy might be not independently associated with PD risk. Higher intake of polyunsaturated fatty acid might be inversely associated with PD risk. Confounding by smoking and coffee/caffeine should be considered regarding the association between fat intake and PD risk in further studies. Geriatr Gerontol Int 2015; 15: 606–616.

AD, a devastating neurodegenerative disorder, is the most common cause of dementia in the elderly. Patients with AD are characterized by three hallmarks of neuropathology including neuritic plaque deposition, neurofibrillary tangle formation, and neuronal loss. Growing evidences indicate that dysregulation of regulator of calcineurin 1 (RCAN1) plays an important role in the pathogenesis of AD. Aberrant RCAN1 expression facilitates neuronal apoptosis and Tau hyperphosphorylation, leading to neuronal loss and neurofibrillary tangle formation. This review aims to describe the recent advances of the regulation of RCAN1 expression and its physiological functions. Moreover, the AD risk factors-induced RCAN1 dysregulation and its role in promoting neuronal loss, synaptic impairments and neurofibrillary tangle formation are summarized. Furthermore, we provide an outlook into the effects of RCAN1 dysregulation on APP processing, Aβ generation and neuritic plaque formation, and the possible underlying mechanisms, as well as the potential of targeting RCAN1 as a new therapeutic approach.

To estimate whether the associations of obesity, physical activity, vision and grip strength with functional mobility were modified by age.Data from The Irish Longitudinal Study on Ageing (2009-2012) were analyzed and 5001 individuals were included in this study. Mobility was assessed by the timed up and go test (TUG-test). Main exposure variables were obesity, physical activity, visual acuity and grip strength at baseline. Multiple linear regression models were fitted to assess the associations of baseline main exposure variables with 2-year follow-up functional mobility and potential confounders were adjusted. Stratified analyses by age were used to assess the interaction between main exposures and age on functional mobility.Multiple linear regression models identified significant interactions of obesity (P 0.001), vigorous physical activity (P = 0.001), vision (P 0.001) and grip strength (P 0.001) with age on functional mobility. Stratified analyses suggested that the risk effect of obesity on functional mobility was greater in middle-aged group (β = 0.025, P 0.001) than in older group (β = 0.016, P = 0.017). The protective effects of high level of physical activity and grip strength on functional mobility were stronger in older group (β = -0.023, P = 0.004 for physical activity; β = -0.002, P 0.001 for grip strength) than in middle-aged group (β = -0.012, P = 0.008 for physical activity; β = -0.0015, P 0.001 for grip strength). The benefit of better vision on functional mobility was observed in middle-aged group only (β = -0.032, P = 0.002).Non-obesity, higher level of physical activity, vision and grip strength at baseline were associated with better mobility performance among middle-aged and older Irish. And these associations were modified by age.

A meta-analysis of cohort studies was conducted to assess the association between serum uric acid (SUA) levels and incidence of impaired fasting glucose (IFG) and type 2 diabetes mellitus (T2DM).A comprehensive search was conducted to identify eligible studies. The fixed or random effect pooled measure was selected based on between-study heterogeneity. Dose-response relationship was assessed by restricted cubic spline model and multivariate random-effect meta-regression.Twelve studies with fifteen results were included involving 6340 cases and 62,834 participants. The pooled multivariate-adjusted relative risk (RR) (95%CI) of IFG and T2DM for the highest vs. lowest level of SUA was 1.54 (1.41-1.68), I(2)=42.2%. The association was consistent and significant across subgroup analysis. A nonlinear relationship was found of SUA levels with incidence of IFG and T2DM (P0.01), and the multivariate-adjusted RRs (95%CI) of IFG and T2DM were 1.02 (0.95-1.10), 1.04 (0.94-1.15), 1.10 (0.99-1.22), 1.25 (1.16-1.35), 1.43 (1.31-1.55), 1.50 (1.38-1.63) and 1.49 (1.34-1.67) for 2.5, 3.5, 4.5, 5.5, 6.5, 7.5 and 8.5mg/dl of SUA. The RR (95%CI) of T2DM for the highest vs. lowest level of SUA was 1.67 (1.51-1.86), and a nonlinear relationship was also found between SUA levels and incidence of T2DM.SUA levels are positively associated with incidence of IFG and T2DM, and the association might be nonlinear.

We conducted an updated meta-analysis to summarize the evidence from published studies regarding the association of coffee and caffeine intake with breast cancer risk.Pertinent studies were identified by a search of PubMed and by reviewing the reference lists of retrieved articles. The fixed or random effect model was used based on heterogeneity test. The dose-response relationship was assessed by restricted cubic spline model and multivariate random-effect meta-regression.37 published articles, involving 59,018 breast cancer cases and 966,263 participants, were included in the meta-analysis. No significant association was found between breast cancer risk and coffee (RR=0.97, P=0.09), decaffeinated coffee (RR=0.98, P=0.55) and caffeine (RR=0.99, P=0.73), respectively. And the association was still not significant when combining coffee and caffeine (coffee/caffeine) (RR=0.97, P=0.09). However, an inverse association of coffee/caffeine with breast cancer risk was found for postmenopausal women (RR=0.94, P=0.02), and a strong and significant association of coffee with breast cancer risk was found for BRCA1 mutation carriers (RR=0.69, P0.01). A linear dose-response relationship was found for breast cancer risk with coffee and caffeine, and the risk of breast cancer decreased by 2% (P=0.05) for every 2 cups/day increment in coffee intake, and 1% (P=0.52) for every 200mg/day increment in caffeine intake, respectively.Findings from this meta-analysis suggested that coffee/caffeine might be weakly associated with breast cancer risk for postmenopausal women, and the association for BRCA1 mutation carriers deserves further investigation.

