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Find video protocols related to scientific articles indexed in Pubmed.
Recent advances in animal model experimentation in autism research.
Acta Neuropsychiatr
PUBLISHED: 11-06-2014
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Autism, a lifelong neuro-developmental disorder is a uniquely human condition. Animal models are not the perfect tools for the full understanding of human development and behavior, but they can be an important place to start. This review focused on the recent updates of animal model research in autism.
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Platelet function monitoring guided antiplatelet therapy in patients receiving high-risk coronary interventions.
Chin. Med. J.
PUBLISHED: 10-02-2014
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Large-scale clinical trials have shown that routine monitoring of the platelet function in patients after percutanous coronary intervention (PCI) is not necessary. However, it is still unclear whether patients received high-risk PCI would benefit from a therapy which is guided by a selective platelet function monitoring. This explanatory study sought to assess the benefit of a therapy guided by platelet function monitoring for these patients.
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Genetic diagnosis of two dopa-responsive dystonia families by exome sequencing.
PLoS ONE
PUBLISHED: 09-02-2014
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Dopa-responsive dystonia, a rare disorder typically presenting in early childhood with lower limb dystonia and gait abnormality, responds well to levodopa. However, it is often misdiagnosed with the wide spectrum of phenotypes. By exome sequencing, we make a rapid genetic diagnosis for two atypical dopa-responsive dystonia pedigrees. One pedigree, presented with prominent parkinsonism, was misdiagnosed as Parkinson's disease until a known mutation in GCH1 (GTP cyclohydrolase 1) gene (NM_000161.2: c.631_632delAT, p.Met211ValfsX38) was found. The other pedigree was detected with a new compound heterozygous mutation in TH (tyrosine hydroxylase) gene [(NM_000360.3: c.911C>T, p.Ala304Val) and (NM_000360.3: c.1358G>A, p.Arg453His)], whose proband, a pregnant woman, required a rapid and less-biased genetic diagnosis. In conclusion, we demonstrated that exome sequencing could provide a precise and rapid genetic testing in the diagnosis of Mendelian diseases, especially for diseases with wide phenotypes.
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AMPD1 functional variants associated with autism in Han Chinese population.
Eur Arch Psychiatry Clin Neurosci
PUBLISHED: 08-26-2014
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Autism is a childhood neurodevelopmental disorder with high heterogeneity. Following our genome-wide associated loci with autism, we performed sequencing analysis of the coding regions, UTR and flanking splice junctions of AMPD1 in 830 Chinese autism individuals as well as 514 unrelated normal controls. Fourteen novel variants in the coding sequence were identified, including 11 missense variants and 3 synonymous mutations. Among these missense variants, 10 variants were absent in 514 control subjects, and conservative and functional prediction was carried out. Mitochondria activity and lactate dehydrogenase assay were performed in 5 patients' lymphoblast cell lines; p.P572S and p.S626C showed decreased mitochondrial complex I activity, and p.S626C increased lactate dehydrogenase release in medium. Conclusively, our data suggested that mutational variants in AMPD1 contribute to autism risk in Han Chinese population, uncovering the contribution of mutant protein to disease development that operates via mitochondria dysfunction and cell necrosis.
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Atoh7 promotes retinal Müller cell differentiation into retinal ganglion cells.
Cytotechnology
PUBLISHED: 08-10-2014
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Glaucoma is one of the leading eye diseases due to the death of retinal ganglion cells. Increasing evidence suggests that retinal Müller cells exhibit the characteristics of retinal progenitor cells and can differentiate to neurons in injured retinas under certain conditions. However, the number of ganglion cells differentiated from retinal Müller cells falls far short of therapeutic needs. This study aimed to promote the differentiation of retinal Müller cells into ganglion cells by introducing Atoh7 into the stem cells dedifferentiated from retinal Müller cells. Rat retinal Müller cells were isolated and dedifferentiated into stem cells, which were transfected with PEGFP-N1 or PEGFP-N1-Atoh7 vector, and then further induced to differentiate into ganglion cells. The proportion of ganglion cells differentiated from Atoh7-tranfected stem cells was significantly higher than that of control transfected or untransfected cells. In summary, Atoh7 promotes the differentiation of retinal Müller cells into retinal ganglion cells. This may open a new avenue for gene therapy of glaucoma by promoting optic nerve regeneration.
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MiR-20a inhibits cutaneous squamous cell carcinoma metastasis and proliferation by directly targeting LIMK1.
Cancer Biol. Ther.
PUBLISHED: 07-14-2014
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MicroRNA-20a (miR-20a) plays a key role in tumorigenesis and progression. But its function is reverse in different kinds of malignant tumor, and its role and mechanism in cutaneous squamous cell carcinoma (CSCC) remains unclear.
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Identification of FLOT2 as a novel target for microRNA-34a in melanoma.
J. Cancer Res. Clin. Oncol.
PUBLISHED: 07-11-2014
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To confirm whether flotillin 2 (FLOT2) is a direct target of miR-34a and miR-34a/FLOT2 pathway plays a key role in melanoma proliferation and metastasis.
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Shorter telomere length in peripheral blood leukocytes is associated with childhood autism.
Sci Rep
PUBLISHED: 07-03-2014
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Telomeres are protective chromosomal structures that play a key role in preserving genomic stability. Epidemiologic studies have shown that the abnormal telomere length in leukocytes is associated with some mental disorders and age-related diseases. However, the association between leukocyte telomere length and autism has not been investigated. Here we investigated the possible association between relative telomere length (RTL) in peripheral blood leukocytes and childhood autism by using an established real-time polymerase chain reaction method. We observed significantly shorter RTL in patients with childhood autism than in controls (p = 0.006). Individuals with shorter RTL had a significantly increased presence of childhood autism compared with those who had long RTL. In patients, we found that family training interventions have a significant effect on telomere length (P = 0.012), but no correlations between RTL and clinical features (paternal age, maternal age, age of onset, illness of duration, CARS score and ABC score) were observed in this study. These results provided the first evidence that shorter leukocytes telomere length is significantly associated with childhood autism. The molecular mechanism underlying telomere length may be implicated in the development of autism.
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Three N-H functionalized metal-organic frameworks with selective CO2 uptake, dye capture, and catalysis.
Inorg Chem
PUBLISHED: 07-02-2014
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Three N-H functionalized metal-organic frameworks, Pb-DDQ, Zn-DDQ, and Cu-DDQ, were synthesized with a new flexible dicarboxylate ligand based on quinoxaline (H2DDQ = N,N'-dibenzoic acid-2,3-diaminoquinoxaline). CO2 adsorptions indicate that Zn-DDQ and Cu-DDQ have greatly enhanced the CO2 uptake due to the opposite N-H groups on pyrazine. With very small adsorption of N2, Cu-DDQ shows high selectivity for CO2 and N2. The three MOFs also have large adsorptions of some selected dyes, while Zn-DDQ and Cu-DDQ with large but different shapes of pores are demonstrated to be promising materials for fast separation of MB/other and CV/other mixtures, respectively. The cyanosilylation of aldehydes and ketones with high yields in a short reaction time for Cu-DDQ indicates that Cu-DDQ has a higher Lewis acidity than the other two MOFs.
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Parasitic loss suppression in photonic and plasmonic photovoltaic light trapping structures.
Opt Express
PUBLISHED: 07-01-2014
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In this paper, we examine the optical loss mechanisms and mitigation strategies in classical photovoltaic light trapping structures consisting of diffractive gratings integrated with a backside reflector, which couple normal incident solar radiation into guided modes in solar cells to enhance optical absorption. Parasitic absorption from metal or dielectric backside reflectors is identified to be a major loss contributor in such light trapping structures. We elucidate the optical loss mechanism based on the classical coupled mode theory. Further, a spacer design is proposed and validated through numerical simulations to significantly suppress the parasitic loss and improve solar cell performance.
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Displacement of p130Cas from focal adhesions links actomyosin contraction to cell migration.
