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The pandemic COVID-19 is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and it is spreading very rapidly worldwide. To date, the origin and intermediate hosts of SARS-CoV-2 remain unclear. In this study, we conducted comparative analysis among SARS-CoV-2 and non-SARS-CoV-2 coronavirus strains to elucidate their phylogenetic relationships. We found: 1, the SARS-CoV-2 strains analyzed could be divided into 3 clades with regional aggregation; 2, the non-SARS-CoV-2 common coronaviruses that infect humans or other organisms to cause respiratory syndrome and epizootic catarrhal gastroenteritis could also be divided into 3 clades; 3, the hosts of the common coronaviruses closest to SARS-CoV-2 were Apodemus chevrieri (a rodent), Delphinapterus leucas (beluga whale), Hypsugo savii (bat) , Camelus bactrianus (camel) and Mustela vison (mink); and 4, the gene sequences of the receptor ACE2 from different hosts could also be divided into 3 clades. The ACE2 gene sequences closest to that of humans in evolution include those from Nannospalax galili (Upper Galilee mountains blind mole rat), Phyllostomus discolor (pale spear-nosed bat), Mus musculus (house mouse), Delphinapterus leucas (beluga whale), and Catharus ustulatus (Swainson's thrush). We conclude that SARS-CoV-2 may have evolved from a distant common ancestor with the common coronaviruses but not a branch of any of them, implying that the prevalent pandemic COVID-19 agent SARS-CoV-2 may have existed in a yet to be identified primary host for a long time.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the causative agent of the coronavirus disease 2019 (COVID-19) pandemic. In this study, we conducted a comparative analysis of the structural genes of SARS-CoV-2 and other CoVs. We found that the sequence of the E gene was the most evolutionarily conserved across 200 SARS-CoV-2 isolates. The E gene and M gene sequences of SARS-CoV-2 and NC014470 CoV were closely related and fell within the same branch of a phylogenetic tree. The absolute diversity of E gene and M gene sequences of SARS-CoV-2 isolates was similar to that of common CoVs (C-CoVs) infecting other organisms. The absolute diversity of the M gene sequence of the KJ481931 CoV that can infect humans was similar to that of SARS-CoV-2 and C-CoVs infecting other organisms. The M gene sequence of KJ481931 CoV (infecting humans), SARS-CoV-2 and NC014470 CoV (infecting other organisms) were closely related, falling within the same branch of a phylogenetic tree. Patterns of variation and evolutionary characteristics of the N gene and S gene were very similar. These data may be of value for understanding the origins and intermediate hosts of SARS-CoV-2.

Congenital heart disease (CHD) is a group of anatomic malformations in the heart with high morbidity and mortality. The mammalian heart is a complex organ, the formation and development of which are strictly regulated and controlled by gene regulatory networks of many signaling pathways such as TGF-β. KAT2B is an important histone acetyltransferase epigenetic factor in the TGF-β signaling pathway, and alteration in the gene is associated with the etiology of cardiovascular diseases. The aim of this work was to validate whether KAT2B variations might be associated with CHD. We sequenced the KAT2B gene for 400 Chinese Han CHD patients and evaluated SNPs rs3021408 and rs17006625. The statistical analyses and Hardy–Weinberg equilibrium tests of the CHD and control populations were conducted by the software SPSS (version 19.0) and PLINK. The experiment-wide significance threshold matrix of LD correlation for the markers and haplotype diagram of LD structure were calculated using the online software SNPSpD and Haploview software. We analyzed the heterozygous variants within the CDS region of the KAT2B genes and found that rs3021408 and rs17006625 were associated with the risk of CHD.

Background: Cerebral infarction is one of the most common cerebral small vessel diseases. Many angiogenesis relevanted factors have special roles on the diseases pathogenesis. The vascular endothelial growth factor A (VEGFA) is the most prominent stimulating molecule factor for angiogenesis. So, we want to evaluate the correlation between VEGFA gene and this disease in this work. Methods: The VEGFA gene was sequenced for 400 cerebral infarction patients and 600 normal controls. SPSS software (version 19.0), Plink (version 1.9), Haploview software and online software SNPSpD were used for the statistical analyses and Hardy-Weinberg equilibrium tests. Results: We found variants rs10434, rs3025040, rs185218985, rs199971699, rs574579489, rs735286 and rs833061 within or near the VEGFA gene. The genetic heterozygosity of rs10434, rs3025040, rs735286 and rs833061 was very high. Statistical analysis showed that the variants rs10434 (P=0.041) and rs735286 (P=0.034) in the gene were associated with the risk of cerebral infarction diseases in the Chinese Han population. Conclusions: VEGFA variants rs10434 and rs735286 were associated with the risk of cerebral infarction diseases in the Chinese Han population.

