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Stevens B Allen NJ Vazquez LE Howell GR Christopherson KS Nouri N Micheva KD Mehalow AK Huberman AD Stafford B Sher A Litke AM Lambris JD Smith SJ John SW Barres BA 《Cell》2007,131(6):1164-1178
During development, the formation of mature neural circuits requires the selective elimination of inappropriate synaptic connections. Here we show that C1q, the initiating protein in the classical complement cascade, is expressed by postnatal neurons in response to immature astrocytes and is localized to synapses throughout the postnatal CNS and retina. Mice deficient in complement protein C1q or the downstream complement protein C3 exhibit large sustained defects in CNS synapse elimination, as shown by the failure of anatomical refinement of retinogeniculate connections and the retention of excess retinal innervation by lateral geniculate neurons. Neuronal C1q is normally downregulated in the adult CNS; however, in a mouse model of glaucoma, C1q becomes upregulated and synaptically relocalized in the adult retina early in the disease. These findings support a model in which unwanted synapses are tagged by complement for elimination and suggest that complement-mediated synapse elimination may become aberrantly reactivated in neurodegenerative disease. 相似文献
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Inhibition of human immunodeficiency virus envelope glycoprotein- mediated single cell lysis by low-molecular-weight antagonists of viral entry
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The coexpression of human immunodeficiency virus type 1 (HIV-1) envelope glycoproteins and receptors leads to the lysis of single cells by a process that is dependent upon membrane fusion. This cell lysis was inhibited by low-molecular-weight compounds that interfere with receptor binding or with receptor-induced conformational transitions in the envelope glycoproteins. A peptide, T20, potently inhibited cell-cell fusion but had no effect on single cell lysis mediated by the HIV-1 envelope glycoproteins. Thus, critical events in the lysis of single cells by the HIV-1 envelope glycoproteins occur in intracellular compartments accessible only to small inhibitory compounds. 相似文献
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Navid Bazghaleh Chantal Hamel Yantai Gan Bunyamin Tar'an Joan Diane Knight 《Applied and environmental microbiology》2015,81(7):2368-2377
Increasing evidence supports the existence of variations in the association of plant roots with symbiotic fungi that can improve plant growth and inhibit pathogens. However, it is unclear whether intraspecific variations in the symbiosis exist among plant cultivars and if they can be used to improve crop productivity. In this study, we determined genotype-specific variations in the association of chickpea roots with soil fungal communities and evaluated the effect of root mycota on crop productivity. A 2-year field experiment was conducted in southwestern Saskatchewan, the central zone of the chickpea growing region of the Canadian prairie. The effects of 13 cultivars of chickpea, comprising a wide range of phenotypes and genotypes, were tested on the structure of root-associated fungal communities based on internal transcribed spacer (ITS) and 18S rRNA gene markers using 454 amplicon pyrosequencing. Chickpea cultivar significantly influenced the structure of the root fungal community. The magnitude of the effect varied with the genotypes evaluated, and effects were consistent across years. For example, the roots of CDC Corrine, CDC Cory, and CDC Anna hosted the highest fungal diversity and CDC Alma and CDC Xena the lowest. Fusarium sp. was dominant in chickpea roots but was less abundant in CDC Corrine than the other cultivars. A bioassay showed that certain of these fungal taxa, including Fusarium species, can reduce the productivity of chickpea, whereas Trichoderma harzianum can increase chickpea productivity. The large variation in the profile of chickpea root mycota, which included growth-promoting and -inhibiting species, supports the possibility of improving the productivity of chickpea by improving its root mycota in chickpea genetic improvement programs using traditional breeding techniques. 相似文献
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Lalonde JM Elban MA Courter JR Sugawara A Soeta T Madani N Princiotto AM Kwon YD Kwong PD Schön A Freire E Sodroski J Smith AB 《Bioorganic & medicinal chemistry》2011,19(1):91-101
