| 1. |
- Deng, Min, et al.
(author)
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Genome-wide association analyses in Han Chinese identify two new susceptibility loci for amyotrophic lateral sclerosis
- 2013
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In: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 45:6, s. 697-
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Journal article (peer-reviewed)abstract
- To identify susceptibility genes for amyotrophic lateral sclerosis (ALS), we conducted a genome-wide association study (GWAS) in 506 individuals with sporadic ALS and 1,859 controls of Han Chinese ancestry. Ninety top SNPs suggested by the current GWAS and 6 SNPs identified by previous GWAS were analyzed in an independent cohort of 706 individuals with ALS and 1,777 controls of Han Chinese ancestry. We discovered two new susceptibility loci for ALS at 1q32 (CAMK1G, rs6703183, P-combined = 2.92 x 10(-8), odds ratio (OR) = 1.31) and 22p11 (CABIN1 and SUSD2, rs8141797, P-combined = 2.35 x 10(-9), OR = 1.52). These two loci explain 12.48% of the overall variance in disease risk in the Han Chinese population. We found no association evidence for the previously reported loci in the Han Chinese population, suggesting genetic heterogeneity of disease susceptibility for ALS between ancestry groups. Our study identifies two new susceptibility loci and suggests new pathogenic mechanisms of ALS.
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| 2. |
- Chen, Dongfeng, et al.
(author)
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Glioma Cell Proliferation Controlled by ERK Activity-Dependent Surface Expression of PDGFRA.
- 2014
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In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:1
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Journal article (peer-reviewed)abstract
- Increased PDGFRA signaling is an essential pathogenic factor in many subtypes of gliomas. In this context the cell surface expression of PDGFRA is an important determinant of ligand sensing in the glioma microenvironment. However, the regulation of spatial distribution of PDGFRA in glioma cells remains poorly characterized. Here, we report that cell surface PDGFRA expression in gliomas is negatively regulated by an ERK-dependent mechanism, resulting in reduced proliferation of glioma cells. Glioma tumor tissues and their corresponding cell lines were isolated from 14 patients and analyzed by single-cell imaging and flow cytometry. In both cell lines and their corresponding tumor samples, glioma cell proliferation correlated with the extent of surface expression of PDGFRA. High levels of surface PDGFRA also correlated to high tubulin expression in glioma tumor tissue in vivo. In glioma cell lines, surface PDGFRA declined following treatment with inhibitors of tubulin, actin and dynamin. Screening of a panel of small molecule compounds identified the MEK inhibitor U0126 as a potent inhibitor of surface PDGFRA expression. Importantly, U0126 inhibited surface expression in a reversible, dose- and time-dependent manner, without affecting general PDGFRA expression. Treatment with U0126 resulted in reduced co-localization between PDGFRA and intracellular trafficking molecules e.g. clathrin, RAB11 and early endosomal antigen-1, in parallel with enhanced co-localization between PDGFRA and the Golgi cisternae maker, Giantin, suggesting a deviation of PDGFRA from the endosomal trafficking and recycling compartment, to the Golgi network. Furthermore, U0126 treatment in glioma cells induced an initial inhibition of ERK1/2 phosphorylation, followed by up-regulated ERK1/2 phosphorylation concomitant with diminished surface expression of PDGFRA. Finally, down-regulation of surface PDGFRA expression by U0126 is concordant with reduced glioma cell proliferation. These findings suggest that manipulation of spatial expression of PDGFRA can potentially be used to combat gliomas.
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| 3. |
- Li, X. T., et al.
(author)
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Association of the adiponectin gene (ADIPOQ) +45 T > G polymorphism with the metabolic syndrome among Han Chinese in Sichuan province of China
- 2012
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In: Asia Pacific Journal of Clinical Nutrition. - 0964-7058. ; 21:2, s. 296-301
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Journal article (peer-reviewed)abstract
- The metabolic syndrome is a cluster of abnormalities characterized by obesity, impaired glucose metabolism, hypertension or elevated blood pressure, and dyslipidemia. The aim of this study was to investigate the association of the adiponectin gene (ADIPOQ) +45 T > G polymorphism with the metabolic syndrome among Han Chinese in Sichuan province of China. A case-control design was used including 116 patients with the metabolic syndrome and 108 unrelated controls, matched on age and gender. The ADIPOQ +45G allele (TG+GG) had a significant association with risk of the metabolic syndrome (odds ratio=1.88, 95% confidence interval: 1.03-3.44, p=0.039) adjusted for education, physical activity, family history of related diseases, smoking and drinking, compared with subjects with IT genotype. The association between the ADIPOQ +45 T>G polymorphism and the metabolic syndrome was independent of multiple confounders.
