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71.
BACKGROUND: We have previously shown that tubulin, the major protein of microtubules, is posttranslationally modified by palmitoylation. In addition, we demonstrated that palmitoylation of tubulin is inhibited in vitro by stoichiometric levels of the chemotherapeutic drug, vinblastine. Here, we sought to determine whether a clinically relevant dose of vinblastine inhibits palmitoylation of tubulin in vivo. METHODS: Human CEM leukemic lymphocytes were incubated with [3H]palmitate in the presence and absence of a low, clinically relevant dose of vinblastine. [3H]palmitoylated tubulin was identified by two-dimensional PAGE and autoradiography. RESULTS: We found, first, that tubulin was palmitoylated in CEM cells. Second, the clinically relevant dose of vinblastine inhibited palmitoylation of tubulin in vivo in CEM cells. In addition, microtubules were disassembled and cells became apoptotic. CONCLUSION: This study identifies a previously unknown mechanism of action of vinblastine, the depalmitoylation of tubulin, and suggests that depalmitoylation of tubulin may be a target for new chemotherapeutic drugs. 相似文献
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Margot Fournier Carina Ferrari Philipp S. Baumann Andrea Polari Aline Monin Tanja Bellier-Teichmann Jacob Wulff Kirk L. Pappan Michel Cuenod Philippe Conus Kim Q. Do 《Schizophrenia bulletin》2014,40(5):973-983
Because increasing evidence point to the convergence of environmental and genetic risk factors to drive redox dysregulation in schizophrenia, we aim to clarify whether the metabolic anomalies associated with early psychosis reflect an adaptation to oxidative stress. Metabolomic profiling was performed to characterize the response to oxidative stress in fibroblasts from control individuals (n = 20) and early psychosis patients (n = 30), and in all, 282 metabolites were identified. In addition to the expected redox/antioxidant response, oxidative stress induced a decrease of lysolipid levels in fibroblasts from healthy controls that were largely muted in fibroblasts from patients. Most notably, fibroblasts from patients showed disrupted extracellular matrix- and arginine-related metabolism after oxidative stress, indicating impairments beyond the redox system. Plasma membrane and extracellular matrix, 2 regulators of neuronal activity and plasticity, appeared as particularly susceptible to oxidative stress and thus provide novel mechanistic insights for pathophysiological understanding of early stages of psychosis. Statistically, antipsychotic medication at the time of biopsy was not accounting for these anomalies in the metabolism of patients’ fibroblasts, indicating that they might be intrinsic to the disease. Although these results are preliminary and should be confirmed in a larger group of patients, they nevertheless indicate that the metabolic signature of reactivity to oxidative stress may provide reliable early markers of psychosis. Developing protective measures aimed at normalizing the disrupted pathways should prevent the pathological consequences of environmental stressors.Key words: mental disorder, glutathione, arginine, extracellular matrix, phospholipid, metabolism 相似文献
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Nirvia Margot Cuaical-Ramos Marynes Montiel Daniel Marcano Zamora 《Enfermedades infecciosas y microbiología clínica》2019,37(2):76-81
Introduction
In Venezuela, there have been some reports of carbapenemase KPC-producing Klebsiella pneumoniae. Nevertheless, since the first report in 2008, only a few studies have been done on their molecular epidemiology in this country.Methods
The aims of this study were to detect extended-spectrum betalactamase (ESBL)-producing (blaTEM and blaCTM-M-1) and to determine the genetic relationship between 30 isolates of carbapenemase KPC-producing K. pneumoniae taken from patients at eleven health centers in different states of Venezuela from January 2008 to December 2012, using pulsed-field gel electrophoresis (PFGE).Results
All isolates were identified as K. pneumoniae subsp. pneumoniae. Isolates showed the highest resistance to the ertapenem, 97%. The KPC gene was detected in all studied strains. Seventy three percent showed ESBL, having the blaTEM in 68% and blaTEM, CTX-M-1 in 27% of the strains. Eleven groups were found using the field-pulsed gel electrophoresis.Conclusion
High genetic diversity was found during 2008-2012 in K. pneumoniae isolated at different states in Venezuela, some of them circulating at eleven health centers. Results showed the importance of performing epidemiologic studies and the need to develop some activities to control this type of microorganisms. 相似文献77.
2-(N-acetoxy-N-acetylamino)fluorene mutagenesis in mammalian cells: sequence-specific hot spot. 总被引:4,自引:0,他引:4
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A Gentil A Margot A Sarasin 《Proceedings of the National Academy of Sciences of the United States of America》1986,83(24):9556-9560
Mutations induced by 2-(N-acetoxy-N-acetylamino)fluorene were studied using temperature-sensitive simian virus 40 (SV40) mutants as probe in monkey kidney cells. In vitro treatment of the SV40 virions with 2-(N-acetoxy-N-acetylamino)fluorene increased mutagenesis and decreased survival in the viral progeny. A lethal hit of approximately 85 acetylaminofluorene adducts per SV40 genome was calculated. UV irradiation of cells prior to infection did not modify the results. Molecular analysis of independent SV40 revertants showed that 2-(N-acetoxy-N-acetylamino)fluorene induces base substitutions that are located not opposite putative acetylaminofluorene adducts but next to them. Moreover, a hot spot of mutation restoring a true wild-type genotype was observed in 10 of the 16 revertants analyzed. This hot spot, not targeted opposite a major DNA lesion, was not observed using UV light as damaging agent in the same genetic assay. Two models involving the stabilization, by acetylaminofluorene adducts, of the secondary structure of a specific quasipalindromic SV40 sequence are proposed to explain this sequence-specific hot spot. 相似文献
78.
Kushel MB Evans JL Perry S Robertson MJ Moss AR 《Archives of internal medicine》2003,163(20):2492-2499
BACKGROUND: Homeless persons experience high rates of sexual and physical assault; homeless women are thought to be at highest risk. To determine the prevalence, distribution, and factors associated with sexual and physical assault, we surveyed homeless and marginally housed adults in San Francisco, Calif. METHODS: We interviewed 2577 respondents about their history of recent sexual and physical assault, housing history, sexual practices, substance use, health status, and criminal justice history. The main outcome measures were self-reported sexual and physical assault in the previous 12 months. RESULTS: Overall, 32.3% of women, 27.1% of men, and 38.1% of transgendered persons reported a history of either sexual or physical assault in the previous year; 9.4% of women, 1.4% of men, and 11.9% of transgendered persons reported sexual assault, and 30.6% of women, 26.6% of men, and 33.3% of transgendered persons reported physical assault. In multivariate models, being homeless (as opposed to marginally housed) was associated with sexual assault for women, but not for men (adjusted odds ratio for homeless women, 3.4 [1.2-9.7]). Housing status was not associated with physical assault for women or men. Mental illness and sex work were both common and associated with high rates of assault in multivariate analyses. CONCLUSIONS: Sexual and physical assault are common experiences for homeless and marginally housed persons. Housing is associated with lower rates of sexual assault among women. Strategies to decrease sexual and physical assault and its consequences are needed in this population. 相似文献
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