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991.
Sanna D Pecoraro VL Micera G Garribba E 《Journal of biological inorganic chemistry》2012,17(5):773-790
Density functional theory (DFT) methods were used to simulate the environment of vanadium in several V proteins, such as vanadyl-substituted carboxypeptidase (sites A and B), vanadyl-substituted chloroplast F(1)-ATPase (CF(1); site 3), the reduced inactive form of vanadium bromoperoxidase (VBrPO; low- and high-pH sites), and vanadyl-substituted imidazole glycerol phosphate dehydratase (IGPD; sites α, β, and γ). Structural, electron paramagnetic resonance, and electron spin echo envelope modulation parameters were calculated and compared with the experimental values. All the simulations were performed in water within the framework of the polarizable continuum model. The angular dependence of [Formula: see text] and [Formula: see text] on the dihedral angle θ between the V=O and N-C bonds and on the angle φ between the V=O and V-N bonds, where N is the coordinated aromatic nitrogen atom, was also found. From the results it emerges that it is possible to model the active site of a vanadium protein through DFT methods and determine its structure through the comparison between the calculated and experimental spectroscopic parameters. The calculations confirm that the donor sets of sites B and A of vanadyl-substituted carboxypeptidase are [[Formula: see text], H(2)O, H(2)O, H(2)O] and [N(His)(||), N(His)(⊥), [Formula: see text], H(2)O], and that the donor set of site 3 of CF(1)-ATPase is [[Formula: see text], OH(Thr), H(2)O, H(2)O, [Formula: see text]]. For VBrPO, the coordination modes [N(His)(||), N(His)(∠), OH(Ser), H(2)O, H(2)O(ax)] for the low-pH site and [N(His)(||), N(His)(∠), OH(Ser), OH(-), H(2)O(ax)] or [N(His)(||), N(His)(∠), [Formula: see text], H(2)O] for the high-pH site, with an imidazole ring of histidine strongly displaced from the equatorial plane, can be proposed. Finally, for sites α, β, and γ of IGPD, the subsequent deprotonation of one, two, and three imidazole rings of histidine and the participation of a carboxylate group of a glutamate residue ([N(His)(||), [Formula: see text], H(2)O, H(2)O], [N(His)(||), N(His)(||), [Formula: see text], H(2)O], and [N(His)(||), N(His)(||), [Formula: see text], OH(-), [Formula: see text]], respectively) seems to be the most plausible hypothesis. 相似文献
992.
993.
994.
Youngsaye W Dockendorff C Vincent B Hartland CL Bittker JA Dandapani S Palmer M Whitesell L Lindquist S Schreiber SL Munoz B 《Bioorganic & medicinal chemistry letters》2012,22(9):3362-3365
Continuing efforts to discover novel means of combating fluconazole resistance in Candida albicans have identified an indole derivative that sensitizes strains demonstrating resistance to fluconazole. This tetracycle (3, ML229) does not appear to act through established Hsp90 or calcineurin pathways to chemosensitize C. albicans, as determined in Saccharomyces cerevisiae models, and may be a useful probe to uncover alternative resistance pathways. 相似文献
995.
Trypanosomatids represent the causative agents of major diseases in humans, livestock and plants, with inevitable suffering and economic hardship as a result. They are also evolutionarily highly divergent organisms, and the many unique aspects of trypanosome biology provide opportunities in terms of identification of drug targets, the challenge of exploiting these putative targets and, at the same time, significant scope for exploration of novel and divergent cell biology. We can estimate from genome sequences that the degree of divergence of trypanosomes from animals and fungi is extreme, with perhaps one third to one half of predicted trypanosome proteins having no known function based on homology or recognizable protein domains/architecture. Two highly important aspects of trypanosome biology are the flagellar pocket and the nuclear envelope, where in silico analysis clearly suggests great potential divergence in the proteome. The flagellar pocket is the sole site of endo- and exocytosis in trypanosomes and plays important roles in immune evasion via variant surface glycoprotein (VSG) trafficking and providing a location for sequestration of various invariant receptors. The trypanosome nuclear envelope has been largely unexplored but, by analogy with higher eukaryotes, roles in the regulation of chromatin and most significantly, in controlling VSG gene expression are expected. Here we discuss recent successful proteomics-based approaches towards characterization of the nuclear envelope and the endocytic apparatus, the identification of conserved and novel trypanosomatid-specific features, and the implications of these findings. 相似文献
996.
