Alzheimer disease (AD) is the most common neurodegenerative disease. An imbalance between the production and clearance of Aβ (amyloid beta) is considered to be actively involved in AD pathogenesis. ...Macroautophagy/autophagy is a major cellular pathway leading to the removal of aggregated proteins, and upregulation of autophagy represents a plausible therapeutic strategy to combat overproduction of neurotoxic Aβ. PPARA/PPARα (peroxisome proliferator activated receptor alpha) is a transcription factor that regulates genes involved in fatty acid metabolism and activates hepatic autophagy. We hypothesized that PPARA regulates autophagy in the nervous system and PPARA-mediated autophagy affects AD. We found that pharmacological activation of PPARA by the PPARA agonists gemfibrozil and Wy14643 induces autophagy in human microglia (HM) cells and U251 human glioma cells stably expressing the human APP (amyloid beta precursor protein) mutant (APP-p.M671L) and this effect is PPARA-dependent. Administration of PPARA agonists decreases amyloid pathology and reverses memory deficits and anxiety symptoms in APP-PSEN1ΔE9 mice. There is a reduced level of soluble Aβ and insoluble Aβ in hippocampus and cortex tissues from APP-PSEN1ΔE9 mice after treatment with either gemfibrozil or Wy14643, which promoted the recruitment of microglia and astrocytes to the vicinity of Aβ plaques and enhanced autophagosome biogenesis. These results indicated that PPARA is an important factor regulating autophagy in the clearance of Aβ and suggested gemfibrozil be assessed as a possible treatment for AD.
Abbreviation: Aβ: amyloid beta; ACTB: actin beta; ADAM10: ADAM metallopeptidase domain 10; AD: Alzheimer disease; AIF1/IBA1: allograft inflammatory factor 1; ANOVA: analysis of variance; APOE: apolipoprotein E; APP: amyloid beta precursor protein; APP-PSEN1ΔE9: APPswe/PSEN1dE9; BAFA1: bafilomycin A
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; BDNF: brain derived neurotrophic factor; BECN1: beclin 1; CD68: CD68 molecule; CREB1: cAMP responsive element binding protein 1; DAPI: 4',6-diamidino-2-phenylindole; DLG4/PSD-95: discs large MAGUK scaffold protein 4; DMSO: dimethyl sulfoxide; ELISA: enzyme linked immunosorbent assay; FDA: U.S. Food and Drug Administration; FKBP5: FK506 binding protein 5; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; gemfibrozil: 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid; GFAP: glial fibrillary acidic protein; GLI2/THP1: GLI family zinc finger 2; HM: human microglia; IL6: interleukin 6; LAMP1: lysosomal associated membrane protein 1; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MTOR: mechanistic target of rapamycin kinase; NC: negative control; OQ: opposite quadrant; PPARA/PPARα, peroxisome proliferator activated receptor alpha; PSEN1/PS1: presenilin 1; SEM: standard error of the mean; SQSTM1: sequestosome 1; SYP: synaptophysin; TFEB: transcription factor EB; TNF/TNF-α: tumor necrosis factor; TQ: target quadrant; WT: wild type; Wy14643: 2-4-chloro-6-(2,3-dimethylanilino)pyrimidin-2-ylsulfanylacetic acid
Understanding the genetic changes underlying phenotypic variation in sheep (Ovis aries) may facilitate our efforts towards further improvement. Here, we report the deep resequencing of 248 sheep ...including the wild ancestor (O. orientalis), landraces, and improved breeds. We explored the sheep variome and selection signatures. We detected genomic regions harboring genes associated with distinct morphological and agronomic traits, which may be past and potential future targets of domestication, breeding, and selection. Furthermore, we found non-synonymous mutations in a set of plausible candidate genes and significant differences in their allele frequency distributions across breeds. We identified PDGFD as a likely causal gene for fat deposition in the tails of sheep through transcriptome, RT-PCR, qPCR, and Western blot analyses. Our results provide insights into the demographic history of sheep and a valuable genomic resource for future genetic studies and improved genome-assisted breeding of sheep and other domestic animals.
