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121.
Nissim I Luhovyy B Horyn O Daikhin Y Nissim I Yudkoff M 《The Journal of biological chemistry》2005,280(18):17715-17724
The main goal of the current study was to elucidate the role of mitochondrial arginine metabolism in the regulation of N-acetylglutamate and urea synthesis. We hypothesized that arginine catabolism via mitochondrially bound arginase augments ureagenesis by supplying ornithine for net synthesis of citrulline, glutamate, N-acetylglutamate, and aspartate. [U-(15)N(4)]arginine was used as precursor and isolated mitochondria or liver perfusion as a model system to monitor arginine catabolism and the incorporation of (15)N into various intermediate metabolites of the urea cycle. The results indicate that approximately 8% of total mitochondrial arginase activity is located in the matrix, and 90% is located in the outer membrane. Experiments with isolated mitochondria showed that approximately 60-70% of external [U-(15)N(4)]arginine catabolism was recovered as (15)N-labeled ornithine, glutamate, N-acetylglutamate, citrulline, and aspartate. The production of (15)N-labeled metabolites was time- and dose-dependent. During liver perfusion, urea containing one (U(m+1)) or two (U(m+2)) (15)N was generated from perfusate [U-(15)N(4)]arginine. The output of U(m+2) was between 3 and 8% of total urea, consistent with the percentage of activity of matrix arginase. U(m+1) was formed following mitochondrial production of [(15)N]glutamate from [alpha,delta-(15)N(2)]ornithine and transamination of [(15)N]glutamate to [(15)N]aspartate. The latter is transported to cytosol and incorporated into argininosuccinate. Approximately 70, 75, 7, and 5% of hepatic ornithine, citrulline, N-acetylglutamate, and aspartate, respectively, were derived from perfusate [U-(15)N(4)]arginine. The results substantiate the hypothesis that intramitochondrial arginase, presumably the arginase-II isozyme, may play an important role in the regulation of hepatic ureagenesis by furnishing ornithine for net synthesis of N-acetylglutamate, citrulline, and aspartate. 相似文献
122.
Jan Brants Kostyantyn Semenchenko Christine Wasylyk Aude Robert Annaick Carles Alberto Zambrano Karine Pradeau-Aubreton Catherine Birck Jack A. Schalken Olivier Poch Jan de Mey Bohdan Wasylyk 《PloS one》2012,7(12)
hTTLL12 is a member of the tubulin tyrosine ligase (TTL) family that is highly conserved in phylogeny. It has both SET-like and TTL-like domains, suggesting that it could have histone methylation and tubulin tyrosine ligase activities. Altered expression of hTTLL12 in human cells leads to specific changes in H4K20 trimethylation, and tubulin detyrosination, hTTLL12 does not catalyse histone methylation or tubulin tyrosination in vitro, as might be expected from the lack of critical amino acids in its SET-like and TTLL-like domains. hTTLL12 misexpression increases mitotic duration and chromosome numbers. These results suggest that hTTLL12 has non-catalytic functions related to tubulin and histone modification, which could be linked to its effects on mitosis and chromosome number stability. 相似文献
123.
A UV-Vis absorption study was performed in order to elucidate the electronic energy levels of three tetragonal chromium (III) complexes, namely trans-[Cr(en)2(CN)2]ClO4, trans-[Cr(cyclam)(CN)2]ClO4, and trans-[Cr(NH3)4(CN)2]ClO4. The absorption spectra of the preceding complexes have been analyzed via Gaussian analysis to locate the quartet band maxima of the tetragonal components. The deconvoluted band maxima were then fitted with the tetragonal energy matrices of d3 configuration with full configuration interaction, neglecting spin-orbit interaction. The ligand field parameters Dq, Dt, and Ds along with the electron correlation parameters have been extracted via the fitting procedure. The significance of these parameters and the translated angular overlap model parameters has been discussed. We have also uncovered in the spectrum of the ethylenediamine complex the low intensity doublet absorption bands and a high intensity charge transfer band which have been tentatively assigned. 相似文献
124.