The low-molecular-weight compound JRC-II-191 inhibits infection of HIV-1 by blocking the binding of the HIV-1 envelope glycoprotein gp120 to the CD4 receptor and is therefore an important lead in the development of a potent viral entry inhibitor. Reported here is the use of two orthogonal screening methods, gold docking and ROCS shape-based similarity searching, to identify amine-building blocks that, when conjugated to the core scaffold, yield novel analogs that maintain similar affinity for gp120. Use of this computational approach to expand SAR produced analogs of equal inhibitory activity but with diverse capacity to enhance viral infection. The novel analogs provide additional lead scaffolds for the development of HIV-1 entry inhibitors that employ protein-ligand interactions in the vestibule of gp120 Phe 43 cavity. 相似文献
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Thomas CJ Briknarová K Hilmer JK Movahed N Bothner B Sumida JP Tall GG Sprang SR 《PloS one》2011,6(8):e23197
Heterotrimeric G protein α subunits are activated upon exchange of GDP for GTP at the nucleotide binding site of Gα, catalyzed by guanine nucleotide exchange factors (GEFs). In addition to transmembrane G protein-coupled receptors (GPCRs), which act on G protein heterotrimers, members of the family cytosolic proteins typified by mammalian Ric-8A are GEFs for Gi/q/12/13-class Gα subunits. Ric-8A binds to Gα?GDP, resulting in the release of GDP. The Ric-8A complex with nucleotide-free Gαi1 is stable, but dissociates upon binding of GTP to Gαi1. To gain insight into the mechanism of Ric-8A-catalyzed GDP release from Gαi1, experiments were conducted to characterize the physical state of nucleotide-free Gαi1 (hereafter referred to as Gαi1[ ]) in solution, both as a monomeric species, and in the complex with Ric-8A. We found that Ric-8A-bound, nucleotide-free Gαi1 is more accessible to trypsinolysis than Gαi1?GDP, but less so than Gαi1[ ] alone. The TROSY-HSQC spectrum of [(15)N]Gαi1[ ] bound to Ric-8A shows considerable loss of peak intensity relative to that of [(15)N]Gαi1?GDP. Hydrogen-deuterium exchange in Gαi1[ ] bound to Ric-8A is 1.5-fold more extensive than in Gαi1?GDP. Differential scanning calorimetry shows that both Ric-8A and Gαi1?GDP undergo cooperative, irreversible unfolding transitions at 47° and 52°, respectively, while nucleotide-free Gαi1 shows a broad, weak transition near 35°. The unfolding transition for Ric-8A:Gαi1[ ] is complex, with a broad transition that peaks at 50°, suggesting that both Ric-8A and Gαi1[ ] are stabilized within the complex, relative to their respective free states. The C-terminus of Gαi1 is shown to be a critical binding element for Ric-8A, as is also the case for GPCRs, suggesting that the two types of GEF might promote nucleotide exchange by similar mechanisms, by acting as chaperones for the unstable and dynamic nucleotide-free state of Gα. 相似文献
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White adipose tissue (WAT) is the source of pro- and anti-inflammatory cytokines and we have recently shown that this tissue is a major source of the anti-inflammatory interleukin (IL)-1 receptor antagonist (IL-1Ra). We now aimed at identifying additional adipose-derived cytokines, which might serve as regulators of IL-1Ra. We demonstrate here for the first time that the antiinflammatory cytokine IL-10 is secreted by human WAT explants and that it is up-regulated by LPS and TNF-alpha in vitro, as well as in obesity in humans (2- and 6-fold increase in subcutaneous and visceral WAT, respectively) and rodents (4-fold increase). 相似文献
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The improved syntheses of methyl 2-O-acetyl-3-O-benzyl-alpha-L-rhamnopyranoside (12) and 1,2-di-O-acetyl-3-O-benzyl-alpha-L-rhamnopyranose (15), which were used as glycosyl acceptor and donor, respectively, are described. Glycosylation of the O-4 position of both rhamnose derivatives with 2,3,4,6-tetra-O-benzoyl-alpha-D-galactopyranosyl bromide (26) provided disaccharides 27 and 29. After partial deprotection of 27 and coupling of the resulting 28 with disaccharide 19, tetrasaccharide 31 was obtained. Furthermore, transforming of 29 into the corresponding bromide 30 and coupling with galacturonates 16 and 32 provided trisaccharides 33 and 34, respectively, which could be regarded as building blocks of ramified rhamnogalacturonan fragments. The preparation of tetra- (21) and hexasaccharide (25) of rhamnogalacturonan I is reported to demonstrate the feasibility of the synthesis of larger pectin fragments using the modular design principle with this type of building blocks. 相似文献