997.
Arvizo RR Giri K Moyano D Miranda OR Madden B McCormick DJ Bhattacharya R Rotello VM Kocher JP Mukherjee P 《PloS one》2012,7(3):e33650
Background
We introduce a promising methodology to identify new therapeutic targets in cancer. Proteins bind to nanoparticles to form a protein corona. We modulate this corona by using surface-engineered nanoparticles, and identify protein composition to provide insight into disease development.Methods/Principal Findings
Using a family of structurally homologous nanoparticles we have investigated the changes in the protein corona around surface-functionalized gold nanoparticles (AuNPs) from normal and malignant ovarian cell lysates. Proteomics analysis using mass spectrometry identified hepatoma-derived growth factor (HDGF) that is found exclusively on positively charged AuNPs (+AuNPs) after incubation with the lysates. We confirmed expression of HDGF in various ovarian cancer cells and validated binding selectivity to +AuNPs by Western blot analysis. Silencing of HDGF by siRNA resulted s inhibition in proliferation of ovarian cancer cells.Conclusion
We investigated the modulation of protein corona around surface-functionalized gold nanoparticles as a promising approach to identify new therapeutic targets. The potential of our method for identifying therapeutic targets was demonstrated through silencing of HDGF by siRNA, which inhibited proliferation of ovarian cancer cells. This integrated proteomics, bioinformatics, and nanotechnology strategy demonstrates that protein corona identification can be used to discover novel therapeutic targets in cancer. 相似文献998.
Shannon K Leiter K Phaladze N Hlanze Z Tsai AC Heisler M Iacopino V Weiser SD 《PloS one》2012,7(1):e28739
Background
There is limited empirical research on the underlying gender inequity norms shaping gender-based violence, power, and HIV risks in sub-Saharan Africa, or how risk pathways may differ for men and women. This study is among the first to directly evaluate the adherence to gender inequity norms and epidemiological relationships with violence and sexual risks for HIV infection.Methods
Data were derived from population-based cross-sectional samples recruited through two-stage probability sampling from the 5 highest HIV prevalence districts in Botswana and all districts in Swaziland (2004–5). Based on evidence of established risk factors for HIV infection, we aimed 1) to estimate the mean adherence to gender inequity norms for both men and women; and 2) to model the independent effects of higher adherence to gender inequity norms on a) male sexual dominance (male-controlled sexual decision making and rape (forced sex)); b) sexual risk practices (multiple/concurrent sex partners, transactional sex, unprotected sex with non-primary partner, intergenerational sex).Findings
A total of 2049 individuals were included, n = 1255 from Botswana and n = 796 from Swaziland. In separate multivariate logistic regression analyses, higher gender inequity norms scores remained independently associated with increased male-controlled sexual decision making power (AORmen = 1.90, 95%CI:1.09–2.35; AORwomen = 2.05, 95%CI:1.32–2.49), perpetration of rape (AORmen = 2.19 95%CI:1.22–3.51), unprotected sex with a non-primary partner (AORmen = 1.90, 95%CI:1.14–2.31), intergenerational sex (AORwomen = 1.36, 95%CI:1.08–1.79), and multiple/concurrent sex partners (AORmen = 1.42, 95%CI:1.10–1.93).Interpretation
These findings support the critical evidence-based need for gender-transformative HIV prevention efforts including legislation of women''s rights in two of the most HIV affected countries in the world. 相似文献999.
1000.
Wildeman MA Fles R Adham M Mayangsari ID Luirink I Sandberg M Vincent AD Fardizza F Musa Z Armiyanto Middeldorp JM Gerritsen G Suwanto R Tan IB 《PloS one》2012,7(3):e32756
In Indonesia, Nasopharyngeal Carcinoma (NPC) is the most frequent cancer of the head and neck region. At first presentation in the hospital most patients already have advanced NPC. Our previous study showed that general practitioners (GPs) working in Yogyakarta, Indonesia lack the knowledge necessary for early detection of NPC. By providing training on early symptoms of NPC we hope that the diagnosis and referral will occur at an earlier stage. Here we assess the current NPC knowledge levels of GPs in Jakarta, evaluate improvement after training, compare the effectiveness of two training formats, and estimate the loss of recall over a two week period.