Disruption of intestinal epithelial permeability in the Co-culture system of Caco-2/HT29-MTX cells exposed individually or simultaneously to acrylamide and ochratoxin A.

Mycotoxins and thermal processing hazards are common contaminants in various foods and cause severe problems in terms of food safety and health. Combined use of acrylamide (AA) and ochratoxin A (OTA) would result in more significant intestinal toxicity than either toxin alone, but the underlying mechanisms behind this poor outcome remain unclear. Herein, we established the co-culture system of Caco-2/HT29-MTX cells for simulating a real intestinal environment that is more sensitive to AA and OTA, and showed that the combination of AA and OTA could up-regulate permeability of the intestine via increasing LY permeabilization, and decreasing TEER, then induce oxidative stress imbalance (GSH, SOD, MDA, and ROS) and inflammatory system disorder (TNF-α, IL-1ß, IL-10, and IL-6), thereby leading a rapid decline in cell viability. Western blot, PAS- and AB-staining revealed that AA and OTA showed a synergistic effect on the intestine mainly through the disruption of tight junctions (TJs) and a mucus layer. Furthermore, based on correlation analysis, oxidative stress was more relevant to the mucus layer and TJs. Therefore, our findings provide a better evaluation model and a potential mechanism for further determining or preventing the combined toxicity caused by AA and OTA.

Causal association of blood lipids with all-cause and cause-specific mortality risk: a Mendelian randomization study.

Dyslipidemia has long been implicated in elevating mortality risk; yet, the precise associations between lipid traits and mortality remained undisclosed. Our study aimed to explore the causal effects of lipid traits on both all-cause and cause-specific mortality. One-sample Mendelian randomization (MR) with linear and nonlinear assumptions was conducted in a cohort of 407,951 European participants from the UK Biobank. Six lipid traits, consisting of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides, apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), and lipoprotein(a), were included to investigate the causal associations with mortality. Two-sample MR was performed to replicate the association between each lipid trait and all-cause mortality. Univariable MR results showed that genetically predicted higher ApoA1 was significantly associated with a decreased all-cause mortality risk (HR[95% CI]:0.93 [0.89-0.97], P value = 0.001), which was validated by the two-sample MR analysis. Higher lipoprotein(a) was associated with an increased risk of all-cause mortality (1.03 [1.01-1.04], P value = 0.002). Multivariable MR confirmed the direct causal effects of ApoA1 and lipoprotein(a) on all-cause mortality. Meanwhile, nonlinear MR found no evidence for nonlinearity between lipids and all-cause mortality. Our examination into cause-specific mortality revealed a suggestive inverse association between ApoA1 and cancer mortality, a significant positive association between lipoprotein(a) and cardiovascular disease mortality, and a suggestive positive association between lipoprotein(a) and digestive disease mortality. High LDL-C was associated with an increased risk of cardiovascular disease mortality but a decreased risk of neurodegenerative disease mortality. The findings suggest that implementing interventions to raise ApoA1 and decrease lipoprotein(a) levels may improve overall health outcomes and mitigate cancer and digestive disease mortality.

Investigating linear and nonlinear associations of LDL cholesterol with incident chronic kidney disease, atherosclerotic cardiovascular disease and all-cause mortality: A prospective and Mendelian randomization study.

