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61.
Ultraviolet radiation triggers apoptosis of fibroblasts and skin keratinocytes mainly via the BH3-only protein Noxa
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To identify the mechanisms of ultraviolet radiation (UVR)-induced cell death, for which the tumor suppressor p53 is essential, we have analyzed mouse embryonic fibroblasts (MEFs) and keratinocytes in mouse skin that have specific apoptotic pathways blocked genetically. Blocking the death receptor pathway provided no protection to MEFs, whereas UVR-induced apoptosis was potently inhibited by Bcl-2 overexpression, implicating the mitochondrial pathway. Indeed, Bcl-2 overexpression boosted cell survival more than p53 loss, revealing a p53-independent pathway controlled by the Bcl-2 family. Analysis of primary MEFs lacking individual members of its BH3-only subfamily identified major initiating roles for the p53 targets Noxa and Puma. In the transformed derivatives, where Puma, unexpectedly, was not induced by UVR, Noxa had the dominant role and Bim a minor role. Furthermore, loss of Noxa suppressed the formation of apoptotic keratinocytes in the skin of UV-irradiated mice. Collectively, these results demonstrate that UVR activates the Bcl-2-regulated apoptotic pathway predominantly through activation of Noxa and, depending on cellular context, Puma. 相似文献
62.
63.
Anand C Umranikar C Shintre P Damle A Kale J Joshi J Watve M 《Journal of biosciences》2007,32(4):769-774
Many species of animal-pollinated flowers are known to vary widely in the nectar content of flowers. Some proportion of flowers
in many species is apparently nectarless, and such flowers are believed to be ‘cheaters’. Cheating may explain a part of the
variability in nectar content. If cheating exists as a qualitatively different strategy then we expect bimodality in the distribution
of nectar content of flowers. It has been shown in a multispecies study that gregarious species have a higher proportion of
cheater flowers. We studied the frequency distribution of total nectar sugar in two gregariously flowering species Lantana camara and Utricularia purpurascens, which differed in other floral and ecological characters. At the population level, both the species showed significant bimodality
in the total sugar content of flowers. The obvious sources of heterogeneity in the data did not explain bimodality. In Lantana camara, bimodality was observed within flowers of some of the individual plants sampled. In Utricularia purpurascens the proportion of nectarless flowers was more in high-density patches, suggesting that the gregariousness hypothesis may
work within a species as well. The results support the hypothesis of cheating as a distinct strategy since two distinct types
of flowers were observed in both the species. The effect of density in Utricularia purpurascens also supports the gregariousness hypothesis. 相似文献
64.
Parker MF Barten DM Bergstrom CP Bronson JJ Corsa JA Deshpande MS Felsenstein KM Guss VL Hansel SB Johnson G Keavy DJ Lau WY Mock J Prasad CV Polson CT Sloan CP Smith DW Wallace OB Wang HH Williams A Zheng M 《Bioorganic & medicinal chemistry letters》2007,17(16):4432-4436
A series of N-alkylbenzenesulfonamides were developed from a high throughput screening hit. Classic and parallel synthesis strategies were employed to produce compounds with good in vitro and in vivo gamma-secretase activity. 相似文献
65.
The problem of predicting the enzymes and non-enzymes from the protein sequence information is still an open problem in bioinformatics. It is further becoming more important as the number of sequenced information grows exponentially over time. We describe a novel approach for predicting the enzymes and non-enzymes from its amino-acid sequence using artificial neural network (ANN). Using 61 sequence derived features alone we have been able to achieve 79 percent correct prediction of enzymes/non-enzymes (in the set of 660 proteins). For the complete set of 61 parameters using 5-fold cross-validated classification, ANN model reveal a superior model (accuracy = 78.79 plus or minus 6.86 percent, Q(pred) = 74.734 plus or minus 17.08 percent, sensitivity = 84.48 plus or minus 6.73 percent, specificity = 77.13 plus or minus 13.39 percent). The second module of ANN is based on PSSM matrix. Using the same 5-fold cross-validation set, this ANN model predicts enzymes/non-enzymes with more accuracy (accuracy = 80.37 plus or minus 6.59 percent, Q(pred) = 67.466 plus or minus 12.41 percent, sensitivity = 0.9070 plus or minus 3.37 percent, specificity = 74.66 plus or minus 7.17 percent). 相似文献
66.
