A Non-Cell-Autonomous Mode of DNA Damage Response in Soma of Caenorhabditis elegans.

Life has evolved a mechanism called DNA damage response (DDR) to sense, signal and remove/repair DNA damage, and its deficiency and dysfunction usually lead to genomic instability and development of cancer. The signaling mode of the DDR has been believed to be of cell-autonomy. However, the paradigm is being shifted with in-depth research into model organism Caenorhabditis elegans. Here, we mainly investigate the effect of DDR activation on the radiosensitivity of vulva of C. elegans, and first found that the vulval radiosensitivity is mainly regulated by somatic DDR, rather than the DDR of germline. Subsequently, the worm lines with pharynx-specific rescue of DDR were constructed, and it is shown that the 9-1-1-ATR and MRN-ATM cascades in pharynx restore approximately 90% and 70% of vulval radiosensitivity, respectively, through distantly regulating the NHEJ repair of vulval cells. The results suggest that the signaling cascade of DDR might also operate in a non-cell autonomous mode. To further explore the underlying regulatory mechanisms, the cpr-4 mutated gene is introduced into the DDR-rescued worms, and CPR-4, a cysteine protease cathepsin B, is confirmed to mediate the inter-tissue and inter-individual regulation of DDR as a signaling molecule downstream of 9-1-1-ATR. Our findings throw some light on the regulation of DNA repair in soma of C. elegans, and might also provide new cues for cancer prevention and treatment.

Association of polymorphisms in endothelial dysfunction-related genes with susceptibility to essential hypertension in elderly Han population in Liaoning province, China.

Hypertension is a complex disease which is mainly influenced by genetic factors. Recently, genome-wide association study (GWAS) found three novel endothelial dysfunction-related sites: Vascular endothelial growth factor A (VEGFA) rs9472135, Faciogenital dysplasia 5 (FGD5) rs11128722, Zinc Finger C3HC-type Containing 1 (ZC3HC1) rs11556924. Endothelial dysfunction is one of the early events in pathophysiology of essential hypertension. To investigate the association of endothelial dysfunction-related genes with essential hypertension, we conducted a case-control study of 431 patients with hypertension and 345 controls. The polymorphisms were detected using Taqman Probe. The alleles and genotypes of ZC3HC1 rs11556924 and VEGFA rs9472135 were not statistically different between the two groups, while the allele of FGD5 rs11128722 was different [P = 0.045, OR = 1.265, 95% CI = (1.009-1.586)], especially in the male [P = 0.035, OR = 1.496, 95% CI = (1.037-2.158)]. Analyzing the different of genotype distribution of 3 SNPs in the two groups under different genetic models, the genotypes of FGD5 rs11128722 showed difference in male under dominant model [P = 0.049, OR = 1.610, 95% CI = (1.018-2.544)]. The polymorphism of FGD5 rs11128722 had a significant difference in Body Mass Index (BMI) among different genotypes; In the additive genetic model, BMI of GA genotype was higher than that of GG (P = 0.038); GA + AA was higher than GG in the dominant genetic model (P = 0.011). In our study, we found that the polymorphisms of VEGFA rs9472135 and ZC3HC1 rs11556924 may not significantly associated with the risk of essential hypertension, and FGD5 rs11128722 may increase the risk of it, especially in elderly men.

Meta-analysis of genotype and phenotype studies to confirm the predictive role of the RNF213 p.R4810K variant for moyamoya disease.