Background There are about 2.4 hundred thousand new cases and 1.5 hundred thousand deaths of ovarian cancer (OC) annually in the world. Chronic inflammation is a risk factor for OC. C-X-C motif chemokine ligand 1 (CXCL1) defects may facilitate inflammation and transactivate EGFR in ovarian cancer, but the precise haplotypes associated with the potential diseases remained largely unknown. In this work, we characterized CXCL1 gene variations to elucidate their possible associations with OC. Methods We analyzed the CXCL1 gene for 300 OC patients with 400 healthy participants as controls. The statistical analyses and Hardy-Weinberg equilibrium tests of the patients and control populations were conducted using the SPSS software (version 19.0) and Plink (version 1.9). Results The variants rs11547681, rs201090116, rs199791199, rs181868085, rs4074 and rs1814092 within or near the CXCL1 gene were characterized. The genetic heterozygosity of rs11547681 and rs4074 was very high. Statistical analysis showed that the variant rs11547681 in the gene was closely associated with the risk of OC in the Chinese Han population, although this variant was not associated with FIGO stages or pathological grades of the patients. Conclusions Rs11547681 in CXCL1 gene was associated with the risk of OC in the Chinese Han population.

We study a non-integrable system in a resonant four-level media at room temperature. Under appropriate parameter conditions, the system can be reduced to the saturated nonlinear Schrodinger equation (SNLSE) and cubic-quintic nonlinear Schrodinger equation (CQNLSE). And we find a scheme to produce (1 + 1)-dimensional [(1 + 1) − D] spatial optical rogue waves, breathers, and solitons in these equations. The generation and disappearance of different nonlinear modes can be manipulated just by adjusting the amplitude and width of the initial Gaussian pulse. We also prove this scheme adapts to not only the integrable model, but also the non-integrable model. In addition, we also find the relation among these different nonlinear modes.

Congenital heart diseases (CHD) are a large group of prevalent and complex anatomic malformations of the heart, with the genetic basis remaining largely unknown. Since genes or factors associated with the differentiation of human embryonic stem (HES) cells would affect the development of all embryonic tissues, including cardiac progenitor cells, we postulated their potential roles in CHD. In this study, we focused on ZW10, a kinetochore protein involved in the process of proper chromosome segregation, and conducted comparative studies between CHD patients and normal controls matched in gender and age in Chinese Han populations. We identified three variations in the ZW10 gene, including rs2885987, rs2271261 and rs2459976, which all had high genetic heterozygosity. Association analysis of these genetic variations with CHD showed correlation between rs2459976 and the risk of CHD. We conclude that rs2459976 in the ZW10 gene is associated with CHD in Chinese Han populations.

// Fei-Feng Li 1, 2, * , Zhi-Xun Zhao 3, * , Peng Yan 3 , Song Wang 3 , Zheng Liu 4 , Qiong Zhang 5 , Xiao-Ning Zhang 5 , Chang-Hao Sun 6 , Xi-Shan Wang 3,4 , Gui-Yu Wang 2, 3 and Shu-Lin Liu 1, 2, 7 1 Systemomics Center, College of Pharmacy, and Genomics Research Center (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), Harbin Medical University, Harbin, China 2 Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Heilongjiang, China 3 Department of Colorectal Surgery of the Second Affiliated Hospital, Harbin Medical University, Harbin, China 4 Department of Colorectal Surgery, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China 5 Department of Antibiotics, Heilongjiang Province Food and Drug Inspection Testing Institute, Harbin, China 6 Department of Nutrition and Food Hygiene, Public Health College, Harbin Medical University, Harbin, China 7 Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, Canada * These authors have contributed equally to this work Correspondance to: Gui-Yu Wang, email: guiywang@gmail.com Shu-Lin Liu, email: slliu@ucalgary.ca Xi-Shan Wang, email: wxshan1208@126.com Keywords: colorectal cancer, APC, mutation, Wnt/β-catenin signaling pathway, gene expression Received: May 04, 2017 Accepted: May 23, 2017 Published: August 05, 2017 ABSTRACT Colorectal cancer (CRC) is among the most common and fatal forms of solid tumors worldwide and more than two thirds of CRC and adenomas patients have APC gene mutations. APC is a key regulator in the Wnt/β-catenin signaling pathway but its roles in CRC remains to be elucidated. In this study, we compared APC genes between CRC patients and controls to determine possible associations of nucleotide changes in the APC gene with the pathways involved in CRC pathogenesis. All participants received physical and enteroscopic examinations. The APC gene was sequenced for 300 Chinese Han CRC patients and 411 normal controls, and the expression levels of genes in the signaling pathway were analyzed using Western Blotting. Statistical analyses were conducted using SPSS (version 19.0) software. We found that rs11954856 in the APC gene was associated with colorectal cancer and could increase the expression levels of APC , β-catenin , TCF7L1 , TCF7L2 and LEF1 genes in the pathway in the CRC patients, demonstrating the involvement of APC in the pathological processes leading to CRC.

