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971.
AL Flamar S Zurawski F Scholz I Gayet L Ni XH Li E Klechevsky J Quinn S Oh DH Kaplan J Banchereau G Zurawski 《Journal of immunology (Baltimore, Md. : 1950)》2012,189(5):2645-2655
Targeting of Ags directly to dendritic cells (DCs) through anti-DC receptor Ab fused to Ag proteins is a promising approach to vaccine development. However, not all Ags can be expressed as a rAb directly fused to a protein Ag. In this study, we show that noncovalent assembly of Ab-Ag complexes, mediated by interaction between dockerin and cohesin domains from cellulose-degrading bacteria, can greatly expand the range of Ags for this DC-targeting vaccine technology. rAbs with a dockerin domain fused to the rAb H chain C terminus are efficiently secreted by mammalian cells, and many Ags not secreted as rAb fusion proteins are readily expressed as cohesin directly fused to Ag either via secretion from mammalian cells or as soluble cytoplasmic Escherichia coli products. These form very stable and homogeneous complexes with rAb fused to dockerin. In vitro, these complexes can efficiently bind to human DC receptors followed by presentation to Ag-specific CD4(+) and CD8(+) T cells. Low doses of the HA1 subunit of influenza hemagglutinin conjugated through this means to anti-Langerin rAbs elicited Flu HA1-specific Ab and T cell responses in mice. Thus, the noncovalent assembly of rAb and Ag through dockerin and cohesin interaction provides a useful modular strategy for development and testing of prototype vaccines for elicitation of Ag-specific T and B cell responses, particularly when direct rAb fusions to Ag cannot be expressed. 相似文献
972.
Despite important clinical benefits of the highly active antiretroviral therapy, neurological disorders affect approximately 50% of AIDS patients. In the brain, infected microglia release pro-inflammatory mediators as well as human immunodeficiency virus type 1 (HIV-1) proteins, like the envelope protein gp120, that sustain inflammation and mediate neuronal damage. Gp120 allows the virus entry in the host cells via binding to the CD4 receptor together with a specific co-receptor (CCR5/CXCR4). The antiretroviral drug maraviroc is a CCR5 receptor antagonist, approved for the treatment of HIV-experienced patients. By interfering with a chemokine receptor, highly expressed in microglia, maraviroc has the potential to modulate their activation during HIV-1 infection. To test this hypothesis, primary cultures of rat cortical microglia were activated by gp120. Gp120(CN54) , a protein derived by macrophage (M)-tropic viruses, showed strong pro-inflammatory action, thus it was used to test the effects of maraviroc. The latter displayed opposite effects, depending on whether or not interferon-γ (IFNγ) was also present in the system. IFNγ significantly enhanced gp120 proinflammatory activity, possibly via up-regulation of CCR5 receptor expression. In this experimental paradigm, maraviroc significantly increased microglial activation, thus suggesting that its chronic use can exacerbate neuronal pathology, especially in HIV-experienced patients with higher cerebral IFNγ levels. 相似文献
973.
Plasma half-life extension of small recombinant antibodies by fusion to immunoglobulin-binding domains 总被引:1,自引:0,他引:1
Hutt M Färber-Schwarz A Unverdorben F Richter F Kontermann RE 《The Journal of biological chemistry》2012,287(7):4462-4469
Many therapeutic proteins possessing a small size are rapidly cleared from circulation. Half-life extension strategies have therefore become increasingly important to improve the pharmacokinetic and pharmacodynamic properties of protein therapeutics. Here, we performed a comparative analysis of the half-life extension properties of various bacterial immunoglobulin-binding domains (IgBDs) derived from Staphylococcus protein A (SpA), Streptococcus protein G (SpG), and Finegoldia (formerly Peptostreptococcus) protein L (PpL). These domains, composed of 50-60 amino acid residues, were fused to the C terminus of a single-chain Fv and a bispecific single-chain diabody, respectively. All fusion proteins were produced in mammalian cells and retained their antigen-binding properties. The half-lives of the antibody molecules were prolonged to varying extents for the different IgBDs. The strongest effects in mice were observed for domain C3 of SpG (SpG(C3)) followed by domains B and D of SpA, suggesting that SpG(C3) is particularly useful to extend the plasma half-life of small proteins. 相似文献
974.
975.
976.
Thaumatoporellacean algae are widespread constituents in Middle Triassic–Cretaceous shallow-marine carbonates of the Tethyan
realm. Based on various examples from Mesozoic limestones of Mediterranean platforms (e.g., Dinaric, Apenninic, Apulia) and
rare records of Iberia (Pyrenees), Saudi Arabia and Mexico, it is shown that thaumatoporellaceans commonly dwelt as cryptoendoliths
in the tests of larger benthic foraminifera and the thalli of dasycladalean algae. Their high morphological plasticity allowed
the test invasion and the adaptation to the available interior spaces (chambers, apertures). The temporal distribution of
cryptoendolithic thaumatoporellaceans with first records in the Late Triassic, shows acme intervals in Early–Middle Jurassic
and Early–Late Cretaceous times. Within the foraminiferans, the thaumatoporellaceans were erroneously considered as an integral
part of the test, respectively, phrenoteca-like structures (species Biokovina gradacensis) in the Lower Jurassic and trematophore (species Scandonea? mediterranea) in the Upper Cretaceous. Therefore, the presence of phrenoteca-like structures in the Biokovinidae, being part of the family
diagnosis, is challenged. The comparably thin walls of the cryptoendolithic thaumatoporellacean algae are interpreted as an
adaptation to the poorly illuminated microhabitats (photoadaptation) in order to maximize light capture for photosynthesis. 相似文献
977.