J. Cell. Sci.
PUBLISHED: 06-13-2014
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Cell adhesion complexes provide platforms where cell-generated forces are transmitted to the extracellular matrix (ECM). Tyrosine phosphorylation of focal adhesion proteins is crucial for cells to communicate with the extracellular environment. However, the mechanisms that transmit actin cytoskeletal motion to the extracellular environment to drive cell migration are poorly understood. We find that the movement of p130Cas (Cas, also known as BCAR1), a mechanosensor at focal adhesions, correlates with actin retrograde flow and depends upon actomyosin contraction and phosphorylation of the Cas substrate domain (CasSD). This indicates that CasSD phosphorylation underpins the physical link between Cas and the actin cytoskeleton. Fluorescence recovery after photobleaching (FRAP) experiments reveal that CasSD phosphorylation, as opposed to the association of Cas with Src, facilitates Cas displacement from adhesion complexes in migrating cells. Furthermore, the stabilization of Src-Cas binding and inhibition of myosin II, both of which sustain CasSD phosphorylation but mitigate Cas displacement from adhesion sites, retard cell migration. These results indicate that Cas promotes cell migration by linking actomyosin contractions to the adhesion complexes through a dynamic interaction with Src as well as through the phosphorylation-dependent association with the actin cytoskeleton.
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SLC39A5 mutations interfering with the BMP/TGF-? pathway in non-syndromic high myopia.
J. Med. Genet.
PUBLISHED: 06-02-2014
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High myopia, with the characteristic feature of refractive error, is one of the leading causes of blindness worldwide. It has a high heritability, but only a few causative genes have been identified and the pathogenesis is still unclear.
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[The effects of tirofiban on acute non-ST segment elevation myocardial infarction patients not receiving early reperfusion intervention].
Zhonghua Nei Ke Za Zhi
PUBLISHED: 04-29-2014
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To study the efficacy and safety of tirofiban in patients with acute non-ST- segment elevation myocardial infarction (NSTEMI) without early reperfusion intervention.
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[Effect of intracoronary tirofiban combined with nitroprusside injection through thrombus aspiration catheter during primary percutaneous coronary intervention on acute anterior myocardial infarction patients with heavy thrombosis burden].
Zhonghua Xin Xue Guan Bing Za Zhi
PUBLISHED: 04-01-2014
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To explore the impact of intracoronary bolus administration of tirofiban combined with nitroprusside through thrombus aspiration catheter or thrombus aspiration alone on myocardial reperfusion and major adverse cardiovascular events rate in acute anterior myocardial infarction patients with heavy thrombosis burden.
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The correlation between the expression of differentiated embryo-chondrocyte expressed gene l and oral squamous cell carcinoma.
Eur. J. Med. Res.
PUBLISHED: 03-31-2014
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This study aims to explore the correlation between expression of differentiated embryo-chondrocyte expressed gene l (DEC1) and oral squamous cell carcinoma (OSCC), which could provide the reference for treatment and prognosis assessment of OSCC.
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Two-year clinical outcomes of patients with overlapping second-generation drug-eluting stents for treatment of long coronary artery lesions: comparison of everolimus-eluting stents with resolute zotarolimus-eluting stents.
Coron. Artery Dis.
PUBLISHED: 03-04-2014
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The aim of this study was to compare the 2-year clinical outcomes of overlapping second-generation everolimus-eluting stents (EES) with those of overlapping resolute zotarolimus-eluting stents (R-ZES) in the treatment of long coronary artery lesions.
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C9orf72 hexanucleotide repeat expansion analysis in Chinese spastic paraplegia patients.
J. Neurol. Sci.
PUBLISHED: 02-25-2014
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Recently, a hexanucleotide repeat expansion in the C9orf72 gene has been identified to cause frontotemporal dementia, amyotrophic lateral sclerosis families and many other neurodegenerative diseases. Owing to the overlapping phenotypes among HSP, frontotemporal dementia and amyotrophic lateral sclerosis we hypothesized that C9orf72 expansions might be a genetic risk factor or modifier of HSP.
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The APOE ?2 allele may decrease the age at onset in patients with spinocerebellar ataxia type 3 or Machado-Joseph disease from the Chinese Han population.
Neurobiol. Aging
PUBLISHED: 02-16-2014
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Polymorphism of the apolipoprotein E (APOE) gene has been defined as a modifying factor for age at onset (AO) in neurodegenerative disorders. The AO of spinocerebellar ataxia type 3 or Machado-Joseph disease (SCA3 or MJD) is inversely correlated with expanded CAG repeat lengths in the ATXN3 gene; however, AO is only partially explained by the expanded CAG repeats. We performed a case-control study to explore whether APOE genotypes play a role in AO of SCA3 or MJD from the Chinese Han population. The APOE genotypes were analyzed in an independent cohort of 155 patients with SCA3 or MJD and 191 controls both from Mainland China. Our study demonstrated that SCA3 or MJD patients experienced an earlier onset if they were carriers of APOE ?2 allele, which decreased the AO by nearly 4 years. This study may also reconfirm the effect of the APOE gene on SCA3 or MJD patients from different races and indicated that certain APOE alleles might be genetic modifiers for AO in SCA3 or MJD.
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Variations analysis of NLGN3 and NLGN4X gene in Chinese autism patients.
Mol. Biol. Rep.
PUBLISHED: 02-13-2014
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Autism is a neurodevelopmental disorder clinically characterized by impairment of social interaction, deficits in verbal communication, as well as stereotypic and repetitive behaviors. Several studies have implicated that abnormal synaptogenesis was involved in the incidence of autism. Neuroligins are postsynaptic cell adhesion molecules and interacted with neurexins to regulate the fine balance between excitation and inhibition of synapses. Recently, mutation analysis, cellular and mice models hinted neuroligin mutations probably affected synapse maturation and function. In this study, four missense variations [p.G426S (NLGN3), p.G84R (NLGN4X), p.Q162 K (NLGN4X) and p.A283T (NLGN4X)] in four different unrelated patients have been identified by PCR and direct sequencing. These four missense variations were absent in the 453 controls and have not been reported in 1000 Genomes Project. Bioinformatic analysis of the four missense variations revealed that p.G84R and p.A283T were "Probably Damaging". The variations may cause abnormal synaptic homeostasis and therefore trigger the patients more predisposed to autism. By case-control analysis, we identified the common SNPs (rs3747333 and rs3747334) in the NLGN4X gene significantly associated with risk for autism [p = 5.09E-005; OR 4.685 (95% CI 2.073-10.592)]. Our data provided a further evidence for the involvement of NLGN3 and NLGN4X gene in the pathogenesis of autism in Chinese population.
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A novel mutation of GATA4 (K319E) is responsible for familial atrial septal defect and pulmonary valve stenosis.
Gene
PUBLISHED: 02-06-2014
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Congenital heart disease (CHD) is the most common birth defect in humans, and the etiology of most CHD remains to be elusive. Atrial septal defect (ASD) makes up 30–40% of all adult CHDs and is thought to be genetically heterogeneous. Previous studies have demonstrated that mutations in transcription factors e.g. NKX2.5, GATA4, and TBX5 contribute to congenital ASD. In this study, we investigate a family of three generations with seven patients with ASD and pulmonary valve stenosis (PS). A novel GATA4 mutation, c.955ANG (p.K319E), was identified and co-segregated with the affected patients in this family. This mutation was predicted to be deleterious by three different bioinformatics programs (The polyphen2, SIFT and MutationTaster). Our finding expands the spectrum of GATA4 mutations and provides additional support that GATA4 plays important roles in cardiac development.
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Resveratrol induces human K562 cell apoptosis, erythroid differentiation, and autophagy.
Tumour Biol.
