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1.
The structure of stryspinolactone, an unusual lactone from Strychnos spinosa, was determined from spectroscopic data. 相似文献
2.
Kayode K. Ojo Ranae M. Ranade Zhongsheng Zhang David M. Dranow Janette B. Myers Ryan Choi Steve Nakazawa Hewitt Thomas E. Edwards Douglas R. Davies Donald Lorimer Stephen M. Boyle Lynn K. Barrett Frederick S. Buckner Erkang Fan Wesley C. Van Voorhis 《PloS one》2016,11(8)
We investigated Brucella melitensis methionyl-tRNA-synthetase (BmMetRS) with molecular, structural and phenotypic methods to learn if BmMetRS is a promising target for brucellosis drug development. Recombinant BmMetRS was expressed, purified from wild type Brucella melitensis biovar Abortus 2308 strain ATCC/CRP #DD-156 and screened by a thermal melt assay against a focused library of one hundred previously classified methionyl-tRNA-synthetase inhibitors of the blood stage form of Trypanosoma brucei. Three compounds showed appreciable shift of denaturation temperature and were selected for further studies on inhibition of the recombinant enzyme activity and cell viability against wild type B. melitensis strain 16M. BmMetRS protein complexed with these three inhibitors resolved into three-dimensional crystal structures and was analyzed. All three selected methionyl-tRNA-synthetase compounds inhibit recombinant BmMetRS enzymatic functions in an aminoacylation assay at varying concentrations. Furthermore, growth inhibition of B. melitensis strain 16M by the compounds was shown. Inhibitor-BmMetRS crystal structure models were used to illustrate the molecular basis of the enzyme inhibition. Our current data suggests that BmMetRS is a promising target for brucellosis drug development. However, further studies are needed to optimize lead compound potency, efficacy and safety as well as determine the pharmacokinetics, optimal dosage, and duration for effective treatment. 相似文献
3.
Gregory J. Crowther Heidi K. Hillesland Katelyn R. Keyloun Molly C. Reid Maria Jose Lafuente-Monasterio Sonja Ghidelli-Disse Stephen E. Leonard Panqing He Jackson C. Jones Mallory M. Krahn Jack S. Mo Kartheek S. Dasari Anna M. W. Fox Markus Boesche Majida El Bakkouri Kasey L. Rivas Didier Leroy Raymond Hui Gerard Drewes Dustin J. Maly Wesley C. Van Voorhis Kayode K. Ojo 《PloS one》2016,11(3)
In 2010 the identities of thousands of anti-Plasmodium compounds were released publicly to facilitate malaria drug development. Understanding these compounds’ mechanisms of action—i.e., the specific molecular targets by which they kill the parasite—would further facilitate the drug development process. Given that kinases are promising anti-malaria targets, we screened ~14,000 cell-active compounds for activity against five different protein kinases. Collections of cell-active compounds from GlaxoSmithKline (the ~13,000-compound Tres Cantos Antimalarial Set, or TCAMS), St. Jude Children’s Research Hospital (260 compounds), and the Medicines for Malaria Venture (the 400-compound Malaria Box) were screened in biochemical assays of Plasmodium falciparum calcium-dependent protein kinases 1 and 4 (CDPK1 and CDPK4), mitogen-associated protein kinase 2 (MAPK2/MAP2), protein kinase 6 (PK6), and protein kinase 7 (PK7). Novel potent inhibitors (IC50 < 1 μM) were discovered for three of the kinases: CDPK1, CDPK4, and PK6. The PK6 inhibitors are the most potent yet discovered for this enzyme and deserve further scrutiny. Additionally, kinome-wide competition assays revealed a compound that inhibits CDPK4 with few effects on ~150 human kinases, and several related compounds that inhibit CDPK1 and CDPK4 yet have limited cytotoxicity to human (HepG2) cells. Our data suggest that inhibiting multiple Plasmodium kinase targets without harming human cells is challenging but feasible. 相似文献
4.