Congenital heart disease (CHD) is among the most prevalent and complex congenital anatomic malformations in newborns. Interactions of cardiac progenitor with a broad range of cellular regulatory factors play key roles in the formation of mammalian heart and pathogenesis of CHD. STX18 is a soluble N-ethylmaleimide-sensitive factor attachment protein receptor, which is involved in numeral cellular activities such as organelle assembly and the cell cycle. The aim of this work was to find evidence on whether STX18 variations might be associated with CHD in Chinese Han populations. We evaluated SNPs rs2044, rs33952588, rs61740788, rs12504020 and rs12644497, which are located within the exon or intron sequences of the STX18 gene, for 310 Chinese Han CHD patients and 400 non-CHD controls. Using SPSS software (version 19.0) and the online software OEGE, we conducted statistical analyses and Hardy-Weinberg equilibrium test, respectively. Among the five SNPs identified in the STX18 gene, rs33952588 and rs61740788 had very low genetic heterozygosity. In contrast, the genetic heterozygosity of the remaining three variations rs12504020 and rs12644497 near the 5'UTR and rs2044 within 3'UTR of the STX18 gene was considerably high. Analysis of associations of these genetic variations with the risk of CHD showed that rs12644497 (P value=0.0170.05) was associated with the risk of CHD, specifically VSD and ASD, whereas rs12504020 (P value=0.5600.05) and rs2044 (P value=0.9720.05) were not. The SNP rs12644497 in the STX18 gene was associated with CHD in Chinese Han populations.

Multiple sclerosis is among the most serious inflammatory demyelinating diseases (IDD). Interleukin-23A (IL23A) regulates and coordinates the activities of immune cells by interacting with its receptor IL23R and plays key roles in the pathogenesis of immune inflammatory diseases. IDD, deemed to be a kind of autoimmune diseases, may involve IL23A in the pathogenesis. The aim of this work was to validate the hypothesized involvement of IL-23A and its receptor in IDD. We sequenced the IL-23A and IL-23R genes for 206 Chinese Han IDD patients and evaluated SNPs within or near those genes. The serum levels of IL23A in IDD participants were analyzed using ELISA. The statistical analyses were conducted using Chi-Square Tests as implemented in SPSS (version 19.0). The Hardy-Weinberg equilibrium test of the population was carried out using online software OEGE. Three variants rs2066808, rs2371494, rs11575248 in IL-23A gene and one variant rs1884444 in IL-23R gene were demonstrated to be associated with the risk of MS or other IDD diseases, and the expression level of serum IL-23A in the MS patients was also altered. We conclude that variants in IL-23A and IL-23R genes were associated with the risk of MS or other IDD diseases.

