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Several epidemiological studies have investigated the association between sugar intake, the levels of systolic blood pressure (SBP) and diastolic blood pressure (DBP) and the risk of hypertension, but findings have been inconsistent. We carried out a systematic review and meta-analysis of observational studies to examine the associations between sugar intake, hypertension risk, and BP levels. Articles published up to February 2, 2021 were sourced through PubMed, EMBASE and Web of Science. Pooled relative risks (RRs) and 95% confidence intervals (CIs) were estimated using a fixed- or random-effects model. Restricted cubic splines were used to evaluate dose-response associations. Overall, 35 studies were included in the present meta-analysis (23 for hypertension and 12 for BP). Sugar-sweetened beverages (SSBs) and artificially sweetened beverages (ASBs) were positively associated with hypertension risk: 1.26 (95% CI, 1.15–1.37) and 1.10 (1.07–1.13) per 250-g/day increment, respectively. For SBP, only SSBs were significant with a pooled β value of 0.24 mmHg (95% CI, 0.12–0.36) per 250 g increase. Fructose, sucrose, and added sugar, however, were shown to be associated with elevated DBP with 0.83 mmHg (0.07–1.59), 1.10 mmHg (0.12–2.08), and 5.15 mmHg (0.09–10.21), respectively. Current evidence supports the harmful effects of sugar intake for hypertension and BP level, especially SSBs, ASBs, and total sugar intake.

To solve the problem of energy crisis in today’s world, energy conservation is more and more get the attention of people, heat exchanger occupies an important place in the field of energy saving, however, because of the heat exchanger is a traditional energy-intensive heavy industry, one of the most widely used equipment in it as preheating, mainly in the process of waste heat recovery, refrigeration equipment, made outstanding contributions to energy saving. In this paper, plate heat exchanger as the research object, select the established model, through the analysis of the existing heat transfer enhancement theory, combined with the classical optimization algorithm genetic algorithm plate heat exchanger programming optimization, through iterative calculation to get the optimal plate heat exchanger structure parameters. Finally, combined with the simulation calculation of the performance of the heat exchanger before and after optimization structure parameters, further analysis of its internal flow. The research in this paper provides a theoretical basis for the design, structure optimization and performance prediction of plate heat exchanger.

Polydactyly is a common congenital malformation characterized by the presence of supernumerary fingers or toes. In this case study, we sought to identify the causative pathogenic factor in a family from a northern region of China affected by non-syndromic postaxial polydactyly (PAP).After recruiting a three-generation family with PAP, whole-exome sequencing was performed to identify the causative variant. In silico analysis and Sanger sequencing were used to validate the variant.We identified a novel heterozygous frameshift variant (NM_000168.6:c.4540delG, p.Asp1514Thrfs*5) in the transcriptional activator (TA1) domain of the GLI3 gene.The novel frameshift variant identified in this study further confirms the relationship between non-syndromic PAP and GLI3 and extends the previously established mutational and phenotypic spectra of GLI3.