Recently, many studies have investigated the association of allelic variants of Wolfram syndrome gene (WFS1) with insulin secretion, insulin sensitivity and the risk of hyperglycemia and type 2 diabetes (T2D). Although it is clear that WFS1 mutations cause diabetes, the genetic basis of the association of common WFS1 variants with T2D is still unclear. To date, many case-control studies have been carried out to investigate the role of the WFS1 gene polymorphism in the development of T2D. However, these studies are controversial and individual studies may have insufficient power to reach a comprehensive and reliable conclusion. The aim of this study was to investigate association of WFS1 genes polymorphisms (rs734312 and rs10010131) with T2D by conducting a meta-analysis. Seven studies with 6705 T2D cases and 11144 controls were enrolled in the meta-analysis of the association between rs734312 polymorphism and T2D, and 12 studies with 16304 T2D cases and 22004 controls were enrolled in the meta-analysis of rs10010131 polymorphism. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using fixed and random-effects models. Heterogeneity among studies was evaluated using the I² and Begg's test was used to evaluate publication bias. Sensitivity analysis was also performed. Our results suggested that the G allele of rs734312 polymorphism [dominant: FEM OR 0.873, 95%CI (0.810 - 0.940), recessive: FEM OR 0.876, 95% CI (0.800 - 0.959)] and A allele of rs10010131 polymorphism [dominant:FEM OR 0.853, 95% CI (0.817 - 0.892), recessive:REM OR 0.833, 95% CI (0.756 - 0.917)] in WFS1 gene had significant protective effects on risk of T2D.

Deposition of amyloid β protein (Aβ) to form neuritic plaques in the brain is the pathological hallmark of Alzheimer's disease (AD). Aβ is generated from sequential cleavages of the β-amyloid precursor protein (APP) by the β- and γ-secretases, and β-site APP-cleaving enzyme 1 (BACE1) is the β-secretase essential for Aβ generation. Previous studies have indicated that glycogen synthase kinase 3 (GSK3) may play a role in APP processing by modulating γ-secretase activity, thereby facilitating Aβ production. There are two highly conserved isoforms of GSK3: GSK3α and GSK3β. We now report that specific inhibition of GSK3β, but not GSK3α, reduced BACE1-mediated cleavage of APP and Aβ production by decreasing BACE1 gene transcription and expression. The regulation of BACE1 gene expression by GSK3β was dependent on NF-κB signaling. Inhibition of GSK3 signaling markedly reduced Aβ deposition and neuritic plaque formation, and rescued memory deficits in the double transgenic AD model mice. These data provide evidence for regulation of BACE1 expression and AD pathogenesis by GSK3β and that inhibition of GSK3 signaling can reduce Aβ neuropathology and alleviate memory deficits in AD model mice. Our study suggests that interventions that specifically target the β-isoform of GSK3 may be a safe and effective approach for treating AD.

Histone acetylation is a major mechanism of chromatin remodeling, contributing to epigenetic regulation of gene transcription. Histone deacetylases (HDACs) are involved in both physiological and pathological conditions by regulating the status of histone acetylation. Although histone deacetylase 4 (HDAC4), a member of the HDAC family, may lack histone deacetylase activity, it is actively involved in regulating the transcription of genes involved in synaptic plasticity, neuronal survival and neurodevelopment by interacting with transcription factors, signal transduction molecules and HDAC3, another member of the HDAC family. HDAC4 is highly expressed in brain and its homeostasis is crucial for the maintenance of cognitive function. Accumulated evidence shows that HDAC4 expression is dysregulated in several brain disorders, including neurodegenerative diseases and mental disorders. Moreover, cognitive impairment is a characteristic feature of these diseases. It indicates that aberrant HDAC4 expression plays a pivotal role in cognitive impairment of these disorders. This review aims to describe the current understanding of HDAC4’s role in the maintenance of cognitive function and its dysregulation in neurodegenerative diseases and mental disorders, discuss underlying molecular mechanisms, and provide an outlook into targeting HDAC4 as a potential therapeutic approach to rescue cognitive impairment in these diseases.

To explore the genetic and environmental influences on cardiovascular risk factors (CVRF) and cognitive function in the world's largest and rapidly aging Chinese population.Cognitive function and CVRF, including body mass index, systolic blood pressure, diastolic blood pressure, pulse pressure, glucose, total cholesterol, triglyceride, high-density lipoprotein cholesterol (HDLC) and low-density lipoprotein cholesterol were measured in 379 complete twin pairs. Univariate and bivariate twin models were fitted to estimate the genetic and environmental components in the variance and covariance of CVRF and cognition.Mild-to-high heritability was estimated for CVRF and cognition (0.27-0.74). Unique environmental factors showed low-to-moderate contributions (0.23-0.56). Only HDLC presented significant common environmental contribution (0.50). Bivariate analysis showed significantly negative genetic correlations (rCognitive function was genetically related to systolic blood pressure, diastolic blood pressure, pulse pressure, total cholesterol, triglyceride and HDLC with a negative or positive direction. Cognition and HDLC might share part of a similar unique environmental factor. Geriatr Gerontol Int 2018; 18: 352-359.

Deposition of amyloid β protein (Aβ) to form neuritic plaques in the brain is the unique pathological hallmark of Alzheimer’s disease (AD). Aβ is derived from amyloid β precursor protein (APP) by β- and γ-secretase cleavages and turned over by glia in the central nervous system (CNS). Vitamin A deficiency (VAD) has been shown to affect cognitive functions. Marginal vitamin A deficiency (MVAD) is a serious and widespread public health problem among pregnant women and children in developing countries. However, the role of MVAD in the pathogenesis of AD remains elusive. Our study showed that MVAD is approximately twofold more prevalent than VAD in the elderly, and increased cognitive decline is positively correlated with lower VA levels. We found that MVAD, mostly prenatal MVAD, promotes beta-site APP cleaving enzyme 1 (BACE1)-mediated Aβ production and neuritic plaque formation, and significantly exacerbates memory deficits in AD model mice. Supplementing a therapeutic dose of VA rescued the MVAD-induced memory deficits. Taken together, our study demonstrates that MVAD facilitates AD pathogenesis and VA supplementation improves cognitive deficits. These results suggest that VA supplementation might be a potential approach for AD prevention and treatment.