BACKGROUND AND PURPOSE: The aim of this meta-analysis study was to assess the predictive effects of RNF213 p.R4810K on phenotype in moyamoya disease (MMD). METHODS: Electronic databases (e.g., Pubmed and EMBASE) were searched, and relevant articles published up to August 2020 were retrieved. Review Manager 5.3 and Stata 12.0 were used for all statistical analyses. Pooled odds ratios, with 95% confidence intervals, and three comparison models were evaluated to analyze the association between RNF213 pR4810K variant and clinical characteristics of MMD patients using a fixed-effects model. RESULTS: A total of 2798 patients with MMD were selected and the effects of the heterozygous or homozygous RNF213 p.R4810K variant on 18 clinical features were identified. There were more patients aged <15 years in the GA and AA groups (AA vs GA: p = 0.009; AA vs GG: p = 0.003; GA vs GG: p = 0.001). Among homozygous patients, the majority experienced MMD onset before the age of 4 years (AA vs. GA: p < 0.00001; AA vs GG: p < 0.00001). The frequency of infarctions and transient ischemic attack was significantly higher in homozygotes and heterozygotes，respectively. However, the frequency of intracerebral/intraventricular hemorrhage was lower in patients with the GA than the GG genotype. More MMD patients with AA and GA genotypes had a family history of the disease (p = 0.003, p < 0.00001, respectively). Posterior cerebral artery involvement was more common in patients with the GA genotype (p < 0.00001). CONCLUSION: The homozygous or heterozygous RNF213 variant may be an efficient biomarker with which to classify different clinical phenotypes of MMD.

Clinical and Genetic Risk Factors of Long-Term Outcomes after Encephaloduroarteriosynangiosis in Moyamoya Disease in China.

OBJECTIVES: This retrospective study was conducted to analyze the associations between ring finger protein 213 p.R4810K variant, clinical features and long-term outcomes in patients with moyamoya disease (MMD) after encephaloduroarteriosynangiosis treatment. MATERIALS AND METHODS: A total of 2,545 patients with MMD in China were included in this study (median of follow-up duration: 32.00 months). Multiple Cox regression models were used to assess the associations between p.R4810K variant, clinical features and long-term outcomes. RESULTS: For all patients, in multivariate Cox analysis, no association was observed between p.R4810K and long-term outcomes. Pediatric onset (HR, 0.38; 95%CI, 0.25-0.59) and headache (HR, 0.26; 95%CI, 0.08-0.83) were inversely and hypertension (HR, 1.43 95%CI, 1.06-1.94), diabetes (HR, 1.55; 95%CI, 1.00-2.40), bilateral lesions (HR, 2.73; 95%CI, 1.12-6.65) and posterior cerebral artery involvement (HR, 1.44; 95%CI, 1.08-1.90) were positively associated with follow-up stroke (all P < 0.05). Pediatric onset (HR, 0.46; 95%CI, 0.26-0.82) was inversely and hyperlipidemia (HR, 1.83; 95%CI, 1.23-2.73), smoking (HR, 1.86; 95%CI, 1.13-3.07), high Suzuki angiographic stage (HR, 1.71, 95%CI, 1.09-2.70), poor admission neurologic status (HR, 8.93; 95%CI, 6.49-12.29) and follow-up stroke (HR, 8.31; 95%CI, 6.01-11.49) were positively associated with poor neurologic outcome at the last follow-up visit (all P < 0.05). The factors were not consistent in the different groups of age at onset. CONCLUSIONS: In our study, p.R4810K may play no role in long-term outcomes in Chinese MMD. Clinical features including age at onset, initial symptoms, risk factors of stroke, imaging, poor admission neurologic status were associated with poor outcomes in MMD after EDAS.

Validation and Extension Study Exploring the Role of RNF213 p.R4810K in 2,877 Chinese Moyamoya Disease Patients.

OBJECTIVE: To validate, update, and extend the role of RNF213 p.R4810K (G>A) for predicting the phenotype of moyamoya disease (MMD) patients and explore the different effects on pediatric and adult groups. METHODS: A total of 2,877 patients conducted from 2004 to 2018 were included. Review Manage 5.3 and SPSS 20.0 were applied to complete all statistical analyses. Information on age at onset, sex, initial symptom, family history and complications were obtained via retrospective chart review. Angiographic records were evaluated. RESULTS: In China, geographic proximity to Korea or Japan may affect the carrying rate of RNF213 p.R4810K. The proportion of patients with the following characteristics was significantly higher (P <0.017) in the GA than in the GG group: female, age at onset < 18 years, infarct after transient ischemic attack, family history of MMD, and posterior cerebral artery involvement. For pediatric patients, GA showed more cerebral hemorrhage (CH) (odds ratios (ORs) [95% confidence intervals (CIs)] = 3.99 (1.61-9.88), P = 0.003), more patients were in the Suzuki early and intermediate stage (P = 0.001; P = 0.001, respectively), while for the adult group, GA indicated more female (OR [95% CIs] = 1.43 [1.15-1.79], P = 0.001), fewer patients with diabetes (0.58 [0.38-0.86], P = 0.007) and intermediate Suzuki stage (P = 3.70 × 10-4). CONCLUSIONS: The incidence and carrying rates of RNF213 p.R4810K in various regions for Chinese MMD patients were obviously different. RNF213 p.R4810K has different predictive effects on phenotypes of pediatric and adult patients.

