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41.
We have identified and synthesized a series of [1,2,4]triazolo[3,4-a]phthalazine derivatives as high-affinity ligands to alpha 2 delta-1 subunit of voltage gated calcium channels. Structure-activity relationship studies directed toward improving the potency and physical properties of 2 lead to the discovery of 20 (IC(50)=15 nM) and (S)-22 (IC(50)=30 nM). A potent and selective radioligand, [(3)H]-(S)-22 was also synthesized to demonstrate that this ligand binds to the same site as gabapentin.  相似文献   
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Genetic aberrations, mostly resulting in changes in gene expression, are critical events in cancer onset and progression. The advent of the cDNA array technology allows the screening and the efficient measurement of expression of thousands genes simultaneously in a wide spectrum of experimental and clinical models. This genomic scale approach is being currently used to obtain global views of human cancer gene expression and to identify genetic markers that might be important for diagnosis, prognosis, and therapy. This review discusses some recent findings obtained by means of cDNA arrays investigating the human melanoma.  相似文献   
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32D cells are a murine hemopoietic cell line that undergoes apoptosis upon withdrawal of interleukin-3 (IL-3) from the medium. 32D cells have low levels of the type 1 insulin-like growth factor (IGF-I) receptor and do not express insulin receptor substrate-1 (IRS-1) or IRS-2. Ectopic expression of IRS-1 delays apoptosis but cannot rescue 32D cells from IL-3 dependence. In 32D/IRS-1 cells, IRS-1 is detectable, as expected, in the cytosol/membrane compartment. The SV40 large T antigen is a nuclear protein that, by itself, also fails to protect 32D cells from apoptosis. Co-expression of IRS-1 with the SV40 T antigen in 32D cells results in nuclear translocation of IRS-1 and survival after IL-3 withdrawal. Expression of a human IGF-I receptor in 32D/IRS-1 cells also results in nuclear translocation of IRS-1 and IL-3 independence. The phosphotyrosine-binding domain, but not the pleckstrin domain, is necessary for IRS-1 nuclear translocation. Nuclear translocation of IRS-1 was confirmed in mouse embryo fibroblasts. These results suggest possible new roles for nuclear IRS-1 in IGF-I-mediated growth and anti-apoptotic signaling.  相似文献   
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The emerging field of evolutionary developmental biology (evo-devo) continues to operate largely under a single paradigm. In this paradigm developmental regulatory genes and processes are compared among a collection of "model organisms" selected primarily on the basis of their historical utility in the study of development. This approach has proven to be extremely informative, revealing an unexpected deep evolutionary conservation among developmental genes and genetic systems. Despite its success, concern has been expressed regarding its limitations. We discuss the "model organism" paradigm in evo-devo research. Based on our interpretation of its limitations, we propose a separate but complementary approach that is centered on "model groups." These groups are selected on the basis of their taxonomic affinity and their relevance to questions of interest to evo-devo biologists. We further discuss the Tetraodontiformes (Teleostei, Pisces) as an example of a "model group" for the evo-devo study of vertebrate skeletal elements.  相似文献   
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Nonvisual arrestins (arr) modulate G protein-coupled receptor (GPCR) desensitization and internalization and bind to both clathrin (CL) and AP-2 components of the endocytic coated pit (CP). This raises the possibility that endocytosis of some GPCRs may be a consequence of arr-induced de novo CP formation. To directly test this hypothesis, we examined the behavior of green fluorescent protein (GFP)-arr3 in live cells expressing beta2-adrenergic receptors and fluorescent CL. After agonist stimulation, the diffuse GFP-arr3 signal rapidly became punctate and colocalized virtually completely with preexisting CP spots, demonstrating that activated complexes accumulate in previously formed CPs rather than nucleating new CP formation. After arr3 recruitment, CP appeared larger: electron microscopy analysis revealed an increase in both CP number and in the occurrence of clustered CPs. Mutant arr3 proteins with impaired binding to CL or AP-2 displayed reduced recruitment to CPs, but were still capable of inducing CP clustering. In contrast, though constitutively present in CPs, the COOH-terminal moiety of arr3, which contains CP binding sites but lacks receptor binding, did not induce CP clustering. Together, these results indicate that recruitment of functional arr3-GPCR complexes to CP is necessary to induce clustering. Latrunculin B or 16 degrees C blocked CP rearrangements without affecting arr3 recruitment to CP. These results and earlier studies suggest that discrete CP zones exist on cell surfaces, each capable of supporting adjacent CPs, and that the cortical actin membrane skeleton is intimately involved with both the maintenance of existing CPs and the generation of new structures.  相似文献   
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New copper(I) complexes have been synthesised from the reaction of CuCl with 4-(diphenylphosphane)benzoic acid and lithium tris(1H-pyrazol-1-yl)methanesulfonate, Li(SO(3))C(pz)(3), sodium hydrotris(3-trifluoromethyl-1H-pyrazol-1-yl)borate, NaHB[3-(CF(3))pz](3), potassium dihydrobis(1H-1,2,4-triazol-1-yl)borate, KH(2)B(tz)(2), hydrotris(1H-1,2,4-triazol-1-yl)borate, KHB(tz)(3), sodium hydrotris(1H-pyrazol-1-yl)borate, NaHB(pz)(3), potassium hydrotris(3,5-dimethyl-1H-pyrazol-1-yl)borate KHB(3,5-Me(2)Pz)(3) or potassium hydrotris(4-bromo-1H-pyrazol-1-yl)borate KHB(4-Brpz)(3). The complexes obtained have been characterized by elemental analyses and FT-IR in the solid state, and by NMR (1H and 31P[(1)H]) spectroscopy and conductivity measurements in solution. The solution data are consistent with partial dissociation of the sterically hindered complexes by way of breaking of Cu-P and Cu-N bonds. Electrospray mass spectrometry has been used to investigate the relative properties of the 4-(diphenylphosphane)benzoic acid and of the "scorpionate" ligands towards copper(I) ions. Chemiluminescence technique was used to evaluate the superoxide scavenging activity of these new copper complexes.  相似文献   
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Using different techniques of molecular biology we investigated the bacterial diversity of the chemocline of the meromictic Lake Cadagno. Cloning of a total community 16S rDNA PCR product and subsequent screening with a combination of amplified ribosomal DNA restriction analysis and temporal temperature gradient gel electrophoresis (TTGE) analysis revealed that 30 of 47 randomly selected clones were unique. Partial sequencing and comparative analysis indicated a high bacterial diversity dominated by the gamma-Proteobacteria (33.3%). Most of these rDNA clone sequences were not closely related to any 16S rDNA sequence in the database. In a second approach, the TTGE pattern from an environmental sample was compared with the migration of the cloned 16S rDNA fragments. Four clone types were identified on the environmental pattern by excising and sequencing comigrating bands, three of which were well represented in the library: two Chromatiaceae species and one sequence affiliated with the Desulfobulbus assemblage. Using the fluorescent in situ hybridization technique we essentially confirmed the results of the cloning experiments and the TTGE analysis.  相似文献   
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