The association between urinary cadmium and diabetes risk remains controversial. PubMed, Web of Science, China National Knowledge Infrastructure, and Wanfang Data updated on 21 June 2016 were searched for eligible publications. Pooled odds ratio (OR) with 95% confidence interval (CI) of diabetes for highest versus lowest level of urinary cadmium was calculated by using fixed-effect model or random-effect model. Dose-response relationship between urinary cadmium and diabetes was estimated by restricted cubic spline. A total of nine studies with 28,691 participants were included in this meta-analysis. The pooled OR of diabetes for the highest versus lowest level of urinary cadmium was 1.02 (95% CI, 1.00, 1.05; I 2 = 42.3%). In subgroup analysis, the ORs were 1.02 (95% CI 1.00, 1.05; I 2 = 0.9%) for studies conducted in Asia and 1.11 (95% CI 0.88, 1.41; I 2 = 86.3%) in America. For dose-response analysis, a linear relationship was found between urinary cadmium and the risk of diabetes (P for nonlinear = 0.5856). For every l μg/g creatinine increment of urinary cadmium, the risk of diabetes increased by 16% (1.16, 95% CI 1.08, 1.25). This meta-analysis suggests that cadmium exposure might be significantly associated with prevalence of diabetes, but large prospective studies are needed to confirm this finding.

A dose-response meta-analysis was conducted to summarize evidence from prospective cohort studies about the association of nighttime sleep duration and 24-hour sleep duration with risk of all-cause mortality among adults. Pertinent studies were identified by a search of Embase and PubMed databases to March 2015. A two-stage random-effects dose–response meta-analysis was used to combine study-specific relative risks and 95% confidence intervals [RRs (95% CIs)]. Thirty-five articles were included. Compared with 7 hours/day, the RRs (95% CIs) of all-cause mortality were 1.07 (1.03–1.13), 1.04 (1.01–1.07), 1.01 (1.00–1.02), 1.07 (1.06–1.09), 1.21 (1.18–1.24), 1.37 (1.32–1.42) and 1.55 (1.47–1.63) for 4, 5, 6, 8, 9, 10 and 11 hours/day of nighttime sleep, respectively (146,830 death cases among 1,526,609 participants), and the risks were 1.09 (1.04–1.14), 1.05 (1.02–1.09), 1.02 (1.00–1.03), 1.08 (1.05–1.10), 1.27 (1.20–1.36), 1.53 (1.38–1.70) and 1.84 (1.59–2.13) for 4, 5, 6, 8, 9, 10 and 11 hours/day of 24-hour sleep, respectively (101,641 death cases among 903,727 participants). The above relationships were also found in subjects without cardiovascular diseases and cancer at baseline, and other covariates did not influence the relationships substantially. The results suggested that 7 hours/day of sleep duration should be recommended to prevent premature death among adults.

A prospective nonrandomized controlled study was conducted to explore the association between ocular dominance and degree of myopia in patients with anisometropia and to investigate the character of visual evoked potential (VEP) in high anisometropias. 1771 young myopia cases including 790 anisometropias were recruited. We found no significant relation between ocular dominance and spherical equivalent (SE) refraction in all subjects. On average for subjects with anisometropia 1.0–1.75 D, there was no significant difference in SE power between dominant and nondominant eyes, while, in SE anisometropia ≥1.75 D group, the degree of myopia was significantly higher in nondominant eyes than in dominant eyes. The trend was more significant in SE anisometropia ≥2.5 D group. There was no significant difference in higher-order aberrations between dominant eye and nondominant eye either in the whole study candidates or in any anisometropia groups. In anisometropias >2.0 D, the N75 latency of nondominant eye was longer than that of dominant eye. Our results suggested that, with the increase of anisometropia, nondominant eye had a tendency of higher refraction and N75 wave latency of nondominant eye was longer than that of dominant eye in high anisometropias.

Aim Previous studies have shown that uric acid (UA) has strong anti-oxidant properties, and that high circulating levels of UA are prospectively associated with improved muscle function and cognitive performances in elderly Caucasians. We carried out a replication study in elderly Chinese using cross-sectional design. Methods Data from 2006 individuals aged 50–74 years who participated in a population-based cross-sectional survey in Qingdao, China, were analyzed. Hand grip strength was measured in kilograms by using an electronic dynamometer. The sit-to-stand (STS) test time was used to represent lower limb strength. The Mini-Mental State Examination (MMSE) was used to estimate the participants' cognitive function. Lifestyle, comorbidities and laboratory measures were considered as potential confounders. Multiple linear regression models and binary logistic regression were fitted to find the association of UA with strength measures and cognitive performances. Results Participants were grouped according to UA tertiles ( 359.00 mmol/L). Hand grip strength significantly increased across UA tertiles (26.4 ± 8.5 kg; 30.1 ± 10.5 kg; 35.0 ± 11.4 kg; P

Abnormal expression of regulator of calcineurin 1 (RCAN1) has been implicated in Alzheimer's disease (AD) and Down's syndrome (DS). There are two major isoforms of RCAN1, isoforms 1 and 4. RCAN1 isoform 1 is predominantly expressed in the brain, particularly in neurons. In this report, we showed that there are two translation start codons in RCAN1 exon 1 serving as a functional translation initiation site to generate a longer 41-kDa isoform 1 (RCAN1.1L) and a shorter 31-kDa isoform 1 (RCAN1.1S). The first translation initiation site has higher translation efficiency than the downstream second one, and the translation initiation of two AUG sites is by a Cap-dependent mechanism. Short-term expression of RCAN1.1L protected SH-SY5Y cells from oxidative stress-induced apoptosis by inhibiting caspase-3 activation. However, long-term accumulation of RCAN1.1L in SH-SY5Y cells promoted oxidative stress-induced apoptosis via caspase-3 activation, and terminal deoxynucleotidyl transferase dUTP nick end labeling assay showed that the apoptosis ratio was increased to 499.03 ± 47.56% in SH-1.1L cells compared with 283.93 ± 28.66% in control cells. Furthermore, we found that RCAN1.1L is significantly elevated in the AD brains and patients with DS. RCAN1.1S is expressed at a low level in both human cells and brain tissues. Our results defined the regulatory mechanism underlying RCAN1 expression and the roles of RCAN1.1 in oxidative stress-induced neurodegeneration in AD and DS pathogenesis.