PUBLISHED: 01-27-2014
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Resveratrol (Res) is a naturally occurring phytoalexin with apoptotic and inducing-glob effects in leukemic cells, but the potential induction of erythroid differentiation in cells is not fully understood. Here, we investigated the effects of Res on human erythro-megakaryoblastic leukemia cell line K562. Among the treated cells, proliferation was inhibited and the occurrence of cell apoptosis and cell death were detected. Erythroid differentiation assay was explored, and we found that Res could increase the expression of glycophorin A (GPA), HBA1, HBB, and ?-globin genes and enforced the expression of GPA, CD71, and Band3 proteins. Res also induced K562 cell autophagy when the concentration of Res was increased up to 50 or 100 ?M. Our findings suggested that Res possesses the potency not only inducing apoptosis but also inducing erythroid differentiation and autophagy in K562 cells. These results provide that Res may be a therapeutic candidate for chronic myelogenous leukemia treatment.
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A novel transgenic mouse model of Chinese Charcot-Marie-Tooth disease type 2L.
Neural Regen Res
PUBLISHED: 01-20-2014
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We previously found that the K141N mutation in heat shock protein B8 (HSPB8) was responsible for Charcot-Marie-Tooth disease type 2L in a large Chinese family. The objective of the present study was to generate a transgenic mouse model bearing the K141N mutation in the human HSPB8 gene, and to determine whether this (K141N)HSPB8 transgenic mouse model would manifest the clinical phenotype of Charcot-Marie-Tooth disease type 2L, and consequently be suitable for use in studies of disease pathogenesis. Transgenic mice overexpressing (K141N)HSPB8 were generated using K141N mutant HSPB8 cDNA cloned into a pCAGGS plasmid driven by a human cytomegalovirus expression system. PCR and western blot analysis confirmed integration of the (K141N)HSPB8 gene and widespread expression in tissues of the transgenic mice. The (K141N)HSPB8 transgenic mice exhibited decreased muscle strength in the hind limbs and impaired motor coordination, but no obvious sensory disturbance at 6 months of age by behavioral assessment. Electrophysiological analysis showed that the compound motor action potential amplitude in the sciatic nerve was significantly decreased, but motor nerve conduction velocity remained normal at 6 months of age. Pathological analysis of the sciatic nerve showed reduced myelinated fiber density, notable axonal edema and vacuolar degeneration in (K141N)HSPB8 transgenic mice, suggesting axonal involvement in the peripheral nerve damage in these animals. These findings indicate that the (K141N)HSPB8 transgenic mouse successfully models Charcot-Marie-Tooth disease type 2L and can be used to study the pathogenesis of the disease.
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Mutation and Clinical Characteristics of Autosomal-Dominant Hereditary Spastic Paraplegias in China.
Neurodegener Dis
PUBLISHED: 01-14-2014
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Background: Hereditary spastic paraplegias constitute a heterogeneous group of inherited neurodegenerative disorders. To date, there has been no systematic mutation and clinical analysis for a large group of autosomal-dominant hereditary spastic paraplegias in China. Objective: The purpose of this study was to investigate the mutation frequencies and the clinical phenotypes of Chinese spastic paraplegia patients. Methods: Direct sequencing and a multiplex ligation-dependent probe amplification assay were applied to detect the mutations of SPAST and ATL1 in 54 autosomal-dominant hereditary spastic paraplegia probands and 66 isolated cases. Next, mutations in NIPA1, KIF5A, REEP1 and SLC33A1 were detected in the negative patients. Subsets of spastic paraplegia patients were genotyped for the modifying variants. Further, detailed clinical data regarding the genetically diagnosed families were analysed. Results: Altogether, 27 families were diagnosed as SPG4, 3 as SPG3A and 1 as SPG6. No mutations in KIF5A, REEP1 or SLC33A1 were found; 9 SPAST mutations were novel. There was no p.S44L or p.P45Q variant in SPAST and no p.G563A variant in HSPD1 in either the 120 spastic paraplegia patients or the 500 controls. There was a remarkable clinical difference between the SPG4 and non-SPG4 patients and even between genders among the SPG4 patients. Non-penetrance and remarkable gender difference were observed in some SPG4 and SPG3A families. Conclusions: Our data confirm that hereditary spastic paraplegias in China represent a heterogeneous group of genetic neurodegenerative disorders in autosomal-dominant and apparently sporadic forms. Novel genotype-phenotype correlations were established. © 2014 S. Karger AG, Basel.
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miR-199a-5p regulates the expression of metastasis-associated genes in B16F10 melanoma cells.
Int J Clin Exp Pathol
PUBLISHED: 01-01-2014
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MicroRNAs are regulatory factors that play important roles in tumor development, invasion and metastasis. Previously, we showed that miR-199a is abnormally expressed in clinical melanoma specimens and expression was closely associated with clinical features of metastasis. However, the exact molecular mechanisms by which miR-199a-5p influences melanoma invasion and metastasis remains unclear. In this study, we investigated gene expression changes of metastasis-associated genes in B16F10 melanoma cells following targeted silencing or overexpression of miR-199a-5p, using mouse tumor metastasis PCR arrays. Comparison of gene expression changes in miR-199a-5p-silenced versus overexpressing cells identified a set of upregulated genes (> 2-fold) including Cd44, Cdh1, Cxcr4, Etv4, Fxyd5, Rpsa, Mmp3, Myc, Rb1, Tcf20, Hprt1, Actb1 and downregulated genes (> 2-fold) including Ctsk, Itga7 and Tnfsf10. Regulation of a subset of these genes (Myc, Tnfsf10 and Cd44) following miR-199a-5p silencing or overexpression was validated by reverse transcription-polymerase chain reaction (RT-PCR) and western blot. In conclusion, our study demonstrates that miR-199a-5p regulates melanoma metastasis-related genes, and may provide a basis for the development of novel, molecularly targeted drugs.
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Expression of tmp21 in normal adult human tissues.
Int J Clin Exp Med
PUBLISHED: 01-01-2014
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TMP21, known as p23 protein, is one important member of the p24 protein families. The degradation of TMP21 is mediated by the ubiquitin-proteasome pathway, as with the other presenilin-associated ?-secretase complex members. NFAT plays a very important role in regulation of human TMP21 gene expression. Compared with the function of TMP21, the studies about the distribution of this protein in human tissues are limited. We collected 19 normal adult human tissues from a healthy adult man died in a traffic accident and did examination of all the tissues collected for ICH, western blot and RT-PCR. It was shown that the expression of TMP21 is at high levels in heart, liver, lung, kidney and adrenal gland; moderate levels in brain, pancreas, prostate gland, testicle, small intestine, colon, stomach, gall bladder, thyroid gland and trachea; low levels in skeletal muscle, skin and lymphonodus. TMP21 is widely existed in normal adult human tissues. The current study provided for the first time a comprehensive expression of TMP21 in normal adult human tissues. It will benefit on helping in the design and interpretation of future studies focused on expounding the function of TMP21.
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New ZNF644 mutations identified in patients with high myopia.
Mol. Vis.
PUBLISHED: 01-01-2014
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Myopia, or near-sightedness, is one of the most common human visual impairments worldwide, and high myopia is one of the leading causes of blindness. In this study, we investigated the mutation spectrum of ZNF644, a causative gene for autosomal dominant high myopia, in a high-myopia cohort from a Chinese population.
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Leukocyte mitochondrial DNA copy number in blood is not associated with major depressive disorder in young adults.
PLoS ONE
PUBLISHED: 01-01-2014
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Major depressive disorder (MDD) is the leading cause of disability worldwide, and has significant genetic predisposition. Mitochondria may have a role in MDD and so mitochondrial DNA (mtDNA) has been suggested as a possible biomarker for this disease. We aimed to test whether the mtDNA copy number of peripheral blood leukocytes is related to MDD in young adults.
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The prognostic value of altered eIF3a and its association with p27 in non-small cell lung cancers.
PLoS ONE
PUBLISHED: 01-01-2014
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Over-expressed eukaryotic initiation factor 3a (eIF3a) in non-small cell lung cancer (NSCLC) contributed to cisplatin sensitivity. However, the role of eIF3a in oncogenesis was still controversial. This study was designed to investigate the prognostic impact of eIF3a and p27 in radically resected NSCLC patients.