Cockburn JJ Navarro Sanchez ME Goncalvez AP Zaitseva E Stura EA Kikuti CM Duquerroy S Dussart P Chernomordik LV Lai CJ Rey FA 《The EMBO journal》2012,31(3):767-779
The four serotypes of dengue virus (DENV-1 to -4) cause the most important emerging viral disease. Protein E, the principal viral envelope glycoprotein, mediates fusion of the viral and endosomal membranes during virus entry and is the target of neutralizing antibodies. However, the epitopes of strongly neutralizing human antibodies have not been described despite their importance to vaccine development. The chimpanzee Mab 5H2 potently neutralizes DENV-4 by binding to domain I of E. The crystal structure of Fab 5H2 bound to E from DENV-4 shows that antibody binding prevents formation of the fusogenic hairpin conformation of E, which together with in-vitro assays, demonstrates that 5H2 neutralizes by blocking membrane fusion in the endosome. Furthermore, we show that human sera from patients recovering from DENV-4 infection contain antibodies that bind to the 5H2 epitope region on domain I. This study, thus, provides new information and tools for effective vaccine design to prevent dengue disease. 相似文献
978.
Edgar Garza-López Alejandro Sandoval Ricardo González-Ramírez María A. Gandini Arn Van den Maagdenberg Michel De Waard Ricardo Felix 《生物化学与生物物理学报:疾病的分子基础》2012,1822(8):1238-1246
Familial hemiplegic migraine type 1 (FHM-1) is a monogenic form of migraine with aura that is characterized by recurrent attacks of a typical migraine headache with transient hemiparesis during the aura phase. In a subset of patients, additional symptoms such as epilepsy and cerebellar ataxia are part of the clinical phenotype. FHM-1 is caused by missense mutations in the CACNA1A gene that encodes the pore-forming subunit of CaV2.1 voltage-gated Ca2 + channels. Although the functional effects of an increasing number of FHM-1 mutations have been characterized, knowledge on the influence of most of these mutations on G protein regulation of channel function is lacking. Here, we explored the effects of G protein-dependent modulation on mutations W1684R and V1696I which cause FHM-1 with and without cerebellar ataxia, respectively. Both mutations were introduced into the human CaV2.1α1 subunit and their functional consequences investigated after heterologous expression in human embryonic kidney 293 (HEK‐293) cells using patch-clamp recordings. When co-expressed along with the human μ-opioid receptor, application of the agonist [d‐Ala2, N‐MePhe4, Gly‐ol]‐enkephalin (DAMGO) inhibited currents through both wild-type (WT) and mutant CaV2.1 channels, which is consistent with the known modulation of these channels by G protein-coupled receptors. Prepulse facilitation, which is a way to characterize the relief of direct voltage-dependent G protein regulation, was reduced by both FHM-1 mutations. Moreover, the kinetic analysis of the onset and decay of facilitation showed that the W1684R and V1696I mutations affect the apparent dissociation and reassociation rates of the Gβγ dimer from the channel complex, suggesting that the G protein-Ca2 + channel affinity may be altered by the mutations. These biophysical studies may shed new light on the pathophysiology underlying FHM-1. 相似文献
979.
Lock Hock Ngu Leo G. Nijtmans Felix DistelmaierHanka Venselaar Sjenet E. van Emst-de VriesMariël A.M. van den Brand Berendien J.M. StoltenborgLiesbeth T. Wintjes Peter H. WillemsLambertus P. van den Heuvel Jan A. SmeitinkRichard J.T. Rodenburg 《生物化学与生物物理学报:疾病的分子基础》2012,1822(2):168-175
In this study, we investigated the pathogenicity of a homozygous Asp446Asn mutation in the NDUFS2 gene of a patient with a mitochondrial respiratory chain complex I deficiency. The clinical, biochemical, and genetic features of the NDUFS2 patient were compared with those of 4 patients with previously identified NDUFS2 mutations. All 5 patients presented with Leigh syndrome. In addition, 3 out of 5 showed hypertrophic cardiomyopathy. Complex I amounts in the patient carrying the Asp446Asn mutation were normal, while the complex I activity was strongly reduced, showing that the NDUFS2 mutation affects complex I enzymatic function. By contrast, the 4 other NDUFS2 patients showed both a reduced amount and activity of complex I. The enzymatic defect in fibroblasts of the patient carrying the Asp446Asn mutation was rescued by transduction of wild type NDUFS2. A 3-D model of the catalytic core of complex I showed that the mutated amino acid residue resides near the coenzyme Q binding pocket. However, the KM of complex I for coenzyme Q analogs of the Asp446Asn mutated complex I was similar to the KM observed in other complex I defects and in controls. We propose that the mutation interferes with the reduction of coenzyme Q or with the coupling of coenzyme Q reduction with the conformational changes involved in proton pumping of complex I. 相似文献
980.