Down syndrome (DS), caused by trisomy of chromosome 21, is one of the most common genetic disorders. Patients with DS display growth retardation and inevitably develop characteristic Alzheimer’s disease (AD) neuropathology, including neurofibrillary tangles and neuritic plaques. The expression of amyloid precursor protein (APP) is increased in both DS and AD patients. To reveal the function of APP and elucidate the pathogenic role of increased APP expression in DS and AD, we performed gene expression profiling using microarray method in human cells overexpressing APP. A set of genes are significantly altered, which are involved in cell cycle, cell proliferation and p53 signaling. We found that overexpression of APP inhibits cell proliferation. Furthermore, we confirmed that the downregulation of two validated genes, PSMA5 and PSMB7, inhibits cell proliferation, suggesting that the downregulation of PSMA5 and PSMB7 is involved in APP-induced cell proliferation impairment. Taken together, this study suggests that APP regulates global gene expression and increased APP expression inhibits cell proliferation. Our study provides a novel insight that APP overexpression may contribute to the growth impairment in DS patients and promote AD pathogenesis by inhibiting cell proliferation including neural stem cell proliferation and neurogenesis.

Aim: Studies carried out in Western populations have shown age-related changes in multiple health domains together with gender-specific patterns. By focusing on five health domains, self-rated health, hand grip strength, sit-to-stand test, cognitive performance and depression, we examined the age trajectories in general health in a cross-sectional Chinese sample representing the world's largest ethnic population and compare with Danish data that represent Western populations in developed countries. Methods: Multiple regression models were fitted to compare patterns across genders and populations together with gender- and population-specific patterns in age-related decline. Results: Better self-rated health for males than for females was observed in both countries, and Danes reported better health than the Chinese for both genders. For hand grip strength, significant gender differences were shown across countries and significant population differences observed in Danish and Chinese males. There was no population difference in sit-to-stand time across genders. Female Danes outperformed males in cognitive performance. No significant gender differences in depression were observed in both populations. Conclusion: Our cross population analysis identified significant gender and population differences suggesting endogenous biological, physical and social environmental determinants in age-related decline in general health. Geriatr Gerontol Int 2012; 12: 431–439.

Grand canonical Monte Carlo (GCMC) simulation is used to investigate the performance of poly(vinyl alcohol) (PVA) membrane in separating the azeotropic water/ethanol mixture (95.57 wt% ethanol) over a wide range of pressures (10–1000 kPa), temperatures (298–338 K) and PVA polymerization degrees (100–1000). By calculating the sorption isotherms and the ethanol-to-water separation factors, we observe that the water/ethanol adsorption amount and separation factor decline slowly with the increase of temperature; as the polymerization degree rises, both of adsorption amounts first increase and then decrease, while the separation factor changes adversely. Concepts such as fractional free volume (FFV) and hydrogen bonding interactions are analyzed to explain the observation. As the polymerization degree increases, the FFV changing trend is similar to the one mentioned in the discussion of adsorption amount, but their inflexions are different. Hydrogen bonding interaction successfully explains this variation. We further deduce that the fact that the change of adsorption amount results from a transition from cooperation to competition between FFV and hydrogen bonding interactions. The optimal operating conditions for separation are 298 K and 101.325 kPa. Under this condition, the PVA membrane (polymerization degree 1000) has a separation factor of ∼80 for the water/ethanol azeotropic mixture, which means that the concentration of ethanol can be refined to 99.96 wt% and anhydrous ethanol is possible to be obtained by PVA membrane separation.

Individuals with Down syndrome (DS) will inevitably develop Alzheimer disease (AD) neuropathology sometime after middle age, which may be attributable to genes triplicated in individuals with DS. The characteristics of AD neuropathology include neuritic plaques, neurofibrillary tangles, and neuronal loss in various brain regions. The mechanism underlying neurodegeneration in AD and DS remains elusive. Regulator of calcineurin 1 (RCAN1) has been implicated in the pathogenesis of DS. Our data show that RCAN1 expression is elevated in the cortex of DS and AD patients. RCAN1 expression can be activated by the stress hormone dexamethasone. A functional glucocorticoid response element was identified in the RCAN1 isoform 1 (RCAN1-1) promoter region, which is able to mediate the up-regulation of RCAN1 expression. Here we show that overexpression of RCAN1-1 in primary neurons activates caspase-9 and caspase-3 and subsequently induces neuronal apoptosis. Furthermore, we found that the neurotoxicity of RCAN1-1 is inhibited by knock-out of caspase-3 in caspase-3(-/-) neurons. Our study provides a novel mechanism by which RCAN1 functions as a mediator of stress- and Aβ-induced neuronal death, and overexpression of RCAN1 due to an extra copy of the RCAN1 gene on chromosome 21 contributes to AD pathogenesis in DS.

TRF2, a telomere-binding protein, is a crucial player in telomere length maintenance. Overexpression of TRF2 results in telomere shortening in both normal primary fibroblasts and telomerase-positive cancer cells. TRF2 is found to be associated with XPF-ERCC1, a structure-specific endonuclease involved in nucleotide excision repair, crosslink repair and DNA recombination. XPF-ERCC1 is implicated in TRF2-dependent telomere loss in mouse keratinocytes, however, whether XPF-ERCC1 and its nuclease activity are required for TRF2-mediated telomere shortening in human cells is unknown. Here we report that TRF2-induced telomere shortening is abrogated in human cells deficient in XPF, demonstrating that XPF-ERCC1 is required for TRF2-promoted telomere shortening. To further understand the role of XPF in TRF2-dependent telomere shortening, we generated constructs containing either wild type XPF or mutant XPF proteins carrying amino acid substitutions in its conserved nuclease domain. We show that wild type XPF can complement XPF-deficient cells for repair of UV-induced DNA damage whereas the nuclease-inactive XPF proteins fail to do so, indicating that the nuclease activity of XPF is essential for nucleotide excision repair. In contrast, both wild type XPF and nuclease-inactive XPF proteins, when expressed in XPF-deficient cells, are able to rescue TRF2-mediated telomere shortening. Thus, our results suggest that the function of XPF in TRF2-mediated telomere shortening is conserved between mouse and human. Furthermore, our findings reveal an unanticipated nuclease-independent function of XPF in TRF2-mediated telomere shortening.