The objective of this study was to construct a BeiDou navigation satellite system (BDS)/global positioning system (GPS)-integrated positioning algorithm that meets the accuracy requirement of forest surveys and to analyze its accuracy to provide theoretical and technical support for accurate positioning and navigation in forests. The Quercus variabilis broad-leaved forest in Jiufeng National Forest Park and the Sabina Coniferous forest in Dongsheng Bajia forest farm were selected as the study area. A Sanding T-23 multi-frequency three-constellation receiver and a u-blox NEO-M8T multi-constellation receiving module were used for continuous observation under the forest canopy. Compared with T-23, the u-blox NEO-M8T is much lighter and more flexible in the forest. The BDS/GPS-integrated positioning algorithm for forests was constructed by temporally and spatially unifying the satellite systems and using a reasonable observed value weighting method. Additionally, the algorithm is also written into the RTKLIB software to calculate the three-dimensional (3D) coordinates of the forest observation point in the World Geodetic System 1984 (WGS-84) coordinate system. Finally, the results were compared with the positioning results obtained using GPS alone. The experimental results indicated that, compared with GPS positioning, there were 13–27 visible satellites available for the BDS/GPS-integrated positioning algorithm for forests, far more than the satellites available for the GPS positioning algorithm alone. The Position Dilution of Precision (PDOP) values for the BDS/GPS-integrated positioning ranged from 0.5 to 1.9, lower than those for GPS positioning. The signal noise ratio (SNR) of the BDS/GPS-integrated satellite signals and GPS satellite signals were both in the range of 10–50 dB-Hz. However, because there were more visible satellites for the BDS/GPS-integrated positioning, the signals from the BDS/GPS-integrated satellites were stronger and had a more stable SNR than those from the GPS satellites alone. The results obtained using the BDS/GPS-integrated positioning algorithm for forests had significantly higher theoretical and actual accuracies in the X, Y and Z directions than those obtained using the GPS positioning algorithm. This suggests that the BDS/GPS-integrated positioning algorithm can obtain more accurate positioning results for complex forest environments.

Objective. To analyze the effect of carrying out continuous nursing based on mobile platform on the life of children with leukemia after discharge. Methods. A total of 104 children diagnosed with leukemia admitted in Pediatric Internal Medicine, Hainan Provincial People’s Hospital, from September 2019 to August 2020 were randomly divided into two groups, observation group and control group, with 52 cases in each group. For the control group, routine follow-up was used for continuous nursing after discharge from hospital, and the observation group was treated with continuous nursing based on mobile platform on the basis of routine follow-up nursing after discharge from hospital. Results. When discharged from hospital, there was no significant difference in SDS and SAS scores between the two groups ( P > 0.05 ). After 8 weeks of discharge, SDS and SAS scores in both groups were significantly decreased, and SDS and SAS scores in the observation group were significantly lower than those in the control group, with statistical significance ( P < 0.05 ). After 8 weeks of discharge, the cancer-related fatigue score of the observation group was significantly lower than that of the control group, and the difference was statistically significant ( P < 0.05 ). When discharged from hospital, there was no significant difference in quality of life between two groups ( P > 0.05 ). Eight weeks after discharge, the quality of life in both groups was significantly improved, and the quality of life in the observation group was significantly better than that in the control group; the difference was statistically significant ( P < 0.05 ). The occurrence of adverse reactions in the observation group was significantly lower than that in the control group, and the difference was statistically significant ( P < 0.05 ). Conclusion. After children with leukemia were discharged from hospital, medical staff used mobile platform to carry out continuous nursing for them, which could relieve the negative emotions of children, reduce the incidence of adverse reactions, and improve the quality of life. This kind of intervention had promotion value.

Background and Aims. Men who have sex with men (MSM) are at high risk of HIV infection. The nonhomologous end joining (NHEJ) pathway is the main way of double-stranded DNA break (DSB) repair in the higher eukaryotes and can repair the DSB timely at any time in cell cycle. It is also indicated that the NHEJ pathway is associated with HIV-1 infection since the DSB in host genome DNA occurs in the process of HIV-1 integration. The aim of the present investigation was to evaluate associations of single-nucleotide polymorphisms (SNPs) in NHEJ pathway genes with susceptibility to HIV-1 infection and AIDS progression among MSM residing in northern China. Methods. A total of 481 HIV-1 seropositive men and 493 HIV-1 seronegative men were included in this case-control study. Genotyping of 22 SNPs in NHEJ pathway genes was performed using the SNPscan™ Kit. Results. Positive associations were observed between XRCC6 rs132770 and XRCC4 rs1056503 genotypes and the susceptibility to HIV-1 infection. In gene-gene interaction analysis, significant SNP-SNP interactions of XRCC6 and XRCC4 genetic variations were found to play a potential role in the risk of HIV-1 infection. In stratified analysis, XRCC5 rs16855458 was significantly associated with CD4+ T cell counts in AIDS patients, whereas LIG4 rs1805388 was linked to the clinical phases of AIDS patients. Conclusions. NHEJ gene polymorphisms can be considered to be risk factors of HIV-1 infection and AIDS progression in the northern Chinese MSM population.

