Plant growth is coordinated with the availability of nutrients that ensure its development. Nitrate is a major source of nitrogen (N), an essential macronutrient for plant growth. It also acts as a ...signaling molecule to modulate gene expression, metabolism, and a variety of physiological processes. Recently, it has become evident that the calcium signal appears to be part of the nitrate signaling pathway. New key players have been discovered and described in
(Arabidopsis). In addition, knowledge of the molecular mechanisms of how N signaling affects growth and development, such as the nitrate control of the flowering process, is increasing rapidly. Here, we review recent advances in the identification of new components involved in nitrate signal transduction, summarize newly identified mechanisms of nitrate signaling-modulated flowering time in Arabidopsis, and suggest emerging concepts and existing open questions that will hopefully be informative for further discoveries.
Genetic variants and lifestyle factors have been associated with gastric cancer risk, but the extent to which an increased genetic risk can be offset by a healthy lifestyle remains unknown. We aimed ...to establish a genetic risk model for gastric cancer and assess the benefits of adhering to a healthy lifestyle in individuals with a high genetic risk.
In this meta-analysis and prospective cohort study, we first did a fixed-effects meta-analysis of the association between genetic variants and gastric cancer in six independent genome-wide association studies (GWAS) with a case-control study design. These GWAS comprised 21 168 Han Chinese individuals, of whom 10 254 had gastric cancer and 10 914 geographically matched controls did not. Using summary statistics from the meta-analysis, we constructed five polygenic risk scores in a range of thresholds (p=5 × 10−4 p=5 × 10−5 p=5 × 10−6 p=5 × 10−7, and p=5 × 10−8) for gastric cancer. We then applied these scores to an independent, prospective, nationwide cohort of 100 220 individuals from the China Kadoorie Biobank (CKB), with more than 10 years of follow-up. The relative and absolute risk of incident gastric cancer associated with healthy lifestyle factors (defined as not smoking, never consuming alcohol, the low consumption of preserved foods, and the frequent intake of fresh fruits and vegetables), was assessed and stratified by genetic risk (low quintile 1 of the polygenic risk score, intermediate quintile 2–4 of the polygenic risk score, and high quintile 5 of the polygenic risk score). Individuals with a favourable lifestyle were considered as those who adopted all four healthy lifestyle factors, those with an intermediate lifestyle adopted two or three factors, and those with an unfavourable lifestyle adopted none or one factor.
The polygenic risk score derived from 112 single-nucleotide polymorphisms (p<5 × 10−5) showed the strongest association with gastric cancer risk (p=7·56 × 10−10). When this polygenic risk score was applied to the CKB cohort, we found that there was a significant increase in the relative risk of incident gastric cancer across the quintiles of the polygenic risk score (ptrend<0·0001). Compared with individuals who had a low genetic risk, those with an intermediate genetic risk (hazard ratio HR 1·54 95% CI 1·22–1·94, p=2·67 × 10−4) and a high genetic risk (2·08 1·61–2·69, p<0·0001) had a greater risk of gastric cancer. A similar increase in the relative risk of incident gastric cancer was observed across the lifestyle categories (ptrend<0·0001), with a higher risk of gastric cancer in those with an unfavourable lifestyle than those with a favourable lifestyle (2·03 1·46–2·83, p<0·0001). Participants with a high genetic risk and a favourable lifestyle had a lower risk of gastric cancer than those with a high genetic risk and an unfavourable lifestyle (0·53 0·29–0·99, p=0·048), with an absolute risk reduction of 1·12% (95% CI 0·62–1·56).
Chinese individuals at an increased risk of incident gastric cancer could be identified by use of our newly developed polygenic risk score. Compared with individuals at a high genetic risk who adopt an unhealthy lifestyle, those who adopt a healthy lifestyle could substantially reduce their risk of incident gastric cancer.
National Key R&D Program of China, National Natural Science Foundation of China, 333 High-Level Talents Cultivation Project of Jiangsu Province, and China Postdoctoral Science Foundation.
Genetic variation has an important role in the development of non-small-cell lung cancer (NSCLC). However, genetic factors for lung cancer have not been fully identified, especially in Chinese ...populations, which limits the use of existing polygenic risk scores (PRS) to identify subpopulations at high risk of lung cancer for prevention. We therefore aimed to identify novel loci associated with NSCLC risk, and generate a PRS and evaluate its utility and effectiveness in the prediction of lung cancer risk in Chinese populations.
To systematically identify genetic variants for NSCLC risk, we newly genotyped 19 546 samples from Chinese NSCLC cases and controls from the Nanjing Medical University Global Screening Array Project and did a meta-analysis of genome-wide association studies (GWASs) of 27 120 individuals with NSCLC and 27 355 without NSCLC (13 327 cases and 13 328 controls of Chinese descent as well as 13 793 cases and 14 027 controls of European descent). We then built a PRS for Chinese populations from all reported single-nucleotide polymorphisms that have been reported to be associated with lung cancer risk at genome-wide significance level. We evaluated the utility and effectiveness of the generated PRS in predicting subpopulations at high-risk of lung cancer in an independent prospective cohort of 95 408 individuals from the China Kadoorie Biobank (CKB) with more than 10 years' follow-up.