Association of Genetic Variants With Moyamoya Disease in 13 000 Individuals: A Meta-Analysis.

Background and Purpose- A growing body of evidence indicates genetic components play critical roles in moyamoya disease (MMD). Firm conclusions from studies of this disease have been stymied by small sample sizes and a lack of replicative results. This meta-analysis was conducted to determine whether these genetic polymorphisms are associated with MMD. Methods- PubMed, Google Scholar, Embase, Wanfang, Web of Science, and China National Knowledge Infrastructure databases were used to identify potentially relevant studies published until January 2020. The Review Manager 5.2 and Stata 15.0 software programs were used to perform the statistical analysis. Heterogeneity was assessed using the Cochran Q test and quantified using the I2 test. Results- Four thousand seven hundred eleven MMD cases and 8704 controls in 24 studies were included, evaluating 7 polymorphisms in 6 genes. The fixed-effect odds ratios (95% CI) in allelic model of MMP-2 rs243865 were 0.60 (0.41-0.88) (P=0.008). In the country-based subgroup analysis, the fixed-effect odds ratios (95% CI) of RNF213 rs112735431 in allelic model were China, 39.74 (26.63-59.31), Japan, 74.65 (42.79-130.24) and Korea, 50.04 (28.83-86.88; all P<0.00001). In the sensitivity analysis, the fixed-effect odds ratios (95% CI) of allelic and dominant models were the RNF213 rs148731719 variant, 2.17 (1.36-3.48; P=0.001), 2.20 (1.35-3.61; P=0.002), the TIMP-2 rs8179090 variant, 0.33 (0.25-0.43; P<0.00001), 0.88 (0.65-1.21; P=0.440) and the MMP-3 rs3025058 variant, 0.61 (0.47-0.79; P=0.0002), 0.55 (0.41-0.75; P=0.0001), respectively. Conclusions- RNF213 rs112735431 and rs148731719 were positively, and TIMP-2 rs8179090, MMP-2 rs243865, and MMP-3 rs3025058 were inversely associated with MMD using multiple pathophysiologic pathways. Studies in larger population should be conducted to clarify whether and how these variants are associated with MMD.

Effects of TNF-α-308G/A Polymorphism on the Risk of Diabetic Nephropathy and Diabetic Retinopathy: An Updated Meta-Analysis.

Diabetic nephropathy (DN) and diabetic retinopathy (DR) are the major factors of morbidity and mortality in the patients with diabetes mellitus (DM). Growing studies have investigated the relationship between the TNF-α-308G/A polymorphism and the susceptibility to DN and DR, without achieving consensus. Thus, we conducted this meta-analysis to reach more comprehensive conclusions for these issues. Eligible studies were retrieved through electronic databases such as PubMed, Embase, Web of Science and China National Knowledge Infrastructure. Summary of odds ratios (OR) and 95% confidence intervals (CIs) were generated to evaluate the intensity of the associations. Statistical analyses were performed by STATA 11.0 and RevMan 5.2. There are fourteen eligible publications involving nineteen studies in this meta-analysis. TNF-α-308G/A polymorphism was significantly related to increasing risk of DN under recessive model (OR=1.37, 95% CI=1.03-1.83) and homozygous model (OR=1.54, 95% CI=1.15-2.06). Moreover, the similar results were also obtained in Asian groups for DN (recessive: OR=1.69, 95% CI=1.18-2.42; homozygous: OR=1.99, 95% CI=1.38-2.86; respectively), and significant association was also detected between TNF-α-308G/A and DN susceptibility in type 2 DM in recessive model (OR=1.39, 95% CI=1.02-1.89). No significant association was observed between TNF-α-308G/A and DR susceptibility in total analyses and subgroup analyses by ethnicity and type of DM. TNF-α-308G/A polymorphism may enhance the susceptibility to diabetic nephropathy, especially in Asian population and in T2DM patients, but not diabetic retinopathy.