// Fei-Feng Li 1, 2, * , Peng Yan 3, * , Zhi-Xun Zhao 3 , Zheng Liu 4 , Da-Wei Song 3 , Xing-Wang Zhao 3 , Xi-Shan Wang 2, 4 , Gui-Yu Wang 2, 3 , Shu-Lin Liu 1, 2, 5 1 Genomics Research Center, State-Province Key Laboratory of Biopharmaceutical Engineering, Harbin Medical University, Harbin, China 2 Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Heilongjiang, China 3 Department of Colorectal Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China 4 Department of Colorectal Surgery, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China 5 Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, Canada * These authors are contributed equally to this work Correspondence to: Shu-Lin Liu, email: slliu@ucalgary.ca Gui-Yu Wang, email: guiywang@gmail.com Xi-Shan Wang, email: wxshan1208@126.com Keywords: colorectal cancer, CHIT1, C-reaction protein, gene expression, microbe Received: January 10, 2016 Accepted: April 16, 2016 Published: May 02, 2016 ABSTRACT Colorectal cancer (CRC) is one of the most common solid tumors worldwide, often associated with inflammation. The microbes in the human intestine have a key role in inflammations and CRC. Chitotriose renders growth advantage to some bacteria, especially some pathogens, and thus has a role in inflammations. The enzyme chitotriosidase, encoded by the CHIT1 gene of the host, may degrade chitotriose with different efficiencies depending on the alleles. We sequenced the CHIT1 gene for 320 Chinese Han CRC patients and 404 normal controls, and focused on variations rs61745299 and rs35920428 within the CHIT1 gene for their possible roles in CRC. Statistical analyses were conducted using Chi-Square Tests as implemented in SPSS (version 19.0). Multiple sequence alignment was conducted using the Vector NTI, and protein expression levels were analyzed by western blotting. The two variations, rs61745299 and rs35920428 within the CDS region of CHIT1 gene, were associated with the risk of CRC (both with P values < 0.001). Western blotting analysis showed that the variations increased the expression levels of the CHIT1 and C-reaction protein genes in the cancer tissue. We conclude that the two variations of CHIT1 , rs61745299 and rs35920428, increase expression of the gene and are associated with CRC in Chinese Han populations.

Neurovascular diseases are among the leading causes of mortality and permanent disability due to stroke, aneurysm, and other cardiovascular complications. Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and Marfan syndrome are two neurovascular disorders that affect smooth muscle cells through accumulation of granule and osmiophilic materials and defective elastic fiber formations respectively. Moyamoya disease, hereditary hemorrhagic telangiectasia (HHT), microcephalic osteodysplastic primordial dwarfism type II (MOPD II), and Fabry's disease are disorders that affect the endothelium cells of blood vessels through occlusion or abnormal development. While much research has been done on mapping out mutations in these diseases, the exact mechanisms are still largely unknown. This paper briefly introduces the pathogenesis, genetics, clinical symptoms, and current methods of treatment of the diseases in the hope that it can help us better understand the mechanism of these diseases and work on ways to develop better diagnosis and treatment.

OBJECTIVE: To evaluate the prognosis and complications of expectant therapy and curettage for retained product of conception (RPOC) after second trimester termination of pregnancy (TOP). METHODS: A total of 270 patients with RPOC following second trimester TOP in Nanfang Hospital between January, 2014 and December, 2015 were included in this study. The duration of vaginal bleeding time and menstruation recovery interval were compared between patients receiving expectant therapy and curettage for RPOC, and binary logistic regression was used to assess the risk factors for complications in bivariate and multivariate analyses. RESULTS: The duration of vaginal bleeding time was significantly longer in expectant therapy group than in curettage group (P=0.005), while the menstruation recovery interval did not differ significantly between the two groups. The incidence of vaginal bleeding time for over 42 days was significantly higher in curettage group than in expectant therapy group (P=0.040), and the incidence of a menstruation recovery interval beyond 60 days was comparable between them. The incidence of complications was significantly higher in curettage group than in expectant therapy group either with adjustment of age, gravidity, parity, history of uterine surgery status, gestational age, type of indications, regimens for TOP and induction-abortion interval (OR=18.26[95% CI: 3.57-93.42], P < 0.001) or without adjustment (OR=10.60, [95% CI: 2.36-47.66], P=0.002). CONCLUSION: Expectant therapy and curettage for RPOC after second trimester TOP have comparable prognosis, but curettage is associated with a significantly higher rate of complications.

Cerebral infarction disease is a severe hypoxic ischemic tissue necrosis in the brain, often leading to long-term functional disability and residual impairments. The Notch signaling pathway plays key roles in proliferation and survival of the stem/progenitor cells of the central and peripheral nervous systems. Notch3 is an important member of the pathway, but the relationships between the genetic abnormalities and cerebral infarction disease still remain unclear. The aim of this work was to evaluate variations in Notch3 gene for their possible associations with the cerebral infarction disease. We sequenced the Notch3 gene for 260 patients with cerebral infarction disease, 300 normal controls with old ages and 300 normal controls with younger ages, and identified the variations. The statistical analyses were conducted using Chi-Square Tests as implemented in SPSS (version 19.0). The Hardy-Weinberg equilibrium test of the population was carried out using the online software OEGE. Six variations, including rs1044116, rs1044009, rs1044006, rs10408676, rs1043996 and rs16980398 within or near the Notch3 gene, were found. The genetic heterozygosity of rs1044116, rs1044009, rs1044006, and rs1043996 was very high, whereas that of rs10408676 and rs16980398 was very low. Statistical analyses showed that rs1044009 and rs1044006 were associated with the risk of cerebral infarction disease in the Chinese Han agedness population. The SNPs rs1044009 and rs1044006 in the Notch3 gene were associated with the risk of cerebral infarction diseases in the Chinese Han agedness population.