We identified 19 susceptibility loci to be significantly associated with NSCLC risk at p≤5·0 × 10
, including six novel loci. When applied to the CKB cohort, the PRS of the risk loci successfully predicted lung cancer incident cases in a dose-response manner in participants at a high genetic risk (top 10%) than those at a low genetic risk (bottom 10%; adjusted hazard ratio 1·96, 95% CI 1·53-2·51; p
=2·02 × 10
). Specially, we observed consistently separated curves of lung cancer events in individuals at low, intermediate, and high genetic risk, respectively, and PRS was an independent effective risk stratification indicator beyond age and smoking pack-years.
We have shown for the first time that GWAS-derived PRS can be effectively used in discriminating subpopulations at high risk of lung cancer, who might benefit from a practically feasible PRS-based lung cancer screening programme for precision prevention in Chinese populations.
National Natural Science Foundation of China, the Priority Academic Program for the Development of Jiangsu Higher Education Institutions, National Key R&D Program of China, Science Foundation for Distinguished Young Scholars of Jiangsu, and China's Thousand Talents Program.
•The NRT1.1 defective mutant exhibited a late-flowering phenotype under both long day and short day conditions.•NRT1.1 affecting flowering time was associated with FLC-dependent flowering ...pathway.•The up-regulation of FLC expression caused by the loss function of NRT1.1 is not related to nitrate availability.
Nitrate Transporter 1.1 (NRT1.1) is a nitrate transporter and sensor that modulates plant metabolism and growth. It has previously been shown that NRT1.1 is involved in the regulation of flowering time in Arabidopsis thaliana. In this study, we mainly used genetic and molecular methods to reveal the key flowering pathway that NRT1.1 may be involved in. Mutant alleles of CO and FLC, two crucial components in the flowering pathway, were introduced into the NRT1.1 defective mutant background by crossing. When the CO mutation was introduced into chl1-5 plants, the double mutant had delayed flowering time, and the CO transcription levels did not change in the chl1-5 plants. These results indicate that the CO-dependent photoperiod may be not associated with the delayed flowering shown by chl1-5. However, FLC loss of function could rescue the late flowering phenotype of the chl1-5 mutant, and FLC expression levels significantly increased in the NRT1.1 defective mutant plants. The FT expression levels in the chl1-5flc-3 double mutant plants recovered when the FLC mutation was introduced into chl1-5 plants and the up-regulation of FLC transcripts in the chl1-5 mutant plants was not related to nitrate availability. Our findings suggest that NRT1.1 affects flowering time via interaction with the FLC-dependent flowering pathway to influence its target gene FT, and that NRT1.1 may be included in an additional signaling pathway that represses the expression of FLC in a nitrate-independent manner.
Abstract Background Inherited variations in DNA double-strand break (DSB) repair pathway are known to influence ovarian cancer occurrence, progression and treatment response. Despite its ...significance, survival-associated genetic variants within the DSB pathway remain underexplored. Methods In the present study, we performed a two-phase analysis of 19,290 single-nucleotide polymorphisms (SNPs) in 199 genes in the DSB repair pathway from a genome-wide association study (GWAS) dataset and explored their associations with overall survival (OS) in 1039 Han Chinese epithelial ovarian carcinoma (EOC) patients. After utilizing multivariate Cox regression analysis with bayesian false-discovery probability for multiple test correction, significant genetic variations were identified and subsequently underwent functional prediction and validation. Results We discovered a significant association between poor overall survival and the functional variant GEN1 rs56070363 C > T (CT + TT vs. TT, adjusted hazard ratio (HR) = 2.50, P < 0.001). And the impact of GEN1 rs56070363 C > T on survival was attributed to its reduced binding affinity to hsa-miR-1287-5p and the resultant upregulation of GEN1 mRNA expression. Overexpression of GEN1 aggregated EOC cell proliferation, invasion and migration presumably by influencing the expression of immune inhibitory factors, thereby elevating the proportion of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) and then constructing an immunosuppressive tumor microenvironment. Conclusions In conclusion, GEN1 rs56070363 variant could serve as a potential predictive biomarker and chemotherapeutic target for improving the survival of EOC patients.
