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21.
Ana Damjanovic Ada Y. Chen Robert L. Rosenberg Daniel R. Roe Xiongwu Wu Bernard R. Brooks 《Proteins》2020,88(3):527-539
The selectivity filter (SF) of bacterial voltage-gated sodium channels consists of four glutamate residues arranged in a C4 symmetry. The protonation state population of this tetrad is unclear. To address this question, we simulate the pore domain of bacterial voltage-gated sodium channel of Magnetococcus sp. (NavMs) through constant pH methodology in explicit solvent and free energy perturbation calculations. We find that at physiological pH the fully deprotonated as well as singly and doubly protonated states of the SF appear feasible, and that the calculated pKa decreases with each additional bound ion, suggesting that a decrease in the number of ions in the pore can lead to protonation of the SF. Previous molecular dynamics simulations have suggested that protonation can lead to a decrease in the conductance, but no pKa calculations were performed. We confirm a decreased ionic population of the pore with protonation, and also observe structural symmetry breaking triggered by protonation; the SF of the deprotonated channel is closest to the C4 symmetry observed in crystal structures of the open state, while the SF of protonated states display greater levels of asymmetry which could lead to transition to the inactivated state which possesses a C2 symmetry in the crystal structure. We speculate that the decrease in the number of ions near the mouth of the channel, due to either random fluctuations or ion depletion due to conduction, could be a self-regulatory mechanism resulting in a nonconducting state that functionally resembles inactivated states. 相似文献
22.
Ada Wróblewska 《Botanical journal of the Linnean Society. Linnean Society of London》2013,173(1):64-76
Surveys of genetic diversity patterns of self‐incompatible clonal polyploid plant species are still scarcer than those of diploid plant species. Therefore, I studied the phylogeographical history of Linnaea borealis subsp. borealis to shed light on the colonization history of this clonal self‐incompatible polyploid plant in Eurasia using selected regions of plastid DNA and genetic diversity patterns of 22 populations of this species employing AFLP markers. I also addressed the question of whether the genetic diversity patterns in L. borealis subsp. borealis in Eurasia are similar to those of earlier published studies of clonal self‐incompatible diploid or polyploid plants. This survey revealed that the shallow phylogeographical history (six plastid haplotypes forming one haplogroup, 100% bootstrap support) and moderate genome‐wide diversity estimated using AFLP markers (Fragpoly = 10.8–38.9%, I = 0.060–0.180, FST = 0.289) were general characteristics of L. borealis subsp. borealis in its Eurasian range. The sampling strategy, in most cases at 1–2‐m or even 3–5‐m intervals, showed that a balance between vegetative and sexual reproduction and limited pollen dispersal among compatible mates can be important for genetic diversity patterns in populations of this taxon. Despite the fact that one‐half of the investigated populations were strongly isolated, they still preserved similar levels of genetic diversity across the geographical range. I found no support for the hypothesis that a bottleneck and/or inbreeding had accompanied habitat fragmentation as factors shaping genetic diversity. © 2013 The Linnean Society of London, Botanical Journal of the Linnean Society, 2013, 173 , 64–76. 相似文献
23.
Christian Burri Patrick D. Yeramian James L. Allen Ada Merolle Kazadi Kyanza Serge Alain Mpanya Pascal Lutumba Victor Kande Betu Ku Mesu Constantin Miaka Mia Bilenge Jean-Pierre Fina Lubaki Alfred Mpoo Mpoto Mark Thompson Blaise Fungula Munungu Francisco Manuel Théophilo Josenando Sonja C. Bernhard Carol A. Olson Johannes Blum Richard R. Tidwell Gabriele Pohlig 《PLoS neglected tropical diseases》2016,10(2)
Background
Sleeping sickness (human African trypanosomiasis [HAT]) is caused by protozoan parasites and characterized by a chronic progressive course, which may last up to several years before death. We conducted two Phase 2 studies to determine the efficacy and safety of oral pafuramidine in African patients with first stage HAT.Methods
The Phase 2a study was an open-label, non-controlled, proof-of-concept study where 32 patients were treated with 100 mg of pafuramidine orally twice a day (BID) for 5 days at two trypanosomiasis reference centers (Angola and the Democratic Republic of the Congo [DRC]) between August 2001 and November 2004. The Phase 2b study compared pafuramidine in 41 patients versus standard pentamidine therapy in 40 patients. The Phase 2b study was open-label, parallel-group, controlled, randomized, and conducted at two sites in the DRC between April 2003 and February 2007. The Phase 2b study was then amended to add an open-label sequence (Phase 2b-2), where 30 patients received pafuramidine for 10 days. The primary efficacy endpoint was parasitologic cure at 24 hours (Phase 2a) or 3 months (Phase 2b) after treatment completion. The primary safety outcome was the rate of occurrence of World Health Organization Toxicity Scale Grade 3 or higher adverse events. All subjects provided written informed consent.Findings/Conclusion
Pafuramidine for the treatment of first stage HAT was comparable in efficacy to pentamidine after 10 days of dosing. The cure rates 3 months post-treatment were 79% in the 5-day pafuramidine, 100% in the 7-day pentamidine, and 93% in the 10-day pafuramidine groups. In Phase 2b, the percentage of patients with at least 1 treatment-emergent adverse event was notably higher after pentamidine treatment (93%) than pafuramidine treatment for 5 days (25%) and 10 days (57%). These results support continuation of the development program for pafuramidine into Phase 3. 相似文献24.