Trial design:Cerebral small vessel diseases (CSVDs) are a group of brain pathological processes involving cerebral small arteries, brain venules, and capillaries. The recombination signal-binding protein Jκ (RBPJ) is implicated in the pathogenesis of these diseases but its actual roles need

To identify the genetic defect in a four-generation Chinese family with autosomal dominant congenital nuclear cataract.Family history data were recorded. Clinical and ophthalmologic examinations were performed on family members. All the members were genotyped with microsatellite markers at loci associated with cataracts. Linkage analysis was performed after genotyping. Candidate genes were screened for mutation using direct sequencing.Linkage analysis was obtained at markers D1S1653 (LOD score [Z] = 1.50, recombination fraction [theta] = 0.0) and D1S498 (LOD score Z = 0.90, recombination fraction [theta] = 0.0), which encompasses the connexin 50 gene (GJA8). Sequencing the coding regions of GJA8 revealed a novel, heterozygous c.773CT transition that resulted in the substitution of a highly conserved serine by phenylalanine at codon 258 (S258F). Bioinformatics analysis showed that the mutation altered the hydrophobicity and secondary structure of the protein. This mutation co-segregated with the disease phenotype in all affected individuals and was not found in the unaffected family members or in 100 normal unrelated individuals.This study has identified a novel missense mutation located in the carboxyl terminus of GJA8 (S258F) associated with autosomal dominant nuclear cataract.

Mutations in the NIPA1 gene cause autosomal dominant hereditary spastic paraplegia (ADHSP). To date, little is known about the relationship between genotype–phenotype correlation. In order to examine the gene mutation associated with the genotype–phenotype of Chinese kindred with ADHSP, linkage analysis and mutation detection were performed. For affected family members, clinical analysis, electrophysiological examination and MRI of the brain and spinal cord were also performed. Every effected patient had a c316 (G106R) mutation in the NIPA1 gene. Neurophysiological examination revealed decreased amplitude of compound muscle action potentials (CMAP) from the tibial and peroneal motor nerves in most patients. Sensory nerve action potential (SNAP) from the tibialis nerve was not elicited in most patients. Central motor conduction time (CMCT) to the abductor pollicis brevis muscle (APB), first metatarsal interosseus muscle (FMI) and anterior tibial muscle (AT) were either absent or clearly prolonged in all patients. Spinal cord MRI showed different levels of atrophy in every affected individual. These lesions present an increased spot or patch signal on transverse axis T2WI and an intense signal of continual longitudinal strip on the anteroposterior axis. Our study supports that mutations in the NIPA1 gene cause ADHSP and further demonstrates genotype–phenotype correlations in SPG6.

Background Nodal/TGF signaling pathway has an important effect at early stages of differentiation of human embryonic stem cells in directing them to develop into different embryonic lineages. SMAD3 is a key intracellular messenger regulating factor in the Nodal/TGF signaling pathway, playing important roles in embryonic and, particularly, cardiovascular system development. The aim of this work was to find evidence on whether SMAD3 variations might be associated with ventricular septal defects (VSD) or other congenital heart diseases (CHD). Methods We sequenced the SMAD3 gene for 372 Chinese Han CHD patients including 176 VSD patients and evaluated SNP rs2289263, which is located before the 5’UTR sequence of the gene. The statistical analyses were conducted using Chi-Square Tests as implemented in SPSS (version 13.0). The Hardy-Weinberg equilibrium test of the population was carried out using the online software OEGE. Results Three heterozygous variants in SMAD3 gene, rs2289263, rs35874463 and rs17228212, were identified. Statistical analyses showed that the rs2289263 variant located before the 5’UTR sequence of SMAD3 gene was associated with the risk of VSD (P value=0.013

Microcephalic osteodysplastic primordial dwarfism type II (MOPD II) is a highly detrimental human autosomal inherited recessive disorder. The hallmark characteristics of this disease are intrauterine and postnatal growth restrictions, with some patients also having cerebrovascular problems such as cerebral aneurysms. The genomic basis behind most clinical features of MOPD II remains largely unclear. The aim of this work was to identify the genetic defects in a Chinese family with MOPD II associated with multiple intracranial aneurysms. The patient had typical MOPD II syndrome, with subarachnoid hemorrhage and multiple intracranial aneurysms. We identified three novel mutations in the PCNT gene, including one single base alteration (9842A>C in exon 45) and two deletions (Del-C in exon 30 and Del-16 in exon 41). The deletions were co-segregated with the affected individual in the family and were not present in the control population. Computer modeling demonstrated that the deletions may cause drastic changes on the secondary and tertiary structures, affecting the hydrophilicity and hydrophobicity of the mutant proteins. In conclusion, we identified two novel mutations in the PCNT gene associated with MOPD II and intracranial aneurysms, and the mutations were expected to alter the stability and functioning of the protein by computer modeling.

