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971.
Alwin M. Hartman Milon Mondal Nedyalka Radeva Gerhard Klebe Anna K. H. Hirsch 《International journal of molecular sciences》2015,16(8):19184-19194
Aspartic proteases are a class of enzymes that play a causative role in numerous diseases such as malaria (plasmepsins), Alzheimer’s disease (β-secretase), fungal infections (secreted aspartic proteases), and hypertension (renin). We have chosen endothiapepsin as a model enzyme of this class of enzymes, for the design, preparation and biochemical evaluation of a new series of inhibitors of endothiapepsin. Here, we have optimized a hit, identified by de novo structure-based drug design (SBDD) and DCC, by using structure-based design approaches focusing on the optimization of an amide–π interaction. Biochemical results are in agreement with SBDD. These results will provide useful insights for future structure-based optimization of inhibitors for the real drug targets as well as insights into molecular recognition. 相似文献
972.
Dr. Alon Silberman Dr. Yona Kalechman Shira Hirsch Ziv Erlich Prof. Benjamin Sredni Prof. Amnon Albeck 《Chembiochem : a European journal of chemical biology》2016,17(10):918-927
Organic TeIV compounds (organotelluranes) differing in their labile ligands exhibited anti‐integrin activities in vitro and anti‐metastatic properties in vivo. They underwent ligand substitution with l ‐cysteine, as a thiol model compound. Unlike inorganic TeIV compounds, the organotelluranes did not form a stable complex with cysteine, but rather immediately oxidized it. The organotelluranes inhibited integrin functions, such as adhesion, migration, and metalloproteinase secretion mediation in B16F10 murine melanoma cells. In comparison, a reduced derivative with no labile ligand inhibited adhesion of B16F10 cells to a significantly lower extent, thus pointing to the importance of the labile ligands of the TeIV atom. One of the organotelluranes inhibited circulating cancer cells in vivo, possibly by integrin inhibition. Our results extend the current knowledge on the reactivity and mechanism of organotelluranes with different labile ligands and highlight their clinical potential. 相似文献
973.
Molecular imprinting in hydrogels using reversible addition‐fragmentation chain transfer polymerization and continuous flow micro‐reactor
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974.
OBJECTIVE: Reconstruction of soft tissue defects on the lower half of the leg. DESIGN: The distally based medial adipofascial flap nourished by the lower perforator originating from the posterior tibial artery was harvested, and the pivot point of flap transposition is 9 to 12 cm above the tip of the medial malleolus. MATERIALS AND METHODS: Twelve cases of open tibial fracture associated with soft tissue defects on the lower half of the leg were reconstructed with this flap. The cases consisted of ten males and two females, and their ages ranged from 16 to 71 (averaging 41 years). MEASUREMENTS AND MAIN RESULTS: Size of the flap varied from 4 x 7 cm to 5 x 18 cm. Eleven flaps had good perfusion and survived completely. Tip necrosis of the flap occurred in one case. In the early postoperative period, take of the meshed split-thickness skin graft on the flap was not complete. All wounds, however, were resurfaced completely without the need of a second grafting. Discharging sinuses occurred in one case, which was managed by removal of infected bony fragments. All the donor sites were closed primarily, and desquamation of wound edges occurred occasionally. CONCLUSIONS: The distally based medial adipofascial flap was a reliable and effect local flap for the reconstruction of soft tissue defects on the lower half of the leg. 相似文献
975.
Neuronal A kinase anchor protein (AKAP) homologs, such as AKAPs 75 and 150, tether cAMP-dependent protein kinase II (PKAII) isoforms to the postsynaptic cytoskeleton, thereby creating target sites for cAMP action. These AKAPs, which bind regulatory subunits (RIIs) of PKAII, are also expressed in certain non-neuronal cells. Non-neuronal cell lines that stably express wild type and mutant AKAP75 transgenes were generated to investigate the extraneuronal function of AKAPs. In non-neuronal cells, AKAP75 accumulates selectively in the actin-rich, cortical cytoskeleton in close proximity with the plasma membrane. AKAP75 efficiently sequesters cytoplasmic RIIalpha and RIIbeta (PKAII isoforms) and translocates these polypeptides to the cell cortex. Two structural modules in AKAP75, T1 (residues 27-48), and T2 (residues 77-100), are essential for targeting AKAP75.RII complexes to the cortical cytoskeleton. Deletions or amino acid substitutions in T1 and/or T2 result in the dispersion of both AKAP75 and RII subunits throughout the cytoplasm. AKAP75 is co-localized with F-actin and fodrin in the cortical cytoskeleton. Incubation of cells with 5 microM cytochalasin D disrupts actin filaments and dissociates actin from the cell cortex. In contrast, the bulk of AKAP75 and fodrin remain associated with the cortical region of cytochalasin D-treated cells. Thus, targeting of AKAP75 does not depend upon direct binding with F-actin. Rather, AKAP75 (like fodrin) may be associated with a multiprotein complex that interacts with integral plasma membrane proteins. 相似文献
976.