Bisphenol F (BPF) and bisphenol S (BPS) are increasingly used as alternatives to endocrine disrupting chemical bisphenol A (BPA). Evidence from in vitro and animal studies demonstrates that BPA, BPF ...and BPS induce oxidative stress, a proposed mechanism that is relevant to various adverse health effects. Evaluation in humans is hampered by the potentially high within-subject variability of urinary measurements.
To evaluate the variability and associations of levels of BPA, BPS, BPF and 3 oxidative stress markers i.e., 8-hydroxy-2-deoxyguanosine (8-OHdG), 8-iso-prostaglandin F2α (8-isoPGF2α) and 4-hydroxy-2-nonenal-mercapturic acid (HNE-MA) in urine collected on multiple occasions over 3 months.
A total of 529 spot urine samples, including 88 first morning voids (FMVs) and 24-h specimens, were gathered from 11 adult men on days 0, 1, 2, 3, 4, 30, 60 and 90 and analyzed for BPA, BPF, BPS, 8-OHdG, 8-isoPGF2α and HNE-MA. Intraclass correlation coefficients (ICCs) were estimated to characterize the reproducibility of urinary bisphenols and oxidative stress markers, and linear mixed models were applied to assess the associations between markers of exposure and response.
BPA and BPF were detected in ≥85% of the spot samples, while BPS in 13% of the samples. High degrees of within-subject variability were found for BPA, BPF, 8-OHdG, 8-isoPGF2α and HNE-MA in spot samples, FMVs and 24-h specimens (creatinine-corrected ICCs ≤ 0.37). The sensitivities were low-to-moderate (0.30–0.63) when using single spot samples or FMVs to predict high (>27th, or 36th percentile) 3-month average urinary levels of BPA, BPF, 8-OHdG, 8-isoPGF2α and HNE-MA. Collecting repeated specimens at different time points improved the accuracy of classification for markers of exposure and response. Elevated urinary BPA and BPF were associated with significantly higher levels of oxidative stress markers.
Repeated urinary specimens are required to characterize bisphenol exposure levels and the oxidative stress status of individuals. Exposure to BPA and BPF may partly contribute to the elevated urinary levels of oxidative stress makers in adult men.
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•Bisphenol A, F and S and 3 oxidative stress markers were measured in 11 adult men.•BPA, BPS and oxidative stress markers in urine varied greatly over 3 months.•Repeated samples are needed to estimate bisphenol exposure and oxidative stress status.•Elevated urinary BPA and BPF were associated with elevated levels of oxidative stress.
Exposure to bisphenol A (BPA) has been associated with various adverse health outcomes. Recently, an increasing concern on its alternatives such as bisphenol S (BPS) and bisphenol F (BPF) has been ...aroused due to the restriction use of BPA. Few studies have identified predictors of exposure to BPA alternatives and assessed their health risks.
The aim of this study was to identify predictors of BPA and its alternatives and to assess their health risks among pregnant women.
We detected first morning urinary concentrations of BPA and its alternatives (BPS and BPF) among 1097 pregnant women from an established Chinese cohort. A questionnaire was conducted to obtain demographic characteristics, dietary habits, and lifestyles. We examined the predictors of creatinine-adjusted urinary BPA and its alternatives concentrations using multivariable linear regression. Risk assessment of exposure to BPA and its alternatives was calculated based on the estimated of daily intake (EDI).
Geometric means of creatinine-adjusted urinary BPA, BPF, and BPS were 0.92, 0.12, and 0.08 μg/g creatinine, respectively. Pregnant women from Wuhan had lower concentrations of BPA, BPF, and ∑BPs (sum of BPA, BPF, and BPS) than those from Xiaogan. Intake of fried food was related to higher concentrations of BPA, and intake of pickled food was associated with higher concentrations of BPF and ∑BPs. The maximum EDI values for exposure to BPA, BPF, BPS, and ∑BPs ranged from 5.6428 to 13.3356 nmol/kg body weight/day, which were below the tolerable daily intake (TDI) for BPA defined by the European Food Safety Authority (EFSA) (18 nmol/kg body weight/day). The maximum hazard index (HI) value was 0.7409.
Several predictors identified in this study may inform public recommendations to reduce exposure to BPA and its alternatives.
