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Beaubois E Girard S Lallechere S Davies E Paladian F Bonnet P Ledoigt G Vian A 《Plant, cell & environment》2007,30(7):834-844
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Disruption of diacylglycerol kinase delta (DGKD) associated with seizures in humans and mice 下载免费PDF全文
Leach NT Sun Y Michaud S Zheng Y Ligon KL Ligon AH Sander T Korf BR Lu W Harris DJ Gusella JF Maas RL Quade BJ Cole AJ Kelz MB Morton CC 《American journal of human genetics》2007,80(4):792-799
We report a female patient with a de novo balanced translocation, 46,X,t(X;2)(p11.2;q37)dn, who exhibits seizures, capillary abnormality, developmental delay, infantile hypotonia, and obesity. The 2q37 breakpoint observed in association with the seizure phenotype is of particular interest, because it lies near loci implicated in epilepsy in humans and mice. Fluorescence in situ hybridization mapping of the translocation breakpoints showed that no known genes are disrupted at Xp11.2, whereas diacylglycerol kinase delta (DGKD) is disrupted at 2q37. Expression studies in Drosophila and mouse suggest that DGKD is involved in central nervous system development and function. Electroencephalographic assessment of Dgkd mutant mice revealed abnormal epileptic discharges and electrographic seizures in three of six homozygotes. These findings implicate DGKD disruption by the t(X;2)(p11.2;q37)dn in the observed phenotype and support a more general role for DGKD in the etiology of seizures. 相似文献
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Boddey JA Day CJ Flegg CP Ulrich RL Stephens SR Beacham IR Morrison NA Peak IR 《Cellular microbiology》2007,9(2):514-531
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Isabel E Powell DA Black WC Chan CC Crane S Gordon R Guay J Guiral S Huang Z Robichaud J Skorey K Tawa P Xu L Zhang L Oballa R 《Bioorganic & medicinal chemistry letters》2011,21(1):479-483
Potent and orally bioavailable SCD inhibitors built on an azetidinyl pyridazine scaffold were identified. In a one-month gDIO mouse model of obesity, we demonstrated that there was no therapeutic index even at low doses; efficacy in preventing weight gain tracked closely with skin and eye adverse events. This was attributed to the local SCD inhibition in these tissues as a consequence of the broad tissue distribution observed in mice for this class of compounds. The search for new structural scaffolds which may display a different tissue distribution was initiated. In preparation for an HTS campaign, a radiolabeled azetidinyl pyridazine displaying low non-specific binding in the scintillation proximity assay was prepared. 相似文献
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