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BAG5 protects against mitochondrial oxidative damage through regulating PINK1 degradation.
PLoS ONE
PUBLISHED: 01-01-2014
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Mutations in PTEN-induced kinase 1 (PINK1) gene cause PARK6 familial Parkinsonism, and loss of the stability of PINK1 may also contribute to sporadic Parkinson's disease (PD). Degradation of PINK1 occurs predominantly through the ubiquitin proteasome system (UPS), however, to date, few of the proteins have been found to regulate the degradation of PINK1. Using the yeast two-hybrid system and pull-down methods, we identified bcl-2-associated athanogene 5 (BAG5), a BAG family member, directly interacted with PINK1. We showed that BAG5 stabilized PINK1 by decreasing the ubiquitination of PINK1. Interestingly, BAG5 rescued MPP(+)- and rotenone-induced mitochondria dysfunction by up-regulating PINK1 in vitro. In PINK1-null mice and MPTP-treated mice, BAG5 significantly increased in the substantia nigra pars compacta (SNpc) although PINK1 was decreased. Our findings indicated that BAG5, as a key protein to stabilize PINK1, is a promising therapeutic tool for preventing mitochondrial dysfunction following oxidative stress.
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SPG35 contributes to the second common subtype of AR-HSP in China: frequency analysis and functional characterization of FA2H gene mutations.
Clin. Genet.
PUBLISHED: 09-26-2013
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Hereditary spastic paraplegias (HSPs) encompasses a clinically and genetically heterogeneous group of neurodegenerative disorders. Recently, mutations in fatty acid 2-hydroxylase gene (FA2H) have been identified responsible for hereditary spastic paraplegias type 35 (SPG35). This study aims to define the contribution of FA2H in Chinese autosomal recessive HSP (AR-HSP) patients and provide insights into the enzymatic functions of the novel mutations. Direct sequencing of FA2H was conducted in 31 AR-HSP families and 55 sporadic cases without SPG11, SPG15, SPG5 and SPG7 gene mutations. Enzymatic activity of the mutated proteins was further examined. Three novel mutations were found in two Chinese families, including two compound heterozygous mutations (c.388C>T/p.L130F and c.506+6C>G) and one homozygous mutation (c.230T>G/p.L77R). The c.506+6C>G splice-site mutation led to the deletion of exon 3. Measurement of enzymatic functions revealed a significant reduction in the enzymatic activity of FA2H associated with p.L130F and p.L77R. Overall, our data widens the spectrum of the mutations on FA2H, and functional analyses indicate that these mutations severely impair the enzymatic activity of FA2H. Furthermore, frequency analysis demonstrates that SPG35 is the second most common subtype of AR-HSP in China.
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Increased expression of reticulon 3 in neurons leads to reduced axonal transport of ? site amyloid precursor protein-cleaving enzyme 1.
J. Biol. Chem.
PUBLISHED: 09-04-2013
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BACE1 is the sole enzyme responsible for cleaving amyloid precursor protein at the ?-secretase site, and this cleavage initiates the generation of ?-amyloid peptide (A?). Because amyloid precursor protein is predominantly expressed by neurons and deposition of A? aggregates in the human brain is highly correlated with the A? released at axonal terminals, we focused our investigation of BACE1 localization on the neuritic region. We show that BACE1 was not only enriched in the late Golgi, trans-Golgi network, and early endosomes but also in both axons and dendrites. BACE1 was colocalized with the presynaptic vesicle marker synaptophysin, indicating the presence of BACE1 in synapses. Because the excessive release of A? from synapses is attributable to an increase in amyloid deposition, we further explored whether the presence of BACE1 in synapses was regulated by reticulon 3 (RTN3), a protein identified previously as a negative regulator of BACE1. We found that RTN3 is not only localized in the endoplasmic reticulum but also in neuritic regions where no endoplasmic reticulum-shaping proteins are detected, implicating additional functions of RTN3 in neurons. Coexpression of RTN3 with BACE1 in cultured neurons was sufficient to reduce colocalization of BACE1 with synaptophysin. This reduction correlated with decreased anterograde transport of BACE1 in axons in response to overexpressed RTN3. Our results in this study suggest that altered RTN3 levels can impact the axonal transport of BACE1 and demonstrate that reducing axonal transport of BACE1 in axons is a viable strategy for decreasing BACE1 in axonal terminals and, perhaps, reducing amyloid deposition.
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Identification of a known GJB6 mutation in an autosomal dominant inherited Chinese family with hidrotic ectodermal dysplasia.
Zhong Nan Da Xue Xue Bao Yi Xue Ban
PUBLISHED: 08-29-2013
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Mutation in the gap junction beta 6 (GJB6) gene has been reported to be associated with an autosomal dominant disorder hidrotic ectodermal dysplasia (HED), characterized by congenital nail clubbing, alopecia and palmoplantar keratoderma. The aim of this study is to investigate relationship between genetic mutation in GJB6 and HED in an affected Chinese family.
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MicroRNA profiling in the serums of SCA3/MJD patients.
Int. J. Neurosci.
PUBLISHED: 08-22-2013
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Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) is the most common type of spinocerebellar ataxia in China. However, the pathogenesis of SCA3/MJD is still unknown. MicroRNAs (miRNAs) have been repeatedly demonstrated to exist in human peripheral serum in a bio-stable form and have been shown to be useful biomarkers for other neurodegenerative disorders. However, no study of SCA3/MJD patients has assessed specific changes in regulatory miRNAs. Therefore, we systematically used the miRCURYTM LNA Array, followed by quantitative real-time polymerase chain reaction validation, to access miRNA expression levels in the serums from SCA3/MJD patients. Our results show that miR-25, miR-125b, miR-29a, and miR-34b could be potential biomarkers for SCA3/MJD and could be used to further investigate the pathogenesis of SCA3/MJD and drug development.
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[Cloning and localization of A3IP -a novel protein that interacts with ataxin-3].
Zhonghua Yi Xue Yi Chuan Xue Za Zhi
PUBLISHED: 08-09-2013
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To clone an A3IP gene and investigate its cellular and histological localization based on previous research which has identified part of A3IP sequence interacting with carboxyl-terminal of ataxin-3.
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Gluten ataxia of sporadic and hereditary cerebellar ataxia in patients from mainland China.
Neurol India
PUBLISHED: 07-18-2013
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Gluten sensitivity (GS) is a spectrum of disorders with diverse manifestations. Recent evidence suggests that ataxia may be the only manifestation of GS and that it may be one of the causes of sporadic ataxia.
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Clinical and Genetic Identification of a Large Chinese Family with Autosomal Dominant Retinitis Pigmentosa.
Ophthalmic Genet.
PUBLISHED: 07-10-2013
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Abstract Background: Retinitis pigmentosa (RP) is a group of inherited retinal dystrophies characterized by night blindness, progressive peripheral visual field loss, and loss of central vision. Fifty-three RP pathogenic genes are responsible for RP. Pre-mRNA processing factor 31(PRPF31) gene is the third most common cause of autosomal dominant retinitis pigmentosa (adRP), and so far more than 40 mutations in PRPF31 have been detected. Purpose: To identify the underlying genetic defect in a five-generation Chinese family affected with adRP and to study the genotype-phenotype relationship of this family. Methods: Detailed clinical investigations were undertaken and peripheral blood samples were collected from 25 individuals. Microsatellite (STR) markers tightly linked to genes known to be responsible for adRP were selected for linkage analysis. Exons and adjacent splice junctions of the candidate gene were amplified and sequenced. Results: This adRP family exhibited an incomplete penetrance of the RP phenotype. In affected individuals, age of disease onset was from infancy to 4 years of age. Typical RP features were associated with this mutation. Linkage analysis identified a maximum two-point LOD score of 3.20 with D19S418, which is close to PRPF31. A mutation PRPF31: (c.358-359 del AA) was identified by linkage analysis. Conclusions: A PRPF31 mutation was identified to be responsible for adRP in a large Chinese family. Our findings expand the mutation spectrum of RP in the Chinese population.