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•Predictors of urinary BPA and its alternatives among pregnant women were identified.•Study city differentially predicted urinary concentrations of BPA and its alternatives.•Intake of fried food was related to higher urinary concentrations of BPA.•Intake of pickled food was related to higher urinary concentrations of BPF and ∑BPs.•Estimated BPA and its alternative exposures were below the reference values.
To identify susceptibility loci for schizophrenia, we performed a two-stage genome-wide association study (GWAS) of schizophrenia in the Han Chinese population (GWAS: 746 individuals with ...schizophrenia and 1,599 healthy controls; validation: 4,027 individuals with schizophrenia and 5,603 healthy controls). We identified two susceptibility loci for schizophrenia at 6p21-p22.1 (rs1233710 in an intron of ZKSCAN4, P(combined) = 4.76 × 10(-11), odds ratio (OR) = 0.79; rs1635 in an exon of NKAPL, P(combined) = 6.91 × 10(-12), OR = 0.78; rs2142731 in an intron of PGBD1, P(combined) = 5.14 × 10(-10), OR = 0.79) and 11p11.2 (rs11038167 near the 5' UTR of TSPAN18, P(combined) = 1.09 × 10(-11), OR = 1.29; rs11038172, P(combined) = 7.21 × 10(-10), OR = 1.25; rs835784, P(combined) = 2.73 × 10(-11), OR = 1.27). These results add to previous evidence of susceptibility loci for schizophrenia at 6p21-p22.1 in the Han Chinese population. We found that NKAPL and ZKSCAN4 were expressed in postnatal day 0 (P0) mouse brain. These findings may lead to new insights into the pathogenesis of schizophrenia.
ARL9 is a newly identified member of the ARF family, and the clinical significance of ARL9 in colon adenocarcinoma is unknown. In this study, we aimed to explore the expression of ARL9 mRNA in colon ...adenocarcinoma, and its effect on the prognosis of patients with colon adenocarcinoma.
We investigated the differential expression of ARL9 between colon adenocarcinoma tissue and adjacent tissues through a bioinformatics analysis using The Cancer Genome Atlas (TCGA) database. The correlation between clinical characteristics and the mRNA expression level of ARL9 were analyzed. A survival analysis and a Cox regression analysis were used to determine the prognostic significance of ARL9. Finally, we conducted a gene set enrichment analysis (GSEA) to explore the ARL9 signaling pathways involved in the development of colon adenocarcinoma. The effect of the expression of ARL9 on the proliferation and migration of colon adenocarcinoma was analyzed by the CCK8 method and a cell scratch test, respectively.
The mRNA expression of ARL9 in colon adenocarcinoma tissues was higher in comparison to the level in normal adjacent tissues (P < 0.05). The mRNA expression of ARL9 was not related to sex, tumor stage, T stage, N stage, M stage, but to age. The 5-year survival rate of colon adenocarcinoma patients with high ARL9 mRNA expression levels was significantly lower than that of patients with low ARL9 mRNA expression levels (P < 0.05). Age and the high mRNA expression of ARL9 were independent risk factors for a poor prognosis in patients with colon adenocarcinoma. The GSEA suggested that ARL9 may be able to upregulate cell adhesion, extracellular matrix receptor interactions, tumor-associated pathways, and downregulate the citrate cycle and tricarboxylic acid cycle pathway, which are involved in the development of colon adenocarcinoma. After knocking down ARL9, the proliferation and migration abilities of colon adenocarcinoma cells were decreased (P < 0.01).
The mRNA expression of ARL9 is upregulated in colon adenocarcinoma, and higher mRNA expression levels are associated with a poor prognosis. Knocking down ARL9 can reduce the proliferation and migration of colon adenocarcinoma cells. ARL9 mRNA can be used as a prognostic biomarker in patients with colon adenocarcinoma.
Two metal templated borates, Ni(atta)(SO4)0.5·B5O6(OH)4 (1) and Cu(1-MI)4·B5O6(OH)42·1-MI2 (2), have been synthesized. The structures were determined by single-crystal X-ray diffraction and ...further characterized by Fourier transform infrared (FTIR), elemental analysis, and powder X-ray diffraction (PXRD). The structure of 1 consists of B5O6(OH)4− clusters and Ni(atta)(SO4)0.5+ complexes, which shows a very rare Ni–O–S bond. 1 and 2 exhibit a hydrogen-bonded network formed by B5O6(OH)4− clusters. Oxygen reduction reaction (ORR) activities of 1 and 2 were explored.
