Advances in the roles and mechanisms of nonsense-mediated mRNA decay in embryonic development / 生理学报

Nonsense-mediated mRNA decay (NMD) is originally identified as a widespread mRNA surveillance machinery in degrading 'aberrant' mRNA species with premature termination codons (PTCs) rapidly, which protects the cells from the accumulation of truncated proteins. Recent studies show that NMD can also regulate the degradation of normal gene transcripts, which execute important cellular and physiological functions. Therefore, NMD is considered as a highly conserved post-transcriptional regulatory mechanism in eukaryotes. NMD modulates 3% to 20% of the transcriptome from yeast to human directly or indirectly, which is essential for various physiological processes, such as cell homeostasis, stress response, proliferation, and differentiation. NMD can regulate the level of transcripts that involves in development, and single knockout of most NMD factors has an embryonic lethal effect. NMD plays an important role in the self-renewal, differentiation of embryonic stem cells and is critical during embryonic development. In this review, we summarized the latest advances in the roles and mechanisms of NMD in embryonic development, in order to provide new ideas for the research on embryonic development and the treatment of embryonic development related diseases.

Functional Investigation of a GRIN2A Variant Associated with Rolandic Epilepsy / 神经科学通报·英文版

N-methyl-D-aspartate receptors (NMDARs), a subtype of glutamate-gated ion channels, play a central role in epileptogenesis. Recent studies have identified an increasing number of GRIN2A (a gene encoding the NMDAR GluN2A subunit) mutations in patients with epilepsy. Phenotypes of GRIN2A mutations include epilepsy-aphasia disorders and other epileptic encephalopathies, which pose challenges in clinical treatment. Here we identified a heterozygous GRIN2A mutation (c.1341T>A, p.N447K) from a boy with Rolandic epilepsy by whole-exome sequencing. The patient became seizure-free with a combination of valproate and lamotrigine. Functional investigation was carried out using recombinant NMDARs containing a GluN2A-N447K mutant that is located in the ligand-binding domain of the GluN2A subunit. Whole-cell current recordings in HEK 293T cells revealed that the N447K mutation increased the NMDAR current density by ~1.2-fold, enhanced the glutamate potency by 2-fold, and reduced the sensitivity to Mg inhibition. These results indicated that N447K is a gain-of-function mutation. Interestingly, alternative substitutions by alanine and glutamic acid at the same residue (N447A and N447E) did not change NMDAR function, suggesting a residual dependence of this mutation in altering NMDAR function. Taken together, this study identified human GluN2A N447K as a novel mutation associated with epilepsy and validated its functional consequences in vitro. Identification of this mutation is also helpful for advancing our understanding of the role of NMDARs in epilepsy and provides new insights for precision therapeutics in epilepsy.

Mutations of N-Methyl-D-Aspartate Receptor Subunits in Epilepsy / 神经科学通报·英文版

Epilepsy is one of the most common neurological diseases. Of all cases, 70%-80% are considered to be due to genetic factors. In recent years, a large number of genes have been identified as being involved in epilepsy. Among them, N-methyl-D-aspartate receptor (NMDAR) subunit-encoding genes represent a large proportion, suggesting an important role for NMDARs in epilepsy. In this review, we summarize and analyze the genotypes, functional alterations, and clinical aspects of NMDAR subunit mutations/variants identified from patients with epilepsy. These data will help to throw light upon the pathogenicity of these NMDAR mutations and advance our understanding of the subtle and complicated role of NMDARs in epilepsy. It will also offer new insights into precision therapy for this disorder.

Environmental and psycho-social factors related to prostate cancer risk in the Chinese population: a case-control study / 生物医学与环境科学（英文）