BACKGROUND AND AIMS: Observational studies suggest potential nonlinear associations of low-density lipoprotein cholesterol (LDL-C) with cardio-renal diseases and mortality, but the causal nature of these associations is unclear. We aimed to determine the shape of causal relationships of LDL-C with incident chronic kidney disease (CKD), atherosclerotic cardiovascular disease (ASCVD) and all-cause mortality, and to evaluate the absolute risk of adverse outcomes contributed by LDL-C itself. METHODS: Observational analysis and one-sample Mendelian randomization (MR) with linear and nonlinear assumptions were performed using the UK Biobank of >0.3 million participants with no reported prescription of lipid-lowering drugs. Two-sample MR on summary-level data from the Global Lipid Genetics Consortium (N = 296,680) and the CKDGen (N = 625,219) was employed to replicate the relationship for kidney traits. The 10-year probabilities of the outcomes was estimated by integrating the MR and Cox models. RESULTS: Observationally, participants with low LDL-C were significantly associated with a decreased risk of ASCVD, but an increased risk of CKD and all-cause mortality. Univariable MR showed an inverse total effect of LDL-C on incident CKD (HR [95% CI]:0.84 [0.73-0.96]; p = 0.011), a positive effect on ASCVD (1.41 [1.29-1.53]; p<0.001), and no significant causal effect on all-cause mortality. Multivariable MR, controlling for high-density lipoprotein cholesterol (HDL-C) and triglycerides, identified a positive direct effect on ASCVD (1.32 [1.18-1.47]; p<0.001), but not on CKD and all-cause mortality. These results indicated that genetically predicted low LDL-C had an inverse indirect effect on CKD mediated by HDL-C and triglycerides, which was validated by a two-sample MR analysis using summary-level data from the Global Lipid Genetics Consortium (N = 296,680) and the CKDGen consortium (N = 625,219). Suggestive evidence of a nonlinear causal association between LDL-C and CKD was found. The 10-year probability curve showed that LDL-C concentrations below 3.5 mmol/L were associated with an increased risk of CKD. CONCLUSIONS: In the general population, lower LDL-C was causally associated with lower risk of ASCVD, but appeared to have a trade-off for an increased risk of CKD, with not much effect on all-cause mortality. LDL-C concentration below 3.5 mmol/L may increase the risk of CKD.

Mendelian randomization and colocalization analyses reveal an association between short sleep duration or morning chronotype and altered leukocyte telomere length.

Observational studies suggest certain sleep traits are associated with telomere length, but the causal nature of these associations is unclear. The study aimed to determine the causal associations between 11 sleep-related traits and leukocyte telomere length (LTL) through two-sample Mendelian randomization and colocalization analyses using the summary statistics from large-scale genome-wide association studies. Univariable Mendelian randomization indicates that genetically determined short sleep is associated with decreased LTL, while morning chronotype is associated with increased LTL. Multivariable Mendelian randomization further supports the findings and colocalization analysis identifies shared common genetic variants for these two associations. No genetic evidence is observed for associations between other sleep-related traits and LTL. Sensitivity MR methods, reverse MR and re-running MR after removing potential pleiotropic genetic variants enhance the robustness of the results. These findings indicate that prioritizing morning chronotype and avoiding short sleep is beneficial for attenuating telomere attrition. Consequently, addressing sleep duration and chronotype could serve as practical intervention strategies.

Integrating plasma proteomes with genome-wide association data for causal protein identification in multiple myeloma.