Association of MTHFR gene polymorphisms with pancreatic cancer: meta-analysis of 17 case-control studies.

BACKGROUND: Pancreatic cancer (PC) is a seriously malignant tumor with a low 5-year survival rate. The relationship between methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and PC has been reported by several studies. However, the results were controversial. Thus, we conducted a meta-analysis to summarize available data on MTHFR gene and PC. METHODS: We searched PubMed, Embase, Web of Science, Wanfang, CNKI databases prior to July 2019. Data were analyzed by RevMan 5.3 and STATA 12.0 software. Odds ratio (OR) and 95% confidence interval (CI) were used to evaluate the strength of the association. Subgroup analysis, sensitivity analysis and assessment of publication bias were performed in this study. RESULTS: Ten articles with 17 reports (10 for C677T, 7 for A1298C) were eligible for inclusion in the meta-analysis (1864 cases and 3165 controls for C677T, and 1488 cases and 1946 controls for A1298C). Our meta-analysis detected that C677T was associated with PC for three genetic models (allele model: OR = 1.24, 95% CI: 1.00-1.53, P = 0.047; recessive model: OR = 1.39, 95% CI: 1.04-1.86, P = 0.027; homozygous model: OR = 1.60, 95% CI: 1.04-2.45, P = 0.034). In the stratified analyses according to ethnicity, source of controls and genotyping method, significant association was observed in genotyping method subgroup. For the A1298C polymorphism, no significant association was observed either in overall analysis or in subgroup analysis under all genetic models. CONCLUSIONS: MTHFR gene C677T rather than A1298C polymorphism may be associated with PC. Larger sample size studies should be performed to find the association between MTHFR gene and PC.

Predictive role of modifiable factors in stroke: an umbrella review.

BACKGROUND: A growing number of meta-analyses reviewed the existing associations between modifiable factors and stroke. However, the methodological quality of them and quality of evidence remain to be assessed by validated tools. Thus, this umbrella review was conducted to consolidate evidence from systematic reviews and meta-analyses of cohort studies investigating the association between modifiable factors and incidence of stroke. METHODS: PubMed, Web of Science, Embase, Wanfang and China National Knowledge Infrastructure databases for systematic reviews and meta-analyses of cohort studies from inception until March 2021. Assess the methodological quality of systematic reviews 2 was used to evaluate the methodological quality of each included published meta-analysis. Excess significance test was used to investigate whether the observed number of studies (O) with nominally significant results ('positive' studies, p<0.05) was larger than the expected number of significant results (E). Statistically significant (p<0.05) associations were rated into five levels (strong, highly suggestive, suggestive, weak and no) using specific criteria. Sensitivity analyses were performed. RESULTS: 2478 records were identified through database searching. At last, 49 meta-analyses including 70 modifiable factors and approximately 856 801 stroke cases were included in the present review. The methodological quality of three meta-analyses was low, while others were critically low. Evidence of walking pace was strong. High suggestive evidence mainly included total meat, processes meat, chocolate, sodium, obesity, pulse pressure, systolic blood pressure, diastolic blood pressure, sleep duration and smoking. Suggestive evidence mainly included dietary approaches to stop hypertension (DASH) diet, vitamin C, magnesium, depression and particulate matter 2.5. After sensitivity analyses, evidence of DASH diet, magnesium and depression turned to weak. No publication bias existed, except only one study which could be explained by reporting bias. DISCUSSION: Diet with rich macronutrients and micronutrients, healthy dietary patterns and favourable physical, emotional health and environmental management should be promoted to decrease the burden of stroke. PROSPERO REGISTRATION NUMBER: CRD42021249921.

Functional analysis of a miRNA-like small RNA derived from Bombyx mori cytoplasmic polyhedrosis virus.

