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991.
Höglinger GU Melhem NM Dickson DW Sleiman PM Wang LS Klei L Rademakers R de Silva R Litvan I Riley DE van Swieten JC Heutink P Wszolek ZK Uitti RJ Vandrovcova J Hurtig HI Gross RG Maetzler W Goldwurm S Tolosa E Borroni B Pastor P;PSP Genetics Study Group Cantwell LB Han MR Dillman A van der Brug MP Gibbs JR Cookson MR Hernandez DG Singleton AB Farrer MJ Yu CE Golbe LI Revesz T Hardy J Lees AJ Devlin B Hakonarson H Müller U Schellenberg GD 《Nature genetics》2011,43(7):699-705
Progressive supranuclear palsy (PSP) is a movement disorder with prominent tau neuropathology. Brain diseases with abnormal tau deposits are called tauopathies, the most common of which is Alzheimer's disease. Environmental causes of tauopathies include repetitive head trauma associated with some sports. To identify common genetic variation contributing to risk for tauopathies, we carried out a genome-wide association study of 1,114 individuals with PSP (cases) and 3,247 controls (stage 1) followed by a second stage in which we genotyped 1,051 cases and 3,560 controls for the stage 1 SNPs that yielded P ≤ 10(-3). We found significant previously unidentified signals (P < 5 × 10(-8)) associated with PSP risk at STX6, EIF2AK3 and MOBP. We confirmed two independent variants in MAPT affecting risk for PSP, one of which influences MAPT brain expression. The genes implicated encode proteins for vesicle-membrane fusion at the Golgi-endosomal interface, for the endoplasmic reticulum unfolded protein response and for a myelin structural component. 相似文献
992.
O'Roak BJ Deriziotis P Lee C Vives L Schwartz JJ Girirajan S Karakoc E Mackenzie AP Ng SB Baker C Rieder MJ Nickerson DA Bernier R Fisher SE Shendure J Eichler EE 《Nature genetics》2011,43(6):585-589
Evidence for the etiology of autism spectrum disorders (ASDs) has consistently pointed to a strong genetic component complicated by substantial locus heterogeneity. We sequenced the exomes of 20 individuals with sporadic ASD (cases) and their parents, reasoning that these families would be enriched for de novo mutations of major effect. We identified 21 de novo mutations, 11 of which were protein altering. Protein-altering mutations were significantly enriched for changes at highly conserved residues. We identified potentially causative de novo events in 4 out of 20 probands, particularly among more severely affected individuals, in FOXP1, GRIN2B, SCN1A and LAMC3. In the FOXP1 mutation carrier, we also observed a rare inherited CNTNAP2 missense variant, and we provide functional support for a multi-hit model for disease risk. Our results show that trio-based exome sequencing is a powerful approach for identifying new candidate genes for ASDs and suggest that de novo mutations may contribute substantially to the genetic etiology of ASDs. 相似文献
993.
Locasale JW Grassian AR Melman T Lyssiotis CA Mattaini KR Bass AJ Heffron G Metallo CM Muranen T Sharfi H Sasaki AT Anastasiou D Mullarky E Vokes NI Sasaki M Beroukhim R Stephanopoulos G Ligon AH Meyerson M Richardson AL Chin L Wagner G Asara JM Brugge JS Cantley LC Vander Heiden MG 《Nature genetics》2011,43(9):869-874
Most tumors exhibit increased glucose metabolism to lactate, however, the extent to which glucose-derived metabolic fluxes are used for alternative processes is poorly understood. Using a metabolomics approach with isotope labeling, we found that in some cancer cells a relatively large amount of glycolytic carbon is diverted into serine and glycine metabolism through phosphoglycerate dehydrogenase (PHGDH). An analysis of human cancers showed that PHGDH is recurrently amplified in a genomic region of focal copy number gain most commonly found in melanoma. Decreasing PHGDH expression impaired proliferation in amplified cell lines. Increased expression was also associated with breast cancer subtypes, and ectopic expression of PHGDH in mammary epithelial cells disrupted acinar morphogenesis and induced other phenotypic alterations that may predispose cells to transformation. Our findings show that the diversion of glycolytic flux into a specific alternate pathway can be selected during tumor development and may contribute to the pathogenesis of human cancer. 相似文献
994.