Colorectal cancer (CRC) is among the most fatal forms of solid tumor in men and women. While the majority of diagnosed CRC cases are sporadic, 15‑25% of patients have a family history of adenomatous polyposis and CRC; however, the associated gene mutations remain largely unidentified. The aim of the present study was to investigate the genomes of a four‑generational Chinese Han family with familial adenomatous polyposis and CRC to identify the potential genetic anomalies associated with the disease. Diagnoses were made by physical and enteroscopic examinations of all the family members. Mutational analyses of the potential CRC‑associated genes were carried out by direct gene sequencing, and the statistically significant differences in polymorphisms between normal and diseased populations were determined. Multiple sequence alignment and protein modeling were conducted using the Vector NTI and DNAMAN software tools. Clinical and pathological features of all the examined patients were consistent with typical familial adenomatous polyposis (FAP) syndrome. From the genomes of these family members, a 131564TC (p.1125ValAla) mutation was identified in exon 15 of the APC gene, and a 1126GC (p.324GlnHis) mutation was identified in exon 12 of the MUTYH gene. The 131564TC mutation co‑segregated with the affected individuals in the family and was specifically associated with the incidence of CRC (P=0.0180.05). The 1125Val residue was highly conserved in the APC protein, and the p.1125ValAla mutation led to changes in the secondary structure and hydrophilicity of the APC protein. In conclusion, the APC gene mutation 131564TC is associated with FAP and the pathogenesis of CRC.

Background The human heart consists of several cell types with distinct lineage origins. Interactions between these cardiac progenitors are very important for heart formation. The muscle segment homeobox gene family plays a key role in the cell morphogenesis and growth, controlled cellular proliferation, differentiation, and apoptosis, but the relationships between the genetic abnormalities and CHD phenotypes still remain largely unknown. The aim of this work was to evaluate variations in MSX1 and MSX2 for their possible associations with CHD. Methods We sequenced the MSX1 and MSX2 genes for 300 Chinese Han CHD patients and 400 normal controls and identified the variations. The statistical analyses were conducted using Chi-Square Tests as implemented in SPSS (version 19.0). The Hardy-Weinberg equilibrium test of the population was carried out using the online software OEGE. Results Six variations rs4647952, rs2048152, rs4242182, rs61739543, rs111542301 and rs3087539 were identified in the MSX2 gene, but the genetic heterozygosity of those SNPs was very low. In contrast, the genetic heterozygosity of two variations rs3821949 near the 5’UTR and rs12532 within 3’UTR of the MSX1 gene was considerably high. Statistical analyses showed that rs3821949 and rs12532 were associated with the risk of CHD (specifically VSD). Conclusions The SNPs rs3821949 and rs12532 in the MSX1 gene were associated with CHD in Chinese Han populations.

Epithelial-mesenchymal transition (EMT) plays an important role in fibrotic diseases. We have previously showed that silica induces EMT in human bronchial epithelial cells (BECs); however, the underlying mechanism of silica-induced EMT is poorly understood. In the present study, we investigated the role of Snail in silica-induced EMT in human BECs in vitro. Human BECs were treated with silica at various concentrations and incubation times. Then MTT assay, western blot, electrophoretic mobility shift assay (EMSA), and small interfering RNA (siRNA) transfection were performed. We found that silica increased the expression and DNA binding activity of Snail in human BECs. SNAI siRNA inhibited the silica-induced expression of Snail. Moreover, SNAI siRNA upregulated the expression of epithelial marker E-cadherin, but attenuated the expression of mesenchymal marker α-smooth muscle actin and vimentin in silica-stimulated cells. These results suggest that Snail mediates the silica-induced EMT in human BECs.