Abstract
STUDY QUESTION
Are sleep characteristics associated with outcomes of IVF/ICSI treatment?
SUMMARY ANSWER
Nocturnal sleep <7 h/night and disturbed sleep are related to impaired oocyte and ...embryo yield, while longer nocturnal sleep might reduce the chance of a successful pregnancy, and the associations between nocturnal sleep duration and IVF/ICSI outcomes are modified by maternal age and subjective sleep quality.
WHAT IS KNOWN ALREADY
Disturbed sleep and circadian rhythm contribute to impaired fecundity in the general population, but the effects of sleep characteristics on IVF/ICSI outcomes are largely unknown.
STUDY DESIGN, SIZE, DURATION
This study was conducted among 1276 women undergoing IVF/ICSI treatment between December 2018 and September 2019 based on the Tongji Reproductive and Environmental cohort. Owing to the limited number of multiple cycles, we included only the outcomes of their first IVF/ICSI cycle in the current analysis.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Data on sleep characteristics were collected via questionnaires on the day of oocyte retrieval. IVF/ICSI outcomes were abstracted from medical records. Quasi-Poisson, quasi-binomial or logistic regression models were used to assess the relations between sleep characteristics and reproductive outcomes after adjusting for relevant confounders. We also performed stratified analyses by subjective sleep quality (good versus poor) and maternal age (≤30 versus >30 years).
MAIN RESULTS AND THE ROLE OF CHANCE
Compared with women who slept 7 to <8 h/night, those who slept <7 h/night exhibited decreases in the number of retrieved and mature oocytes of 11.5% (95% CI: −21.3%, −0.48%) and 11.9% (95% CI: −22.4%, −0.03%), respectively. A mid-sleep time (MST) earlier than 2:21 a.m. (<2:21 a.m.) or later than 3:00 a.m. (≥3:00 a.m.) and poor subjective sleep quality were inversely associated with the fertilization rate. Women who had trouble falling asleep more than three times per week had a lower number of mature oocytes (−10.5%, 95% CI: −18.6%, −1.6%), normal fertilized oocytes (−14.8%, 95% CI: −23.7%, −4.8%) and good-quality embryos (−15.1%, 95% CI: −25.4%, −3.5%) than those who had no such trouble. In addition, women who slept 9 to <10 h/night had a lower chance of clinical pregnancy compared to women who slept 7 to <8 h/night (odds ratio = 0.65, 95% CI: 0.44, 0.98). In the stratified analyses, the positive associations of nocturnal sleep duration with the number of good-quality embryos and fertilization rate existed only among the women with poor subjective sleep quality (P for interaction = 0.02 and 0.03, respectively). Additionally, we found that the positive associations of nocturnal sleep duration with implantation or clinical pregnancy only existed among women aged over 30 years (P for interaction = 0.04 and 0.01, respectively).
LIMITATIONS, REASONS FOR CAUTION
Sleep characteristics are self-reported, which may lead to misclassification. MST serves as a proxy of chronotype and may be non-differentially misclassified resulting in an underestimate of the association of interest. Measuring sleep characteristics on the day of oocyte retrieval may lead to bias. Chance findings cannot be excluded because of the limited number of women with <7 h or ≥10 h nocturnal sleep and multiple testing. Our results may be biased by other confounders and may not be generalizable to women of other ethnicities.
WIDER IMPLICATIONS OF THE FINDINGS
Unhealthy sleep characteristics, including short nocturnal sleep, inappropriate sleep time, poor subjective sleep quality and having trouble falling asleep, may impair oocyte quantity and its potential to mature or be fertilized. Long nocturnal sleep might reduce the chance of clinical pregnancy among infertile females, especially women younger than 30 years old. Prolonged nocturnal sleep duration may be a potential beneficial behavior for improving IVF/ICSI outcomes for women aged over 30 years and women with poor subjective sleep quality, which requires further investigation.