Bombyx mori cytoplasmic polyhedrosis virus (BmCPV) is a major pathogen of the economic insect silkworm, Bombyx mori. Virus-encoded microRNAs (miRNAs) have been proven to play important roles in host-pathogen interactions. In this study we identified a BmCPV-derived miRNA-like 21 nt small RNA, BmCPV-miR-1, from the small RNA deep sequencing of BmCPV-infected silkworm larvae by stem-loop quantitative real-time PCR (qPCR) and investigated its functions with qPCR and lentiviral expression systems. Bombyx mori inhibitor of apoptosis protein (BmIAP) gene was predicted by both target prediction software miRanda and Targetscan to be one of its target genes with a binding site for BmCPV-miR-1 at the 5' untranslated region. It was found that the expression of BmCPV-miR-1 and its target gene BmIAP were both up-regulated in BmCPV-infected larvae. At the same time, it was confirmed that BmCPV-miR-1 could up-regulate the expression of BmIAP gene in HEK293T cells with lentiviral expression systems and in BmN cells by transfecting mimics. Furthermore, BmCPV-miR-1 mimics could up-regulate the expression level of BmIAP gene in midgut and fat body in the silkworm. In the midgut of BmCPV-infected larvae, BmCPV-miR-1 mimics could be further up-regulated and inhibitors could lower the virus-mediated expression of BmIAP gene. With the viral genomic RNA segments S1 and S10 as indicators, BmCPV-miR-1 mimics could up-regulate and inhibitors down-regulate their replication in the infected silkworm. These results implied that BmCPV-miR-1 could inhibit cell apoptosis in the infected silkworm through up-regulating BmIAP expression, providing the virus with a better cell circumstance for its replication.

Predictive role of heterozygous p.R4810K of RNF213 in the phenotype of Chinese moyamoya disease.

OBJECTIVE: Precise genetic analyses were conducted with ring finger protein 213 (RNF213) in relation to a particular clinical phenotype in Chinese patients with moyamoya disease (MMD) to determine whether heterozygosity is responsible for the early-onset and severe form of this disease. METHODS: A case-control study for RNF213 p.R4810K involving 1,385 Chinese patients with MMD and 2,903 normal control participants was performed. Correlation analyses between genotype and phenotype or different clinical features were also statistically explored. RESULTS: An obvious trend was observed: the carrying rate of RNF213 p.R4810K gradually decreased when moving from coastal cities in northeast, north, and east China to southern cities or inland areas. Higher frequencies of p.R4810K were observed in patients with MMD compared with control participants (odds ratio, 48.1; 95% confidence interval, 29.1-79.6; p = 1.6 × 10-141). In addition, the onset age of all patients with the GA and AA genotypes were lower than with the GG genotype, and the median onset age was 40.0, 36.0, and 11.5 years with GG, GA, and AA, respectively, thereby confirming that those with GA or AA could acquire MMD during early life stages. Patients with MMD with the GA genotype were more susceptible to posterior cerebral artery (PCA) involvement compared to those with the GG genotype (38.4% vs 23.3%, p = 8.3 × 10-7). CONCLUSIONS: Strong evidence suggests that the carrying rate of RNF213 p.R4810K is closely related MMD risk in China and has given rise to an earlier onset age and more severe PCA involvement.

NINJ2 Gene Polymorphisms and Susceptibility to Ischemic Stroke: An Updated Meta-Analysis.

BACKGROUND: Ischemic stroke (IS) is a significant disease which threatens human health condition. Genome-wide association studies (GWAS) have demonstrated that two intergenic single- nucleotide polymorphisms (SNPs) rs11833579 and rs12425791 G>A on chromosome 12p13 are associated with IS susceptibility. However, later studies came to contradictory outcomes. Thus, we carried out a meta-analysis to identify the association between nerve injury-induced protein 2 (NINJ2) gene polymorphisms (rs11833579 and rs12425791) and the risk of IS. METHODS: PubMed, Embase, Web of Science, CBM, Wanfang, VIP, and CNKI databases were searched until March 2019. Data was analyzed by RevMan 5.3 and STATA 12.0 software. The pooled odds ratio (OR) and 95% confidence interval (CI) were used to evaluate the strength of the association. RESULTS: Eighteen qualified articles were selected in total. For rs12425791 and rs11833579, a total of 14055 cases with 13148 controls and 10635 cases with 10462 controls, respectively, were identified for the present study. Our meta-analysis found that rs12425791 was associated with IS for three genetic models (allele model: OR=1.04, 95% CI: 1.00-1.08, P=0.04; dominant model: OR=1.06, 95% CI: 1.01-1.12, P=0.01 and heterozygous model: OR=1.07, 95% CI: 1.01-1.12, P=0.02). Whereas rs11833579 polymorphism was not associated with IS among different genetic models. CONCLUSION: NINJ2 gene rs12425791 confers a susceptible factor for IS, while there is no association between NINJ2 gene rs11833579 and IS. Larger sample size studies should be performed to find the association between NINJ2 gene and IS.