BACKGROUND: Nodal/TGF-Lefty signaling pathway has important effects at early stages of differentiation of human embryonic stem cells in directing them to differentiate into different embryonic lineages. LEFTY, one of transforming growth factors in the Nodal/TGF-Lefty signaling pathway, plays an important role in the development of heart. The aim of this work was to find evidence on whether Lefty variations are associated with congenital heart diseases (CHD). METHODS: We sequenced the Lefty gene for 230 Chinese Han CHD patients and evaluated SNPs rs2295418, rs360057 and g.G169A, which are located within the translated regions of the genes. The statistical analyses were conducted using Chi-Square Tests as implemented in SPSS (version 13.0). The Hardy-Weinberg equilibrium test of the population was carried out using online software OEGE, and multiple-sequence alignments of LEFTY proteins were carried out using the Vector NTI software. RESULTS: Two heterozygous variants in Lefty1 gene, g.G169A and g.A1035C, and one heterozygous variant in Lefty2 gene, g.C925A, were identified. Statistical analyses showed that the rs2295418 (g.C925A) variant in Lefty2 gene was obviously associated with the risk of CHD (P value = 0.0160.05). CONCLUSIONS: The SNP rs2295418 in the Lefty2 gene is associated with CHD in Chinese Han populations.

Background: Autosomal dominant Charcot Marie Tooth disease (CMT) diseases is an inherited peripheral neuropathies disease, the prevalence is 17-40 per 100,000 individuals 17-40 per 100,000 individuals. The complex genetic mode and large number of CMT causing genes and loci made it is very hard for clinicians and researchers when trying to determine the underlying genetic diagnosis. In this work, we want to identify the cause for a Chinese family with Charcot-Marie-Tooth disease. Methods: Family history data were recorded. Clinical and Electromyography examinations were performed on the ten affected and ten unaffected family members. All the members were genotyped with microsatellite markers at loci considered to be associated with CMT. Two-point LOD scores were calculated using the Linkage software after genotyping. Some highly suspect genes were excluded by direct sequencing. Results and Conclusions: The clinical and pathological features were relatively gently, but which became gradually worse, with the increased genetic generation, and the onset age of the affected members. Linkage analysis was obtained at markers D19S433 (LOD score [Z]=2.03, recombination fraction [θ]=0.0) and D19S916 (Z=1.6, θ=0.0). Sequencing the dynamin 2 gene (DNM2) didn’t found any variation in the translated region. There may be some other gene or loci associated with this disease.

Background MicroRNA-101 (miR-101) expression is negatively associated with tumor growth and blood vessel formation in several solid epithelial cancers. However, the role of miR-101 in human breast cancer remains elusive. Results MiR-101 was significantly decreased in different subtypes of human breast cancer tissues compared with that in adjacent normal breast tissues (P

Background Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited disease leading to recurrent ischemic stroke and vascular dementia. Numerous mutations in the 23 exons of the NOTCH3 gene have been reported to cause CADASIL in Caucasian populations, but the full spectrum of genetic changes leading to this disease is yet to be known and, especially, very few reports are available on CADASIL in Asian populations. Methods and Results We genotyped members of a 5-generational Han Chinese family with CADASIL patients and identified an R133C mutation in the NOTCH3 gene. Clinical analysis demonstrated that the penetrance of the mutation was not complete. Five of the mutation carriers, not exposed to the known vascular risk factors, did not show any clinical feature of CADASIL, suggesting the importance of environmental factors to the development of this disease. Conclusions Members of a 5-generational Han Chinese family with CADASIL patients had an R133C mutation in the NOTCH3 gene but only individuals exposed to known vascular risk factors developed CADASIL.

ABStrA ct Purpose: We sought to identify the genetic defect in a four-generation Chinese family with autosomal dominant congenital nuclear cataracts, examine the clinical features in detail and demonstrate the functional analysis of a candidate gene in the family. Methods: Family history data were recorded. Clinical and ophthalmological examinations were performed on affected and unaffected family members. All the members were genotyped with microsatellite markers at loci considered to be associated with cataracts. Two-point LOD scores were calculated using the LINKAGE program package after genotyping. A mutation was detected by dilff521229rect sequencing and verified by denaturing high-performance liquid chromatography (DHPLC). Wild-type and mutant proteins were analyzed with online softwares. Results: All affected members of this family had nuclear cataracts. Genetic analysis revealed a heterozygous previously described Arg116Cys mutation in the CRYAA gene in all of the affected members of the family but not in unaffected or 100 normal, unrelated individuals. Data generated with online software revealed that the different amino acid side chain, impact the aa116 interaction with other amino acids, thereby affecting the proteins secondary structure. Conclusions: This study identified a mutation in the CRYAA gene causing autosomal dominant nuclear cataracts and some patients show nystagmus or small blepharophimosis clinical features. These results provide evidence that CRYAA is a pathogenic gene for congenital cataracts, congenital cataracts are a clinically and genetically heterogeneous lens condition; at the same time, demonstrates a possible mechanism of action for the mutant gene.

