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191.
Kristina M. Fetalvero Yenyen Yu Margaret Goetschkes Guiqing Liang Reginald A. Valdez Ty Gould Ellen Triantafellow Sebastian Bergling Joseph Loureiro John Eash Victor Lin Jeffrey A. Porter Peter M. Finan Kenneth Walsh Yi Yang Xiaohong Mao Leon O. Murphy 《Molecular and cellular biology》2013,33(1):98-110
Autophagy is a vesicular trafficking pathway that regulates the degradation of aggregated proteins and damaged organelles. Initiation of autophagy requires several multiprotein signaling complexes, such as the ULK1 kinase complex and the Vps34 lipid kinase complex, which generates phosphatidylinositol 3-phosphate [PtdIns(3)P] on the forming autophagosomal membrane. Alterations in autophagy have been reported for various diseases, including myopathies. Here we show that skeletal muscle autophagy is compromised in mice deficient in the X-linked myotubular myopathy (XLMTM)-associated PtdIns(3)P phosphatase myotubularin (MTM1). Mtm1-deficient muscle displays several cellular abnormalities, including a profound increase in ubiquitin aggregates and abnormal mitochondria. Further, we show that Mtm1 deficiency is accompanied by activation of mTORC1 signaling, which persists even following starvation. In vivo pharmacological inhibition of mTOR is sufficient to normalize aberrant autophagy and improve muscle phenotypes in Mtm1 null mice. These results suggest that aberrant mTORC1 signaling and impaired autophagy are consequences of the loss of Mtm1 and may play a primary role in disease pathogenesis. 相似文献
192.
Nicotinic acetylcholine receptors (nAChR) are pentameric ligand gated ion channels whose activity can be modulated by endogenous neurotransmitters as well as by synthetic ligands that bind the same or distinct sites from the natural ligand. The subtype of α7 nAChR has been considered as a potenial therapeutic target for Alzheimer's disease, schizophrenia and other neurological and psychiatric disorders. Here we have developed a homology model of α7 nAChR based on two high resolution crystal structures with Brookhaven Protein Data Bank (PDB) codes 2QC1 and 2WN9 for threading on one monomer and then for building a pentamer, respectively. A number of small molecule binding sites are identified using Pocket Finder (J. An, M. Tortov, and R. Abagyan, Molecular & Cellular Proteomics, 4.6, 752-761 (2005)) of Internal Coordinate Mechanics (ICM). Remarkably, these computer-identified sites match perfectly with ordered solvent densities found in the high-resolution crystal structure of α1 nAChR, suggesting that the surface cavities in the α7 nAChR model are likely binding sites of small molecules. A high throughput virtual screening by flexible ligand docking of 5008 small molecule compounds was performed at three potential allosteric modulator (AM) binding sites of α7 nAChR using Molsoft ICM software (R. Abagyan, M. Tortov and D. Kuznetsov, J Comput Chem 15, 488-506, (1994)). Some experimentally verified allosteric modulators of α7 like CCMI comp-6, LY 7082101, 5-HI, TQS, PNU-120596, genistein, and NS-1738 ranked among top 100 compounds, while the rest of the compounds in the list could guide further search for new allosteric modulators. 相似文献
193.
Tramadol hydrochloride (TH), has become the most prescribed opioid worldwide. However, its neurotoxicity and abuse potential are not well documented. In the present study, TH administration induced abnormal behavior and body and brain mean weight loss. Two principal metabolites O- and N-desmethyltramadol were detected in the brain tissue, and N-desmethyltramadol was the main metabolite produced. A total of 30 differential protein spots were identified using semi-quantitative 2D-PAGE and proteomic analyses, and classified into 13 categories, in which subtypes of 14-3-3 proteins, creatine kinase, ATP synthase beta chain, and tubulin were identified at the separated location on the gels 3, 3, 4, and 11 times respectively. Many TH responsive proteins have functions related to oxidative stress, including 14-3-3 proteins, creatine kinase BB, ubiquitin carboxy-terminal hydrolase L-1, ATP synthase, synaptosome-associated protein, tubulin and actin. Irrespective of oxidative damage, other pathways affected include apoptosis, energy metabolism, signal disorders, and cytoskeletal structure. Ultrastructural observation of mitochondria showed a series of morphological changes in the case of TH exposure. 相似文献
194.