STUDY FUNDING/COMPETING INTEREST(S)
This work was supported by the National Natural Science Foundation of China (81771654) and the National Key R&D Program of China (No. 2018YFC1004201). There are no conflicts of interest to declare.
TRIAL REGISTRATION NUMBER
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•Exposures to BPA analogues in associations with serum hormones were examined.•Higher BPF and BPS exposures were associated with lower E2 levels and E2/T ratio.•Higher BPS exposure was associated ...with lower SHBG levels.•Age and BMI had modifying effects on these associations.
Bisphenol A (BPA) as an endocrine disrupting chemical has been shown to alter reproductive endocrine function, but little is known on its analogues such as bisphenol F (BPF) and bisphenol S (BPS) with increasing usage and exposure.
To explore the associations between exposures to BPA, BPF and BPS and serum reproductive hormones among reproductive-aged Chinese men.
We measured BPA, BPF and BPS concentrations in repeated urine samples and multiple reproductive hormones in the serum samples collected from 462 men attending an infertility clinic in Wuhan, China. Linear regression models were applied to assess the associations between averaged urinary BPA, BPF and BPS levels and serum hormone concentrations, and restricted cubic spline (RCS) models were further utilized to explore potential non-linear associations. We also examined potential modifying effects by age and body mass index (BMI).
There was little evidence of associations between BPA exposure and altered reproductive hormones. However, we found that elevated BPF and BPS exposures were in negative associations with estrogen (E2) levels and E2/T (total testosterone) ratio (all P for trends < 0.05), and that elevated BPS exposure was negatively associated with SHBG levels (P for trend = 0.09). Based on the RCS models, these linear negative associations except that between BPS exposure and E2/T ratio were further confirmed. In stratified analyses, BPF and BPS exposures in relation to reduced E2 and E2/T ratio were more pronounced among men aged > 30 years, whereas their associations with reduced SHBG levels were more pronounced among men aged ≤ 30. Also, BPS exposure in negative association with FSH only emerged among men with BMI ≥ 24 kg/m2 (P for interaction = 0.03).
BPF and BPS exposures were negatively associated with male serum E2, E2/T ratio and SHBG levels, and these associations varied by age and BMI.
Nitrosamines, as a class of emerging frequently detected nitrogenous disinfection byproducts (N-DBPs) in drinking water, have gained increasing attention due to their potentially high health risk. ...Few studies focus on the occurrence variation and carcinogenic health risk of nitrosamines in drinking water systems. Our study aimed to investigate the spatial and temporal variability of nitrosamines in a drinking water system and to conduct a carcinogenic health risk assessment. Three types of water samples, including influent water, treated water and tap water, were collected monthly during an entire year in a drinking water system utilizing a combination of chlorine dioxide and chlorine in central China, and 9 nitrosamines were measured. The nitrosamine formation potentials (FPs) in influent water were also determined. N-nitrosodimethylamine (NDMA) was the most prevalent compound and was dominant in the water samples with average concentrations ranging from 2.5 to 67.4 ng/L, followed by N-nitrosodiethylamine (NDEA) and N-nitrosopiperidine (NPIP). Nitrosamine occurrence varied monthly, and significant seasonal differences were observed in tap water (p < .05). There were decreasing mean NDMA, NDEA and NPIP concentrations from influent water to treated water to tap water, but no significant spatial variability was observed within the water distribution system (p > .05). The average and 95th percentile total lifetime cancer risks for the three main nitrosamines were 4.83 × 10−5 and 4.48 × 10−4, respectively, exceeding the negligible risk level (10−6) proposed by the USEPA. Exposure to nitrosamines in drinking water posed a higher cancer risk for children than for adults, and children aged 0.75 to 1 years suffered the highest cancer risk. These results suggest that nitrosamine occurrence in tap water varied temporally but not spatially. Exposure to drinking water nitrosamines may pose a carcinogenic risk to human health, especially to children.
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•NDMA, NDEA and NPIP in this drinking water system were frequently detected.•Nitrosamine concentrations decreased from influent water to finished water to tap water.•Nitrosamine occurrence in tap water varied temporally but not significantly spatially.•Exposure to drinking water nitrosamines posed higher cancer risk for children than for adults.
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