BACKGROUND: Multiple myeloma (MM) is a severely debilitating and fatal B-cell neoplastic disease. The discovery of disease-associated proteins with causal genetic evidence offers a chance to uncover novel therapeutic targets. METHODS: First, we comprehensively investigated the causal association between 2994 proteins and MM through two-sample mendelian randomization (MR) analysis using summary-level data from public genome-wide association studies of plasma proteome (N = 3301 healthy individuals) and MM (598 cases and 180,756 controls). Sensitivity analyses were performed for these identified causal proteins. Furthermore, we pursued the exploration of enriched biological pathways, prioritized the therapeutic proteins, and evaluated their druggability using the KEGG pathway analysis, MR-Bayesian model averaging analysis, and cross-reference with current databases, respectively. RESULTS: We identified 13 proteins causally associated with MM risk (false discovery rate corrected P < 0.05). Six proteins were positively associated with the risk of MM, including nicotinamide phosphoribosyl transferase (NAMPT; OR [95% CI]: 1.35 [1.18, 1.55]), tyrosine kinase with immunoglobulin-like and EGF-like domains 1 (TIE1; 1.14 [1.06, 1.22]), neutrophil cytosol factor 2 (NCF2; 1.27 [1.12, 1.44]), carbonyl reductase 1, cAMP-specific 3',5'-cyclic phosphodiesterase 4D (PDE4D), platelet-activating factor acetylhydrolase IB subunit beta (PAFAH1B2). Seven proteins were inversely associated with MM, which referred to suppressor of cytokine signaling 3 (SOCS3; 0.90 [0.86, 0.94]), Fc-gamma receptor III-B (FCGR3B; 0.75 [0.65,0.86]), glypican-1 (GPC1; 0.69 [0.58,0.83]), follistatin-related protein 1, protein tyrosine phosphatase non-receptor type 4 (PTPN4), granzyme B, complement C1q subcomponent subunit C (C1QC). Three of the causal proteins, SOCS3, FCGR3B, and NCF2, were enriched in the osteoclast differentiation pathway in KEGG enrichment analyses while GPC1 (marginal inclusion probability (MIP):0.993; model averaged causal effects (MACE): - 0.349), NAMPT (MIP:0.433; MACE: - 0.113), and NCF2 (MIP:0.324; MACE:0.066) ranked among the top three MM-associated proteins according to MR-BMA analyses. Furthermore, therapeutics targeting four proteins are currently under evaluation, five are druggable and four are future breakthrough points. CONCLUSIONS: Our analysis revealed a set of 13 novel proteins, including six risk and seven protective proteins, causally linked to MM risk. The discovery of these MM-associated proteins opens up the possibility for identifying novel therapeutic targets, further advancing the integration of genome and proteome data for drug development.

RNA polymerase common subunit ZmRPABC5b is transcriptionally activated by Opaque2 and essential for endosperm development in maize.

Maize (Zea mays) kernel size is an important factor determining grain yield; although numerous genes regulate kernel development, the roles of RNA polymerases in this process are largely unclear. Here, we characterized the defective kernel 701 (dek701) mutant that displays delayed endosperm development but normal vegetative growth and flowering transition, compared to its wild type. We cloned Dek701, which encoded ZmRPABC5b, a common subunit to RNA polymerases I, II and III. Loss-of-function mutation of Dek701 impaired the function of all three RNA polymerases and altered the transcription of genes related to RNA biosynthesis, phytohormone response and starch accumulation. Consistent with this observation, loss-of-function mutation of Dek701 affected cell proliferation and phytohormone homeostasis in maize endosperm. Dek701 was transcriptionally regulated in the endosperm by the transcription factor Opaque2 through binding to the GCN4 motif within the Dek701 promoter, which was subjected to strong artificial selection during maize domestication. Further investigation revealed that DEK701 interacts with the other common RNA polymerase subunit ZmRPABC2. The results of this study provide substantial insight into the Opaque2-ZmRPABC5b transcriptional regulatory network as a central hub for regulating endosperm development in maize.

Mapping the field of microalgae CO2 sequestration: a bibliometric analysis.

Microalgae CO2 sequestration has gained considerable attention in the last three decades as a promising technology to slow global warming caused by CO2 emissions. To provide a comprehensive and objective analysis of the research status, hot spots, and frontiers of CO2 fixation by microalgae, a bibliometric approach was recently chosen for review. In this study, 1561 articles (1991-2022) from the Web of Science (WOS) on microalgae CO2 sequestration were screened. A knowledge map of the domain was presented using VOSviewer and CiteSpace. It visually demonstrates the most productive journals (Bioresource Technology), countries (China and USA), funding sources, and top contributors (Cheng J, Chang JS, and their team) in the field of CO2 sequestration by microalgae. The analysis also revealed that research hotspots changed over time and that recent research has focused heavily on improving carbon sequestration efficiency. Finally, commercialization of carbon fixation by microalgae is a key hurdle, and supports from other disciplines could improve carbon sequestration efficiency.