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Lithium chloride alleviates neurodegeneration partly by inhibiting activity of GSK3? in a SCA3 Drosophila model.
Cerebellum
PUBLISHED: 07-02-2013
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Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant neurodegenerative disorder caused by the expansion of a CAG trinucelotide repeat that encodes an abnormal polyglutamine (PolyQ) tract in the disease protein, ataxin-3. The formation of neuronal intranuclear inclusions in the specific brain regions is one of the pathological hallmarks of SCA3. Acceleration of the degradation of the mutant protein aggregates is proven to produce beneficial effects in SCA3 and other PolyQ diseases. Lithium is known to be neuroprotective in various models of neurodegenerative disease and can reduce the mutant protein aggregates by inducing autophagy. In this study, we explored the therapeutic potential of lithium in a SCA3 Drosophila model. We showed that chronic treatment with lithium chloride at specific doses notably prevented eye depigmentation, alleviated locomotor disability, and extended the median life spans of SCA3 transgenic Drosophila. By means of genetic approaches, we showed that co-expressing the mutant S9E, which mimicked the phosphorylated S9 state of Shaggy as done by lithium, also partly decreased toxicity of gmr-SCA3tr-Q78. Taken together, our findings suggest that lithium is a promising therapeutic agent for the treatment of SCA3 and other PolyQ diseases.
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TNFSF4 gene polymorphism rs3861950 but not rs3850641 is associated with the risk of cerebral infarction in a Chinese population.
J. Thromb. Thrombolysis
PUBLISHED: 06-25-2013
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Tumor necrosis factor superfamily member 4 (TNFSF4) plays a key role in the process of atherosclerosis, a common risk factor for both myocardial and cerebral infarctions. Recent studies indicate that the single nucleotide polymorphism (SNP) rs3850641 in TNFSF4 is associated with higher risk of myocardial infarction, but little is known about the association between TNFSF4 variation and cerebral infarction (CI). A case-control study involving 385 CI patients and 385 age-matched, sex-matched non-CI controls was conducted in a Chinese population, only the most common subtype, atherosclerosis CI, was recruited. Two SNPs of TNFSF4, rs3850641 and rs3861950, were genotyped by the TaqMan SNP genotyping method, and verified partly by genomic DNA sequencing. The results revealed a significant allelic association between rs3861950 and CI (Odds ration = 1.733, 95 % confidence interval = 1.333-2.254, P = 0.000). Genotypic association analysis demonstrated that the CC genotype of rs3861950 confers susceptibility to CI (Odds ration = 2.896, 95 % confidence interval = 1.368-6.132), and it was associated with a significantly higher risk of ischemic stroke (Odds ration = 3.520, 95 % confidence interval = 1.546-8.015, P = 0.003) after adjusting for the other confirmed risk factors such as the history of hypertension, diabetes, CAD, smoking and alcohol drinking. While the odds ratio of the T allele to the C allele was 1.733 (95 % confidence interval: 1.333-2.254). However, there was no significant association between rs3850641 and CI (Odds ration = 1.288, 95 % confidence interval = 0.993-1.670, P = 0.056). TNFSF4 gene polymorphism rs3861950, but not rs3850641, is associated with the risk of atherosclerosis CI in a Chinese population.
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Mutation analysis of PRRT2 in two Chinese BFIS families and nomenclature of PRRT2 related paroxysmal diseases.
Neurosci. Lett.
PUBLISHED: 06-24-2013
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Benign familial infantile seizure (BFIS) and paroxysmal kinesigenic dyskinesia (PKD) are autosomal-dominant inherited self-limited neurological disorders. BFIS is characterized by clusters of epileptic seizures in infancy while, in some cases, infantile seizures and adolescent-onset paroxysmal kinesigenic choreoathetosis co-occurred, which is called infantile convulsions and choreoathetosis (ICCA) syndrome. We and other researchers have reported the proline-rich transmembrane protein 2 (PRRT2) as the causative gene of PKD. We and our collaborators also identified PRRT2 mutations in ICCA and other phenotypes. Here we collected two BFIS families of Chinese Han origin. The linkage analysis has mapped the BFIS-causing locus to 16p12.1-q12.2, where PRRT2 is located. We then performed mutation analysis of PRRT2 by direct sequencing and identified c.649-650insC mutation in all BFIS patients. We also noticed that paroxysmal diseases (such as BFIS, PKD and ICCA) with PRRT2 mutations, instead of other forms, share some characteristics like being responded well to anti-epiletic treatment, we thus suggest to name them as PRRT2-related paroxysmal diseases (PRPDs) in order to assist clinical diagnosis and treatment.
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Identification of C9orf72 repeat expansions in patients with amyotrophic lateral sclerosis and frontotemporal dementia in mainland China.
Neurobiol. Aging
PUBLISHED: 06-21-2013
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The GGGGCC repeat expansion in the C9orf72 gene was recently identified as a major cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in white populations. To estimate the frequency of hexanucleotide repeats in patients with ALS and FTD from mainland China, we screened for C9orf72 in a cohort of 128 patients and 150 control subjects using the repeat-primed polymerase chain reaction method. We observed pathogenic repeat expansions in a family with ALS-FTD and in a patient with sporadic FTD. In the family with ALS-FTD, the proband and the 2 asymptomatic siblings exhibited C9orf72 repeat expansions, and the clinical feature of the proband was characterized by pure motor syndrome with no cognitive impairment. The patient with sporadic FTD presented primarily with deteriorating behavior and mental status. Genotype analysis revealed that the proband shared the previously reported 20-single nucleotide polymorphism risk haplotype, whereas the patient with sporadic FTD carried all single nucleotide polymorphisms except rs2814707-A. To our knowledge, this study is the first to report 2 C9orf72 mutation patients in mainland China, and they shared the similar risk haplotype identified in white populations, suggesting that ALS and FTD associated with C9orf72 mutation was probably derived from a single founder.
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Transglutaminase 6 interacts with polyQ proteins and promotes the formation of polyQ aggregates.
Biochem. Biophys. Res. Commun.
PUBLISHED: 06-11-2013
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A common feature of polyglutamine (polyQ) diseases is the presence of aggregates in neuronal cells caused by expanded polyglutamine tracts. PolyQ proteins are the substrates of transglutaminase 2, and the increased activity of transglutaminase in polyQ diseases suggests that transglutaminase may be directly involved in the formation of the aggregates. We previously identified the transglutaminase 6 gene to be causative of spinocerebellar ataxia type 35 (SCA35), and we found that SCA35-associated mutants exhibited reduced transglutaminase activity. Here we report that transglutaminase 6 interacts and co-localizes with both normal and expanded polyQ proteins in HEK293 cells. Moreover, the overexpression of transglutaminase 6 promotes the formation of polyQ aggregates and the conversion of soluble polyQ into insoluble polyQ aggregates. However, SCA35-associated mutants do not affect their interactions with polyQ proteins. These data suggest that transglutaminase 6 could be involved in polyQ diseases and there may exist a common pathological link between polyQ associated SCA and SCA35.
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Association study between SNP rs150689919 in the DNA demethylation gene, TET1, and Parkinsons disease in Chinese Han population.
BMC Neurol
PUBLISHED: 06-08-2013
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Recent studies suggest that epigenetic factors may play an important role in the pathogenesis of Parkinsons disease (PD). In our previous work, we sequenced the exomes of sixteen patients from eight Chinese PD families using whole exome sequencing technology, consequently three patients from different pedigrees were found sharing the variant c.1460C?>?T (rs150689919) in the coding region of the Tet methyl cytosine dioxygenase 1 (TET1) gene.
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Two novel MPZ mutations in Chinese CMT patients.