Gabriela B. Gomez Nicola Foster Daniella Brals Heleen E. Nelissen Oladimeji A. Bolarinwa Marleen E. Hendriks Alexander C. Boers Diederik van Eck Nicole Rosendaal Peju Adenusi Kayode Agbede Tanimola M. Akande Michael Boele van Hensbroek Ferdinand W. Wit Catherine A. Hankins Constance Schultsz 《PloS one》2015,10(9)
Background
While the Nigerian government has made progress towards the Millennium Development Goals, further investments are needed to achieve the targets of post-2015 Sustainable Development Goals, including Universal Health Coverage. Economic evaluations of innovative interventions can help inform investment decisions in resource-constrained settings. We aim to assess the cost and cost-effectiveness of maternal care provided within the new Kwara State Health Insurance program (KSHI) in rural Nigeria.Methods and Findings
We used a decision analytic model to simulate a cohort of pregnant women. The primary outcome is the incremental cost effectiveness ratio (ICER) of the KSHI scenario compared to the current standard of care. Intervention cost from a healthcare provider perspective included service delivery costs and above-service level costs; these were evaluated in a participating hospital and using financial records from the managing organisations, respectively. Standard of care costs from a provider perspective were derived from the literature using an ingredient approach. We generated 95% credibility intervals around the primary outcome through probabilistic sensitivity analysis (PSA) based on a Monte Carlo simulation. We conducted one-way sensitivity analyses across key model parameters and assessed the sensitivity of our results to the performance of the base case separately through a scenario analysis. Finally, we assessed the sustainability and feasibility of this program’s scale up within the State’s healthcare financing structure through a budget impact analysis. The KSHI scenario results in a health benefit to patients at a higher cost compared to the base case. The mean ICER (US$46.4/disability-adjusted life year averted) is considered very cost-effective compared to a willingness-to-pay threshold of one gross domestic product per capita (Nigeria, US$ 2012, 2,730). Our conclusion was robust to uncertainty in parameters estimates (PSA: median US$49.1, 95% credible interval 21.9–152.3), during one-way sensitivity analyses, and when cost, quality, cost and utilization parameters of the base case scenario were changed. The sustainability of this program’s scale up by the State is dependent on further investments in healthcare.Conclusions
This study provides evidence that the investment made by the KSHI program in rural Nigeria is likely to have been cost-effective; however, further healthcare investments are needed for this program to be successfully expanded within Kwara State. Policy makers should consider supporting financial initiatives to reduce maternal mortality tackling both supply and demand issues in the access to care. 相似文献5.
6.
The coupling of succinate oxidation to the reduction of ubiquinone by succinate dehydrogenase (SDH) constitutes a pivotal reaction in the aerobic generation of energy. In Saccharomyces cerevisiae, SDH is a tetramer composed of a catalytic dimer comprising a flavoprotein subunit, Sdh1p and an iron-sulfur protein, Sdh2p and a heme b-containing membrane-anchoring dimer comprising the Sdh3p and Sdh4p subunits. In order to investigate the role of heme in SDH catalysis, we constructed an S. cerevisiae strain expressing a mutant enzyme lacking the two heme axial ligands, Sdh3p His-106 and Sdh4p Cys-78. The mutant enzyme was characterized for growth on a non-fermentable carbon source, for enzyme assembly, for succinate-dependent quinone reduction and for its heme b content. Replacement of both Sdh3p His-106 and Sdh4p Cys-78 with alanine residues leads to an undetectable level of cytochrome b562. Although enzyme assembly is slightly impaired, the apocytochrome SDH retains a significant ability to reduce quinone. The enzyme has a reduced affinity for quinone and its catalytic efficiency is reduced by an order of magnitude. To better understand the effects of the mutations, we employed atomistic molecular dynamic simulations to investigate the enzyme's structure and stability in the absence of heme. Our results strongly suggest that heme is not required for electron transport from succinate to quinone nor is it necessary for assembly of the S. cerevisiae SDH. 相似文献
7.
Julie Orjuela François Sabot Sophie Chéron Yves Vigouroux Hélène Adam Harold Chrestin Kayode Sanni Mathias Lorieux Alain Ghesquière 《TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik》2014,127(10):2211-2223
Key message
We present here the first curated collection of wild and cultivated African rice species. For that, we designed specific SNPs and were able to structure these very low diverse species.Abstract
Oryza glaberrima, the cultivated African rice, is endemic from Africa. This species and its direct ancestor, O. barthii, are valuable tool for improvement of Asian rice O. sativa in terms of abiotic and biotic stress resistance. However, only a few limited studies about the genetic diversity of these species were performed. In the present paper, and for the first time at such extend, we genotyped 279 O. glaberrima, selected both for their impact in current breeding and for their geographical distribution, and 101 O. barthii, chosen based on their geographic origin, using a set of 235 SNPs specifically designed for African rice diversity. Using those data, we were able to structure the individuals from our sample in three populations for O. barthii, related to geography, and two populations in O. glaberrima; these two last populations cannot be linked however to any currently phenotyped trait. Moreover, we were also able to identify misclassification in O. glaberrima as well as in O. barthii and identified new form of O. sativa from the set of African varieties. 相似文献8.
