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991.
Peachey NS Ray TA Florijn R Rowe LB Sjoerdsma T Contreras-Alcantara S Baba K Tosini G Pozdeyev N Iuvone PM Bojang P Pearring JN Simonsz HJ van Genderen M Birch DG Traboulsi EI Dorfman A Lopez I Ren H Goldberg AF Nishina PM Lachapelle P McCall MA Koenekoop RK Bergen AA Kamermans M Gregg RG 《American journal of human genetics》2012,90(2):331-339
Complete congenital stationary night blindness (cCSNB) is a clinically and genetically heterogeneous group of retinal disorders characterized by nonprogressive impairment of night vision, absence of the electroretinogram (ERG) b-wave, and variable degrees of involvement of other visual functions. We report here that mutations in GPR179, encoding an orphan G protein receptor, underlie a form of autosomal-recessive cCSNB. The Gpr179(nob5/nob5) mouse model was initially discovered by the absence of the ERG b-wave, a component that reflects depolarizing bipolar cell (DBC) function. We performed genetic mapping, followed by next-generation sequencing of the critical region and detected a large transposon-like DNA insertion in Gpr179. The involvement of GPR179 in DBC function was confirmed in zebrafish and humans. Functional knockdown of gpr179 in zebrafish led to a marked reduction in the amplitude of the ERG b-wave. Candidate gene analysis of GPR179 in DNA extracted from patients with cCSNB identified GPR179-inactivating mutations in two patients. We developed an antibody against mouse GPR179, which robustly labeled DBC dendritic terminals in wild-type mice. This labeling colocalized with the expression of GRM6 and was absent in Gpr179(nob5/nob5) mutant mice. Our results demonstrate that GPR179 plays a critical role in DBC signal transduction and expands our understanding of the mechanisms that mediate normal rod vision. 相似文献
992.
In recent years, fluorescence microscopy has enabled researchers to observe the dynamics of clathrin-coated pit (CCP) assembly in real time. The assembly dynamics of CCPs shows striking heterogeneity. Some CCPs are long-lived (productive CCPs); they bind cargo and grow in size to form clathrin-coated vesicles. In contrast, other CCPs (abortive CCPs) are relatively short-lived and disassemble well before reaching vesicle size. Within both populations there is significant variance in CCP lifetime. We propose a stochastic biophysical model that links these observations with the energetics of CCPs and kinetics of their assembly. We show that without cargo, CCP assembly faces a high energy barrier that is difficult to overcome. As a consequence, CCPs without cargo are almost always abortive. We suggest a mechanism by which cargo binding stabilizes CCPs and facilitates their growth. The lifetime distribution of abortive pits calculated from our model agrees well with published experimental data. We also estimate the lifetimes of productive CCPs and show that the stochastic nature of CCP assembly plays a crucial role in causing their observed wide distribution. 相似文献
993.
994.
Randel, N. and Bick, A. 2011. Development, morphology and ultrastructure of the branchial crown of Fabricia stellaris (Müller, 1774) (Polychaeta: Sabellida: Fabriciinae). —Acta Zoologica (Stockholm) 93 : 409–421. Sabellidae and Serpulidae are well‐known tube‐building polychaetes with a distinctive and often spectacularly colourful branchial crown. Morphological investigations suggest that these taxa form the monophyletic clade Sabellida, with the adelphotaxa Sabellidae and Serpulidae, but the relationship between these taxa remains ambiguous. Molecular investigations have indicated that the Fabriciinae, major taxon of Sabellidae, belongs to Serpulidae, thereby making Sabellidae paraphyletic; however, morphological characters are absent to support this result. We investigate the development, anatomy and ultrastructure of the branchial crown of Fabricia stellaris (Müller, 1774), describing morphological characteristics useful not only for constructing morphological phylogenies but also for understanding the evolution of the branchial crown. The morphology of the radioles and pinnules does not differ from each other. The supporting tissue of the branchial crown consists of myoepithelial cells and a solid extracellular matrix (ECM). Both ciliated and non‐ciliated cells form the epidermal layer; ciliated cells shape the food groove. Most important is the result that radioles and pinnules within Sabellida may not be homologous, because the morphology and the branching of radioles and pinnules are completely different between Sabellinae, Fabriciinae and Serpulidae. The terms ‘primary branch’ for radioles and ‘secondary branch’ for pinnules are proposed for Fabriciinae. The phylogeny of the Sabellida is discussed. 相似文献
995.
Mammary epithelial cells undergo structural and functional differentiation at late pregnancy and parturition to produce and secrete milk. Both TGF-β and prolactin pathways are crucial regulators of this process. However, how the activities of these two antagonistic pathways are orchestrated to initiate lactation has not been well defined. Here, we show that SnoN, a negative regulator of TGF-β signaling, coordinates TGF-β and prolactin signaling to control alveologenesis and lactogenesis. SnoN expression is induced at late pregnancy by the coordinated actions of TGF-β and prolactin. The elevated SnoN promotes Stat5 signaling by enhancing its stability, thereby sharply increasing the activity of prolactin signaling at the onset of lactation. SnoN(-/-) mice display severe defects in alveologenesis and lactogenesis, and mammary epithelial cells from these mice fail to undergo proper morphogenesis. These defects can be rescued by an active Stat5. Thus, our study has identified a new player in the regulation of milk production and revealed a novel function of SnoN in mammary alveologenesis and lactogenesis in vivo through promotion of Stat5 signaling. 相似文献
996.