Background An investigation was carried out to find the distribution of central corneal thickness (CCT) and the association between CCT and ocular factors in a cohort of myopic Chinese adults who underwent laser refractive surgery. Methods Medical records of 1,190 subjects (754 males) aged from 18 to 44 years (21.5 ± 3.5 years for males and 24.9 ± 5.5 years for females) undergoing myopic refractive surgery were filtered and analysed. Each parameter was stratified by gender and eye, respectively. Multi-linear and linear regressions were used to analyse the effect of intraocular pressure (IOP), period of contact lens wearing, gender, age, refractive error, mean corneal curvature (K) and ocular high-order aberration at 5.0-mm zone on CCT. Results The mean CCT was 539.2 ± 37.8 µm in the whole study population. Males had greater CCT than females (p

Drug-associated contextual cues contribute to drug craving and relapse after abstinence, which is a major challenge to drug addiction treatment. Previous studies showed that disrupting memory reconsolidation impairs drug reward memory. However, the underlying mechanisms remain elusive. Although actin polymerization is involved in memory formation, its role in the reconsolidation of drug reward memory is unknown. In addition, the specific brain areas responsible for drug memory have not been fully identified. In the present study, we found that inhibiting actin polymerization in the nucleus accumbens (NAc) shell, but not the NAc core, abolishes morphine-induced conditioned place preference (CPP) by disrupting its reconsolidation in rats. Moreover, this effect persists for more than 2 weeks by a single injection of the actin polymerization inhibitor, which is not reversed by a morphine-priming injection. Furthermore, the application of actin polymerization inhibitor outside the reconsolidation window has no effect on morphine-associated contextual memory. Taken together, our findings first demonstrate that inhibiting actin polymerization erases morphine-induced CPP by disrupting its reconsolidation. Our study suggests that inhibition of actin polymerization during drug memory reconsolidation may be a potential approach to prevent drug relapse.

Commercial unsaturated polyester (UPE) resins typically contain a high amount of volatile toxic styrene. A non-volatile acrylated epoxidized soybean oil (AESO) was found to be an excellent replacement of styrene in a commercially available UPE resin [designated as Styrene-(PG-IPA-MA)] that is derived from propylene glycol (PG), isophthalic acid (IPA), and maleic anhydride (MA) in terms of the mechanical properties of the resulting kenaf fiber-reinforced composites. The AESO-(PG-IPA-MA) resins had low viscosity and long pot life below 70°C for a typical fiber-reinforced composite application. AESO and PG-IPA-MA were not able to form a strong polymer matrix individually for fiber-reinforced composites. However, a combination of AESO and PG-IPA-MA saw strong synergistic effects between them. The flexural, tensile, and water absorption properties of kenaf fiber-reinforced composites made from AESO-(PG-IPA-MA) resins were comparable with or even superior to those from the Styrene-(PG-IPA-MA) resin. The AESO/(PG-IPA-MA) weight ratio was investigated for maximizing the mechanical properties of the kenaf fiber-reinforced composites. The curing mechanism of the AESO-(PG-IPA-MA) resins is discussed in detail. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016, 133, 43052.

Objective: The results from observation studies on the relationship between coffee intake and risk of depression and the relationship between caffeine consumption and depression remain controversial. We conducted a meta-analysis with a dose–response analysis to quantitatively summarize the evidence about the association between coffee and caffeine intakes and risk of depression. Method: Relevant articles were identified by researching PubMed, Web of Science, China National Knowledge Infrastructure and WANFANG DATA in English or Chinese from 1 January 1980 to 1 May 2015. Case-control, cohort or cross-sectional studies evaluating coffee or caffeine consumption and depression were included. A random-effects model was used to combine study-specific relative risk and 95% confidence interval. Dose–response relationship was assessed by restricted cubic spline functions. Results: Data were obtained from 11 observation articles; 330,677 participants from seven studies in seven articles were included in the coffee-depression analysis, while 38,223 participants from eight studies in seven articles were involved in the caffeine-depression analysis. Compared with the lowest level consumption, the pooled relative risk (95% confidence interval) for coffee-depression and caffeine-depression was 0.757 [0.624, 0.917] and 0.721 [0.522, 0.997], respectively. For dose–response analysis, evidence of a linear association was found between coffee consumption and depression, and the risk of depression decreased by 8% (relative risk = 0.92, 95% confidence interval = [0.87, 0.97], p = 0.002) for each cup/day increment in coffee intake; a nonlinear association was found between caffeine consumption and depression, the risk of depression decreased faster and the association became significant when the caffeine consumption was above 68 mg/day and below 509 mg/day. Conclusions: Coffee and caffeine consumption were significantly associated with decreased risk of depression.

Systolic and diastolic blood pressure, pulse pressure (PP), and body mass index (BMI) are heritable traits in human metabolic health but their common genetic and environmental backgrounds are not well investigated. The aim of this article was to explore the phenotypic and genetic associations among PP, systolic blood pressure (SBP), diastolic blood pressure (DBP), and BMI. The studied sample contained 615 twin pairs (17–84 years) collected in the Qingdao municipality. Univariate and multivariate structural equation models were fitted for assessing the genetic and environmental contributions. The AE model combining additive genetic (A) and unique environmental (E) factors produced the best fit for each four phenotypes. Heritability estimated in univariate analysis ranged from 0.42 to 0.74 with the highest for BMI (95% CI 0.70–0.78), and the lowest for PP (95% CI 0.34–0.49). The multivariate model estimated (1) high genetic correlations for DBP with SBP (0.87), PP with SBP (0.75); (2) low–moderate genetic correlations between PP and DBP (0.32), each BP component and BMI (0.24–0.37); (3) moderate unique environmental correlation for PP with SBP (0.68) and SBP with DBP (0.63); (4) there was no significant unique environmental correlation between PP and BMI. Overall, our multivariate analyses revealed common genetic and environmental backgrounds for PP, BP, and BMI in Chinese twins.