Tai‐Wen Lin Chi‐Chih Chen Shu‐Mei Wu Yu‐Ching Chang Yi‐Chuan Li Yu‐Wang Su Chwan‐Deng Hsiao Hsin‐Yang Chang 《The Plant journal : for cell and molecular biology》2019,99(1):128-143
In mammals and yeast, tail‐anchored (TA) membrane proteins destined for the post‐translational pathway are safely delivered to the endoplasmic reticulum (ER) membrane by a well‐known targeting factor, TRC40/Get3. In contrast, the underlying mechanism for translocation of TA proteins in plants remains obscure. How this unique eukaryotic membrane‐trafficking system correctly distinguishes different subsets of TA proteins destined for various organelles, including mitochondria, chloroplasts and the ER, is a key question of long standing. Here, we present crystal structures of algal ArsA1 (the Get3 homolog) in a distinct nucleotide‐free open state and bound to adenylyl‐imidodiphosphate. This approximately 80‐kDa protein possesses a monomeric architecture, with two ATPase domains in a single polypeptide chain. It is capable of binding chloroplast (TOC34 and TOC159) and mitochondrial (TOM7) TA proteins based on features of its transmembrane domain as well as the regions immediately before and after the transmembrane domain. Several helices located above the TA‐binding groove comprise the interlocking hook‐like motif implicated by mutational analyses in TA substrate recognition. Our data provide insights into the molecular basis of the highly specific selectivity of interactions of algal ArsA1 with the correct sets of TA substrates before membrane targeting in plant cells. 相似文献
195.
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197.
Chu-Fang Chou Xiaolin Zhu Yi-Yu Lin Karen L. Gamble W. Timothy Garvey Ching-Yi Chen 《Journal of lipid research》2015,56(2):227-240
Hepatic lipid metabolism is controlled by integrated metabolic pathways. Excess accumulation of hepatic TG is a hallmark of nonalcoholic fatty liver disease, which is associated with obesity and insulin resistance. Here, we show that KH-type splicing regulatory protein (KSRP) ablation reduces hepatic TG levels and diet-induced hepatosteatosis. Expression of period 2 (Per2) is increased during the dark period, and circadian oscillations of several core clock genes are altered with a delayed phase in Ksrp−/− livers. Diurnal expression of some lipid metabolism genes is also disturbed with reduced expression of genes involved in de novo lipogenesis. Using primary hepatocytes, we demonstrate that KSRP promotes decay of Per2 mRNA through an RNA-protein interaction and show that increased Per2 expression is responsible for the phase delay in cycling of several clock genes in the absence of KSRP. Similar to Ksrp−/− livers, both expression of lipogenic genes and intracellular TG levels are also reduced in Ksrp−/− hepatocytes due to increased Per2 expression. Using heterologous mRNA reporters, we show that the AU-rich element-containing 3′ untranslated region of Per2 is responsible for KSRP-dependent mRNA decay. These findings implicate that KSRP is an important regulator of circadian expression of lipid metabolism genes in the liver likely through controlling Per2 mRNA stability. 相似文献
198.
Mulla Aziz J. Lin Che-Hung Takahashi Shunichi Nozawa Yoko 《Coral reefs (Online)》2021,40(4):1297-1306
Coral Reefs - Behaviour can have profound consequences for the dispersal potential of an organism. In the marine environment, larvae rely heavily on oceanic currents to migrate from one area to... 相似文献
199.
小麦耐盐种质遗传多样性的RAPD分析 总被引:8,自引:0,他引:8
选用22个引物对24份小麦耐盐种质进行RAPD分析,共产生200条扩增片段,多态性片段数为172条,扩增片段的多态性百分率为86%,利用NYSTS软件根据Jaccard系统分析RAPD结果,并按UPGMA类平均法进行聚类。24份材料相似系数在0.21 ̄0.97之间,其中含有多枝赖草、黑麦和偃麦草等外源染色体的多174、WR830和南前127被分别在3个独立的组,多174和南前127的亲关系最远,相 相似文献
200.
Chen CP Lin SP Chern SR Lee CC Huang JK Wang W 《Genetic counseling (Geneva, Switzerland)》2006,17(2):185-189
A 34-year-old mother presented moderate mental retardation, short stature, microcephaly, and characteristic facial dysmorphism. Her 12-year-old daughter manifested moderate mental retardation, short stature, microcephaly, dysplastic external ear canals, hearing impairment, and characteristic facial dysmorphism. Cytogenetic analysis of the family revealed a normal karyotype, 46,XY, in the father, and a 46,XX,del(18)(q22.2) karyotype in both mother and daughter. Molecular marker analysis determined direct transmission of the distal 18q deletion from mother to daughter. The present case provides evidence of fertility of the affected females and a mother-to-daughter direct transmission in the familial 18q- syndrome. Identification of affected females with the 18q- syndrome should include genetic counseling of possible direct transmission and consideration of birth control or prenatal genetic testing at reproductive age. 相似文献