Large-scale genome-wide association studies in East Asians identify new genetic loci influencing metabolic traits 总被引:1,自引:0,他引:1
Kim YJ Go MJ Hu C Hong CB Kim YK Lee JY Hwang JY Oh JH Kim DJ Kim NH Kim S Hong EJ Kim JH Min H Kim Y Zhang R Jia W Okada Y Takahashi A Kubo M Tanaka T Kamatani N Matsuda K;MAGIC consortium Park T Oh B Kimm K Kang D Shin C Cho NH Kim HL Han BG Lee JY Cho YS 《Nature genetics》2011,43(10):990-995
To identify the genetic bases for nine metabolic traits, we conducted a meta-analysis combining Korean genome-wide association results from the KARE project (n = 8,842) and the HEXA shared control study (n = 3,703). We verified the associations of the loci selected from the discovery meta-analysis in the replication stage (30,395 individuals from the BioBank Japan genome-wide association study and individuals comprising the Health2 and Shanghai Jiao Tong University Diabetes cohorts). We identified ten genome-wide significant signals newly associated with traits from an overall meta-analysis. The most compelling associations involved 12q24.11 (near MYL2) and 12q24.13 (in C12orf51) for high-density lipoprotein cholesterol, 2p21 (near SIX2-SIX3) for fasting plasma glucose, 19q13.33 (in RPS11) and 6q22.33 (in RSPO3) for renal traits, and 12q24.11 (near MYL2), 12q24.13 (in C12orf51 and near OAS1), 4q31.22 (in ZNF827) and 7q11.23 (near TBL2-BCL7B) for hepatic traits. These findings highlight previously unknown biological pathways for metabolic traits investigated in this study. 相似文献
995.
996.
997.
Cancer spheres from gastric cancer patients provide an ideal model system for cancer stem cell research 总被引:1,自引:1,他引:0
Han ME Jeon TY Hwang SH Lee YS Kim HJ Shim HE Yoon S Baek SY Kim BS Kang CD Oh SO 《Cellular and molecular life sciences : CMLS》2011,68(21):3589-3605
Cancer stem cells have been hypothesized to drive the growth and metastasis of tumors. Because they need to be targeted for cancer treatment, they have been isolated from many solid cancers. However, cancer stem cells from primary human gastric cancer tissues have not been isolated as yet. For the isolation, we used two cell surface markers: the epithelial cell adhesion molecule (EpCAM) and CD44. When analyzed by flow cytometry, the EpCAM+/CD44+ population accounts for 4.5% of tumor cells. EpCAM+/CD44+ gastric cancer cells formed tumors in immunocompromised mice; however, EpCAM?/CD44?, EpCAM+/CD44? and EpCAM?/CD44+ cells failed to do so. Xenografts of EpCAM+/CD44+ gastric cancer cells maintained a differentiated phenotype and reproduced the morphological and phenotypical heterogeneity of the original gastric tumor tissues. The tumorigenic subpopulation was serially passaged for several generations without significant phenotypic alterations. Moreover, EpCAM+/CD44+, but not EpCAM?/CD44?, EpCAM+/CD44? or EpCAM?/CD44+ cells grew exponentially in vitro as cancer spheres in serum-free medium, maintaining the tumorigenicity. Interestingly, a single cancer stem cell generated a cancer sphere that contained various differentiated cells, supporting multi-potency and self-renewal of a cancer stem cell. EpCAM+/CD44+ cells had greater resistance to anti-cancer drugs than other subpopulation cells. The above in vivo and in vitro results suggest that cancer stem cells, which are enriched in the EpCAM+/CD44+ subpopulation of gastric cancer cells, provide an ideal model system for cancer stem cell research. 相似文献
998.
S. John Calise Wendy C. Carcamo Claire Krueger Joyce D. Yin Daniel L. Purich Edward K. L. Chan 《Cellular and molecular life sciences : CMLS》2014,71(15):2963-2973
Rods and rings (RR) are protein assemblies composed of cytidine triphosphate synthetase type 1 (CTPS1) and inosine monophosphate dehydrogenase type 2 (IMPDH2), key enzymes in CTP and GTP biosynthesis. Small-molecule inhibitors of CTPS1 or IMPDH2 induce RR assembly in various cancer cell lines within 15 min to hours. Since glutamine is an essential amide nitrogen donor in these nucleotide biosynthetic pathways, glutamine deprivation was examined to determine whether it leads to RR formation. HeLa cells cultured in normal conditions did not show RR, but after culturing in media lacking glutamine, short rods (<2 μm) assembled after 24 h, and longer rods (>5 μm) formed after 48 h. Upon supplementation with glutamine or guanosine, these RR underwent almost complete disassembly within 15 min. Inhibition of glutamine synthetase with methionine sulfoximine also increased RR assembly in cells deprived of glutamine. Taken together, our data support the hypothesis that CTP/GTP biosynthetic enzymes polymerize to form RR in response to a decreased intracellular level of glutamine. We speculate that rod and ring formation is an adaptive metabolic response linked to disruption of glutamine homeostasis. 相似文献
999.
1000.
John R. Millburn 《Annals of science》2013,70(6):511-528
Relations between J. A. C. Chaptal, pioneer of heavy chemical industry in France, and A. L. Lavoisier, reformer of chemical theory, are examined in the light of unpublished correspondence they exchanged in the period 1784–1790. The letters, together with Chaptal's early publications, allow a reconstruction of his conversion to Lavoisier's antiphlogistic chemistry. They also reveal a series of petitions that Chaptal made to Lavoisier, in the latter's official capacity as a director of the Régie des poudres et salpêtres, for relief from the controlled price of saltpetre for his acid works in Languedoc. Finally, the relationship is explored as a window on the interplay between chemical theory and industrial practice during the period of the Industrial Revolution. 相似文献