<p><b>OBJECTIVE</b>To study the risk environmental and psycho-social factors associated to prostate cancer (PCa) in Chinese population.</p><p><b>METHODS</b>250 PCa patients and 500 controls were enrolled in this case-control study. Information was collected and logistic regression analysis was used to estimate the odds ratios (OR) and 95% confidence intervals (95% CI) for relationship between lifestyle, eating habits and psycho-social factors with PCa risk.</p><p><b>RESULTS</b>Green vegetables and green tea were associated with a decreased risk of PCa (OR=0.39, 95% CI: 0.28-0.53; OR=0.59, 95% CI: 0.40-0.87, respectively). Family history of PCa (OR=7.16, 95% CI: 2.01-25.49), history of prostate diseases (OR=2.28, 95% CI: 1.53-3.41), alcohol consumption (OR=1.97, 95% CI: 1.33-2.90), red meat consumption (OR=1.74, 95% CI: 1.20-2.52), barbecued (OR=2.29, 95% CI: 1.11-4.73) or fried (OR=2.35, 95% CI: 1.24-4.43) foods were related with increased PCa risk. Negative psycho-social factors including occupational setbacks (OR=1.61, 95% CI: 1.00-2.59), marital separation (OR=1.94, 95% CI: 1.29-2.91), self-contained suffering (OR=2.37, 95% CI: 1.58-3.55), and high sensitivity to the personal comments (OR=1.73, 95% CI: 1.18-2.54) were related to PCa.</p><p><b>CONCLUSION</b>Regular consumption of green vegetables and green tea may suggest protective effects on PCa. Alcohol consumption, red meat consumption and barbecued or fried foods were associated with PCa. Negative psycho-social factors may also play a role in the incidence of PCa in Chinese population.</p>

Bioinformatic prediction of the relationship between PPP4RI gene with tumor and its preliminary application in gastric cancer / 第二军医大学学报

Objective: To investigate the relationship of PPP4R1 gene with the oncogenesis and metastasis of gastric carcinoma by using bioinformatics analysis, and to verify the result by RT-PCR. Methods: IntNetDB was used to search for the neighborhoods of gene PPP4R1 and cliques by CFinder; Chilibot was used to explore the association between the cliques and carcinoma, then the association of PPP4R1 with gastric carcinoma was deduced. Eighteen pairs of primary and metastatic specimens from the same patient and 12 pairs primary carcinoma and the adjacent normal specimens from the same patient were analyzed by RT-PCR for PPP4R1 expression. Results: It was found that the community genes of PPP4R1 included PPP2R5E, MTMR4, PPP3CC, CTDP1, CTDSP1, FLJ22405, PPP1CB, PPP1CC, PPP2R2A, PPP2R5A, PPP2R5C, CTDSP2, and PPP1CA as searched by Cfinder2. 0 when k = 14. Nine of the genes were associated with carcinoma and 2 associated with carcinoma and metastasis. The result of RT-PCR showed that higher expression of PPP4R1 was found in 15 of the 18 primary gastric cancer specimens compared with the paired metastatic specimens (P<0.01); higher expression was also found in 9 of the 12 adjacent normal specimens compared with the paired cancer specimens (P< 0.01). Conclusion: Gene PPP4R1 may be associated with the oncogeriesis and metastasis of gastric carcinoma; bioinformatics is an efficient way to investigate function of new genes.

Relationship of GSTP1, RASSF1A polymorphisms and environmental agent with susceptibility to prostate cancer: A case-control study / 第二军医大学学报

Objective: To investigate relationship of GSTP1, RASSF1A polymorphisms and environmental agent with susceptibility to prostate cancer (Pca). Methods: The GSTP1 and RASSF1A genotypes were determined by TaqMan/MGB Probe Technology in 103 patients with Pca and 103 normal controls. Multivariate logistic regression model was used to assess the association of smoking, alcohol drinking, tea drinking, weekly pork and beef consumption, and the genetic polymorphisms with the susceptibility to Pca, while taking into consideration of the environmental agent. Results: The frequencies of the GSTP1 AA, AG and GG genotypes were 66.02%, 22.33%, and 11.65% in patients with Pca and 67.96%, 29.13% and 2.91% in controls, respectively, with significant difference found between the two groups (X2 = 6.35, P = 0.04). The frequencies of RASSF1A CC, CA and AA genotypes were 88.34%, 5.83%, and 5.83% in patients with Pca, and 85.44%, 12.62%, and 1.94% in the controls, respectively, with no significant difference found between the two groups (X2 = 4.63, P = 0.10). Multivariate analysis showed a decreased risk in those who had a tea drinking history (OR = 0.40, 95% CI, 0.19-0. 82) and an increased risk in those who had a smoking history (OR = 3.02, 95% CI, 1.44-6. 32). Conclusion: Our results indicate that GSTP1, RASSF1A polymorphisms are not associated with Pca susceptibility in Chinese Han nationality. Smoking is the risk factor of Pca, and tea drinking is a protective factor against Pca.