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31.
SOCS-1 inhibits expression of the antiviral proteins 2',5'-OAS and MxA induced by the novel interferon-lambdas IL-28A and IL-29 总被引:5,自引:0,他引:5
Brand S Zitzmann K Dambacher J Beigel F Olszak T Vlotides G Eichhorst ST Göke B Diepolder H Auernhammer CJ 《Biochemical and biophysical research communications》2005,331(2):543-548
Recently, we have shown that SOCS-1/3 overexpression in hepatic cells abrogates signaling of type I interferons (IFN) which may contribute to the frequently observed IFN resistance of hepatitis C virus (HCV). IFN-lambdas (IL-28A/B and IL-29), a novel group of IFNs, also efficiently inhibit HCV replication in vitro with potentially less hematopoietic side effects than IFN-alpha because of limited receptor expression in hematopoietic cells. To further evaluate the potential of IFN-lambdas in chronic viral hepatitis, we examined the influence of SOCS protein expression on IFN-lambda signaling. First, we show that hepatic cell lines express the IFN-lambda receptor complex consisting of IFN-lambdaR1 (IL-28R1) and IL-10R2. Whereas in mock-transfected HepG2 cells, IL-28A and IL-29 induced STAT1 and STAT3 phosphorylation, overexpression of SOCS-1 completely abrogated IL-28A and IL-29-induced STAT1/3 phosphorylation. Similarly, IL-28A and IL-29 induced mRNA expression of the antiviral proteins 2',5'-OAS and MxA was abolished by overexpression of SOCS-1. In conclusion, we assume that despite antiviral properties of IFN-lambdas, their efficacy as antiviral agents may have similar limitations as IFN-alpha due to inhibition by SOCS proteins. 相似文献
32.
Higher‐order assemblies of oligomeric cargo receptor complexes form the membrane scaffold of the Cvt vesicle
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Arjen J Jakobi Abul K Tarafder Yury S Bykov Andrea Picco Wanda Kukulski Jan Kosinski Wim JH Hagen Arvind C Ravichandran Matthias Wilmanns Marko Kaksonen John AG Briggs Carsten Sachse 《EMBO reports》2016,17(7):1044-1060
Selective autophagy is the mechanism by which large cargos are specifically sequestered for degradation. The structural details of cargo and receptor assembly giving rise to autophagic vesicles remain to be elucidated. We utilize the yeast cytoplasm‐to‐vacuole targeting (Cvt) pathway, a prototype of selective autophagy, together with a multi‐scale analysis approach to study the molecular structure of Cvt vesicles. We report the oligomeric nature of the major Cvt cargo Ape1 with a combined 2.8 Å X‐ray and negative stain EM structure, as well as the secondary cargo Ams1 with a 6.3 Å cryo‐EM structure. We show that the major dodecameric cargo prApe1 exhibits a tendency to form higher‐order chain structures that are broken upon interaction with the receptor Atg19 in vitro. The stoichiometry of these cargo–receptor complexes is key to maintaining the size of the Cvt aggregate in vivo. Using correlative light and electron microscopy, we further visualize key stages of Cvt vesicle biogenesis. Our findings suggest that Atg19 interaction limits Ape1 aggregate size while serving as a vehicle for vacuolar delivery of tetrameric Ams1. 相似文献
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35.
C Adam Middleton Upendra Nongthomba Katherine Parry Sean T Sweeney John C Sparrow Christopher JH Elliott 《BMC biology》2006,4(1):17-14
Background
The processes by which eggs develop in the insect ovary are well characterized. Despite a large number of Drosophila mutants that cannot lay eggs, the way that the egg is moved along the reproductive tract from ovary to uterus is less well understood. We remedy this with an integrative study on the reproductive tract muscles (anatomy, innervation, contractions, aminergic modulation) in female flies. 相似文献36.
Magne D Palmer G Barton JL Mézin F Talabot-Ayer D Bas S Duffy T Noger M Guerne PA Nicklin MJ Gabay C 《Arthritis research & therapy》2006,8(3):R80-11
Six novel members of the IL-1 family of cytokines were recently identified, primarily through the use of DNA database searches for IL-1 homologues, and were named IL-1F5 to IL-1F10. In the present study, we investigated the effect of IL-1F8 on primary human joint cells, and examined the expression of the new IL-1 family members in human and mouse joints. Human synovial fibroblasts (hSFs) and human articular chondrocytes (hACs) expressed the IL-1F8 receptor (IL-1Rrp2) and produced pro-inflammatory mediators in response to recombinant IL-1F8. IL-1F8 mRNA expression was increased in hSFs upon stimulation with proinflammatory cytokines, whereas in hACs IL-1F8 mRNA expression was constitutive. However, IL-1F8 protein was undetectable in hSF and hAC culture supernatants. Furthermore, although IL-1beta protein levels were increased in inflamed human and mouse joint tissue, IL-1F8 protein levels were not. IL-1F8 levels in synovial fluids were similar to or lower than those in matched serum samples, suggesting that the joint itself is not a major source of IL-1F8. Serum levels of IL-1F8 were similar in healthy donors, and patients with rheumatoid arthritis, osteoarthritis and septic shock, and did not correlate with inflammatory status. Interestingly however, we observed high IL-1F8 levels in several serum samples in all groups. In conclusion, IL-1F8 exerts proinflammatory effects in primary human joint cells. Joint and serum IL-1F8 protein levels did not correlate with inflammation, but they were high in some human serum samples tested, including samples from patients with rheumatoid arthritis. It remains to be determined whether circulating IL-1F8 can contribute to joint inflammation in rheumatoid arthritis. 相似文献
37.