Association of single nucleotide polymorphisms of MTHFR, TCN2, RNF213 with susceptibility to hypertension and blood pressure.

Methylenetetrahydrofolate reductase gene (MTHFR), transcobalaminII (TCN2) and ring finger protein 213 (RNF213) are related to homocysteine (Hcy) level and are of great significance for hypertension. We aimed to evaluate the associations of MTHFR (rs1801133, rs1801131, rs9651118), TCN2 (rs117353193) and RNF213 (rs9916351) with hypertension and blood pressure (BP). A total of 953 patients with hypertension and 1103 controls were enrolled. Genotyping was performed by Taqman. Logistic regression analysis indicated that A allele of TCN2 rs117353193 under the dominant model had a significantly protective effect (P=0.045) after adjustment, which showed that AA+GA genotype has a lower risk than GG. Additionally, the average diastolic BP (DBP) (P=0.044) and mean arterial pressure (MAP) (P=0.035) levels were significantly different between genotypes of RNF213 rs9916351. Further pairwise comparison showed that the average systolic BP (SBP) level of the TT genotype carriers were significantly higher than in CC (P=0.024), and the average DBP and MAP levels of the TT genotype carriers were higher than in CT (P=0.044, P=0.012, respectively) and CC (P=0.048, P=0.010, respectively). In the recessive model, the average SBP (P=0.043), DBP (P=0.018) and MAP (P=0.017) levels with the TT genotype carriers were significantly higher than in CT+CC. Multiple linear regression analysis suggested that RNF213 rs9916351 in the recessive model had significant effects on SBP (P=0.025), DBP (P=0.017) and MAP (P=0.010) as a risk factor. However, no associations were observed between MTHFR and hypertension. TCN2 rs117353193 might serve as a protective factor in hypertension, and RNF213 rs9916351 might be a risk factor that is linked to increase BP level in Northeast Chinese population.

Association between ADIPOQ G276T and C11377G polymorphisms and the risk of non-alcoholic fatty liver disease: An updated meta-analysis.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a significant contributor to global hepatic disorders. ADIPOQ gene single-nucleotide polymorphisms have been associated with NAFLD susceptibility, but with inconsistent results across the studies. This study aimed to investigate the association between ADIPOQ polymorphisms (+276G>T, rs1501299 and -11377C>G, rs266729) and the risk of NAFLD. METHODS: PubMed, Embase, Wanfang, Web of Science, and China National Knowledge Infrastructure databases were used to identify the relevant published literature. Statistical analyses were calculated with STATA 11.0 software and RevMan 5.2. Summary odds ratios (OR) and 95% confidence intervals (CIs) were generated to assess the strength of the associations. RESULTS: Eleven relevant articles with a total of 3,644 participants (1,847 cases/1,797 controls) were included. Our meta-analysis results revealed that ADIPOQ gene +276G>T polymorphism was not associated with NAFLD under various genetic models (allele model: OR = 0.99, 95% CI [0.69, 1.41]; dominant model: OR = 1.06, 95% CI [0.71, 1.58]; recessive model: OR = 0.83, 95% CI [0.42, 1.65]; homozygous model: OR = 0.86, 95% CI [0.38, 1.95]; heterozygous model: OR = 1.10, 95% CI [0.80, 1.53]; respectively). Moreover, no statistical significant association was found between +276G>T and NAFLD risk in the subgroups. ADIPOQ gene -11377C>G polymorphism significantly increased the risk of NAFLD (allele model: OR = 1.49, 95% CI [1.28, 1.75]; dominant model: OR = 1.64, 95% CI [1.35, 1.99]; recessive model: OR = 1.77, 95% CI [1.16, 2.70]; homozygous model: OR = 2.13, 95% CI [1.38, 3.28]; heterozygous model: OR = 1.58, 95% CI [1.29, 1.93]; respectively). CONCLUSION: ADIPOQ gene -11377C>G may be a risk factor for NAFLD, while there was no association between ADIPOQ gene +276G>T polymorphism and the risk of NAFLD. Further studies are needed to detect the relationship between these ADIPOQ polymorphisms and NAFLD.