This study analyzed the process of vegetation restoration in the eastern margin ecotone of Qinghai-Tibet Plateau (EMEQTP) from 2001 to 2019 under different restoration modes based on the vegetation net primary productivity (NPP) which was estimated by the Carnegie-Ames-Stanford approach (CASA) model. Then the potential NPP was calculated and the durations of NPP restoration were predicted based on the Autoregressive Integrated Moving Average (ARIMA) model. Finally, the relative importance of main parameters in the CASA model as well as global sensitivity and uncertainty were discussed. The results showed that the NPP under a natural restoration mode had the highest increase with 20.1%, and its spatial change showed an overall trend of restoration. The NPP under the comprehensive restoration mode achieved an increase of 11.5%, with the southwestern area experiencing an insignificant trend of degradation, whereas the northeastern area experiencing a significant restoration trend. As for the NPP under the artificial restoration mode, it experienced the lowest increase with 10.5%, and the northern part experiencing a significant restoration trend, whereas the southeastern part experiencing an insignificant degradation trend. In addition, the highest potential NPP of vegetation restoration would be appeared in the area under a comprehensive restoration mode. The area under an artificial restoration mode would have the lowest potential NPP of vegetation restoration, but the duration of restoration would be longest under this mode, reaching up to 64 years. Although the natural restoration mode achieved the best effect of vegetation restoration, considering the limited scope of the promotion of this mode, further attention should be placed on restoration measures and the effects of the artificial and comprehensive restoration modes. Finally, APAR, GST and PET were relatively important for the CASA model, and the parameters including Topt, GST, and PET were sensitive. Those results can offer scientific references for the management of ecological environment in the EMEQTP.

Background DAL-1 gene was reported to inhibit proliferation, migration, invasion, and epithelial to mesenchymal transition (EMT) of gastric cancer (GC) cells in our previous study. The association between the genomic variants in DAL-1 gene with risk of GC is still unclear. Methods In this study, 505 GC cases and 544 healthy controls (HCs) were collected to evaluate the association between six single nucleotide polymorphisms (SNPs) (rs7240736, rs73937194, rs3817466, rs8082898, rs73381527, rs9953490) of DAL-1 gene and GC risk in the Han population in Northeast China. Results The TA + AA genotypes of rs9953490 were significantly associated with an increased risk in N3 compared with N0 subgroup (adjusted OR = 4.56, 95% CI = 1.49–13.98, P = 0.008), and also showed evident association with an increased risk in TNM stage III compared with stage I-II (adjusted OR = 2.33, 95% CI = 1.16–4.67, P = 0.017). Conclusion The rs9953490 of DAL-1 gene may play an important role in the occurrence and development of GC in the Han population in Northeast China.

RNA detection is crucial for biological research and clinical diagnosis. The current methods include both direct and amplification-based RNA detection. These methods require complicated procedures, suffering from low sensitivity, slow turnaround, and amplification bias. The CRISPR/Cas13a system is a direct RNA detection method via target RNA induced collateral cleavage activity. However, to detect low concentration RNA with CRISPR/Cas13a, target amplification is always required. Herein, we optimize the components of the CRISPR/Cas13a assay to enhance the sensitivity of viral RNA detection which improve the detection limit from 1 pM up to 100 fM. In addition, the integration of CRISPR/Cas13a biosensing and single molecule super resolution imaging is a novel strategy for direct and amplification-free RNA detection. After surface modification, fluorescent RNA reporters are immobilized on the glass coverslip surface and fluorescent signals are captured by total internal reflection fluorescence microscopy (TIRFM), shifting the measurement from spectroscopy to imaging. We quantify the fluorescence signal intensity before and after collateral cleavage of the CRISPR system when viral RNA is present and achieve a detection limit of 10 fM. Therefore, we provide a novel TIRFM-based system to visualize the CRISPR trans-cleavage for direct and robust RNA detection.

