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The calcineurin pathway regulates antifungal drug resistance and the virulence of several major human-pathogenic fungi, including the recalcitrant Mucorales. We hypothesized that the fungistatic triazoles posaconazole (PCZ) and itraconazole (ICZ) become fungicidal in the setting of the calcineurin inhibitor tacrolimus (TCR) and that such an effect is mediated through apoptosis. Fungicidal activity and apoptosis were studied using standard microbiological techniques and hyphal metabolic and vital dye reduction assays at 37°C in RPMI 1640. Apoptosis was characterized by detecting intracellular Ca2+, phosphatidylserine (PS) externalization, DNA fragmentation, plasma membrane integrity, chromatin condensation, reactive oxygen species (ROS) generation, caspase-like activity, ATP, and cytochrome c release. MICs for PCZ and ICZ alone were significantly higher (8 to 128 μg/ml) than those of PCZ or ICZ plus TCR (0.25 to 4 μg/ml) for Rhizopus oryzae, Cunninghamella bertholletiae, and Mucor circinelloides. Both PCZ and ICZ in combination with TCR became fungicidal, and their activity was mediated through increased apoptotic cell death of R. oryzae (10 to 50%), C. bertholletiae (5 to 50%), and M. circinelloides (5 to 55%) germlings, with morphological apoptotic changes characterized by externalization of PS, nuclear condensation, and DNA fragmentation. Moreover, activation of the caspase-like activity was correlated with cell death induced by TCR plus PCZ or ICZ. These changes correlated with elevated intracellular Ca2+ and ROS levels and disturbance of mitochondrial potential. We found that PCZ or ICZ in combination with TCR renders Mucorales sensitive to triazoles via apoptotic death. These observations could serve as a new paradigm for the development of new therapeutic strategies. 相似文献
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Although the extensive use of Aspergillus-active antifungals has been recently associated with an increase in zygomycosis in several cancer centers, the frequency of this opportunistic mycosis began to rise earlier, since the mid 1990s. The reasons for that emergence are unclear. Recent evidence suggests that endosymbiotic bacteria of Rhizopus species produce toxins that enhance fungal pathogenicity. We postulate that, although Zygomycetes appear equally ubiquitous and virulent to Aspergillus, zygomycosis was rare in the past in immunosuppressed patients specifically because of the widespread use of antibacterials in this patient population. Such use may have resulted in inhibition of endosymbiotic, toxin-producing bacteria and led indirectly in attenuation of Zygomycetes virulence. Thus, the growing rates of antimicrobial resistance over the past decade selected for multidrug-resistant endosymbiotic bacteria of Zygomycetes, which could facilitate the emergence of zygomycosis. This hypothesis, if true, will be the first paradigm of modulation of virulence of opportunistic fungi by antibacterials. 相似文献
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Intrinsic protein fluorescence may interfere with the visualization of proteins after SDS-polyacrylamide electrophoresis. In an attempt to analyze tear glycoproteins in gels, we ran tear samples and stained the proteins with a glycoprotein-specific fluorescent dye. The fluorescence detected was not limited to glycoproteins. There was strong intrinsic fluorescence of proteins normally found in tears after soaking the gels in 40% methanol plus 1-10% acetic acid and, to a lesser extent, in methanol or acetic acid alone. Nanograms of proteins gave visible native fluorescence and interfere with extrinsic fluorescent dye detection. Poly-L-lysine, which does not contain intrinsically fluorescent amino acids, did not fluoresce. 相似文献
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Fazal Shirazi Dimitrios Farmakiotis Yuanqing Yan Nathaniel Albert Do Kim-Anh Dimitrios P. Kontoyiannis 《PloS one》2014,9(9)
In an experimental model of obesity and hyperglycemia in Drosophila melanogaster we studied the effect of diet modification and administration of metformin on systemic infection with Rhizopus, a common cause of mucormycosis in diabetic patients. Female Wt-type Drosophila flies were fed regular (RF) or high-fat diet (HFD; 30% coconut oil) food with or without metformin for 48 h and then injected with R. oryzae. Survival rates, glucose and triglyceride levels were compared between 1) normal-weight flies (RF), 2) obese flies (HFD), 3) obese flies fed with RF, 4) flies continuously on HFD + metformin, 5) flies fed on HFD + metformin, then transferred to RF, and 6) obese flies administered metformin after infection. Glucose levels were compared across groups of non-infected flies and across groups of infected flies. Survival was significantly decreased (P = 0.003) in obese flies, while post-infection glucose levels were significantly increased (P = 0.0001), compared to normal-weight flies. Diet and administration of metformin led to weight loss, normalized glucose levels during infection, and were associated with decreased mortality and tissue fungal burden. In conclusion, diet and metformin help control infection-associated hyperglycemia and improve survival in Drosophila flies with mucormycosis. Fly models of obesity bear intriguing similarities to the pathophysiology of insulin resistance and diabetes in humans, and can provide new insights into the pathogenesis and treatment of infections in obese and diabetic patients. 相似文献
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Transgenic mice expressing the human inducible Hsp70 have hippocampal neurons resistant to ischemic injury 总被引:10,自引:0,他引:10 下载免费PDF全文
J.-C. L. Plumier A. M. Krueger R. W. Currie D. Kontoyiannis G. Kollias G. N. Pagoulatos 《Cell stress & chaperones》1997,2(3):162-167