Lilach Moyal Nataly Feldbaum Neta Goldfeiz Ada Rephaeli Abraham Nudelman Michal Weitman Nataly Tarasenko Batia Gorovitz Leah Maron Shiran Yehezkel Iris Amitay-Laish Ido Lubin Emmilia Hodak 《PloS one》2016,11(1)
The 2 histone deacetylase inhibitors (HDACIs) approved for the treatment of cutaneous T-cell lymphoma (CTCL) including mycosis fungoides/sezary syndrome (MF/SS), suberoylanilide hydroxamic acid (SAHA) and romidepsin, are associated with low rates of overall response and high rates of adverse effects. Data regarding combination treatments with HDACIs is sparse. Butyroyloxymethyl diethylphosphate (AN-7) is a novel HDACI, which was found to have selective anticancer activity in several cell lines and animal models. The aim of this study was to compare the anticancer effects of AN-7 and SAHA, either alone or combined with doxorubicin, on MF/SS cell lines and peripheral blood lymphocytes (PBL) from patients with Sezary syndrome (SPBL). MyLa cells, Hut78 cells, SPBL, and PBL from healthy normal individuals (NPBL) were exposed to the test drugs, and the findings were analyzed by a viability assay, an apoptosis assay, and Western blot. AN-7 was more selectively toxic to MyLa cells, Hut78 cells, and SPBL (relative to NPBL) than SAHA and also acted more rapidly. Both drugs induced apoptosis in MF/SS cell lines, SAHA had a greater effect on MyLa cell line, while AN-7 induced greater apoptosis in SPBL; both caused an accumulation of acetylated histone H3, but AN-7 was associated with earlier kinetics; and both caused a downregulation of the HDAC1 protein in MF/SS cell lines. AN-7 acted synergistically with doxorubicin in both MF/SS cell lines and SPBL, and antagonistically with doxorubicin in NPBL. By contrast, SAHA acted antagonistically with doxorubicin on MF/SS cell lines, SPBL, and NPBL, leaving <50% viable cells. In conclusion, AN-7 holds promise as a therapeutic agent in MF/SS and has several advantages over SAHA. Our data provide a rationale for combining AN-7, but not SAHA, with doxorubicin to induce the cell death in MF/SS. 相似文献
25.
Okon EB Chung AW Zhang H Laher I van Breemen C 《Canadian journal of physiology and pharmacology》2007,85(5):562-567
Diabetes mellitus impairs endothelial function, which can be considered as the hallmark in the development of cardiovascular diseases. Hyperglycemia, hyperinsulinemia, and hyperlipidemia are believed to contribute to endothelial dysfunction. In the present study, we investigated the possible links among these plasma metabolic markers and endothelial function in a mouse model during the development of type 2 diabetes. C57BL/6J-Lepob/ob mice at 8, 12, and 16 weeks were used to study endothelial function during the establishment of type 2 diabetes. Endothelial function was accessed in vitro in the thoracic aorta by measuring acetylcholine (ACh)-stimulated vasodilatation. Blood plasma was obtained for the measurements of glucose, insulin, triglycerides, and cholesterol levels. Correlation and multiple regression analysis revealed strong negative associations between the ACh responsiveness and the plasma levels of glucose, insulin, and lipid profiles at the age of 8 weeks. Associations were observed at neither older age nor in C57BL/6J mice. In conclusion, the increase in plasma levels of glucose, insulin, and lipids is associated with the impairment of the endothelial function during the early stage of the development of type 2 diabetes. The loss of correlation at an older age suggests multifactorial regulation of endothelial function and cardiovascular complications at later stages of the disease. 相似文献
26.
