Nonrandom selection in one-sample Mendelian Randomization (MR) results in biased estimates and inflated type I error rates only when the selection effects are sufficiently large. In two-sample MR, the different selection mechanisms in two samples may more seriously affect the causal effect estimation. Firstly, we propose sufficient conditions for causal effect invariance under different selection mechanisms using two-sample MR methods. In the simulation study, we consider 49 possible selection mechanisms in two-sample MR, which depend on genetic variants (G), exposures (X), outcomes (Y) and their combination. We further compare eight pleiotropy-robust methods under different selection mechanisms. Results of simulation reveal that nonrandom selection in sample II has a larger influence on biases and type I error rates than those in sample I. Furthermore, selections depending on X+Y, G+Y, or G+X+Y in sample II lead to larger biases than other selection mechanisms. Notably, when selection depends on Y, bias of causal estimation for non-zero causal effect is larger than that for null causal effect. Especially, the mode based estimate has the largest standard errors among the eight methods. In the absence of pleiotropy, selections depending on Y or G in sample II show nearly unbiased causal effect estimations when the casual effect is null. In the scenarios of balanced pleiotropy, all eight MR methods, especially MR-Egger, demonstrate large biases because the nonrandom selections result in the violation of the Instrument Strength Independent of Direct Effect (InSIDE) assumption. When directional pleiotropy exists, nonrandom selections have a severe impact on the eight MR methods. Application demonstrates that the nonrandom selection in sample II (coronary heart disease patients) can magnify the causal effect estimation of obesity on HbA1c levels. In conclusion, nonrandom selection in two-sample MR exacerbates the bias of causal effect estimation for pleiotropy-robust MR methods. 相似文献
With the development of genome sequencing, many researchers have investigated the mechanism by which the intestinal microbiota influences sleep across the brain-gut axis. However, the relationship between gut microbiota and sleep disorder remains unclear. Thus, we studied the difference in gut microbiota composition between poor sleep quality- and normal populations, which helps set the ground for future research. The recruited college students provided baseline information and stool samples and completed the Pittsburgh Sleep Quality Index (PSQI). We compared the two groups’ gut microbiota composition and functional differentiation by using the 16S rRNA gene sequencing analysis. The main bacterial difference and the most critical effect were mainly concentrated within Tenericutes and Elusimicrobia. Compared with the healthy control group, some functions of the gut microbiota were impaired in the poor sleep quality group, such as butanoate metabolism and propanoate metabolism. Bacterial taxa with significant differences raised the possibility for future diagnosis and treatment of sleep problems. 相似文献
(13)C-NMR has yielded to the dynamics study of ethanol as carbon and energy source in the metabolic oscillation of Saccharomyces cerevisiae. Three ethanol fractions such as media, cytoplasm and mitochondria were observed and characterised by different longitudinal relaxation times and chemical shifts. 相似文献
Calcium (Ca2+) has been firmly established as ubiquitous second messengers functioning in plant growth development and response to environmental conditions. Calcineurin B-like (CBL) proteins, a unique group of calcium sensors, play a key role in plant response to various abiotic stresses. Here, eight ZmCBLs genes were retrieved. In terms of the gene structure, maize CBL gene had greater variability compared with rice and Arabidopsis CBLs. Phylogenetic analysis revealed that ZmCBL proteins display a close relation to OsCBLs and a little far relation to AtCBLs. Expression analysis indicated that all the eight ZmCBLs expressions were regulated by low potassium and in a tissue-dependent manner. In general, the ZmCBLs expressions in roots were more sensitive under low potassium environment, especially for ZmCBL5, 6 and 8. In leaves, only ZmCBL3, 8 and 10 expressions were upregulated. Moreover, the expression patterns of the ZmCBLs in tissues of germinated seeds and seedlings were also analyzed. The results showed that all the expressions of ZmCBLs were tissue specific except for ZmCBL6, suggesting that they may involve in seed germination and seedlings’ early growth. 相似文献
