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Exposure to persistent organic pollutants (POPs) may contribute to colorectal cancer risk, but the underlying mechanisms of crucial POPs exposure remain unclear. Hence, we systematically investigated the associations among POPs exposure, genetics and epigenetics and their effects on colorectal cancer. A case-control study was conducted in the Chinese population for detecting POPs levels. We measured the concentrations of 24 POPs in the plasma using gas chromatography-tandem mass spectrometry (GC–MS/MS) and evaluated the clinical significance of POPs by calculating the area under the receiver operating characteristic curve (AUC). To assess the associations between candidate genetic variants and colorectal cancer risk, unconditional logistic regression was used. Compared with healthy control individuals, individuals with colorectal cancer exhibited higher concentrations of the majority of POPs. Exposure to PCB153 was positively associated with colorectal cancer risk, and PCB153 demonstrated superior accuracy (AUC=0.72) for predicting colorectal cancer compared to other analytes. On PCB153-related genes, the rs67734009 C allele was significantly associated with reduced colorectal cancer risk and lower plasma levels of PCB153. Moreover, rs67734009 exhibited an expression quantitative trait locus (eQTL) effect on ESR1, of which the expression level was negatively related to PCB153 concentration. Mechanistically, the risk allele of rs67734009 increased ESR1 expression via miR-3492 binding and m6A modification. Collectively, this study sheds light on potential genetic and epigenetic mechanisms linking PCB153 exposure and colorectal cancer risk, thereby providing insight into the accurate protection against POPs exposure.

Abstract Catalpa bungei is a precious timber species distributed in North China where drought often occurs. To clarify adaptive responses of C. bungei to partial- and full- root-zone drought under the influence of nitrogen forms, a two-factor experiment was conducted in which well-watered (WW), partial root-zone drought in horizontal direction (H-PRD) and in vertical direction (V-PRD), and full root-zone drought (FRD) were combined with nitrate-nitrogen (NN) and ammonium-nitrogen (AN) treatments. C. bungei responded to FRD by sharply closing stomata, decreasing gas exchange rate and increasing leaf instantaneous water use efficiency (WUE i). Under FRD condition, the growth of seedlings was severely inhibited and the effect of N forms was covered up by the drastic drought effect. In comparison, stomata conductance and gas exchanges were moderately inhibited by PRDs. WUE i in V-PRD treatment was superior to H-PRD due to the active stomata regulation resulting from a higher ABA level and active transcription of genes in abscisic acid (ABA) signaling pathway under V-PRD. Under both PRDs and FRD, nitrate benefited antioxidant defense, stomata regulation and leaf WUE i. Under V-PRD, WUE i in nitrate treatment was superior to that in ammonium treatment due to active stomata regulation by signaling network of nitric oxide (NO), Ca2+ and ABA. Under FRD, WUE i was higher in nitrate treatment due to the favoring photosynthetic efficiency resulting from active NO signal and antioxidant defense. The interactive effect of water and N forms was significant on wood xylem development. Superoxide dismutase (SOD) and catalase (CAT) largely contributes to stress tolerance and xylem development.

Abstract Topology created by quasi-continuous spatial variations of a local polarization direction represents an exotic state of matter, but field-driven manipulation has been hitherto limited to creation and destruction. Here we report that relatively small electric or mechanical fields can drive the non-volatile rotation of polar spirals in discretized microregions of the relaxor ferroelectric polymer poly(vinylidene fluoride-ran-trifluoroethylene). These polar spirals arise from the asymmetric Coulomb interaction between vertically aligned helical polymer chains, and can be rotated in-plane through various angles with robust retention. Given also that our manipulation of topological order can be detected via infrared absorption, our work suggests a new direction for the application of complex materials.