A light-addressable potentiometric sensor (LAPS) is a semiconductor-based chemical sensor, in which the measurement area is defined by a probe light illuminating the sensor plate. In this study, a ...novel method to detect hydrogen permeation through metal was proposed using a measurement system, in which a LAPS was combined with a micro-volume measurement cell. The sensing surface of the LAPS was placed in the vicinity of the hydrogen exit surface of an iron sheet to form the micro-volume cell. The cell was filled with a Na2HPO4 solution, and then the pH change of the solution due to production of protons during the electrochemical hydrogen permeation was detected. After loading hydrogen atoms from the hydrogen entry side into the iron sheet, the photocurrent – bias voltage characteristics of the LAPS showed a shift indicating production of protons. The result suggested the possibility of applying the LAPS to visualization of hydrogen permeation sites on the metal surface.
Cutaneous melanoma (CM) is one of the most aggressive cancers with highly metastatic ability. To make things worse, there are limited effective therapies to treat advanced CM. Our study aimed to ...investigate new biomarkers for CM prognosis and establish a novel risk score system in CM.
Gene expression data of CM from Gene Expression Omnibus (GEO) datasets were downloaded and analyzed to identify differentially expressed genes (DEGs). The overlapped DEGs were then verified for prognosis analysis by univariate and multivariate COX regression in The Cancer Genome Atlas (TCGA) datasets. Based on the gene signature of multiple survival associated DEGs, a risk score model was established, and its prognostic and predictive role was estimated through Kaplan-Meier (K-M) analysis and log-rank test. Furthermore, the correlations between prognosis related genes expression and immune infiltrates were analyzed
Tumor Immune Estimation Resource (TIMER) site.
A total of 103 DEGs were obtained based on GEO cohorts, and four genes were verified in TCGA datasets. Subsequently, four genes (
, and
) model was developed by univariate and multivariate Cox regression analyses. The K-M plots showed that the high-risk group was associated with shortened survival than that in the low-risk group (
< 0.0001). Multivariate analysis suggested that the model was an independent prognostic factor (high-risk vs. low-risk, HR= 2.06,
< 0.001). Meanwhile, the high-risk group was prone to have larger breslow depth (
< 0.001) and ulceration (
< 0.001).
The four-gene risk score model functions well in predicting the prognosis and treatment response in CM and will be useful for guiding therapeutic strategies for CM patients. Additional clinical trials are needed to verify our findings.
An inhibited neural response to reward is typical of clinical depression and can predict an individual's overall depressive symptoms. However, the mechanism underlying this are unclear. Previous ...studies have found that anhedonia and inattention may mediate the relationship between reward sensitivity and depressive symptoms. Therefore, this study aimed to verify the relationship between reward sensitivity and overall depressive symptoms in a depressive tendency sample as well as to explore the mechanism underlying the ability of neural responses to reward to predict overall depressive symptoms via a mediation model. Sixty-four participants (33 with depressive tendencies and 31 without; dichotomized by BDI-II) finished simple gambling tasks while their event-related potential components (ERPs) were recorded and compared. Linear regression was conducted to verify the predictive effect of ERPs on overall depressive symptoms. A multiple mediator model was used, with anhedonia and distractibility as mediators reward sensitivity and overall depressive symptoms. The amplitude of reward positivity (ΔRewP) was greater in healthy controls compared to those with depressive tendencies (p = 0.006). Both the gain-locked ERP component (b = - 1.183, p = 0.007) and the ΔRewP (b = - 0.991, p = 0.024) could significantly negatively predict overall depressive symptoms even after controlling for all anxiety symptoms. The indirect effects of anhedonia and distractibility were significant (both confidence intervals did not contain 0) while the direct effect of reward sensitivity on depressive symptom was not significant (lower confidence interval = - 0.320, upper confidence interval = 0.065). Individuals with depressive tendencies display impaired neural responses to reward compared to healthy controls and reduced individual neural responses to reward may reflect the different biotypes of depression such as anhedonia and inattention.
Accumulating evidence indicates the absence of paternally derived miRNAs, piwiRNAs, and proteins may be one important factor contributing to developmental failure in somatic cell cloned embryos. In ...the present study, we found microRNA-449b (miR-449b) was highly expressed in sperm. Target gene predictions and experimental verification indicate that several embryonic development-related genes, including CDK6, c-MYC, HDAC1 and BCL-2, are targets of miR-449b. We therefore investigated the role of miR-449b using somatic cell nuclear transfer (SCNT) embryo model. Bovine fetal fibroblasts, expressing miR-449b through a doxycycline (dox) induced expression system were used as nuclear donor cells for SCNT. The results showed that miR-449b expression in SCNT embryos significantly enhanced the cleavage rate at 48 h after activation and the levels of H3K9 acetylation at the 2-cell to 8-cell stages, meanwhile, significantly decreased the apoptosis index of blastocysts. In addition, we verified miR-449b could regulate the expression levels of CDK6, c-MYC, HDAC1 and BCL-2. In conclusion, the present study shows that miR-449b expression improves the first cleavage division, epigenetic reprogramming and apoptotic status of bovine preimplantation cloned embryos.
PDF