The Play of Genes and Non-genetic Factors on Type 2 Diabetes.

Diabetes has been a disease of public health concern for a number of decades. It was in the 1930s when scientists made an interesting discovery that the disease is actually divided into two types as some patients were insensitive to insulin treatment then. Type 2 Diabetes which happens to be the non-insulin dependent one is the most common form of the disease and is caused by the interaction between genetic and non-genetic factors. Despite conflicting results, numerous studies have identified genetic and non-genetic factors associated with this common type of diabetes. This review has summarized literature on some genes and non-genetic factors which have been identified to be associated with Type 2 diabetes. It has sourced literature from PubMed, Web of Science and Medline without any limitation to regions, publication types, or languages. The paper has started with the introduction, the play of non-genetic factors, the impact of genes in general, and ended with the interaction between some genes and environmental factors.

iTRAQ-based quantitative proteomic analysis of midgut in silkworm infected with Bombyx mori cytoplasmic polyhedrosis virus.

Bombyx mori cytoplasmic polyhedrosis virus (BmCPV) specifically infects the epithelial cells in the midgut of silkworm and causes them to death, which negatively affects the sericulture industry. In order to determine the midgut response at the protein levels to the virus infection, differential proteomes of the silkworm midgut responsive to BmCPV infection were identified with isobaric tags for relative and absolute quantitation (iTRAQ) labeling followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). 193, 408, 189 differentially expressed proteins (DEPs) were reliably quantified by iTRAQ analysis in the midgut of BmCPV-infected and control larvae at 24, 48, 72h post infection (hpi) respectively. KEGG enrichment analysis showed that Oxidative phosphorylation, amyotrophic lateral sclerosis, Toll-like receptor signaling pathway, steroid hormone biosynthesis were the significant pathways (Q value≤0.05) both at 24 and 48hpi. qRT-PCR was used to further verify gene transcription of 30 DEPs from iTRAQ, showing that the regulations of 24 genes at the transcript level were consistent with those at the proteomic level. Moreover, the cluster analysis of the three time groups showed that there were seven co-regulated DEPs including BGIBMGA002620-PA, which was a putative p62/sequestosome-1 protein in silkworm. It was upregulated at both the mRNA level and the proteomic level and may play an important role in regulating the autophagy and apoptosis (especially apoptosis) induced by BmCPV infection. This was the first report using an iTRAQ approach to analyze proteomes of the silkworm midgut against BmCPV infection, which contributes to understanding the defense mechanisms of silkworm midgut to virus infection. SIGNIFICANCE: The domesticated silkworm, Bombyx mori, is renowned for silk production as well as being a traditional lepidopteron model insect served as a subject for morphological, genetic, physiological, and developmental studies. Bombyx mori cytoplasmic polyhedrosis virus (BmCPV) specifically infects the epithelial cells in the midgut of silkworm and causes the silkworm to death, which negatively affects the sericulture industry. Studies on insect antiviral immunity and on interactive mechanisms between host cells and BmCPV are in their infancy and remain insufficient. In order to obtain an overall view of silkworm response to BmCPV infection, we performed a proteomic analysis of the midgut of silkworm responses to BmCPV infection by iTRAQ. This was the first report using an iTRAQ approach to analyze proteomes of the silkworm midgut against BmCPV infection, which contributes to understanding the defense mechanisms of silkworm midgut to virus infection.