We used a combination of bioinformatics, electron cryomicroscopy, and biochemical techniques to identify an oxidoreductase-like domain in the skeletal muscle Ca 2+ release channel protein (RyR1). The initial prediction was derived from sequence-based fold recognition for the N-terminal region (41–420) of RyR1. The putative domain was computationally localized to the clamp domain in the cytoplasmic region of a 22Å structure of RyR1. This localization was subsequently confirmed by difference imaging with a sequence specific antibody. Consistent with the prediction of an oxidoreductase domain, RyR1 binds [ 3 H]NAD + , supporting a model in which RyR1 has a oxidoreductase-like domain that could function as a type of redox sensor.

A nonvolatile, vegetable-oil based chemical, acrylated epoxidized soybean oil (AESO) was investigated as a replacement of volatile and toxic styrene in one of commercial UPE resins styrene-(PG-MA) that is a mixture of styrene and a UPE plastic from propylene glycol and maleic anhydride (PG-MA). Neither AESO nor PG-MA was capable of forming a strong matrix, respectively, for glass fiber-reinforced composites. However, a mixture of AESO and PG-MA resulted in glass fiber-reinforced AESO-(PG-MA) composites that were comparable or even superior to those from styrene-(PG-MA) in terms of the flexural and tensile properties. Effects of AESO contents on the mechanical and viscoelastic properties of the glass fiber-reinforced AESO-(PG-MA) composites were investigated. Resin viscosity and resin pot life as a function of temperature were studied. The curing mechanism of the AESO-(PG-MA) resins is also discussed. © 2017 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2017, 134, 45056.

Parkinson’s disease (PD) is one of the major neurodegenerative disorders. Mitochondrial malfunction is implicated in PD pathogenesis. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN)-induced putative kinase 1 (PINK1), a serine/threonine kinase, plays an important role in the quality control of mitochondria and more than 70 PINK1 mutations have been identified to cause early-onset PD. However, the regulation of PINK1 gene expression remains elusive. In the present study, we identified the transcription start site (TSS) of the human PINK1 gene using switching mechanism at 5’end of RNA transcription (SMART RACE) assay. The TSS is located at 91 bp upstream of the translation start site ATG. The region with 104 bp was identified as the minimal promoter region by deletion analysis followed by dual luciferase assay. Four functional cis-acting nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB)-binding sites within the PINK1 promoter were identified. NFκB overexpression led to the up-regulation of PINK1 expression in both HEK293 cells and SH-SY5Y cells. Consistently, lipopolysaccharide (LPS), a strong activator of NFκB, significantly increased PINK1 expression in SH-SY5Y cells. Taken together, our results clearly suggested that PINK1 expression is tightly regulated at its transcription level and NFκB is a positive regulator for PINK1 expression.

Novel pressure sensitive adhesives (PSAs) were developed from renewable methyl oleate (MO) and fully evaluated for their peel strength, tack force and shear resistance. MO was epoxidized and selectively hydrolyzed on the ester group to form epoxidized oleic acid (EOA) that is a bifunctional monomer containing both a carboxylic acid group and an epoxy group. EOA was step-growth polymerized to form a hydroxyl-containing polyester, which was then cured in the presence of a small amount of a polyfunctional epoxide [epoxidized soybean oil or trimethylolpropane triglycidyl ether (TMPTGE)] to afford PSAs. The PSAs from the polyester cured with TMPTGE exhibited high peel strength (2.4 N/10 mm), high tack force (5.8 N), and sufficient shear resistance (9.0 min). The PSAs can be fully based on renewable natural materials, and their preparations are environmentally friendly. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014, 131, 41143.

Individuals with Down syndrome (DS), caused by trisomy of chromosome 21, inevitably develop characteristic Alzheimer's disease (AD) neuropathology, including neuritic plaques, neurofibrillary tangles, and neuronal loss. Amyloid-β protein, the major component of neuritic plaques, is the proteolytic product of amyloid-β precursor protein (APP). APP and the regulator of calcineurin 1 (RCAN1) genes on chromosome 21 play a pivotal role in promoting plaque formation and neuronal apoptosis. However, the mechanism underlying AD pathogenesis in DS is not well defined. In this study, we demonstrated that APP significantly increased RCAN1 level in both cells and transgenic mice. Overexpression of APP significantly reduced the expression of 2 proteasome subunits, proteasome subunit α type-5 and proteasome subunit β type-7, leading to the inhibition of proteasomal degradation of RCAN1. Furthermore, knockdown of RCAN1 expression attenuated APP-induced neuronal apoptosis. Taken together, the results clearly showed that APP has a previously unknown function in regulating RCAN1-mediated neuronal apoptosis through the proteasome pathway. Our study demonstrates a novel mechanism by which overexpression of APP and RCAN1 causes neurodegeneration and AD pathogenesis in DS, and it provides new insights into the potential of targeting APP-induced proteasomal impairment and RCAN1 accumulation for AD and DS treatment.

We carried out a meta-analysis to summarize the evidence from published studies on macronutrients intake and risk of Parkinson's disease (PD).Pertinent studies were identified by a search of PubMed and Embase. Study-specific effect was combined with the random-effect model. The dose-response relationship was assessed by the restricted cubic spline.For highest versus lowest level of intake, the relative risk (RR) of PD was 1.13 (95% CI 0.88-1.44) for protein (7 articles including 1570 PD cases among 357,827 subjects), RR 1.24 (95% CI 1.05-1.48) for carbohydrate (8 articles including 1482 PD cases among 232,869 subjects), RR 0.88 (95% CI 0.74-1.06) for fat (12 articles including 2936 PD cases among 374,124 subjects), RR 0.97 (95% CI 0.75-1.26) for cholesterol (6 articles including 1713 PD cases among 170,058 subjects) and 1.39 (95% CI 1.01-1.92) for energy (8 articles including 1553 PD cases among 170,317 subjects), respectively. Among prospective studies adjusting for smoking and coffee/caffeine, no associations were found between PD risk and intake of protein (RR 1.02, 95% CI 0.80-1.30), carbohydrate (RR 1.11, 95% CI 0.86-1.43), fat (RR 0.90, 95% CI 0.70-1.16), cholesterol (RR 0.89, 95% CI 0.74-1.09) and energy (RR 0.97, 95% CI 0.93-1.02); however, polyunsaturated fatty acid (RR 0.78, 95% CI 0.64-0.96) was inversely associated with PD risk. Limited data showed a linear dose-response relationship between the aforementioned macronutrients and PD risk.Dietary intake of protein, carbohydrate, cholesterol and energy might be not independently associated with PD risk. Higher intake of polyunsaturated fatty acid might be inversely associated with PD risk. Confounding by smoking and coffee/caffeine should be considered regarding the association between fat intake and PD risk in further studies.