Objective To examine the gene mutation associated with clinical phenotype from a Chinese kindred with autosomal dominant hereditary spastic paraplegia (ADHSP). Method To perform linkage analysis and mutation detection. For two affected individual of the family, clinical analysis, electrophysiological examination, and MRI of brain and spinal cord were also performed. Result A novel splice-site mutation (REEP1 c417+1g>a) was identified. Central motor conduction time to the first metatarsal interosseus and anterior tibial muscles were clearly prolonged. Thoracic cord atrophy was found from T1 to T10. Conclusion Our study supports that mutations in REEP1 cause ADHSP and demonstrates genetic heterogeneity in ADHSP. Synapse

Purpose We sought to identify the genetic defect in a four-generation Chinese family with autosomal dominant congenital lamellar cataracts and demonstrate the functional analysis with biosoftware of a candidate gene in the family. Methods Family history data were recorded. Clinical and ophthalmologic examinations were performed on family members. All the members were genotyped with microsatellite markers at loci considered to be associated with cataracts. Two-point LOD scores were calculated by using the Linkage Software after genotyping. A mutation was detected by using gene-specific primers in direct sequencing. Wild type and mutant proteins were analyzed with Online Bio-Software. Results Affected members of this family had lamellar cataracts. Linkage analysis was obtained at markers D3S2322 (LOD score [Z]=7.22, recombination fraction [θ]=0.0) and D3S1541 (Z=5.42, θ=0.0). Haplotype analysis indicated that the cataract gene was closely linked to these two markers. Sequencing the beaded filament structural protein 2 (BFSP2) gene revealed a G>A transversion in exon 5, which caused a conservative substitution of Arg to His at codon 339 (P.R339H). This mutation cosegregated with the disease phenotype in all affected individuals and was not observed in the unaffected family members or in 100 normal, unrelated individuals. Bioinformatic analyses showed that a highly conserved region was located around Arg339. Data generated with Online Bio-Software revealed that the mutation altered the protein’s hydrophobicity, hydrophobic moment, and chaperone and regulation activities. Conclusions This is the first reported case of a congenital lamellar cataract phenotype associated with the mutation of Arg339His (P.R339H) in BFSP2. It highlights the physiologic importance of the beaded filament protein and demonstrates a possible mechanism of action for the mutant gene.

To develop a new denaturing high performance liquid chromatograph (DHPLC)-based method to screen patients with EXT gene mutation and to study the gene mutation in three families with multiple exostoses.All the exons of EXT gene, including the intro-exon boundaries, were amplified by PCR. Linkage analysis and DHPLC screening were carried out to identify the mutations. DNA sequencing was used to confirm the mutations.Two known splice site mutations, IVS2+1 G to A and IVS7+1 G to T, and two SNPs have been detected in EXT2 or EXT1 gene.The transversions of IVS2+1 G to A and IVS7+1 G to T in EXT2 gene are suggested to be the disease-causing mutations and the DHPLC is a high throughout, sensitive, simple, quick, economical method to screen gene mutation in hereditary multiple exostosis.

γD-crystallin is one of the major structural proteins in human eye lens. The solubility and stability of γD-crystallin play a crucial role in maintaining the optical properties of the lens during the life span of an individual. Previous study has shown that the inherited mutation G61C results in autosomal dominant congenital cataract. In this research, we studied the effects of the G61C mutation on γD-crystallin structure, stability and aggregation via biophysical methods. CD, intrinsic and extrinsic fluorescence spectroscopy indicated that the G61C mutation did not affect the native structure of γD-crystallin. The stability of γD-crystallin against heat- or GdnHCl-induced denaturation was significantly decreased by the mutation, while no influence was observed on the acid-induced unfolding. The mutation mainly affected the transition from the native state to the intermediate but not that from the intermediate to the unfolded or aggregated states. At high temperatures, both proteins were able to form aggregates, and the aggregation of the mutant was much more serious than the wild type protein at the same temperature. At body temperature and acidic conditions, the mutant was more prone to form amyloid-like fibrils. The aggregation-prone property of the mutant was not altered by the addition of reductive reagent. These results suggested that the decrease in protein stability followed by aggregation-prone property might be the major cause in the hereditary cataract induced by the G61C mutation.