A computational framework for optimal masking in the synthesis of oligonucleotide microarrays
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High-throughput genomic technologies are revolutionizing modern biology. In particular, DNA microarrays have become one of the most powerful tools for profiling global mRNA expression in different tissues and environmental conditions, and for detecting single nucleotide polymorphisms. The broad applicability of gene expression profiling to the biological and medical realms has generated expanding demand for mass production of microarrays, which in turn has created considerable interest in improving the cost effectiveness of microarray fabrication techniques. We have developed the computational framework for an optimal synthesis strategy for oligonucleotide microarrays. The problem was introduced by Hubbell et al. Here, we formalize the problem, obtain precise bounds on its complexity and devise several computational solutions. 相似文献
38.
Bradley RD; Adkins RM; Honeycutt RL; McDonald JH 《Molecular biology and evolution》1998,15(6):709-717
Using the strictly neutral model as a null hypothesis, we tested for
deviations from expected levels of nucleotide polymorphism at the alcohol
dehydrogenase locus (Adh-1) within and among four species of pocket gophers
(Geomys bursarius major, G. knoxjonesi, G. texensis llanensis, and G.
attwateri). The complete protein-encoding region was examined, and 10
unique alleles, representing both electromorphic and cryptic alleles, were
used to test hypotheses (e.g., the neutral model) concerning the
maintenance of genetic variation. Nineteen variable sites were identified
among the 10 alleles examined, including 9 segregating sites occurring in
synonymous positions and 10 that were nonsynonymous. Several statistical
methods, including those that test for within-species variation as well as
those that examine variation within and among species, failed to reject the
null hypothesis that variation (both within and between species of Geomys)
at the Adh locus is consistent with the neutral theory. However, there was
significant heterogeneity in the ratio of polymorphism to divergence across
the gene, with polymorphisms clustered in the first half of the coding
region and fixed differences clustered in the second half of the gene. Two
alternative hypotheses are discussed as possible explanations for this
heterogeneity: an old balanced polymorphism in the first half of the gene
or a recent selective sweep in the second half of the gene.
相似文献
39.
Evidence for contractile protein translocation in macrophage spreading, phagocytosis, and phagolysosome formation 总被引:5,自引:4,他引:1
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Macrophage pseudopodia that surround objects during phagocytosis contain a meshwork of actin filaments and exclude organelles. Between these pseudopodia at the base of developing phagosomes, the organelle exclusion ceases, and lysosomes enter the cell periphery to fuse with the phagosomes. Macrophages also extend hyaline pseudopodia on the surface of nylon wool fibers and secrete lysosomal enzymes into the extracellular medium instead of into phagosomes. To analyze biochemically these concurrent alterations in cytoplasmic architecture, we allowed rabbit lung macrophages to spread on nylon wool fibers and then subjected the adherent cells to shear. This procedure caused the selective release of β-glucoronidase into the extracellular medium and yielded two fractions, cell bodies and isolated pseudopod blebs resembling podosomes, which are plasma-lemma-bounded sacs of cortical cytoplasm. Cytoplasmic extracts of the cell bodies eluted from nylon fibers contained two-thirds less actin-binding protein and myosin, and approximately 20 percent less actin and two-thirds of the other two proteins were accounted for in podosomes. The alterations in protein composition correlated with assays of myosin-associated EDTA-activated adenosine triphosphatase activity, and with a diminution in the capacity of extracts of nylon wool fiber-treated cell bodies to gel, a property dependent on the interaction between actin-binding protein and F-actin. However, the capacity of the remaining actin in cell bodies to polymerize did not change. We propose that actin-binding protein and myosin are concentrated in the cell cortex and particularly in pseudopodia where prominent gelation and syneresis of actin occur. Actin in the regions from which actin-binding protein and myosin are displaced disaggregates without depolymerizing, permitting lysosomes to gain access to the plasmalemma. Translocation of contractile proteins could therefore account for the concomitant differences in organelle exclusion that characterize phagocytosis. 相似文献
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