Leonard RC Kreckmann KH Lineker GA Marsh G Buchanich J Youk A 《Chemico-biological interactions》2007,166(1-3):317-322
The DuPont Company has maintained a mortality registry for all active and pensioned U.S. employees since 1957. Standardized mortality ratios (SMRs) for each plant site in the U.S. can be calculated based on the comparison with the entire U.S. DuPont population or with a regional subset of DuPont employees. We compared the SMRs derived from a large, international cohort mortality study of chloroprene workers (IISRP study) with those derived from the entire DuPont Registry and appropriate subpopulations of the registry for two U.S. neoprene plants--Louisville (Kentucky) and Pontchartrain (Louisiana). SMRs from the IISRP study for the Louisville cohort based on national rates for all causes of death, all cancers, respiratory cancer, and liver cancer are higher than those based on local mortality rates. Both the national and local comparisons (several counties surrounding each plant) for all-cancer SMRs are lower than 1.0, the local comparison being statistically significantly reduced. In contrast, the SMRs based on the total U.S. DuPont worker mortality rates for all causes of death (1.13), all cancers (1.11), and respiratory cancers (1.37) are statistically significantly increased. The SMR for liver cancer (1.27), although elevated, is not statistically significant. SMRs based on DuPont Region 1 were closer to 1.0, and the SMR for all cancers was no longer significant. Stratification of the Louisville subcohort of males using the same cumulative exposure categories used in the IISRP study yielded SMRs calculated against DuPont Region 1 that were generally higher than those calculated against U.S. and local rates. Only the third exposure category showed SMRs statistically significantly above 1.0 for all cancers and for cancer of bronchus, trachea, and lung. However, there does not appear to be an exposure-response trend. The SMRs from the IISRP study for the Pontchartrain cohort based on national rates are higher than those based on local rates for all causes of death, but all are less than 1.0. The all-cause SMRs for both local and national comparisons are significantly reduced. There were no deaths from liver cancers observed in this cohort. Comparisons of the Pontchartrain cohort against the total U.S. DuPont worker mortality rates resulted in higher SMRs for all causes of death (0.98), all cancers (1.03), and respiratory cancer (1.08), but none were statistically significant. SMRs based on DuPont Region 2 showed very little change from those based on the total registry. The use of reference rates based on regional workers in the same large company produces SMRs lower than those based on the entire company population (regional socio-cultural effects) but higher than those based on geographically closer local general populations (healthy worker effect). The healthy worker effect is seen in cancer mortality rates as well as in other chronic diseases. 相似文献
27.
Beta-arrestin and Mdm2 mediate IGF-1 receptor-stimulated ERK activation and cell cycle progression 总被引:1,自引:0,他引:1
Girnita L Shenoy SK Sehat B Vasilcanu R Vasilcanu D Girnita A Lefkowitz RJ Larsson O 《The Journal of biological chemistry》2007,282(15):11329-11338
Beta-arrestin1, which regulates many aspects of seven transmembrane receptor (7TMR) biology, has also been shown to serve as an adaptor, which brings Mdm2, an E3 ubiquitin ligase to the insulin-like growth factor-1 receptor (IGF-1R), leading to its proteasome-dependent destruction. Here we demonstrate that IGF-1R stimulation also leads to ubiquitination of beta-arrestin1, which regulates vesicular trafficking and activation of ERK1/2. This beta-arrestin1-dependent ERK activity can occur even when the classical tyrosine kinase signaling is impaired. siRNA-mediated suppression of beta-arrestin1 in human melanoma cells ablates IGF-1-stimulated ERK and prolongs the G1 phase of the cell cycle. These data suggest that beta-arrestin-dependent ERK signaling by the IGF-1R regulates cell cycle progression and may thus be an important regulator of the growth of normal and malignant cells. 相似文献
28.
29.
Tiamulin, a prominent member of the pleuromutilin class of antibiotics, is a potent inhibitor of protein synthesis in bacteria. Up to now the effect of pleuromutilins on the ribosome has not been determined on a molecular level. The 3.5 A structure of the 50S ribosomal subunit from Deinococcus radiodurans in complex with tiamulin provides for the first time a detailed picture of its interactions with the 23S rRNA, thus explaining the molecular mechanism of the antimicrobial activity of the pleuromutilin class of antibiotics. Our results show that tiamulin is located within the peptidyl transferase center (PTC) of the 50S ribosomal subunit with its tricyclic mutilin core positioned in a tight pocket at the A-tRNA binding site. Also, the extension, which protrudes from its mutilin core, partially overlaps with the P-tRNA binding site. Thereby, tiamulin directly inhibits peptide bond formation. Comparison of the tiamulin binding site with other PTC targeting drugs, like chloramphenicol, clindamycin and streptogramins, may facilitate the design of modified or hybridized drugs that extend the applicability of this class of antibiotics. 相似文献
30.
Linkage disequilibrium and sequence diversity in a 500-kbp region around the adh1 locus in elite maize germplasm 总被引:6,自引:0,他引:6
Jung M Ching A Bhattramakki D Dolan M Tingey S Morgante M Rafalski A 《TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik》2004,109(4):681-689
Linkage disequilibrium (LD) at the adh1 locus was examined in two sets of maize inbreds. A set of 32 was chosen to represent most of the genetic diversity in the cultivated North American elite maize breeding pool. A second set of 192 inbreds was chosen to sample more deeply the two major heterotic groups in elite maize germplasm. Analysis of several loci in the vicinity of the adh1 gene shows that LD as measured by D and r2 extends greater than 500 kbp in this germplasm. The presence of this exceptionally long segment of high LD may be suggestive of selection acting on one of the genes in the vicinity of adh1 or of a locally reduced rate of recombination.Electronic Supplementary Material Supplementary material is available for this article at . 相似文献