J. Peripher. Nerv. Syst.
PUBLISHED: 06-07-2013
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To investigate the myelin protein zero (MPZ) gene mutation and related clinical features in Chinese Charcot-Marie-Tooth (CMT) patients, we screened the coding sequence of MPZ in 70 unrelated CMT index patients after excluding the PMP22 duplication, Cx32 and MFN2 mutations. We found four different missense mutations: c.194C>T, c.242A>T, c.371C>T, and c.419C>G. The frequency of MPZ mutation was approximately 4.35% of the total, 3.08% of CMT1, and 6% of CMT2. Mutations c.242A>T and c.419C>G are novel. The mutation c.242A>T exhibited late onset and rapidly progressive CMT2 phenotype. The mutation c.419C>G exhibited relatively late onset and slowly progressive CMT1 phenotype.
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Distribution of transglutaminase 6 in the central nervous system of adult mice.
Anat Rec (Hoboken)
PUBLISHED: 05-18-2013
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Our previous study identified a new form of spinocerebellar ataxia (SCA), in which mutations in the gene coding for transglutaminase 6 (TG6) were suggested to be causative. However, the data concerning cellular distribution of TG6 in the brain is still fragmentary. Therefore, we now report a comprehensive immunohistochemical examination of the expression profile of TG6 in adult mouse brain. TG6 was abundantly expressed in the septal region, basal ganglia, hypothalamus and brainstem. Notably, numerous TG6-positive neurons were found in the key brain regions involved in regulating locomotion activity, including the globus pallidus, subthalamic nucleus, substantia nigra, cerebellum, some precerebellar nuclei, and spinal motor neurons. Double immunostaining showed that the vast majority of TG6-positive neurons in the reticular nigra were GABAergic and those in the compact nigra were not dopaminergic. In addition, double staining for TG6 with either anti-NeuN or glial fibrillary acidic protein (GFAP) antibodies demonstrated exclusive NeuN-TG6 co-localization. This study presents a comprehensive overview of TG6 expression in the mouse brain, and provides insight for investigating the role of TG6 in the development of SCA.
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A deletion mutation of the VHL gene associated with a patient with sporadic von Hippel-Lindau disease.
J Clin Neurosci
PUBLISHED: 04-28-2013
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Von Hippel-Lindau (VHL) disease is an autosomal dominantly inherited familial cancer syndrome resulting from mutations in the VHL tumor suppressor gene, which leads to the development of a variety of benign and malignant tumors, especially central nervous system hemangioblastomas, retinal angiomas, clear-cell renal cell carcinomas and pheochromocytomas, with age-dependent penetrance. To date, nearly 400 germline mutations have been found to be involved in VHL disease according to the public Human Gene Mutation Database (HGMD). Although most index cases have a positive family history of VHL, some do not and may represent de novo cases. Patients diagnosed without family histories of VHL have been reported in as many as 23% of affected individuals with VHL. In this paper, we report the presence of a heterozygous deletion mutation of c.227_229delTCT in the VHL gene, causing the deletion of phenylalanine at codon 76 (p.Phe76del) of the VHL protein in a patient with sporadic VHL with a benign prognosis. The mutation involved may be de novo or the seemingly unaffected parent may be mosaic for the disease.
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[Changes in serum insulin-like growth factor-1 and insulin-like growth factor-binding protein-3, and their significance in children with left-to-right shunt congenital heart disease associated with heart failure].
Zhongguo Dang Dai Er Ke Za Zhi
PUBLISHED: 04-24-2013
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To investigate changes in serum insulin-like growth factor-1 (IGF-1) and insulin-like growth factor-binding protein-3 (IGFBP-3) and their significance in children with left-to-right shunt congenital heart disease (CHD) associated with heart failure (HF).
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Analysis of EIF4G1 in ethnic Chinese.
BMC Neurol
PUBLISHED: 04-22-2013
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Eukaryotic translation initiation factor 4-gamma 1 (EIF4G1) gene mutations have recently been reported in autosomal dominant, late-onset Parkinsons disease (LOPD). We carried out genetic analysis to determine the prevalence of EIF4G1 variants in an ethnic Chinese population and to better understand the association between EIF4G1 and PD.
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Using next-generation sequencing as a genetic diagnostic tool in rare autosomal recessive neurologic Mendelian disorders.
Neurobiol. Aging
PUBLISHED: 04-18-2013
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Next-generation sequencing was used to investigate 9 rare Chinese pedigrees with rare autosomal recessive neurologic Mendelian disorders. Five probands with ataxia-telangectasia and 1 proband with chorea-acanthocytosis were analyzed by targeted gene sequencing. Whole-exome sequencing was used to investigate 3 affected individuals with Joubert syndrome, nemaline myopathy, or spastic ataxia Charlevoix-Saguenay type. A list of known and novel candidate variants was identified for each causative gene. All variants were genetically verified by Sanger sequencing or quantitative polymerase chain reaction with the strategy of disease segregation in related pedigrees and healthy controls. The advantages of using next-generation sequencing to diagnose rare autosomal recessive neurologic Mendelian disorders characterized by genetic and phenotypic heterogeneity are demonstrated. A genetic diagnostic strategy combining the use of targeted gene sequencing and whole-exome sequencing with the aid of next-generation sequencing platforms has shown great promise for improving the diagnosis of neurologic Mendelian disorders.
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Exome sequencing released a case of X-linked adrenoleukodystrophy mimicking recessive hereditary spastic paraplegia.
Eur J Med Genet
PUBLISHED: 04-10-2013
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Genetic heterogeneity is common in many Mendelian disorders such as hereditary spastic paraplegia (HSP), which makes the genetic diagnosis more complicated. The goal of this study was to investigate a Chinese family with recessive hereditary spastic paraplegia, of which causative mutations could not be identified using the conventional PCR-based direct sequencing. Next-generation sequencing of all the transcripts of whole genome exome, after on-array hybrid capture, was performed on two affected male subjects (the proband and his brother). A missense mutation (c.1661G>A, p.R554H) was identified in ABCD1. Subsequently, PCR-based direct sequencing of other family members revealed that the mutation was co-segregating with the disease, indicating that ABCD1 mutation was the pathogenic event for this family. Very long-chain fatty acids (VLCFA) assay in the two affected cases confirmed X-ALD. Our study suggests exome sequencing can be used not only to find a novel causative gene, but also to quickly identify mutations of known genes when the clinical elements are etiologically misleading.
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Simultaneous detection of kinase and phosphatase activities of polynucleotide kinase using molecular beacon probes.
Anal. Biochem.
PUBLISHED: 03-31-2013
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Phosphorylation and dephosphorylation of DNA by polynucleotide kinase (PNK) has an important role in DNA damage repair, replication, and recombination. Traditionally, it is assayed by denaturing gel electrophoresis and autoradiography, which are tedious and not sensitive. We report on the development of a sensitive and simple method for PNK assay based on DNA ligation using a molecular beacon. Enzyme activity of PNK is measured down to a limit of 0.002 unit/ml. The method not only provides a universal platform for simultaneous monitoring of kinase and phosphatase activities, but also shows great potential in biological research, drug discovery, and clinical diagnostics.
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MicroRNA-106b induces mitochondrial dysfunction and insulin resistance in C2C12 myotubes by targeting mitofusin-2.
Mol. Cell. Endocrinol.