To explore the role of gut microbiota in Graves’ disease (GD) and Hashimoto’s thyroiditis (HT). Seventy fecal samples were collected, including 27 patients with GD, 27 with HT, and 16 samples from healthy volunteers. Chemiluminescence was used to detect thyroid function and autoantibodies (FT3, FT4, TSH, TRAb, TGAb, and TPOAb); thyroid ultrasound and 16S sequencing were used to analyze the bacteria in fecal samples; KEGG (Kyoto Encyclopedia of Genes and Genomes) and COG (Clusters of Orthologous Groups) were used to analyze the functional prediction and pathogenesis. The overall structure of gut microbiota in the GD and HT groups was significantly different from the healthy control group. Proteobacteria and Actinobacteria contents were the highest in the HT group. Compared to the control group, the GD and HT groups had a higher abundance of Erysipelotrichia, Cyanobacteria, and Ruminococcus_2 and lower levels of Bacillaceae and Megamonas. Further analysis of KEGG found that the “ABC transporter” metabolic pathway was highly correlated with the occurrence of GD and HT. COG analysis showed that the GD and HT groups were enriched in carbohydrate transport and metabolism compared to the healthy control group but not in amino acid transport and metabolism. Our data suggested that Bacillus, Blautia, and Ornithinimicrobium could be used as potential markers to distinguish GD and HT from the healthy population and that “ABC transporter” metabolic pathway may be involved in the pathogenesis of GD and HT. 相似文献
Lead and di-2-ethylhexyl phthalate (DEHP) are widely distributed in the environment, and their neurotoxicity has caused a widespread concern. The complexity of environmental exposure provides the possibility of their combined exposure. The present study aims to describe a joint neurotoxicity and clarify the potential mechanism after combined exposure to lead and DEHP. A 2 × 3 factorial design was used to analyze either single effects or their interaction by a subchronic lead and DEHP exposure model of the male weaning rats. Similar to the previous study, lead or DEHP single exposure showed an increased neurotoxicity. Interestingly, our neurobehavioral test showed the rats in the combined exposure groups had a better ability of learning and memory compared with the single-exposure ones. It seemed to reflect an antagonism joint action in neurotoxicity after combined exposure. The content of dehydroepiandrosterone (DHEA) in serum and the mRNA level of brain-derived neurotrophic factor (Bdnf) in the hippocampus showed a similar trend to the ability of learning and memory. However, there was insufficient evidence to support the joint action on some indexes of oxidative stress such as malondialdehyde (MDA), the ratio of reduced glutathione(GSH) to oxidized glutathione(GSSG), γglutamylcysteine synthetase (γ-GCS), glutathione-s transferase (GST), and nuclear factor E2-related factor 2 (Nrf2) mRNA expression in the hippocampus. In a word, our current study reminded a unique antagonism joint action of neurotoxicity after combined exposure to lead and DEHP, which may contribute to understanding some shallow mechanism of the joint toxicity due to the complexity of environmental pollutant exposure.
Although protein-tyrosine phosphatase 1B (PTP-1B) is a negative regulator of insulin action, adipose tissue from PTP-1B-/- mice does not show enhanced insulin-stimulated insulin receptor phosphorylation. Investigation of glucose uptake in isolated adipocytes revealed that the adipocytes from PTP-1B-/- mice have a significantly attenuated insulin response as compared with PTP-1B+/+ adipocytes. This insulin resistance manifests in PTP-1B-/- animals older than 16 weeks of age and could be partially rescued by adenoviral expression of PTP-1B in null adipocytes. Examination of adipose signaling pathways found that the basal p70S6K activity was at least 50% higher in adipose from PTP-1B-/- mice compared with wild type animals. The increased basal activity of p70S6K in PTP-1B-/- adipose correlated with decreases in IR substrate-1 protein levels and insulin-stimulated Akt/protein kinase B activity, explaining the decrease in insulin sensitivity even as insulin receptor phosphorylation was unaffected. The insulin resistance of the of the PTP-1B-/- adipocytes could also be rescued by treatment with rapamycin, suggesting that in adipose the loss of PTP-1B results in basal activation of mTOR (mammalian target of rapamycin) complex 1 leading to a tissue-specific insulin resistance. 相似文献