Gram-positive merA gene in gram-negative oral and urine bacteria 总被引:1,自引:0,他引:1
Clinical mercury resistant (Hg(r)) Gram-negative bacteria carrying Gram-positive mercury reductase (merA)-like genes were characterized using DNA-DNA hybridization, PCR and sequencing. A PCR assay was developed which discriminated between the merA genes related to Staphylococcus and those related to the Bacillus/Streptococcus merA genes by the difference in size of the PCR product. DNA sequence analysis correlated with the PCR assay. The merA genes from Acinetobacter junii, Enterobacter cloacae and Escherichia coli were sequenced and shared 98-99% identical nucleotide (nt) and 99.6-100% amino acid identity with the Staphylococcus aureus MerA protein. A fourth merA gene, from Pantoeae agglomerans, was partially sequenced (60%) and had 99% identical nt and 100% amino acid identity with the Streptococcus oralis MerA protein. All the Hg(r) Gram-negative bacteria transferred their Gram-positive merA genes to a Gram-positive Enterococcus faecalis recipient with the resulting transconjugants expressing mercury resistance. These Gram-positive merA genes join Gram-positive tetracycline resistance and Gram-positive macrolide resistance genes in their association with mobile elements which are able to transfer and express in Gram-negative bacteria. 相似文献
9.
Kayode Ezekiel Ogunsola Omena Bernard Ojuederie Blessing Emmanuel 《Plant Cell, Tissue and Organ Culture》2016,127(3):613-622
Morphogenic responses of two accessions of African yam bean to different concentrations of plant growth regulator supplements to Murashige and Skoog basal medium was investigated to develop a more efficient regeneration system. Mature embryo explants were cultured on growth regulator-free and BAP + NAA supplemented media. Nodal cuttings excised from 4-week old shoots of the regenerated embryos were cultured on media containing varying concentrations and combinations of 6-benzyl aminopurine (BAP), kinetin and α-naphthalene acetic acid (NAA). Growth regulator-free medium favored embryo regeneration and growth over supplemented media and both enhanced shoot regeneration and rooting, but could not induce multiple shoot formation on embryo explants. Multiple shoots were produced by nodal explants and the highest average number of shoots (5.3 ± 2.3), leaves (7.7 ± 3.6), roots (3.7 ± 2.9) and root length (3.1 ± 0.0 cm) were obtained on a medium with 0.6 mg l?1 BAP + 0.03 mg l?1 NAA for accession TSs154, while in TSs5, highest number of shoots (3.2 ± 2.5) and leaves (5.9 ± 1.5) were induced by 2.0 mg l?1 Kinetin + 0.05 mg l?1 NAA. Such differential morphogenic responses to culture media underline the genotypic control of in vitro propagation of this crop. Embryo and nodal explants rooted directly on shoot regeneration media, and regenerated plantlets were successfully acclimatized. The efficient regeneration system obtained will enhance genetic improvement of African yam bean by facilitating molecular genetic transformation for advanced breeding. 相似文献
10.
Jamiu Oladipupo Azeez Olabisi Adenike Hassan Johnson Kayode Adesodun Toyin Ayodele Arowolo 《Soil & Sediment Contamination》2013,22(8):930-957
Heavy metal pollution in soils and the high costs of remediation necessitate the evaluation of cheaper alternatives. The aim of this experiment was to evaluate Cd, Pb, Zn, and Cu sorption characteristics of three soils and their influence on the comparative effectiveness of EDTA and legume intercrop on the remediative abilities of maize, mucuna, okra, and kenaf. The sorption studies were done using standard procedures. The EDTA-assisted phytoextraction (6 mmol kg?1) and the cowpea intercrop trials were conducted in triplicate. The metal-spiked soils were planted with maize, kenaf, and mucuna in the EDTA trial and maize, kenaf, and okra were planted in the cowpea intercrop experiment. Cadmium was prefentially sorbed in acid and alkaline soils and Cu in slightly acid soil. Cadmium uptake was significantly lower (P < 0.05) in all the plants. Bioconcentration factors of Pb, Cu, and Zn were higher (P < 0.05) in maize compared with other plants. Phytoremediative ability of the plants in trials were maize > kenaf > mucuna and okra > maize > kenaf, respectively. It was concluded that a legume intercrop can substitute EDTA- assisted phytoextraction to prevent groundwater contamination resulting from high solubility of metals by EDTA. 相似文献