Effects of metabolic factors in mediating the relationship between Type 2 diabetes and depression in East Asian populations: A two-step, two-sample Mendelian randomization study.

BACKGROUND: Observational studies suggested a close link between type 2 diabetes (T2D), metabolic factors and depression, while the causal relationships remained poorly understood. OBJECTIVE: To determine the causality between T2D and depression, and to investigate the roles of metabolic factors in mediating the relationship between T2D and depression in East Asians. METHODS: Using summary statistics from the largest and most up-to-date genome-wide association studies of depression (12,588 cases and 85,914 controls) and T2D (36,614 cases and 155,150 controls) among East Asians, two-step and two-sample MR analyses were performed to estimate the causal mediation effects of metabolic factors including lipid profiles, blood pressure (BP) and fasting insulin (FI) on the relationship between T2D and depression. RESULTS: Genetically predicted T2D was significantly associated with depression (OR [95 % CI]:1.06 [1.01, 1.11], P = 0.043), but not vice versa. T2D was causally associated with lower levels of HDL-C and higher levels of LDL-C, triglycerides (TG), BP and FI. Furthermore, the causal effects of T2D on depression were significantly mediated by LDL-C (ß [95 % CI]: -0.003 [-0.005, -0.001], P = 0.007), and suggestively mediated by TG (0.001 [0.001, 0.003], P = 0.049) and FI (0.006 [0.001, 0.012], P = 0.049). LIMITATIONS: First, depression was defined by several methods, like symptom questionnaires or self-completed surveys. Second, two-sample MR approach is unable to detect the non-linear causal relationships. Third, independent data sets were not available for replication of our findings. CONCLUSION: T2D was causally associated with the risk of depression, and LDL-C, TG, and FI were potential causal mediators of the effect of T2D on depression. Understanding the causality among T2D, metabolic factors and depression is crucial for identifying potential targets for early intervention.

Comparative genomics reveals key molecular targets for mutant Pediococcus pentosaceus C23221 producing pediocin.

Listeria monocytogenes is a common microorganism that causes food spoilage. Pediocins are some biologically active peptides or proteins encoded by ribosomes, which have a strong antimicrobial activity against L. monocytogenes. In this study, the antimicrobial activity of previously isolated P. pentosaceus C-2-1 was enhanced by ultraviolet (UV) mutagenesis. A positive mutant strain P. pentosaceus C23221 was obtained after 8 rounds of UV irradiation with increased antimicrobial activity of 1448 IU/mL, which was 8.47 folds higher than that of wild-type C-2-1. The genome of strain C23221 and wild-type C-2-1 was compared with identify the key genes for higher activity. The genome of the mutant strain C23221 consists of a chromosome of 1,742,268 bp, with 2052 protein-coding genes, 4 rRNA operons, and 47 tRNA genes, which is 79,769 bp less than the original strain. Compared with strain C-2-1, a total of 19 deduced proteins involved in 47 genes are unique to C23221 analyzed by GO database; the specific ped gene related to bacteriocin biosynthesis were detected using antiSMASH in mutant C23221, indicating mutant C23221 produced a new bacteriocin under mutagenesis conditions. This study provides genetic basis for further constituting a rational strategy to genetically engineer wild-type C-2-1 into an overproducer.

Women's reproductive traits and cerebral small-vessel disease: A two-sample Mendelian randomization study.