Background Most the HCC susceptible loci identified by GWAS are located in non-coding regions, and the mechanism of action remains unclear. The objective of this study was to explore the relationship among SNPs on lncRNA that affects ceRNA mechanism and the risk and prognosis of HCC. Methods In this study, combined with multiple databases, eight lncRNA genes that affect HCC were systematically screened through the mechanism of lncRNA-mediated ceRNA, and 15 SNPs that affect miRNA binding in the eight lncRNA genes were annotated. Genotyping was conducted in 800 HCC cases and 801 healthy controls from a Han population in Northeast China to examine the genetic risk associated with HCC. Results The GG, GC and GG + GC genotypes of HOTAIR rs7958904 were found to be associated with a 0.65, 0.59 and 0.63-fold decreased HCC risk, respectively. Moreover, in the stratified analysis of clinical characteristics, HCC patients with PVT1 rs3931282 AA + GA genotypes were less prone to develop late-stage tumors. When stratified by clinical biochemical indexes, rs1134492 and rs10589312 in PVT1 and rs84557 in EGFR-AS1 showed significant associations with AST, ALT or AST/ALT ratio. In addition, the potential ceRNA regulatory axes might be affected by the five positive SNPs were constructed to explain the causes of these genetic associations. Conclusions This first study demonstrated the association of SNPs on lncRNA -mediated ceRNAs with HCC. The results provide new insights of how non-coding loci confer the interindividual differences to susceptibility and progression of HCC.

Background: Men who have sex with men (MSM) are at high risk of HIV infection. Non-homologous end joining (NHEJ) pathway is the main way of double-stranded DNA break (DSB) repair in the higher eukaryotes, and can repair the DSB timely at any time in cell cycle. The objective of this study was to investigate the association of SNPs of the NHEJ pathway genes with susceptibility to HIV-1 infection and AIDS progression among MSM residing in northern China.Results: In the present study, a total of 481 HIV-1 seropositive men and 493 HIV-1 seronegative men were included. And genotyping of 22 SNPs in NHEJ pathway genes was performed using the SNPscanTM Kit. Our results disclosed significant associations of XRCC6 rs132770 and XRCC4 rs1056503 genotypes with susceptibility to HIV-1 infection. The generalized multifactor dimensionality reduction (GMDR) analysis found a significant SNP-SNP interaction between the XRCC6 and XRCC4 variants in the risk of HIV-1 infection. In stratified analysis, the positive effects of XRCC5 rs16855458 and LIG4 rs1805388 on the CD4+ T cell count and clinical phase of disease were validated.Conclusions: Our results confirmed that the NHEJ gene polymorphisms played an important role in HIV-1 infection and AIDS progression in the northern Chinese MSM population.

Objective:The impact of baseline hypertension status on the BMI–mortality association is still unclear. We aimed to examine the moderation effect of hypertension on the BMI–mortality association using a rural Chinese cohort.Design:In this cohort study, we investigated the incident of mortality according to different BMI categories by hypertension status.Setting:Longitudinal population-based cohort.Participants:17 262 adults ≥18 years were recruited from July to August of 2013 and July to August of 2014 from a rural area in China.Results:During a median 6-year follow-up, we recorded 1109 deaths (610 with and 499 without hypertension). In adjusted models, as compared with BMI 22–24 kg/m2, with BMI ≤ 18, 18–20, 20–22, 24–26, 26–28, 28–30 and >30 kg/m2, the hazard ratios for mortality in normotensive participants were 1·92 (95% CI 1·23, 3·00), 1·44 (95% CI 1·01, 2·05), 1·14 (95% CI 0·82, 1·58), 0·96 (95% CI 0·70, 1·31), 0·96 (95% CI 0·65, 1·43), 1·32 (95% CI 0·81, 2·14) and 1·32 (95% CI 0·74, 2·35), respectively, and in hypertensive participants were 1·85 (95% CI 1·08, 3·17), 1·67 (95% CI 1·17, 2·39), 1·29 (95% CI 0·95, 1·75), 1·20 (95% CI 0·91, 1·58), 1·10 (95% CI 0·83, 1·46), 1·10 (95% CI 0·80, 1·52) and 0·61 (95% CI 0·40, 0·94), respectively. The risk of mortality was lower in individuals with hypertension with overweight or obesity v. normal weight, especially in older hypertensives (≥60 years old). Sensitivity analyses gave consistent results for both normotensive and hypertensive participants.Conclusions:Low BMI was significantly associated with increased risk of all-cause mortality regardless of hypertension status in rural Chinese adults, but high BMI decreased the mortality risk among individuals with hypertension, especially in older hypertensives.

