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991.
Rastelli G Costantino L Gamberini MC Del Corso A Mura U Petrash JM Ferrari AM Pacchioni S 《Bioorganic & medicinal chemistry》2002,10(5):1427-1436
The relative binding affinities to human aldose reductase (ALR2) of three new 7-hydroxy-2-benzyl-4H-1-benzopyran-4-one inhibitors were predicted by free energy perturbation (FEP) simulations. Molecular substitutions were specifically designed to investigate the role of hydrogen bonding at the active site of ALR2. Starting from the lead inhibitor 7-hydroxy-2-(4'-hydroxybenzyl)-4H-1-benzopyran-4-one, the 4'-hydroxyl was mutated to methyl and to trifluoromethyl, and an hydroxyl at position 8 was additionally introduced. Once synthesized and tested as inhibitors of ALR2, the compounds displayed variations of K(i) that were in qualitative to quantitative agreement with the calculated relative free energies of binding. The results, discussed in terms of balance between free energies of solvation and free energies of binding to ALR2, elucidate the importance of hydrogen bonding with Thr113 and with Trp111 and cofactor, and provide a rationale to the observed differences in binding affinities. 相似文献
992.
Molecular basis of resistance to azole antifungals 总被引:12,自引:0,他引:12
The increased incidence of invasive mycoses and the emerging problem of antifungal drug resistance has prompted investigations of the underlying molecular mechanisms, particularly for the azole compounds central to current therapy. The target site for the azoles is the ERG11 gene product, the cytochrome P450 lanosterol 14alpha-demethylase, which is part of the ergosterol biosynthetic pathway. The resulting ergosterol depletion renders fungal cells vulnerable to further membrane damage. Development of azole resistance in fungi may occur through increased levels of the cellular target, upregulation of genes controlling drug efflux, alterations in sterol synthesis and decreased affinity of azoles for the cellular target. Here, we review the adaptative changes in fungi, in particular Candida albicans, in response to inhibitors of ergosterol biosynthesis. The molecular mechanisms of azole resistance might help in devising more effective antifungal therapies. 相似文献
993.
Véronique Gosselain Christiane Hudon Antonella Cattaneo Pierre Gagnon Dolors Planas Denis Rochefort 《Hydrobiologia》2005,534(1-3):11-22
The variables affecting epiphyton biomass were examined in a sheltered, multispecies macrophyte bed in the St. Lawrence River. Alteration of light penetration, resulting from the presence of dense macrophytes forming a thick subsurface canopy, primarily determined epiphyton biomass. Seasonal decrease of water levels also coincided with major increases in biomass. Plant morphology was the next important variable influencing epiphytic biomass, whereas the contribution of other variables (sampling depth, macrophyte species, relative abundance of macrophytes, and temperature) was low. Groups of lowest epiphyte biomass (0.1–0.6 mg Chla g–1 DW) were defined by the combination of a low percentage of incident light (<13% surface light) and simple macrophyte stem types found below the macrophyte canopy. Highest epiphyte biomass (0.7–1.8 mg Chla g–1 DW) corresponded to samples collected in mid-July and August, under high irradiance (>20% surface light) and supported by ramified stems. Our results suggest that epiphyton sampling should be stratified according to the fraction of surface light intensity, macrophyte architecture, and seasonal water level variations, in decreasing order of influence. 相似文献
994.
Autism encompasses a wide spectrum of disorders arising during brain development. Recent studies reported that sequence polymorphisms in neuroligin-3 (NLGN3) and neuroligin-4 (NLGN4) genes have been linked to autism spectrum disorders indicating neuroligin genes as candidate targets in brain disorders. We have characterized a single mutation found in two affected brothers that substituted Arg451 to Cys in NL3. Our data show that the exposed Cys causes retention of the protein in the endoplasmic reticulum (ER) when expressed in HEK-293 cells. To examine whether the introduction of a Cys in the C-terminal region of other alpha/beta-hydrolase fold proteins could promote the same cellular phenotype, we made homologous mutations in acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) and found a similar processing deficiency and intracellular retention (De Jaco et al., J Biol Chem. 2006, 281:9667-76). NL3, AChE and BChE mutant proteins are recognized as misfolded in the ER, and degraded via the proteasome pathway. A 2D electrophoresis coupled with mass spectrometry based approach was used to analyze proteins co-immunoprecipitating with NL3 and show differential expression of factors interacting with wild type and mutant NL3. We identified several proteins belonging to distinct ER resident chaperones families, including calnexin, responsible for playing a role in the folding steps of the AChE and NLs. 相似文献
995.
Granato M Feederle R Farina A Gonnella R Santarelli R Hub B Faggioni A Delecluse HJ 《Journal of virology》2008,82(8):4042-4051
Previous genetic and biochemical studies performed with several members of the Alphaherpesvirus subfamily have shown that the UL31 and UL34 proteins are essential components of the molecular machinery that mediates the primary egress of newly assembled capsids across the nuclear membrane. Further, there is substantial evidence that BFLF2 and BFRF1, the respective positional homologs of UL31 and UL34 in the Epstein-Barr virus (EBV) genome, are also their functional homologs, i.e., that the UL31/UL34 pathway is common to distant herpesviruses. However, the low degree of protein sequence identity between UL31 and BFLF2 would argue against such a hypothesis. To further clarify this issue, we have constructed a recombinant EBV strain devoid of BFLF2 (DeltaBFLF2) and show that BFLF2 is crucial for efficient virus production but not for lytic DNA replication or B-cell transformation. This defective phenotype could be efficiently restored by trans complementation with a BFLF2 expression plasmid. Detailed analysis of replicating cells by electron microscopy revealed that, as expected, DeltaBFLF2 viruses not only failed to egress from the nucleus but also showed defective DNA packaging. Nonfunctional primary egress did not, however, impair the production and extracellular release of enveloped but empty viral particles that comprised L particles containing tegument-like structures and a few virus-like particles carrying empty capsids. The DeltaBFLF2 and DeltaUL31 phenotypes therefore only partly overlap, from which we infer that BFLF2 and UL31 have substantially diverged during evolution to fulfil related but distinct functions. 相似文献
996.