Background: Observational studies have suggested that women's reproductive factors (age at menarche (AAM), age at first birth (AFB), age at first sexual intercourse (AFS), age at natural menopause (ANM), and pregnancy loss) may influence the risk of cerebral small-vessel disease (CSVD) although the causality remains unclear. Methods: We conducted two-sample univariable Mendelian randomization (UVMR) and multivariable MR (MVMR) to simultaneously investigate the causal relationships between five women's reproductive traits and CSVD clinical [intracerebral hemorrhage (ICH) by location or small-vessel ischemic stroke (SVS)] and subclinical measures [white matter hyperintensities (WMH), fractional anisotropy (FA), and mean diffusivity (MD)], utilizing data from large-scale genome-wide association studies of European ancestry. For both UVMR and MVMR, the inverse-variance-weighted (IVW) estimates were reported as the main results. The MR-Egger, weighted median, generalized summary-data-based MR (GSMR), and MR-pleiotropy residual sum and outlier (MR-PRESSO) methods for UVMR and MVMR-Egger, and the MVMR-robust methods for MVMR were used as sensitivity analyses. Sex-combined instruments for AFS and AFB were used to assess the impact of sex instrumental heterogeneity. Positive control analysis was implemented to measure the efficacy of selected genetic instruments. Results: We found no evidence to support causal associations between genetic liability for women's reproductive factors and the risk of CSVD in UVMR (all P-values > 0.05). Using MVMR, the results were consistent with the findings of UVMR after accounting for body mass index and educational attainment (all P-values > 0.05). Sensitivity analyses also provided consistent results. The putative positive causality was observed between AAM, ANM, and ovarian cancer, ensuring the efficacy of selected genetic instruments. Conclusion: Our findings do not convincingly support a causal effect of women's reproductive factors on CSVD. Future studies are warranted to investigate specific estrogen-related physiological changes in women, which may inform current researchers on the causal mechanisms involved in cerebral small-vessel disease progression.

Association between antihypertensive drugs and hepatocellular carcinoma: A trans-ancestry and drug-target Mendelian randomization study.

BACKGROUND AND AIMS: Antihypertensive drugs were recently reported to have an oncogenic role in common cancer, however, whether these drugs would affect the risk of hepatocellular carcinoma (HCC) remains unclear. METHODS: A drug-target Mendelian randomization method was adopted to examine the long-term effect of 12 antihypertensive drugs classes on the risk of HCC in Europeans and East Asians. To proxy antihypertensive drugs, we leveraged genetic variants located near or within drug target genes that were associated with systolic blood pressure (SBP). Genetically proxied drugs associated with reduced risk of coronary artery disease were included in primary analysis. Genetic summary statistics of SBP and HCC were derived from publicly available large-scale genome-wide association studies in Europeans and East Asians respectively. Expression quantitative trait loci (eQTLs) of drugs target genes were used to proxy drugs in a sensitivity analysis. RESULTS: Genetically proxied thiazides and related diuretics were associated with decreased risk of HCC in both Europeans (OR [95% CI]: 0.79 [0.73, 0.86] per 1 mmHg reduction in SBP; p < 0.001) and East Asians (0.60 [0.45, 0.82]; p = 0.001). Genetically proxied beta-adrenoceptor blockers (BBs) were strongly associated with increased risk of HCC in Europeans (1.46 [1.12, 1.91]; p = 0.004). These findings were replicated in deCODE genetics study and remained consistent when using eQTLs to proxy antihypertensive drugs. CONCLUSIONS: Our findings suggested that thiazides diuretics may lower the risk of HCC in both Europeans and East Asians, while BBs may increase the risk of HCC specifically in Europeans. Further studies are warranted to explore the potential of repurposing or retargeting antihypertensive drugs for HCC prevention.

Combined Effects of Acrylamide and Ochratoxin A on the Intestinal Barrier in Caco-2 Cells.