Nawrotzki R Islinger M Vogel I Völkl A Kirsch J 《Histochemistry and cell biology》2012,137(4):471-482
Gephyrin is a scaffolding protein required for the accumulation of inhibitory neurotransmitter receptors at neuronal postsynaptic
membranes. In non-neuronal tissues, gephyrin is indispensible for the biosynthesis of molybdenum cofactor, the prosthetic
group of oxidoreductases including sulfite oxidase and xanthine oxidase. However, the molecular and cellular basis of gephyrin’s
non-neuronal function is poorly understood; in particular, the roles of its splice variants remain enigmatic. Here, we used
cDNA screening as well as Northern and immunoblot analyses to show that mammalian liver contains only a limited number of
gephyrin splice variants, with the C3-containing variant being the predominant isoform. Using new and established anti-gephyrin
antibodies in immunofluorescence and subcellular fractionation studies, we report that gephyrin localizes to the cytoplasm
of both tissue hepatocytes and cultured immortalized cells. These findings were corroborated by RNA interference studies in
which the cytosolic distribution was found to be abolished. Finally, by blue-native PAGE we show that cytoplasmic gephyrin
is part of a ~600 kDa protein complex of yet unknown composition. Our data suggest that the expression pattern of non-neuronal
gephyrin is simpler than indicated by previous evidence. In addition, gephyrin’s presence in a cytosolic 600 kDa protein complex
suggests that its metabolic and/or other non-neuronal functions are exerted in the cytoplasm and are not confined to a particular
subcellular compartment. 相似文献
997.
Nadine S. Lossi Eleni Manoli Pete Simpson Cerith Jones Kailyn Hui Sarah J. Coulthurst Paul Freemont Alain Filloux 《Molecular microbiology》2012,86(2):437-456
In Pseudomonas aeruginosa three type VI secretion systems (T6SSs) coexist, called H1‐ to H3‐T6SSs. Several T6SS components are proposed to be part of a macromolecular complex resembling the bacteriophage tail. The T6SS protein HsiE1 (TagJ) is unique to the H1‐T6SS and absent from the H2‐ and H3‐T6SSs. We demonstrate that HsiE1 interacts with a predicted N‐terminal α‐helix in HsiB1 (TssB) thus forming a novel subcomplex of the T6SS. HsiB1 is homologous to the Vibrio cholerae VipA component, which contributes to the formation of a bacteriophage tail sheath‐like structure. We show that the interaction between HsiE1 and HsiB1 is specific and does not occur between HsiE1 and HsiB2. Proteins of the TssB family encoded in T6SS clusters lacking a gene encoding a TagJ‐like component are often devoid of the predicted N‐terminal helical region, which suggests co‐evolution. We observe that a synthetic peptide corresponding to the N‐terminal 20 amino acids of HsiB1 interacts with purified HsiE1 protein. This interaction is a common feature to other bacterial T6SSs that display a TagJ homologue as shown here with Serratia marcescens. We further show that hsiE1 is a non‐essential gene for the T6SS and suggest that HsiE1 may modulate incorporation of HsiB1 into the T6SS. 相似文献
998.
The last decade has seen a rapid increase in the number of tools to acquire volume electron microscopy (EM) data. Several new scanning EM (SEM) imaging methods have emerged, and classical transmission EM (TEM) methods are being scaled up and automated. Here we summarize the new methods for acquiring large EM volumes, and discuss the tradeoffs in terms of resolution, acquisition speed, and reliability. We then assess each method's applicability to the problem of reconstructing anatomical connectivity between neurons, considering both the current capabilities and future prospects of the method. Finally, we argue that neuronal 'wiring diagrams' are likely necessary, but not sufficient, to understand the operation of most neuronal circuits: volume EM imaging will likely find its best application in combination with other methods in neuroscience, such as molecular biology, optogenetics, and physiology. 相似文献
999.
Sanchez RM Erhard K Hardwicke MA Lin H McSurdy-Freed J Plant R Raha K Rominger CM Schaber MD Spengler MD Moore ML Yu H Luengo JI Tedesco R Rivero RA 《Bioorganic & medicinal chemistry letters》2012,22(9):3198-3202
A series of 1,2,4-triazolo[1,5-a]pyrimidin-7(3H)-ones with excellent enzyme inhibition, improved isoform selectivity, and excellent inhibition of downstream phosphorylation of AKT has been identified. Several compounds in the series demonstrated potent (~ 0.100 μM IC(50)) growth inhibition in a PTEN deficient cancer cell line. 相似文献
1000.
Chang W Mosley RT Bansal S Keilman M Lam AM Furman PA Otto MJ Sofia MJ 《Bioorganic & medicinal chemistry letters》2012,22(8):2938-2942
The HCV non-structural protein NS5A has been established as a viable target for the development of direct acting antiviral therapy. From computational modeling studies strong intra-molecular hydrogen bonds were found to be a common structural moiety within known NS5A inhibitors that have low pico-molar replicon potency. Efforts to reproduce these γ-turn-like substructures provided a novel NS5A inhibitor based on a fluoro-olefin isostere. This fluoro-olefin containing inhibitor exhibited picomolar activity (EC(50)=79 pM) against HCV genotype 1b replicon without measurable cytotoxicity. This level of activity is comparable to the natural peptide-based inhibitors currently under clinic evaluation, and demonstrates that a peptidomimetic approach can serve as a useful strategy to produce potent and structurally unique inhibitors of HCV NS5A. 相似文献