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| 4. |
- McKay, James D., et al.
(author)
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A Genome-Wide Association Study of Upper Aerodigestive Tract Cancers Conducted within the INHANCE Consortium
- 2011
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In: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 7:3
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Journal article (peer-reviewed)abstract
- Genome-wide association studies (GWAS) have been successful in identifying common genetic variation involved in susceptibility to etiologically complex disease. We conducted a GWAS to identify common genetic variation involved in susceptibility to upper aero-digestive tract (UADT) cancers. Genome-wide genotyping was carried out using the Illumina HumanHap300 beadchips in 2,091 UADT cancer cases and 3,513 controls from two large European multi-centre UADT cancer studies, as well as 4,821 generic controls. The 19 top-ranked variants were investigated further in an additional 6,514 UADT cancer cases and 7,892 controls of European descent from an additional 13 UADT cancer studies participating in the INHANCE consortium. Five common variants presented evidence for significant association in the combined analysis (p <= 5 x 10(-7)). Two novel variants were identified, a 4q21 variant (rs1494961, p = 1 x 10(-8)) located near DNA repair related genes HEL308 and FAM175A (or Abraxas) and a 12q24 variant (rs4767364, p = 2 x 10(-8)) located in an extended linkage disequilibrium region that contains multiple genes including the aldehyde dehydrogenase 2 (ALDH2) gene. Three remaining variants are located in the ADH gene cluster and were identified previously in a candidate gene study involving some of these samples. The association between these three variants and UADT cancers was independently replicated in 5,092 UADT cancer cases and 6,794 controls non-overlapping samples presented here (rs1573496-ADH7, p = 5 x 10(-8); rs1229984-ADH1B, p = 7 x 10(-9); and rs698-ADH1C, p = 0.02). These results implicate two variants at 4q21 and 12q24 and further highlight three ADH variants in UADT cancer susceptibility.
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| 5. |
- Shen, Yong-Feng, et al.
(author)
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Deformation mechanisms of a 20Mn TWIP steel investigated by in situ neutron diffraction and TEM
- 2013
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In: Acta Materialia. - : Elsevier. - 1359-6454 .- 1873-2453. ; 61:16, s. 6093-6106
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Journal article (peer-reviewed)abstract
- The deformation mechanisms and associated microstructure changes during tensile loading of an annealed twinning-induced plasticity steel with chemical composition Fe-20Mn-3Si-3Al-0.045C (wt.%) were systematically investigated using in situ time-of-flight neutron diffraction in combination with post mortem transmission electron microscopy (TEM). The initial microstructure of the investigated alloy consists of equiaxed gamma grains with the initial alpha'-phase of similar to 7% in volume. In addition to dislocation slip, twinning and two types of martensitic transformations from the austenite to alpha'- and epsilon-martensites were observed as the main deformation modes during the tensile deformation. In situ neutron diffraction provides a powerful tool for establishing the deformation mode map for elucidating the role of different deformation modes in different strain regions. The critical stress is 520 MPa for the martensitic transformation from austenite to alpha'-martensite, whereas a higher stress (>600 MPa) is required for actuating the deformation twin and/or the martensitic transformation from austenite to epsilon-martensite. Both epsilon- and alpha'-martensites act as hard phases, whereas mechanical twinning contributes to both the strength and the ductility of the studied steel. TEM observations confirmed that the twinning process was facilitated by the parent grains oriented with < 1 1 1 > or < 1 1 0 > parallel to the loading direction. The nucleation and growth of twins are attributed to the pole and self-generation formation mechanisms, as well as the stair-rod cross-slip mechanism.
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| 6. |
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| 7. |
- Zhang, Mei, et al.
(author)
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Discovery and Structural Modification of 1-Phenyl-3-(1-phenylethyl)urea Derivatives as Inhibitors of Complement
- 2012
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In: ACS Medicinal Chemistry Letters. - : American Chemical Society (ACS). - 1948-5875. ; 3:4, s. 317-321
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Journal article (peer-reviewed)abstract
- A series of 1-phenyl-3-(1-phenylethyl)urea derivatives were identified as novel and potent complement inhibitors through structural modification of the original compound from high-throughput screening. Various analogues (7 and 13-15) were synthesized and identified as complement inhibitors, with the introduction of a five- or six-carbon chain (7c, 7d, 7k, 7I, and 7o) greatly improving their activity. Optimized compound 7I has an excellent inhibition activity with IC50 values as low as 13 nM. We demonstrated that the compound 7I inhibited C9 deposition through the classical, the lectin, and the alternative pathways but had no influence on C3 and C4 depositions.
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