PUBLISHED: 03-27-2013
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MicroRNA-106b (miR-106b) is reported to correlate closely with skeletal muscle insulin resistance and type 2 diabetes. The aim of this study was to identify an mRNA targeted by miR-106b which regulates skeletal muscle insulin sensitivity. MiR-106b was found to target the 3 untranslated region (3 UTR) of mitofusin-2 (Mfn2) through miR-106b binding sites and to downregulate Mfn2 protein abundance at the post-transcriptional level by luciferase activity assay combined with mutational analysis and immunoblotting. Overexpression of miR-106b resulted in mitochondrial dysfunction and insulin resistance in C2C12 myotubes. MiR-106b was increased in insulin-resistant cultured C2C12 myotubes induced by TNF-?, and accompanied by increasing Mfn2 level, miR-106b loss of function improved mitochondrial function and insulin sensitivity impaired by TNF-? in C2C12 myotubes. In addition, both overexpression and downregulation of miR-106b upregulated peroxisome proliferator-activated receptor gamma coactivator (PGC)-1? and estrogen-related receptor (ERR)-? expression. MiR-106b targeted Mfn2 and regulated skeletal muscle mitochondrial function and insulin sensitivity. Therefor, Inhibition of miR-106b may be a potential new strategy for treating insulin resistance and type 2 diabetes.
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SUMO-1 modification on K166 of polyQ-expanded ataxin-3 strengthens its stability and increases its cytotoxicity.
PLoS ONE
PUBLISHED: 01-31-2013
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Post-translational modification by SUMO was proposed to modulate the pathogenesis of several neurodegenerative diseases. Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) is an autosomal dominant neurodegenerative disease caused by polyQ-expanded ataxin-3. We have previously shown that ataxin-3 was a new target of SUMOylation in vitro and in vivo. Here we identified that the major SUMO-1 binding site was located on lysine 166. SUMOylation did not influence the subcellular localization, ubiquitination or aggregates formation of mutant-type ataxin-3, but partially increased its stability and the cell apoptosis. Our findings revealed the role of ataxin-3 SUMOylation in SCA3/MJD pathogenesis.
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Hutchinson-Gilford progeria syndrome accompanied by severe skeletal abnormalities in two Chinese siblings: two case reports.
J Med Case Rep
PUBLISHED: 01-28-2013
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Hutchinson-Gilford progeria syndrome is a rare pediatric genetic syndrome with an incidence of one per eight million live births. The disorder is characterized by premature aging, generally leading to death due to myocardial infarction or stroke at approximately 13.4 years of age. The genetic diagnosis and special clinical manifestation in two Han Chinese siblings observed at our clinic for genetic counseling are described in this report. We screened the LMNA gene in these two siblings as well as in their unaffected parents. A homozygous mutation R527C was identified in the affected siblings, and both parents were heterozygous for this variant.
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A diagnostic gene chip for hereditary spastic paraplegias.
Brain Res. Bull.
PUBLISHED: 01-17-2013
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Hereditary spastic paraplegias (HSPs) are a group of clinically and genetically heterogeneous monogenic neurodegenerative disorders. The gene screen of hereditary spastic paraplegias patients remains time consuming and costly because of their highly heterogeneous. As we know, there are some hot spots of mutation in many genes causing HSPs. Our aim was to develop a quick method for gene screen of HSP patients. The online mutation data banks of HSPs were searched and Chinese data for point mutations were mainly considered. Then mutations were comprehensively analyzed and ninety-six more common point mutations of HSPs disease genes were chose for the 96-plex GoldenGate assay diagnostic gene chip for HSPs. After that, we used this diagnostic gene chip to detect ninety-six clinically diagnosed HSP patients. For validation purpose, six previously Sanger sequenced cases with known point mutations were redetected on this array. The scores of all the ninety-six point mutations were between 0.601 and 0.993, and the call rate of the whole gene chip was 97.7% and its consistency was 99.0%. A patient suspected with a c.316G>C substitution in SPG6 was detected by the chip, which was further confirmed by polymerase chain reaction and sequencing. The high successful performance of this GoldenGate assay makes it a useful technique for preliminary genetic screening for HSP patients and it may be used in clinic in the future.
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Increase of the plasma ?-synuclein levels in patients with multiple system atrophy.
Mov. Disord.
PUBLISHED: 01-04-2013
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Multiple system atrophy, a sporadic neurodegenerative disease, is characterized by the presence of high numbers of glial cytoplasmic inclusions mainly formed by ?-synuclein protein, which is encoded by the SNCA gene. To date, however, few studies have investigated the plasma ?-synuclein levels in patients with multiple system atrophy. We studied plasma ?-synuclein concentrations by using an enzyme-linked immunosorbent assay in 74 patients with multiple system atrophy and 90 healthy controls. The plasma ?-synuclein levels were significantly elevated in patients who had multiple system atrophy compared with the control group (P?=?0.000). In a subgroup of 48 patients who had probable multiple system atrophy, there was a weakly negative correlation between plasma ?-synuclein levels and subscores on Unified Multiple System Atrophy Rating Scale item VI (rs ?=?-0.307; P?=?0.034). Plasma ?-synuclein levels were elevated in patients with multiple system atrophy, and these levels may be decreased with the development of disease. © 2013 International Parkinson and Movement Disorder Society.
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Identification of CHIP as a Novel Causative Gene for Autosomal Recessive Cerebellar Ataxia.
PLoS ONE
PUBLISHED: 01-01-2013
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Autosomal recessive cerebellar ataxias are a group of neurodegenerative disorders that are characterized by complex clinical and genetic heterogeneity. Although more than 20 disease-causing genes have been identified, many patients are still currently without a molecular diagnosis. In a two-generation autosomal recessive cerebellar ataxia family, we mapped a linkage to a minimal candidate region on chromosome 16p13.3 flanked by single-nucleotide polymorphism markers rs11248850 and rs1218762. By combining the defined linkage region with the whole-exome sequencing results, we identified a homozygous mutation (c.493CT) in CHIP (NM_005861) in this family. Using Sanger sequencing, we also identified two compound heterozygous mutations (c.389AT/c.441GT; c.621C>G/c.707GC) in CHIP gene in two additional kindreds. These mutations co-segregated exactly with the disease in these families and were not observed in 500 control subjects with matched ancestry. CHIP colocalized with NR2A, a subunit of the N-methyl-D-aspartate receptor, in the cerebellum, pons, medulla oblongata, hippocampus and cerebral cortex. Wild-type, but not disease-associated mutant CHIPs promoted the degradation of NR2A, which may underlie the pathogenesis of ataxia. In conclusion, using a combination of whole-exome sequencing and linkage analysis, we identified CHIP, encoding a U-box containing ubiquitin E3 ligase, as a novel causative gene for autosomal recessive cerebellar ataxia.
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C9orf72 mutation is rare in Alzheimers disease, Parkinsons disease, and essential tremor in China.
Front Cell Neurosci
PUBLISHED: 01-01-2013
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GGGGCC repeat expansions in the C9orf72 gene have been identified as a major contributing factor in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Given the overlapping of clinical phenotypes and pathological characteristics between these two diseases and Alzheimers disease (AD), Parkinsons disease (PD), and essential tremor (ET), we speculated regarding whether C9orf72 repeat expansions also play a major role in these three diseases. Using the repeat-primed polymerase chain reaction method, we screened for C9orf72 in three groups of patients with PD (n = 911), AD (n = 279), and ET (n = 152) in the Chinese Han population. There were no pathogenic repeats (>30 repeats) detected in either the patients or controls (n = 314), which indicated that the pathogenic expansions of C9orf72 might be rare in these three diseases. However, the analysis of the association between the number of repeats (p = 0.001), short/intermediate genotype (short: <7 repeats; intermediate: ?7 repeats) (odds ratio 1.37 [1.05, 1.79]), intermediate/intermediate genotype (Odds ratio 2.03 [1.17, 3.54]), and PD risks indicated that intermediate repeat alleles could act as contributors to PD. To the best of our knowledge, this study is the first to reveal the correlation between C9orf72 and Chinese PD, AD, or ET patients. Additionally, the results of this study suggest the novel idea that the intermediate repeat allele in C9orf72 is most likely a risk factor for PD.
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Identification of PRRT2 as the causative gene of paroxysmal kinesigenic dyskinesias.