Background Results from longitudinal studies on sleep duration and incidence of obesity remain controversial. Methods PubMed and Web of Science updated on 20 February 2014 were searched for eligible publications. Pooled odds ratio (OR) with 95% confidence interval (CI) was calculated using a random-effects model. Results Eleven published articles were included, involving 197,906 participants for short sleep duration and 164,016 participants for long sleep duration. Compared with the normal sleep duration, the pooled OR for obesity was 1.45 (95% CI, 1.25–1.67) for the short sleep duration overall. After removing the three studies that had strong effects on heterogeneity, the pooled OR was 1.25 (95% CI, 1.14–1.38). The positive association was consistent among all subgroups analysis except in the European group (OR, 1.45; 95% CI, 0.79–2.64). No significant association was found between long sleep duration and risk of obesity overall (OR, 1.06; 95% CI, 0.98–1.15) and in subgroup analysis. Conclusion This meta-analysis indicated that short sleep duration was significantly associated with incidence of obesity, whereas long sleep duration had no effect on future obesity among adults.

Down syndrome (DS) is one of the most common genetic diseases. Patients with DS display growth delay and intellectual disabilities and develop Alzheimer's disease (AD) neuropathology after middle age, including neuritic plaques and neurofibrillary tangles. Beta-site amyloid β precursor protein (APP) cleaving enzyme 1 (BACE1), essential for Aβ production and neuritic plaque formation, is elevated in DS patients. However, its homolog, β-site APP cleaving enzyme 2 (BACE2), functions as θ-secretase and plays a differential role in plaque formation. In this study, by using Two-dimensional sodium dodecyl sulfate polyacrylamide gel electrophoresis (2D SDS-PAGE) and LC-MS/MS proteomic profiling analysis, we found that the SET oncogene protein (SET) expression was associated with BACE1 but not BACE2. SET protein was increased in BACE1 overexpressing cells and was markedly reduced in the BACE1 knockout mice. We found that the overexpression of BACE1 or SET significantly inhibited cell proliferation. Moreover, knockdown of SET in BACE1 overexpression cells significantly rescued BACE1-induced cell growth suppression. Furthermore, both BACE1 and SET protein levels were increased in Down syndrome patients. It suggests that BACE1 overexpression-induced SET upregulation may contribute to growth delay and cognitive impairment in DS patients. Our work provides a new insight that BACE1 overexpression not only promotes neuritic plaque formation but may also potentiate neurodegeneration mediated by SET elevation in Alzheimer-associated dementia in DS.

Purpose The association of dairy products consumption with risk of obesity remains controversial. Therefore, we reviewed and quantitatively synthesized the evidence from observational studies with a meta-analysis. Methods A literature search was performed in relevant databases. Random-effects model was used to pool odds ratios with 95% confidence intervals. Dose–response relationship was assessed by restricted cubic spline model. Results Seventeen studies for total dairy products and 16 studies for milk with risk of obesity were eligible. The pooled odds ratios (95% confidence intervals) of obesity for the highest versus lowest category of total dairy products consumption were 0.54 (0.38–0.77) in children, 0.75 (0.69–0.81) in adults, and 0.74 (0.68–0.80) for both. Evidence of a nonlinear relationship was found ( P for nonlinearity = .009). Milk consumption was also associated with risk of obesity [0.81 (0.75–0.88)] both in children [0.87 (0.80–0.95)] and in adults [0.77 (0.68–0.87)], and a linear relationship ( P for nonlinearity = .598) suggested that risk of obesity decreased by 16% [0.84 (0.77–0.92)] for every 200 g/d increment of milk consumption. Conclusions This meta-analysis indicates that dairy products consumption may be associated with a decreased risk of obesity. This association may be of public health significance.

The skeletal muscle Ca2+ release channel (RYR1), which plays a critical role in excitation-contraction coupling, is a homotetramer with a subunit molecular mass of 565 kDa. Oxidation of the channel increases its activity and produces intersubunit cross-links within the RYR1 tetramer (Aghdasi, B., Zhang, J., Wu, Y., Reid, M. B., and Hamilton, S. L. (1997) J. Biol. Chem. 272, 3739-3748). Alkylation of hyperreactive sulfhydryls on RYR1 with N-ethylmaleimide (NEM) inhibits channel function and blocks the intersubunit cross-linking. We used calpain and tryptic cleavage, two-dimensional SDS-polyacrylamide gel electrophoresis, N-terminal sequencing, sequence-specific antibody Western blotting, and [14C]NEM labeling to identify the domains involved in these effects. Our data are consistent with a model in which 1) diamide, an oxidizing agent, simultaneously produces an intermolecular cross-link between adjacent subunits within the RYR1 tetramer and an intramolecular cross-link within a single subunit; 2) all of the cysteines involved in both cross-links are in either the region between amino acids approximately 2100 and 2843 or the region between amino acids 2844 and 4685; 3) oxidation exposes a new calpain cleavage site in the central domain of the RYR1 (in the region around amino acid 2100); 4) sulfhydryls that react most rapidly with NEM are located in the N-terminal domain (between amino acids 426 and 1396); 5) alkylation of the N-terminal cysteines completely inhibits the formation of both inter- and intrasubunit cross-links. In summary, we present evidence for interactions between the N-terminal region and the putatively cytoplasmic central domains of RYR1 that appear to influence subunit-subunit interactions and channel activity.