A Inoue CS Koh M Yamazaki M Ichikawa M Isobe Y Ishihara H Yagita BS Kim 《Canadian Metallurgical Quarterly》1997,9(12):1837-1847
We examined the role of leukocyte function-associated antigen (LFA)-1 and its counter-receptor intercellular adhesion molecule (ICAM)-1, one of the most important pairs of adhesion molecules, in the development of Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD). Immunohistochemical study showed hyper-expression of ICAM-1 on vascular endothelial cells and expression of LFA-1 on mononuclear infiltrating cells in the spinal cords of TMEV-infected mice. Treatment with mAb to ICAM-1 and/or LFA-1 molecules resulted in significant suppression of the development of demyelinating disease, both clinically and histologically, with down-regulation in the CNS of the respective adhesion molecules after treatment. In mice treated with these mAb, the specific delayed-type hypersensitivity and T cell proliferative responses for TMEV were decreased. The production of tumor necrosis factor-alpha and IFN-gamma in spleen cells was also decreased, but IL-4 production remained unchanged. These data suggest that ICAM-1/LFA-1 interaction is critically involved in the pathogenesis of TMEV-IDD and that antibodies to these adhesion molecules could be a novel therapeutic approach to the treatment of demyelinating diseases such as human multiple sclerosis. 相似文献
977.
978.
AL Edinger JL Mankowski BJ Doranz BJ Margulies B Lee J Rucker M Sharron TL Hoffman JF Berson MC Zink VM Hirsch JE Clements RW Doms 《Canadian Metallurgical Quarterly》1997,94(26):14742-14747
Brain capillary endothelial cells (BCECs) are targets of CD4-independent infection by HIV-1 and simian immunodeficiency virus (SIV) strains in vitro and in vivo. Infection of BCECs may provide a portal of entry for the virus into the central nervous system and could disrupt blood-brain barrier function, contributing to the development of AIDS dementia. We found that rhesus macaque BCECs express chemokine receptors involved in HIV and SIV entry including CCR5, CCR3, CXCR4, and STRL33, but not CCR2b, GPR1, or GPR15. Infection of BCECs by the neurovirulent strain SIV/17E-Fr was completely inhibited by aminooxypentane regulation upon activation, normal T cell expression and secretion in the presence or absence of ligands, but not by eotaxin or antibodies to CD4. We found that the envelope (env) proteins from SIV/17E-Fr and several additional SIV strains mediated cell-cell fusion and virus infection with CD4-negative, CCR5-positive cells. In contrast, fusion with cells expressing the coreceptors STRL33, GPR1, and GPR15 was CD4-dependent. These results show that CCR5 can serve as a primary receptor for SIV in BCECs and suggest a possible CD4-independent mechanism for blood-brain barrier disruption and viral entry into the central nervous system. 相似文献
979.
H Cáceres-Ríos J Rodríguez-Tafur F Bravo-Puccio C Magui?a-Vargas CS Díaz DC Ramos R Patarca 《Canadian Metallurgical Quarterly》1995,6(1):47-56
Microbial-related dysplastic and neoplastic angiomatous proliferative processes are seen with increased frequency, particularly in the acquired immunodeficiency syndrome (AIDS). The microbial-encoded or -induced mediators of angiopathogenesis in AIDS-associated Kaposi's sarcoma and bacillary angiomatosis are actively being sought. The present review addresses the historical, epidemiologic, clinical, etio- and histopathogenic aspects of the verruga peruana (VP). VP is a disease thus far endemic to high Andean valleys and characterized by dermal angioblastic proliferation in association with reactivation of latent Bartonella bacilliformis organisms. VP closely resembles AIDS-associated angiopathogenic manifestations at the clinical, histopathologic, and etiologic levels and therefore has been proposed as a model for the study of angiogenesis and endothelial cell dysplasia and neoplasia. Moreover, the recent epidemic outbreaks in endemic areas, the increased frequency of international travel to the region, the variable incubation period, and the possibility of not recognizing VP due to its rarity further underscore the relevance of studying this rare disorder and of including it in the differential diagnosis of angiomatous-proliferative disorders. 相似文献
980.
Certain biological properties, which generally are thought to play a role in the bacterial pathogenicity, were compared in short rods, swarm cells and penicillin-induced filaments of Proteus mirabilis S1959. Swarm cells of P. mirabilis S1959 weakly adhere to human uroepithelial cells and also do not penetrate L929 line of mouse fibroblasts. They do not show any cytotoxic activity, are poorly phagocytized by macrophages and granulocytes and start to divide by the end of the phagocytosis process. Their well-marked cell-bound haemolytic activity is correlated with fast division to the short rods. In in vivo experiments we have demonstrated the presence of long filamentous multinucleate nonseptate cells in the bladder and in the kidneys of infected animals. However there was no correlation between the number of swarm cells seen under microscopic examination and the intensity of infection. 相似文献