Bozza S Zelante T Moretti S Bonifazi P DeLuca A D'Angelo C Giovannini G Garlanda C Boon L Bistoni F Puccetti P Mantovani A Romani L 《Journal of immunology (Baltimore, Md. : 1950)》2008,180(6):4022-4031
TLRs contribute to the inflammatory response in fungal infections. Although inflammation is an essential component of the protective response to fungi, its dysregulation may significantly worsen fungal diseases. In this study, we tested the hypothesis that Toll IL-1R8 (TIR8)/single Ig IL-1-related receptor, a member of the IL-1R family acting as a negative regulator of TLR/IL-1R signaling, affects TLR responses in fungal infections. Genetically engineered Tir8(-/-) mice were assessed for inflammatory and adaptive Th cell responses to Candida albicans and Aspergillus fumigatus. Inflammatory pathology and susceptibility to infection were higher in Tir8(-/-) mice and were causally linked to the activation of the Th17 pathway. IL-1R signaling was involved in Th17 cell activation by IL-6 and TGF-beta in that limited inflammatory pathology and relative absence of Th17 cell activation were observed in IL-1RI(-/-) mice. These data demonstrate that TIR8 is required for host resistance to fungal infections and that it functions to negatively regulate IL-1-dependent activation of inflammatory Th17 responses. TIR8 may contribute toward fine-tuning the balance between protective immunity and immunopathology in infection. 相似文献
997.
Romani L Zelante T De Luca A Fallarino F Puccetti P 《Journal of immunology (Baltimore, Md. : 1950)》2008,180(8):5157-5162
Largely viewed as proinflammatory, innate responses combine with adaptive immunity to generate the most effective form of antifungal resistance, and T cells exercise feedback control over diverse effects of inflammation on infection. Some degree of inflammation is required for protection, particularly in mucosal tissues, during the transitional response occurring between the rapid innate and slower adaptive response. However, progressive inflammation worsens disease and ultimately prevents pathogen eradication. IDO, tryptophan catabolites ("kynurenines"), and regulatory T cells help to tame overzealous and exaggerated inflammatory responses. In this context, IL-23 and the Th17 pathway, which down-regulate tryptophan catabolism, may instead favor pathology and serve to accommodate the seemingly paradoxical association of chronic inflammation with fungal persistence. Recent data support a view in which IL-23/IL-17 antagonistic strategies, including the administration of synthetic kynurenines, could represent a new means of harnessing progressive or potentially harmful inflammation. 相似文献
998.
999.
Giovanni Pedicillo Francesca Merulli Antonella Carosi Paolo Viali Massimo Lorenzoni 《Hydrobiologia》2008,609(1):219-223
Lake Piediluco is a naturally regulated lake used for hydroelectric purposes. Management of the lake and the eutrophic conditions
of its waters have had a negative impact on fish populations, particularly that of Eurasian perch (Perca fluviatilis L.). In order to increase the natural reproduction of this species, an experimental program was undertaken from 1997 to 2003
to facilitate reproduction by providing artificial spawning substrates. In Lake Piediluco perch spawn from March to May. Egg
ribbons ranged in length from 30 to 180 cm and contained from 12,740 to 205,466 eggs. The fraction of degenerated eggs ranged
from 0.20% to 63.30% (average 10.20%). The results demonstrate the effectiveness of artificial substrates as suitable substrates
for the reproduction of perch.
Guest editors: R. L. Welcomme & G. Marmulla
Hydropower, Flood Control and Water Abstraction: Implications for Fish and Fisheries 相似文献
1000.
Caci E Caputo A Hinzpeter A Arous N Fanen P Sonawane N Verkman AS Ravazzolo R Zegarra-Moran O Galietta LJ 《The Biochemical journal》2008,413(1):135-142
CFTR (cystic fibrosis transmembrane conductance regulator) is an epithelial Cl- channel inhibited with high affinity and selectivity by the thiazolidinone compound CFTR(inh)-172. In the present study, we provide evidence that CFTR(inh)-172 acts directly on the CFTR. We introduced mutations in amino acid residues of the sixth transmembrane helix of the CFTR protein, a domain that has an important role in the formation of the channel pore. Basic and hydrophilic amino acids at positions 334-352 were replaced with alanine residues and the sensitivity to CFTR(inh)-172 was assessed using functional assays. We found that an arginine-to-alanine change at position 347 reduced the inhibitory potency of CFTR(inh)-172 by 20-30-fold. Mutagenesis of Arg347 to other amino acids also decreased the inhibitory potency, with aspartate producing near total loss of CFTR(inh)-172 activity. The results of the present study provide evidence that CFTR(inh)-172 interacts directly with CFTR, and that Arg347 is important for the interaction. 相似文献