BACKGROUND Previous studies reported that DNA damage repair (DDR) genes may play an important role in HIV-1 infection. The MRE11 gene, a member of the MRN complex, plays an essential part in the homologous recombination pathway, which is one of the classical DDR pathways. Previous reports have demonstrated that MRE11 has an effect on HIV-1 replication. However, the role of SNPs in the MRE11 gene and their impact on HIV-1 infection and AIDS progression remain unknown. METHODS In this study, 434 MSM HIV-1-infected patients in northern China and 431 age-matched healthy controls were enrolled. Five SNPs (rs2155209, rs10831234, rs13447720, rs601341 and rs11020803) at the MRE11 gene were genotyped. Another series of cases (409 MSM HIV-1-infected patients) and controls (403 age-matched healthy males) were recruited as the validation set. RESULTS In our study, rs10831234 showed differences in allele frequencies between cases and controls (P = 0.005). Additionally, there was an association between rs10831234 and HIV-1 infection susceptibility in dominant and additive models (P = 0.005 and P = 0.006, respectively). All significant associations were replicated in the validation set, and the associations were still significant after Bonferroni correction for multiple testing when the two data sets were combined. Furthermore, in haplotype association analyses between the case and control groups, the frequencies of the haplotypes Crs11020803Crs10831234 and Trs11020803Trs10831234 showed significant differences (P = 0.0181 and P = 0.0068, respectively). CONCLUSIONS We demonstrated that the MRE11 rs10831234-T allele may confer increased risk of HIV-1 infection.

Background Polycystic kidney disease (PKD) is an inherited disease that is life‐threatening. Multiple cysts are present in the bilateral kidneys of PKD patients. The progressively enlarged cysts cause structural damage and loss of kidney function. Methods This study examined and analyzed 12 families with polycystic kidney disease. Whole exome sequencing (WES) or whole genome sequencing (WGS) of the probands was performed to detect the pathogenic genes. The candidate gene segments for lineal consanguinity in the family were amplified by the nest PCR followed by Sanger sequencing. The variants were assessed by pathogenic and conservational property prediction analysis and interpreted according to the American College of Medical Genetics and Genomics. Results Nine of the 12 pedigrees were identified the disease causing variants. Among them, four novel variants in PKD1, c.6930delG:p.C2311Vfs*3, c.1216T>C:p.C406R, c.8548T>C:p.S2850P, and c.3865G>A:p.V1289M (NM_001009944.2) were detected. After assessment, the four novel variants were considered to be pathogenic variants and cause autosomal dominant polycystic kidney disease in family. The detected variants were interpreted. Conclusion The four novel variants in PKD1, c.6930delG:p.C2311Vfs*3, c.1216T>C:p.C406R, c.8548T>C:p.S2850P, and c.3865G>A:p.V1289M (NM_001009944.2) are pathogenic variants and cause autosomal dominant polycystic kidney disease in family., This study examined and analyzed 12 families with polycystic kidney disease using whole exome sequencing or whole genome sequencing and several prediction tools. After assessment and interpretion, the four novel variants were considered to be pathogenic variants and cause autosomal dominant polycystic kidney disease in family. The present study enriched the knowledge of the pathogenicity for autosomal dominant polycystic kidney disease and would improve the understanding of this autosomal dominant disorder.