Brain
PUBLISHED: 11-26-2011
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Paroxysmal kinesigenic dyskinesias is a paroxysmal movement disorder characterized by recurrent, brief attacks of abnormal involuntary movements induced by sudden voluntary movements. Although several loci, including the pericentromeric region of chromosome 16, have been linked to paroxysmal kinesigenic dyskinesias, the causative gene has not yet been identified. Here, we identified proline-rich transmembrane protein 2 (PRRT2) as a causative gene of paroxysmal kinesigenic dyskinesias by using a combination of exome sequencing and linkage analysis. Genetic linkage mapping with 11 markers that encompassed the pericentromeric of chromosome 16 was performed in 27 members of two families with autosomal dominant paroxysmal kinesigenic dyskinesias. Then, the whole-exome sequencing was performed in three patients from these two families. By combining the defined linkage region (16p12.1-q12.1) and the results of exome sequencing, we identified an insertion mutation c.649_650InsC (p.P217fsX7) in one family and a nonsense mutation c.487C>T (p.Q163X) in another family. To confirm our findings, we sequenced the exons and flanking introns of PRRT2 in another three families with paroxysmal kinesigenic dyskinesias. The c.649_650InsC (p.P217fsX7) mutation was identified in two of these families, whereas a missense mutation, c.796C>T (R266W), was identified in another family with paroxysmal kinesigenic dyskinesias. All of these mutations completely co-segregated with the phenotype in each family. None of these mutations was identified in 500 normal unaffected individuals of matched geographical ancestry. Thus, we have identified PRRT2 as the first causative gene of paroxysmal kinesigenic dyskinesias, warranting further investigations to understand the pathogenesis of this disorder.
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[The effect of HSPB8 gene mutation on cell viability in Charcot-Marie-Tooth disease type 2L].
Zhonghua Yi Xue Yi Chuan Xue Za Zhi
PUBLISHED: 10-11-2011
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To study the effect of Charcot-Marie-Tooth 2L disease causing gene K141N mutation in heat shock protein B8 gene (HSPB8) on cell viability.
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[Cellular expression of (R127W)HSPB1 and its co-localization with neurofilament light chain].
Zhonghua Yi Xue Yi Chuan Xue Za Zhi
PUBLISHED: 10-11-2011
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To observe the cellular expression of (R127W) HSPB1 and its influence on neurofilament light chain (NFL) self-assembly and co-localization with NFL.
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Genetics of autism spectrum disorders.
Zhong Nan Da Xue Xue Bao Yi Xue Ban
PUBLISHED: 09-23-2011
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Autism is a group of etiology and clinical heterogeneous neurodevelopmental disorders with an onset before 3 years old. It has 3 core characteristics: deficits in verbal communication; impairment of social interaction; restricted interests and repetitive behaviors. The incidence is increasing over time worldwide. Twin and family studies have demonstrated that autism has a high heritability (>90%). Although certain progress of autism genetic study has been made in the last decades and several autism susceptibility genes and loci have been identified, there are still about 70%-80% of patients for whom an autism-related genetic change cannot be identified.
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[The efficacy and safety of transradial versus transfemoral approach for percutaneous coronary intervention in acute myocardial infarction].
Zhonghua Nei Ke Za Zhi
PUBLISHED: 07-26-2011
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To compare the safety and efficacy of radial artery access versus femoral artery access for percutaneous coronary intervention in acute myocardial infarction population.
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Functional analysis of Waardenburg syndrome-associated PAX3 and SOX10 mutations: report of a dominant-negative SOX10 mutation in Waardenburg syndrome type II.
Hum. Genet.
PUBLISHED: 07-19-2011
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Waardenburg syndrome (WS) is an auditory-pigmentary disorder resulting from melanocyte defects, with varying combinations of sensorineural hearing loss and abnormal pigmentation of the hair, skin, and inner ear. WS is classified into four subtypes (WS1-WS4) based on additional symptoms. PAX3 and SOX10 are two transcription factors that can activate the expression of microphthalmia-associated transcription factor (MITF), a critical transcription factor for melanocyte development. Mutations of PAX3 are associated with WS1 and WS3, while mutations of SOX10 cause WS2 and WS4. Recently, we identified some novel WS-associated mutations in PAX3 and SOX10 in a cohort of Chinese WS patients. Here, we further identified an E248fsX30 SOX10 mutation in a family of WS2. We analyzed the subcellular distribution, expression and in vitro activity of two PAX3 mutations (p.H80D, p.H186fsX5) and four SOX10 mutations (p.E248fsX30, p.G37fsX58, p.G38fsX69 and p.R43X). Except H80D PAX3, which retained partial activity, the other mutants were unable to activate MITF promoter. The H80D PAX3 and E248fsX30 SOX10 were localized in the nucleus as wild type (WT) proteins, whereas the other mutant proteins were distributed in both cytoplasm and nucleus. Furthermore, E248fsX30 SOX10 protein retained the DNA-binding activity and showed dominant-negative effect on WT SOX10. However, E248fsX30 SOX10 protein seems to decay faster than the WT one, which may underlie the mild WS2 phenotype caused by this mutation.
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Mutation analysis of PINK1 gene in patients with early-onset Parkinsonism.
Zhong Nan Da Xue Xue Bao Yi Xue Ban
PUBLISHED: 07-12-2011
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To determine the frequency of mutations in PINK1 in Chinese Han people with sporadic early-onset Parkinsonism (EOP).
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Spinocerebellar ataxias in mainland China: an updated genetic analysis among a large cohort of familial and sporadic cases.
Zhong Nan Da Xue Xue Bao Yi Xue Ban
PUBLISHED: 07-12-2011
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To undertake an updated genetic spectrum analysis in patients with hereditary spinocerebellar ataxia (SCA) in mainland China.
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Gene localization in a Chinese family with autosomal dominant non-syndromic deafness.
Acta Otolaryngol.
PUBLISHED: 06-08-2011
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There could be another candidate gene in DFNA2, which could be responsible for the hearing loss phenotype.
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[Linkage analysis of susceptibility loci in 2 target chromosomes in pedigrees with paranoid schizophrenia and undifferentiated schizophrenia].
Zhonghua Yi Xue Yi Chuan Xue Za Zhi
PUBLISHED: 06-07-2011
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To investigate the relationship of susceptibility loci in chromosomes 1q21-25 and 6p21-25 and schizophrenia subtypes in Chinese population.
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UCP4 overexpression improves fatty acid oxidation and insulin sensitivity in L6 myocytes.
J. Bioenerg. Biomembr.
PUBLISHED: 05-24-2011
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Obesity, which is caused by energy uptake being greater than energy expenditure, is widely prevalent today. Currently, only a limited number of efficient interventional strategies are available for the prevention of obesity. Previous studies have shown that UCP4 transcription occurs at a considerable level in mouse skeletal muscle; however, the exact functions of UCP4 remain unclear. In this study, we investigated the effect of UCP4 on mitochondrial function and insulin sensitivity in mature L6 myocytes. UCP4 overexpression in L6 myocytes induced increased mitochondrial carnitine palmitoyltransferase 1A (CPT1A) and decreased citrate synthase (CS) mRNA in the basal condition (i.e., in the absence of insulin). UCP4 overexpression significantly improved insulin sensitivity, increased tyrosine phosphorylation of IRS-1 in the presence of insulin, and significantly reduced intracellular triglyceride (TG). Additionally, intracellular ATP content and mitochondrial membrane potential were downregulated. We also observed that intracellular ROS, mitochondrial morphology, and mitochondrial mtDNA copy number were maintained upon UCP4 expression, with no change in mitochondrial fusion and fission. In summary, our findings provide evidence to show that UCP4 overexpression reduced the insulin sensitivity and mitochondrial fatty acid oxidation of L6 myocytes. These findings support the notion that UCPs are ideal targets for treatment of insulin resistance.
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Novel mutations in the SOX10 gene in the first two Chinese cases of type IV Waardenburg syndrome.
Biochem. Biophys. Res. Commun.
PUBLISHED: 04-11-2011
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We analyzed the clinical features and family-related gene mutations for the first two Chinese cases of type IV Waardenburg syndrome (WS4).
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.