Abstract The peripheral T cell pool is maintained at dynamic homeostasis through fine‐tuning of thymic output and self‐renewal of naïve T cells. Lymphopenia or reduced lymphocyte number is implicated in autoimmune diseases, yet little is known about the homeostatic mechanisms. Here, it is reported that the replication protein A1 (RPA1) plays a critical role in T cell homeostasis. Utilizing T cell‐specific Rpa1‐deficient (Rpa1fl/fl Cd4‐cre) mice, loss of Rpa1 results in lymphopenia through restraining peripheral T cell population and limiting TCR repertoire diversity. Moreover, Rpa1fl/fl Cd4‐cre mice exhibit increased susceptibility to inflammatory diseases, including colitis and hepatitis. Clinical analysis reveals that the expression of RPA1 is reduced in patients with ulcerative colitis or other autoinflammatory diseases. Mechanistically, depletion of RPA1 activates ZBP1‐RIPK3 signaling through triggering the genomic DNA leakage into cytosol, consequently resulting in T cell necroptosis. This necroptotic T cell death induced by RPA1 deficiency allows the release of damage‐associated molecular patterns (DAMPs), which in turn recruits leukocytes and exacerbates inflammatory response. Reciprocally, chemical or genetic inhibition of necroptosis signaling can ameliorate the Rpa1 deficiency‐induced inflammatory damage. The studies thus uncover the importance of RPA1‐ZBP1‐RIPK3 axis in T cell homeostasis and provide a promising strategy for autoinflammatory disease treatment.

Core 1 synthase glycoprotein-N-acetylgalactosamine 3-β-galactosyltransferase 1 (C1GALT1) is known to play a critical role in the development of gastric cancer, but few studies have elucidated associations between genetic variants in C1GALT1 and gastric cancer risk. By using the genome-wide association study data from the database of Genotype and Phenotype (dbGAP), we evaluated such associations with a multivariable logistic regression model and identified that the rs35999583G>C in C1GALT1 was associated with gastric cancer risk (odds ratio, 0.83; 95% confidence interval [CI], 0.75–0.92; P = 3.95 × 10−4). C1GALT1 mRNA expression levels were significantly higher in gastric tumor tissues than in normal tissues, and gastric cancer patients with higher C1GALT1 mRNA levels had worse overall survival rates (hazard ratio, 1.33; 95% CI, 1.05–1.68; Plog-rank = 1.90 × 10−2). Furthermore, we found that C1GALT1 copy number differed in various immune cells and that C1GALT1 mRNA expression levels were positively correlated with the infiltrating levels of CD4+ T cells and macrophages. These results suggest that genetic variants of C1GALT1 may play an important role in gastric cancer risk and provide a new insight for C1GALT1 as a promising predictor of gastric cancer susceptibility and immune status. [ABSTRACT FROM AUTHOR]

Aberrant alternative polyadenylation (APA) events play an important role in cancers, but little is known about whether APA-related genetic variants contribute to the susceptibility to bladder cancer. Previous genome-wide association study performed APA quantitative trait loci (apaQTL) analyses in bladder cancer, and identified 17 955 single nucleotide polymorphisms (SNPs). We found that gene symbols of APA affected by apaQTLassociated SNPs were closely correlated with cancer signaling pathways, high mutational burden, and immune infiltration. Association analysis showed that apaQTL-associated SNPs rs34402449 C>A, rs2683524 C>T, and rs11540872 C>G were significantly associated with susceptibility to bladder cancer (rs34402449: OR = 1.355, 95% confidence interval [CI]: 1.159-1.583, P = 1.33 x 10-4; rs2683524: OR = 1.378, 95% CI: 1.164-1.632, P = 2.03 x 10-4; rs11540872: OR = 1.472, 95% CI: 1.193-1.815, P = 3.06 x 10-4). Cumulative effect analysis showed that the number of risk genotypes and smoking status were significantly associated with an increased risk of bladder cancer (Ptrend = 2.87 x 10-12). We found that PRR13, being demonstrated the most significant effect on cell proliferation in bladder cancer cell lines, was more highly expressed in bladder cancer tissues than in adjacent normal tissues. Moreover, the rs2683524 T allele was correlated with shorter 3' untranslated regions of PRR13 and increased PRR13 expression levels. Collectively, our findings have provided informative apaQTL resources and insights into the regulatory mechanisms linking apaQTL-associated variants to bladder cancer risk. [ABSTRACT FROM AUTHOR]