Radiolabeled divalent peptidomimetic vitronectin receptor antagonists as potential tumor radiotherapeutic and imaging agents 总被引:1,自引:0,他引:1
Harris TD Cheesman E Harris AR Sachleben R Edwards DS Liu S Bartis J Ellars C Onthank D Yalamanchili P Heminway S Silva P Robinson S Lazewatsky J Rajopadhye M Barrett J 《Bioconjugate chemistry》2007,18(4):1266-1279
The integrin receptor alphavbeta3 is overexpressed on the endothelial cells of growing tumors and on some tumor cells themselves. A radiolabeled alphavbeta3 antagonists belonging to the quinolin-4-one class of peptidomimetics (TA138) was previously shown to exhibit high affinity for integrin alphavbeta3 and high selectivity versus other integrin receptors. 111In-TA138 exhibited high tumor uptake in the c-neu Oncomouse mammary adenocarcinoma model and produced excellent scintigraphic images. This study describes the synthesis of eight divalent versions of TA138 and their evaluation as potential tumor radiotherapeutic agents. The two main variables in this study were the length of the spacer bridging the biotargeting moieties and the total negative charge of the molecules imparted by the cysteic acid pharmacokinetic modifiers. Receptor affinity was evaluated in a panel of integrin receptor affinity assays, and biodistribution studies using the 111In-labeled derivatives were carried out in the c-neu Oncomouse model. All divalent agents maintained the high receptor affinity and selectivity of TA138, and six of the eight 111In derivatives exhibited blood clearance that was faster than 111In-TA138 at 24 h postinjection (PI). All divalent agents exhibited tumor uptake and retention at 24 h PI that was higher than 111In-TA138. Tumor/organ ratios were improved for most of the divalent agents at 24 h PI in critical nontarget organs marrow, kidney, and liver, with the agents having intermediate-length spacers (29-43 A) showing the largest improvement. As an example, 111In-15 showed tumor uptake of 14.3% ID/g at 24 h PI and tumor/organ ratios as follows: marrow, 3.24; kidney, 7.29; liver, 8.51. A comparison of therapeutic indices for 90Y-TA138 and 177Lu-15 indicate an improved therapeutic index for the divalent agent. The implications for radiotherapeutic applications and the mechanism of this multivalent effect are discussed. 相似文献
67.
Dewasthaly SS Bhonde GS Shankarraman V Biswas SM Ayachit VM Gore MM 《Protein and peptide letters》2007,14(6):543-551
Virus neutralizing MAb binding and T helper cell stimulating peptide epitopes from structural and non-structural proteins of Japanese encephalitis virus were delineated. It was observed that priming by T helper peptides potentiated neutralizing antibody response against JE virus. Immunization with chimeric T helper - B cell peptides could thus protect mice from lethal challenge with JE virus. 相似文献
68.
The leishmaniases are a group of diseases caused by protozoan parasites of the genus Leishmania. Various Leishmania species can cause human infection, producing a spectrum of clinical manifestations. It is estimated that 350 million people are at risk, with a global yearly incidence of 1-1.5 million for cutaneous and 500,000 for visceral leishmaniasis (VL). VL is a major cause of morbidity and mortality in East Africa and the Indian subcontinent. Coinfection with HIV enhances the risk of the disease. The only control measure currently available in India is case detection and treatment with antimonial drugs, which are expensive, not always available and cannot be self-administered. Newer drugs like oral miltefosine have not become widely available. Vector and reservoir control is difficult due to the elusive nature of the vector and the diversity of the animal reservoir. A detailed knowledge of immune response to the parasite would help in designing prophylactic and therapeutic strategies against this infection. 相似文献
69.
The developmental pathways that lead to the production of antigen-presenting dendritic cells (DCs) are beginning to be understood. These are the last of the pathways of haematopoiesis to be mapped. The existence of many specialized subtypes of DC has complicated this endeavour, as has the need to distinguish the DCs formed in steady state from those produced during an inflammatory response. Here we review studies that lead to the concept that different types of DC develop through different branches of haematopoietic pathways that involve different immediate precursor cells. Furthermore, these studies show that many individual tissues generate their own DCs locally, from a reservoir of immediate DC precursors, rather than depending on a continuous flux of DCs from the bone marrow. 相似文献