Acrylamide (AA) and ochratoxin A (OTA) are contaminants that co-exist in the same foods, and may create a serious threat to human health. However, the combined effects of AA and OTA on intestinal epithelial cells remain unclear. The purpose of this research was to investigate the effects of AA and OTA individually and collectively on Caco-2 cells. The results showed that AA and OTA significantly inhibited Caco-2 cell viability in a concentration- and time-dependent manner, decreased transepithelial electrical resistance (TEER) values, and increased the lucifer yellow (LY) permeabilization, lactate dehydrogenase (LDH) release and reactive oxygen species (ROS) levels. In addition, the levels of IL-1ß, IL-6, and TNF-α increased, while the levels of IL-10 decreased after AA and OTA treatment. Western blot analysis revealed that AA and OTA damaged the intestinal barrier by reducing the expression of the tight junction (TJ) protein. The collective effects of AA and OTA exhibited enhanced toxicity compared to either single compound and, for most of the intestinal barrier function indicators, AA and OTA combined exposure tended to produce synergistic toxicity to Caco-2 cells. Overall, this research suggests the possibility of toxic reactions arising from the interaction of toxic substances present in foodstuffs with those produced during processing.

Systemic inflammatory regulators and proliferative diabetic retinopathy: A bidirectional Mendelian randomization study.

Background: Increasing evidence shows that systemic inflammation is an embedded mechanism of proliferative diabetic retinopathy (PDR). However, the specific systemic inflammatory factors involved in this process remained obscure. The study aimed to identify the upstream and downstream systemic regulators of PDR by using Mendelian randomization (MR) analyses. Methods: We performed a bidirectional two-sample MR analysis implementing the results from genome-wide association studies for 41 serum cytokines from 8,293 Finnish individuals, and PDR from FinnGen consortium (2,025 cases vs. 284,826 controls) and eight cohorts of European ancestry (398 cases vs. 2,848 controls), respectively. The inverse-variance-weighted method was adopted as the main MR method, and four additional MR methods (MR-Egger, weighted-median, MR-pleiotropy residual sum and outlier (MR-PRESSO), and MR-Steiger filtering methods) were used for the sensitivity analyses. Results from FinnGen and eight cohorts were pooled into a meta-analysis. Results: Our results showed that genetically predicted higher stem cell growth factor-ß (SCGFb) and interleukin-8 were positively associated with an elevated risk of PDR, with a combined effect of one standard deviation (SD) increase in SCGFb and interleukin-8 causing 11.8% [95% confidence interval (CI): 0.6%, 24.2%]) and 21.4% [95% CI: 3.8%, 41.9%]) higher risk of PDR, respectively. In contrast, genetically predisposition to PDR showed a positive association with the increased levels of growth-regulated oncogene-α (GROa), stromal cell-derived factor-1 alpha (SDF1a), monocyte chemotactic protein-3 (MCP3), granulocyte colony-stimulating factor (GCSF), interleukin-12p70, and interleukin-2 receptor subunit alpha (IL-2ra). Conclusions: Our MR study identified two upstream regulators and six downstream effectors of PDR, providing opportunities for new therapeutic exploitation of PDR onset. Nonetheless, these nominal associations of systemic inflammatory regulators and PDR require validation in larger cohorts.

Women's reproductive traits and major depressive disorder: A two-sample Mendelian randomization study.

BACKGROUND: Evidence suggested strong associations between women's reproductive factors and major depressive disorder (MDD), but their causalities are unclear. METHODS: Using female-specific SNPs as genetic instruments obtained from large-scale genome-wide association studies for women's reproductive traits, we designed two-sample univariable and multivariable Mendelian randomization (MR) analysis to evaluate the causal effects of women's reproductive traits on MDD. For both univariable MR (UVMR) and multivariable MR (MVMR), the inverse variance weighting estimates were reported as main results. MR-Egger, weighted median, and generalized summary-data-based MR (GSMR) methods for UVMR, and MVMR-Egger and MVMR-robust methods for MVMR were used as sensitivity analyses. Negative control analyses, MVMR of age at first birth (AFB) and age at first sexual intercourse (AFS) on MDD, and sex-combined genetic variants for AFB and AFS were performed to enhance the robustness of our study. RESULTS: There was substantial evidence for associations of genetically predicted later age at menarche (AAM) (odds ratio (OR) = 0.97, 95 % confidence interval (CI) = 0.94-0.99, P = 0.007), AFB (OR = 0.91, 95 % CI = 0.86-0.97, P = 0.002) and AFS (OR = 0.70, 95 % CI = 0.60-0.80, P < 0.001) with lower MDD risk in UVMR. After adjustment of BMI and educational attainment using MVMR, we found consistently significant causal effects of AAM (OR = 0.95, 95 % CI = 0.92-0.99, P = 0.006), AFB (OR = 0.88, 95 % CI = 0.84-0.91, P < 0.001) and AFS (OR = 0.71, 95 % CI = 0.64-0.79, P < 0.001) on MDD. CONCLUSIONS: Our results provide compelling evidence that early AAM, AFB, and AFS are risk factors for MDD. Promoting the cognition of reproductive health care for women may reduce the risk of MDD.