The increasing scale of urbanization and human activities has resulted in the fragmentation of natural habitats, leading to the reduction of ecological landscape connectivity and biodiversity. Taking Nanping as the study area, the core areas with good connectivity were extracted as ecological sources using a morphological spatial pattern analysis (MSPA) and landscape connectivity index. Then the ecosystem service functions of the ecological sources were evaluated based on the InVEST model. Finally, we extracted the potential ecological corridor based on the land type, elevation and ecosystem service functions. The results showed that the ecological source with higher landscape connectivity is distributed in the north and there are clear landscape connectivity faults in the northern and southern regions. Moreover, the areas with high habitat quality, soil retention and water production are mainly distributed in the northern ecological source areas. The 15 potential ecological corridors extracted were distributed unevenly. Among them, the important ecological corridors formed a triangle network, while the general ecological corridors were concentrated in the northwest. Therefore, it is suggested that the important core patches in the north be protected, and the effective connection between the north and south be improved. These results can provide a scientific basis for ecological construction and hierarchical management of the ecological networks.

This systematic review and meta-analysis aimed to investigate the association between air pollution and DNA methylation in adults from published observational studies. PubMed, Web of Science and Embase databases were systematically searched for available studies on the association between air pollution and DNA methylation published up to March 9, 2021. Three DNA methylation approaches were considered: global methylation, candidate-gene, and epigenome-wide association studies (EWAS). Meta-analysis was used to summarize the combined estimates for the association between air pollutants and global DNA methylation levels. Heterogeneity was assessed with the Cochran Q test and quantified with the I2 statistic. In total, 38 articles were included in this study: 16 using global methylation, 18 using candidate genes, and 11 using EWAS, with 7 studies using more than one approach. Meta-analysis revealed an imprecise but inverse association between exposure to PM2.5 and global DNA methylation (for each 10-μg/m3 PM2.5, combined estimate: 0.39; 95% confidence interval: 0.97 - 0.19). The candidate-gene results were consistent for the ERCC3 and SOX2 genes, suggesting hypermethylation in ERCC3 associated with benzene and that in SOX2 associated with PM2.5 exposure. EWAS identified 201 CpG sites and 148 differentially methylated regions that showed differential methylation associated with air pollution. Among the 307 genes investigated in 11 EWAS, a locus in nucleoredoxin gene was found to be positively associated with PM2.5 in two studies. Current meta-analysis indicates that PM2.5 is imprecisely and inversely associated with DNA methylation. The candidate-gene results consistently suggest hypermethylation in ERCC3 associated with benzene exposure and that in SOX2 associated with PM2.5 exposure. The Kyoto Encyclopedia of Genes and Genomes (KEGG) network analyses revealed that these genes were associated with African trypanosomiasis, Malaria, Antifolate resistance, Graft-versus-host disease, and so on. More evidence is needed to clarify the association between air pollution and DNA methylation.

Background MSM has a high risk of HIV infection. Previous studies showed that the cell cycle regulation played an important role in HIV-1 infection, especially in G2/M checkpoint. The ATR, Chk1, Cdc25C and CDK1 are key genes in G2/M checkpoint. However, the association between the SNPs of these genes and susceptibility to HIV-1 infection and AIDS progression remains unknown. Results 42 tSNPs of G2/M checkpoint genes were genotyped to analyze the association between these tSNPs and susceptibility to HIV-1 infection and AIDS progression among MSM (529 HIV − 1 seropositive men and 529 HIV-1 seronegative men) in northern China. The results showed that rs34660854-A and rs75368165-A in ATR gene and rs3756766-A in Cdc25C gene could increase the risk of HIV-1 infection (P = 0.049, P = 0.020 and P = 0.010, respectively), and ATR rs75069062 and Chk1 rs10893405 were significantly associated with AIDS progression (P = 0.026 and P = 0.029, respectively). Besides, rs34660854 and rs75368165 in ATR gene, rs12576279 and rs540436 in Chk1 gene, rs3756766 in Cdc25C gene and rs139245206 in CDK1 gene were significantly associated with HIV-1 infection under different models (P