Two sulfhydryl reagents, N-ethylmaleimide (NEM), an alkylating agent, and diamide, an oxidizing agent, were examined for effects on the skeletal muscle Ca2+ release channel. NEM incubated with the channel for increasing periods of time displays three distinct phases in its functional effects on the channel reconstituted into planar lipid bilayers; first it inhibits, then it activates, and finally it again inhibits channel activity. NEM also shows a three-phase effect on the binding of [3H]ryanodine by first decreasing binding (phase 1), followed by a recovery of the binding (phase 2), and then a final phase of inhibition (phase 3). In contrast, diamide 1) activates the channel, 2) enhances [3H]ryanodine binding, 3) cross-links subunits within the Ca2+ release channel tetramer, and 4) protects against phase 1 inhibition by NEM. All diamide effects can be reversed by the reducing agent, dithiothreitol. Diamide induces intersubunit dimer formation of both the full-length 565-kDa subunit of the channel and the 400-kDa generated by endogenous calpain digestion, suggesting that the cross-link does not involve sulfhydryls within the N-terminal 170-kDa fragment of the protein. NEM under phase 1 conditions blocks the formation of the intersubunit cross-links by diamide. In addition, single channels activated by diamide are further activated by the addition of NEM. Diamide either cross-links phase 1 sulfhydryls or causes a conformational change in the Ca2+ release channel which leads to inaccessibility of phase 1 sulfhydryls to NEM alkylation. The data presented here lay the groundwork for mapping the location of one of the sites of subunit-subunit contact in the Ca2+ release channel tetramer and for identifying the functionally important sulfhydryls of this protein.

Gray level co-occurrence matrix (GLCM) is an important method to extract the image texture features of synthetic aperture radar (SAR). However, GLCM can only extract the textures under single scale and single direction. A kind of texture feature extraction method combining nonsubsampled contour transformation (NSCT) and GLCM is proposed, so as to achieve the extraction of texture features under multi-scale and multi-direction. We firstly conducted multi-scale and multi-direction decomposition on the SAR images with NSCT, secondly extracted the symbiosis amount with GLCM from the obtained sub-band images, then conducted the correlation analysis for the extracted symbiosis amount to remove the redundant characteristic quantity; and combined it with the gray features to constitute the multi-feature vector. Finally, we made full use of the advantages of the support vector machine in the aspects of small sample database and generalization ability, and completed the division of multi-feature vector space by SVM so as to achieve the SAR image segmentation. The results of the experiment showed that the segmentation accuracy rate could be improved and good edge retention effect could be obtained through using the GLCM texture extraction method based on NSCT domain and multi-feature fusion in the SAR image segmentation.

Impairment of the ubiquitin proteasome pathway is believed to play an important role in the pathogenesis of Parkinson's disease. This process is carried out under tight regulation by deubiquitinating enzymes. Genetic linkage studies indicated that the region of the human ubiquitin-specific protease 24 (USP24) gene is significantly correlated with Parkinson's disease. In this study, we cloned a 1648 bp 5' flanking region of the human USP24 gene coding sequence and a series of nested deletions into the pGL3-Basic vector. We analyzed promoter activities of these regions with a luciferase-based reporter assay system. A 64-bp region was identified to contain the transcription initiation site and a minimum promoter sequence for transcriptional activation of the USP24 gene expression. Expression of USP24 is controlled by a TATA-box-less promoter with several putative cis-acting elements. Transcriptional activation and gel-shift assay demonstrated that the USP24 gene promoter contains a functional NFκB-binding site. Over-expression of nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) and tumor-necrosis factor alpha (TNFα) treatment significantly increased the USP24 promoter activity, mRNA expression and protein level in human HEK293 cells, mouse N2a cells and human neuroblastoma SH-SY5Y cells. Deletion and mutation of the binding site abolished the regulatory effect of NFκB on human USP24 gene transcription. These results suggested that USP24 expression is tightly regulated at its transcription level and NFκB plays an important role in this process.

Abnormal deposition of neuriticplaques is the uniqueneuropathological hallmark of Alzheimer’s disease (AD).Amyloid β protein (Aβ), the major component of plaques, is generated from sequential cleavage of amyloidβ precursor protein (APP) by β-secretase and γ-secretase complex. Patients with diabetes mellitus (DM), characterized by chronic hyperglycemia,have increased risk of AD development.However, the role of high blood glucose in APP processing and Aβ generation remains elusive. In this study, we investigated the effect of high glucose on APP metabolism and Aβ generation in cultured human cells. We found that high glucose treatment significantly increased APP protein level in both neuronal-like and non-neuronal cells, and promoted Aβ generation. Furthermore, we found that high glucose-induced increase of APP level was not due to enhancement of APP gene transcription but resulted from inhibition of APP protein degradation. Taken together, our data indicated that hyperglycemia could promote AD pathogenesis by inhibiting APP degradation and enhancing Aβ production. More importantly, the elevation of APP level and Aβ generation by high glucose was caused by reduction of APP turnover rate.Thus,our study provides a molecular mechanism of increased risk of developing AD in patients withDMand suggests thatglycemic control might be potentially beneficial for reducing the incidence of AD in diabetic patients and delaying the AD progression.

A meta-analysis was performed to assess the association of endothelial nitric oxide synthase (NOS3) gene polymorphisms [4b4a VNTR and G894T (rs1799983)] with type 2 diabetes mellitus (T2DM). A comprehensive search was conducted to identify all eligible articles. Fixed or random effect pooled measure was selected based on homogeneity test. Heterogeneity among studies was evaluated using the I2. Meta-regression was used to explore potential sources of between-study heterogeneity. Publication bias was estimated using Egger's linear regression test. 19 articles involving 8,009 subjects for 4b4a VNTR and 19 articles involving 8,600 subjects for G894T were included. After excluding articles that deviated from Hardy-Weinberg equilibrium in controls and sensitivity analysis, significant association was found between 4a and increased risk of T2DM considering dominant model [OR (95% CI)=1.32 (1.17-1.48)], a vs. b [OR (95% CI)=1.34 (1.21-1.48)], and aa vs. bb [OR (95% CI)=1.52 (1.05-2.22)]. The 894T allele was also found associated with increased risk of T2DM considering dominant model [OR (95% CI)=1.14 (1.03-1.26)], recessive model [OR (95%CI)=1.28 (1.06-1.54)], T vs. G [OR (95% CI)=1.18 (1.09-1.27)], and TT vs. GG [OR (95% CI)=1.33 (1.09-1.62)]. The findings were consistent in Asian population. The meta-analysis indicated that NOS3 gene 4b4a VNTR and G894T polymorphisms might be associated with T2DM risk.