Combined population transcriptomic and genomic analysis reveals cis-regulatory differentiation of non-coding RNAs in maize.

KEY MESSAGE: Long intergenic non-coding RNA (lincRNA), cis-acting expression quantitative trait locus (cis-eQTL), maize, regulatory evolution. The law of genetic variation during domestication explains the evolutionary mechanism and provides a theoretical basis for improving existing varieties of maize. Previous studies focused on exploiting regulatory variations controlling the expression of protein-coding genes rather than of non-protein-coding genes. Here, we examined the genetic and evolutionary features of long non-coding RNAs from intergenic regions (long intergenic non-coding RNAs, lincRNAs) using population-scale transcriptome data and identified 1168 lincRNAs with cis-acting expression quantitative trait loci (cis-eQTLs). We found that lincRNAs are more likely to be regulated by cis-eQTLs, which exert stronger effects than the protein-coding genes. During maize domestication and improvement, upregulated alleles of lincRNAs, which originated from both standing variation and new mutation, accumulate more frequently and show larger effect sizes than the coding genes. A stronger signature of genetic differentiation was observed in their regulatory regions compared to those of randomly sampled lincRNAs. In addition, we found that cis-regulatory differentiation of lincRNAs is related to the sequence conservation of lincRNA transcripts. Non-conserved lincRNAs more tend to gain upregulated alleles and show a stronger relationship with selected traits than conserved lincRNAs between maize and its wild relatives. Our findings in maize improve the understanding of cis-regulatory variation in lincRNA genes during domestication and improvement and provide an effective approach for prioritizing candidates for further investigation.

Women's reproductive traits and ischemic stroke: a two-sample Mendelian randomization study.

OBJECTIVE: We conducted a Mendelian randomization (MR) study to disentangle causal associations between women's reproductive behaviors and ischemic stroke (IS) and investigate the roles of two modifiable risk factors (body mass index (BMI) and educational attainment (EA)) in these associations. METHODS: Using summary-level data from large-scale genome-wide association studies, we performed univariable MR to examine whether there is genetic evidence that women's reproductive traits are causally associated with IS and its subtypes. Multivariable MR and MR mediation analysis were used to investigate whether BMI and EA are common mechanisms or mediators for these associations. A set of sensitivity analyses were conducted to test valid MR assumptions. RESULTS: We observed consistent and statistically significant associations across female and sex-combined analyses for earlier age at first birth (AFB) and age at first sexual intercourse (AFS) with a higher risk of IS and large-artery atherosclerotic stroke (LAS) risk in the primary analysis. The odds ratios of IS per 1 SD increase in genetically predicted early AFB and AFS were 0.93 (95% CI, 0.86-0.99; p = 0.046) and 0.83 (95% CI, 0.70-0.97, p = 0.020), respectively. Further analyses indicated that BMI played a shared role in AFS and IS/LAS while EA played a shared role in AFS/AFB and IS/LAS as well as a mediator in the path from AFS to IS/LAS. INTERPRETATION: These findings may inform prevention strategies and interventions directed toward relative women's reproductive behaviors and IS. Future studies are warranted to explore other factors related to EA which are responsible for these causalities.