Colorectal cancer (CRC) is the third most developing cancer worldwide and Lynch syndrome (LS) accounts for 3–4% of CRC. Genetic alteration in any of DNA mismatch repair (MMR) gene is the major cause of LS that disrupt the normal upstream and downstream MMR events. Germline mutation of MLH1 in heterozygous state have an increased risk for CRC. Defective MMR pathway mostly results in microsatellite instability (MSI) that occurs in high percentage of CRC associated tumors. Here, we reported a patient with LS like metastatic CRC (mCRC) associated with other related cancers. Whole exome sequencing (WES) of the proband was performed to identify potential causative gene. Genetic screening validated by Sanger sequencing identified a heterozygous missense mutation in exon 12 of MLH1 (c.1151T>A, p.V384D). The clinical significance of identified variant was elucidated on the basis of clinicopathological data, computational predictions and various in vitro functional analysis. In silico predictions classified the variant to be deleterious and evolutionary conserved. In vitro functional studies revealed a significant decrease in protein expression because of stability defect leading to loss of MMR activity. Mutant residue found in MutL transducer domain of MLH1 that localized in the nucleus but translocation was not found to be significantly disturbed. In conclusion, our study give insight into reliability of combinatorial prediction approach of in silico and in vitro expression analysis. Hence, we highlighted the pathogenic correlation of MLH1 variant with LS associated CRC as well as help in earlier diagnosis and surveillance for improved management and genetic counselling.

Background: Prenatal intake of folic acid is important for prevention of NSCL/P (nonsyndromic cleft lip with or without cleft palate). Associated genes in folate pathway are major enzymes of folic acid metabolism that is crucial for preventing birth defects. The present meta-analysis aims to investigate the association between four SNPs in folate pathway genes and the risk of NSCL/P. Methods: Comprehensive bioinformatics analysis was used to predict the functional pathogenicity of genetic variation. The PubMed, Embase database and Google Scholar were searched by two researchers. Stata 11.0 software was used to analyze the results. Subgroup analysis was carried out to assess the influence of genetic background. Sensitivity analysis, regression analysis and publication analysis were also conducted to enhance the strength of our results. Results: It is estimated that the probability of two missense mutation rs1801133 in MTHFR and rs1801394 in MTRR are more likely to be damaging by bioinformatics analysis. A significant association between rs1801133 and risk of NSCL/P in two genetic models: TT genotype vs CC genotype (OR = 1.333 95%CI = 1.062–1.674, P = 0.013), and recessive model (OR = 1.325 95%CI = 1.075–1.634, P = 0.008). A significant protective association between rs1801394 GG genotype and NSCL/P in Asian (GG vs AA, OR = 0.520 95%CI = 0.321–0.841, P = 0.008) was observed. Meta-regression, sensitivity analysis, and publication bias analysis confirmed that the results of the present study were statistically significant. Conclusions: The present study identified that rs1801133 in MTHFR is associated with the risk of NSCL/P, and rs1801394 GG genotype in MTRR play a protective role in Asian. Further, larger studies should be performed to confirm these findings.