Using transgenic mice constitutively expressing the human inducible Hsp70, we examined the role of Hsp70 on cell survival after focal cerebral oschemia. Twenty-four hours after premanent occlusion of the middle cerebral artery, no difference in infarct area was detected between Hsp70-transgenic and non-transgenic mice. In the non-transgenic mice, many pyramidal neurons of the ipsilateral hippocampus were observed to be pykontic. However, in all Hsp70-transgenic mice, hippocampal pyramidal neurons showed normal morphology and no evidence of pyknosis. This suggests that constitutive expression of Hsp70 reduces the extent of damage following permanent middle cerebral artery occlusion. 相似文献
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A study of bacterial surface oligosaccharides were investigated among
different strains of Neisseria gonorrhoeae to correlate structural features
essential for binding to the MAb 2C7. This epitope is widely expressed and
conserved in gonococcal isolates, characteristics essential to an effective
candidate vaccine antigen. Sample lipooligosaccharides (LOS), was prepared
by a modification of the hot phenol-water method from which de-O-acetylated
LOS and oligosaccharide (OS) components were analyzed by ES-MS-CID-MS and
ES-MSnin a triple quadrupole and an ion trap mass spectrometer,
respectively. Previously documented natural heterogeneity was apparent from
both LOS and OS preparations which was admixed with fragments induced by
hydrazine and mild acid treatment. Natural heterogeneity was limited to
phosphorylation and antenni extensions to the alpha-chain. Mild acid
hydrolysis to release OS also hydrolyzed the beta(1-->6) glycosidic
linkage of lipid A. OS structures were determined by collisional and
resonance excitation combined with MS and multistep MSn which provided
sequence information from both neutral loss, and nonreducing terminal
fragments. A comparison of OS structures, with earlier knowledge of MAb
binding, enzyme treatment, and partial acid hydrolysis indicates a generic
overlapping domain for 2C7 binding. Reoccurring structural features include
a Hepalpha(1-->3)Hepbeta(1-->5)KDO trisaccharide core branched on the
nonreducing terminus (Hep-2) with an alpha(1-->2) linked GlcNAc
(gamma-chain), and an alpha-linked lactose (beta-chain) residue. From the
central heptose (Hep-1), a beta(1-->4) linked lactose (alpha-chain),
moiety is required although extensions to this residue appear unnecessary.
相似文献
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Thomas GH; Newbern EC; Korte CC; Bales MA; Muse SV; Clark AG; Kiehart DP 《Molecular biology and evolution》1997,14(12):1285-1295
Many structural, signaling, and adhesion molecules contain tandemly
repeated amino acid motifs. The alpha-actinin/spectrin/dystrophin
superfamily of F-actin-crosslinking proteins contains an array of triple
alpha-helical motifs (spectrin repeats). We present here the complete
sequence of the novel beta-spectrin isoform beta(Heavy)- spectrin (beta H).
The sequence of beta H supports the origin of alpha- and beta-spectrins
from a common ancestor, and we present a novel model for the origin of the
spectrins from a homodimeric actin-crosslinking precursor. The pattern of
similarity between the spectrin repeat units indicates that they have
evolved by a series of nested, nonuniform duplications. Furthermore, the
spectrins and dystrophins clearly have common ancestry, yet the repeat unit
is of a different length in each family. Together, these observations
suggest a dynamic period of increase in repeat number accompanied by
homogenization within each array by concerted evolution. However, today,
there is greater similarity of homologous repeats between species than
there is across repeats within species, suggesting that concerted evolution
ceased some time before the arthropod/vertebrate split. We propose a
two-phase model for the evolution of the spectrin repeat arrays in which an
initial phase of concerted evolution is subsequently retarded as each new
protein becomes constrained to a specific length and the repeats diverge at
the DNA level. This evolutionary model has general applicability to the
origins of the many other proteins that have tandemly repeated motifs.
相似文献
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Hasan Metin Aktulga Ioannis Kontoyiannis L Alex Lyznik Lukasz Szpankowski Ananth Y Grama Wojciech Szpankowski 《EURASIP Journal on Bioinformatics and Systems Biology》2007,2007(1):14741
Questions of understanding and quantifying the representation and amount of information in organisms have become a central part of biological research, as they potentially hold the key to fundamental advances. In this paper, we demonstrate the use of information-theoretic tools for the task of identifying segments of biomolecules (DNA or RNA) that are statistically correlated. We develop a precise and reliable methodology, based on the notion of mutual information, for finding and extracting statistical as well as structural dependencies. A simple threshold function is defined, and its use in quantifying the level of significance of dependencies between biological segments is explored. These tools are used in two specific applications. First, they are used for the identification of correlations between different parts of the maize zmSRp32 gene. There, we find significant dependencies between the untranslated region in zmSRp32 and its alternatively spliced exons. This observation may indicate the presence of as-yet unknown alternative splicing mechanisms or structural scaffolds. Second, using data from the FBI''s combined DNA index system (CODIS), we demonstrate that our approach is particularly well suited for the problem of discovering short tandem repeats—an application of importance in genetic profiling.[1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22] 相似文献