Molecular Mechanisms Associated with Protecting IEC-6 Cells from Acrylamide-Induced Tight Junction Damage by Ganoderma atrum Polysaccharide.

SCOPE: The previous in vivo studies show Ganoderma atrum polysaccharide (PSG-F2 ) has a protective effect against the acrylamide (AA)-induced intestinal oxidative damage in rats. Now, this study aims to explore the protective mechanism with IEC-6 cell model. METHODS AND RESULTS: Based on RNA Sequencing (RNA-Seq), the study screens MAPK signaling pathway as one of the most crucial pathways for pretreatment with PSG-F2   against AA-induced damage in IEC-6 cells. In total, six key MAPK signaling pathway-related proteins (p-P38/P38, p-ERK/ERK, and p-JNK/JNK), and three tight junction key proteins (Zonula Occludens protein-1, Claudin-1, and Occludin) are detected by Western blot and immunofluorescence, which verify the RNA-Seq data. Moreover, PD98059 interference inhibits critical proteins in the MAPK signaling pathway, thus uncovering the precise molecular mechanisms of MAPK/ERK signaling pathway involve in the protective effects of PSG-F2 against AA-induced intestinal barrier damage. CONCLUSION: These findings confirm that PSG-F2 can be used as a daily dietary supplement to protect the intestinal cells from damage caused by thermal processing hazards AA.

Linear and non-linear Mendelian randomization analyses of sex-specific associations between sleep duration and hyperuricemia.

Background: Observational studies have suggested a potential non-linear association between sleep duration and hyperuricemia. However, the causal nature and sex-specific differences are poorly understood. We aimed to determine the shape of sex-specific causal associations between sleep duration and hyperuricemia in the UK Biobank. Methods: Logistic regression was used to investigate the observational association between self-reported sleep duration and hyperuricemia among 387,980 white British participants (mean age: 56.9 years and 46.0% males). Linear and non-linear Mendelian Randomization (MR) analyses were performed to assess the causal association between continuous sleep duration and hyperuricemia. The causal effects of genetically predicted short (<7 h) and long (>8 h) sleep durations on hyperuricemia were further estimated, respectively. Results: Traditional observational analysis suggested U- and J-shaped associations between sleep duration and hyperuricemia in females and males, respectively. Linear MR did not support the causal effect of sleep duration on hyperuricemia. Non-linear MR demonstrated an approximately U-shaped causal association between continuous sleep duration and hyperuricemia in overall participants and females, but not in males. Genetically predicted short sleep duration was significantly associated with hyperuricemia in females (OR [95% CI]: 1.21 [1.08-1.36]; P = 0.001), but not in males (1.08 [0.98-1.18]; P = 0.137). By contrast, genetically predicted long sleep duration was not significantly associated with the risk of hyperuricemia in either females or males. Conclusion: Genetically predicted short sleep duration is a potential causal risk factor for hyperuricemia for females but has little effect on males. Long sleep duration does not appear to be causally associated with hyperuricemia.

Sex-specific exposures and sex-combined outcomes in two-sample Mendelian randomization may mislead the causal inference.

With great interest, we have read the recent article "Age at menarche, age at natural menopause, and risk of rheumatoid arthritis - a Mendelian randomization study" by Zhu et al. While we have a great appreciation for the work conducted by the authors, there are some methodological issues that need to be reconsidered. First, the gender description of the sample for age at first birth in this study is wrong according to the original genome-wide association study. Second, the study exploited sex-specific SNPs for age at menarche (AAM) and age at natural menopause (ANM) but sex-combined effects of the SNPs on rheumatoid arthritis (RA) that possibly lead no evidence for the causation of AAM and ANM on RA. We suggested the author add the possible biases due to the issue in the limitations. With problems mentioned above, we recommend solutions to make this article more perfect.