The aim of this study was to identify the potential key candidate genes of multiple sclerosis (MS) and uncover mechanisms in MS. We combined data from the microarray expression profile of three MS stages and performed bioinformatics analysis. Differentially expressed genes (DEGs) were identified among the distinct stages of MS and healthy controls, and a total of 349 shared DEGs were identified. Gene ontology (GO) and pathway enrichment analyses showed that the DEGs were significantly enriched in the biological processes (BPs) of purine-related metabolic processes and signaling, especially the common DEGs, which were enriched in some immunological processes. Most of the DEGs were enriched in signaling pathways associated with the immune system, some immune diseases and infectious disease pathways. Through a protein–protein interaction (PPI) network analysis and a gene expression regulatory network constructed with MS-related miRNAs, we confirmed FOS, TP53, VEGFA, JUN, HIF1A, RB1, PTGS2, CXCL8, OAS2, NFKBIA and OAS1 as candidate genes of MS. Furthermore , we explored the potential SNPs associated with MS by database mining. In conclusion, this study provides the identified genes, SNPs, biological processes, and cellular pathways associated with MS. The uncovered candidate genes may be potential biomarkers involved in the diagnosis and therapy of MS.

Lynch syndrome (LS) is the most common hereditary colorectal cancer (CRCs) inherited in an autosomal-dominant manner. Here, we reported a multigeneration Chinese family clinically diagnosed with LS according to the Amsterdam II criteria. To identify the underlying causative gene for LS in this family, whole-exome sequencing (WES) was performed. A germline missense variant (c.2054C>T:p.S685F) in exon 18 of MLH1 was successfully identified by WES. Sanger sequencing verified the results of WES and also confirmed the cosegregation of the MLH1 missense variant in all affected members of the family including two unaffected family members. Bioinformatic tools predicted the identified MLH1 variant as deleterious. Immunohistochemistry (IHC) staining showed loss of MLH1 and PMS2 protein expression. In vitro expression analysis also revealed that the identified MLH1 missense variant (c.2054C>T:p.S685F) results in reduced expression of both MLH1 and PMS2 proteins. Based on the American College of Medical Genetics and Genomics (ACMG) guidelines, the missense mutation c.2054C>T in MLH1 was classified as a “pathogenic” variant. Two unaffected family members were later recommended for colonoscopy and other important cancer diagnostic inspections every 1-2 years as both were at higher risk of LS. In conclusion, our findings widen the genotypic spectrum of MLH1 mutations responsible for LS. This study increases the phenotypic spectrum of LS which will certainly help the clinicians in diagnosing LS in multigeneration families. This study also puts emphasis on the importance of genetic counselling for the benefit of asymptomatic carriers of MMR gene variants who are at higher risk of LS.

Background Prenatal intake of folic acid is important for prevention of nonsyndromic cleft lip with or without cleft palate (NSCL/P). Associated genes in folate pathway are major enzymes of folic acid metabolism that is crucial for preventing birth defects. The present study aims to investigate the association between four single nucleotide polymorphisms (SNPs) in folate pathway genes and the risk of NSCL/P. Methods Comprehensive bioinformatics analysis was used to predict the functional pathogenicity of genetic variation. The PubMed, Embase database and Google Scholar were intensively searched by two researchers to ascertain all relevant studies. Stata 11.0 software was used to analyze the results. Subgroup analysis was carried out to assess the influence of genetic background. Sensitivity analysis, regression analysis and publication analysis were also conducted to enhance the strength of our results. Results It is estimated that the probability of two missense mutation rs1801133 in MTHFR and rs1801394 in MTRR are more likely to be damaging by bioinformatics analysis. A total of 34 publications were included in the present study analysis. Our results showed a significant association between rs1801133 and risk of NSCL/P in two genetic models: TT allele vs CC allele (OR=1.333 95%CI=1.062-1.674, P =0.013), and recessive model (OR=1.325 95%CI=1.075-1.634, P =0.008). A significant association between rs1801394 and the risk of NSCL/P in Asian (GG allele vs AA allele, OR=0.520 95%CI=0.321-0.841, P =0.008) was also observed. Meta-regression, sensitivity analysis, and publication bias analysis confirmed that the results of the present study were statistically significant. Conclusions The present study highlights two SNPs rs1801133 in MTHFR and rs1801394 in MTRR, associated with the increasing risk of NSCL/P. Further, larger studies should be performed to confirm these findings.