Andriy Kryshtafovych Sony Malhotra Bohdan Monastyrskyy Tristan Cragnolini Agnel-Praveen Joseph Wah Chiu Maya Topf 《Proteins》2019,87(12):1128-1140
Structures of seven CASP13 targets were determined using cryo-electron microscopy (cryo-EM) technique with resolution between 3.0 and 4.0 Å. We provide an overview of the experimentally derived structures and describe results of the numerical evaluation of the submitted models. The evaluation is carried out by comparing coordinates of models to those of reference structures (CASP-style evaluation), as well as checking goodness-of-fit of modeled structures to the cryo-EM density maps. The performance of contributing research groups in the CASP-style evaluation is measured in terms of backbone accuracy, all-atom local geometry and similarity of inter-subunit interfaces. The results on the cryo-EM targets are compared with those on the whole set of eighty CASP13 targets. A posteriori refinement of the best models in their corresponding cryo-EM density maps resulted in structures that are very close to the reference structure, including some regions with better fit to the density. 相似文献
125.
Cecilia A. L. Dahlsjö Petr Stiblik Jana Jaklová Matěj Zídek Juan Wicman Huaycama Bohdan Lojka Jakub Houška 《Biotropica》2020,52(2):242-251
Agricultural expansion is a major driver of deforestation which has negative consequences for biodiversity and habitat stability. While sustainable farming is known to be beneficial for biodiversity and crop resilience, little is known about the impact of macrofauna and land-use intensity on soil quality. In this study, we examine the relative effects of (a) soil macrofauna and (b) land use (primary forest, agroforestry, and annual crop) on element depletion rates, concentration, and exchangeability in standardized soil. We used microcosms with two different mesh sizes, 0.25 mm and 5 mm, to exclude and include macrofauna, respectively. The microcosms were incubated for up to a year throughout which samples were collected without replacement. Macrofauna did not have a significant impact on any of the soil parameters which is likely to be due to the low diversity of termites in the sites. Land-use intensity significantly affected cation depletion rates whose effects increased in order of primary forest<agroforestry<annual crop. At the end of the study, soil Mg+2 concentration and Ca/Mg ratio in the agroforestry site differed from other land-use sites. Our results suggest that both bottom-up and top-down interactions have major effects on soil conditions, and the results should therefore be used to advise future research and policy around land-use management. Abstract in Spanish is available with online material. 相似文献
126.
Bohdan Nosyk Daphne P. Guh Nicholas J. Bansback Eugenia Oviedo-Joekes Suzanne Brissette David C. Marsh Evan Meikleham Martin T. Schechter Aslam H. Anis 《CMAJ》2012,184(6):E317-E328
Background:
Although diacetylmorphine has been proven to be more effective than methadone maintenance treatment for opioid dependence, its direct costs are higher. We compared the cost-effectiveness of diacetylmorphine and methadone maintenance treatment for chronic opioid dependence refractory to treatment.Methods:
We constructed a semi-Markov cohort model using data from the North American Opiate Medication Initiative trial, supplemented with administrative data for the province of British Columbia and other published data, to capture the chronic, recurrent nature of opioid dependence. We calculated incremental cost-effectiveness ratios to compare diacetylmorphine and methadone over 1-, 5-, 10-year and lifetime horizons.Results:
Diacetylmorphine was found to be a dominant strategy over methadone maintenance treatment in each of the time horizons. Over a lifetime horizon, our model showed that people receiving methadone gained 7.46 discounted quality-adjusted life-years (QALYs) on average (95% credibility interval [CI] 6.91–8.01) and generated a societal cost of $1.14 million (95% CI $736 800–$1.78 million). Those who received diacetylmorphine gained 7.92 discounted QALYs on average (95% CI 7.32–8.53) and generated a societal cost of $1.10 million (95% CI $724 100–$1.71 million). Cost savings in the diacetylmorphine cohort were realized primarily because of reductions in the costs related to criminal activity. Probabilistic sensitivity analysis showed that the probability of diacetylmorphine being cost-effective at a willingness-to-pay threshold of $0 per QALY gained was 76%; the probability was 95% at a threshold of $100 000 per QALY gained. Results were confirmed over a range of sensitivity analyses.Interpretation:
Using mathematical modelling to extrapolate results from the North American Opiate Medication Initiative, we found that diacetylmorphine may be more effective and less costly than methadone among people with chronic opioid dependence refractory to treatment.Opioid substitution with methadone is the most common treatment of opioid dependence.1–3 Participation in a methadone maintenance treatment program has been associated with decreases in illicit drug use,4 criminality5 and mortality.6,7 However, longitudinal studies have shown that most people who receive opioid substitution treatment are unable to abstain from illicit drug use for sustained periods, either switching from treatment to regular opioid use or continuing to use opioids while in treatment.8–13 An estimated 15%–25% of the most marginalized methadone clients do not benefit from treatment in terms of sustained abstention from the use of illicit opioids.14The North American Opiate Medication Initiative was a randomized controlled trial that compared supervised, medically prescribed injectable diacetylmorphine and optimized methadone maintenance treatment in people with long-standing opioid dependence and multiple failed treatment attempts with methadone or other forms of treatment.15 The trial was conducted in two Canadian cities (Vancouver, British Columbia; and Montréal, Quebec). Both treatment protocols included a comprehensive range of psychosocial services (e.g., addiction counselling, relapse prevention, case management, and individual and group interventions) and primary care services (e.g., testing for blood-borne diseases, provision of HIV treatment, and treatment of acute and chronic physical and mental health complications of substance use) in keeping with Health Canada best practices.16 The results of the trial confirmed findings of prior studies showing diacetylmorphine to be more effective than methadone maintenance treatment in retaining opioid-dependent patients in treatment15,17–20 and improving health and social functioning.19,21,22 Diacetylmorphine treatment has been proposed to reach a specific population of people with opioid dependence refractory to treatment who are at high risk of adverse health consequences and engagement in criminal activities to acquire the illicit drugs.For guiding policy-makers, the North American Opiate Medication Initiative alone does not address all the important considerations for decision-making. In addition to political challenges associated with the therapy,23 there remains concern over the direct cost of diacetylmorphine over the long term, because it can be as much as 10 times greater than conventional methadone maintenance treatment.21 The North American Opiate Medication Initiative was only one year in duration, but a policy to introduce diacetylmorphine might have both positive and negative longer-term implications.We extrapolated outcomes from the North American Opiate Medication Initiative to estimate the long-term cost-effectiveness of diacetylmorphine versus methadone maintenance treatment for chronic, refractory opioid dependence. 相似文献127.
Sutherlin DP Baker S Bisconte A Blaney PM Brown A Chan BK Chantry D Castanedo G DePledge P Goldsmith P Goldstein DM Hancox T Kaur J Knowles D Kondru R Lesnick J Lucas MC Lewis C Murray J Nadin AJ Nonomiya J Pang J Pegg N Price S Reif K Safina BS Salphati L Staben S Seward EM Shuttleworth S Sohal S Sweeney ZK Ultsch M Waszkowycz B Wei B 《Bioorganic & medicinal chemistry letters》2012,22(13):4296-4302
A potent inhibitor of PI3Kδ that is ≥ 200 fold selective for the remaining three Class I PI3K isoforms and additional kinases is described. The hypothesis for selectivity is illustrated through structure activity relationships and crystal structures of compounds bound to a K802T mutant of PI3Kγ. Pharmacokinetic data in rats and mice support the use of 3 as a useful tool compound to use for in vivo studies. 相似文献
128.
Respiration characteristics of mitochondria of the parental and giant cells of murine NK/Ly (Nemeth-Kellner lymphoma) were studied. The giant cell-enriched ascites were obtained by serial intraperitoneal injections of vinblastine in tumour-bearing mice. Ascites containing >70% giant cells were used. Their diameter of was over 17 μm (~2800 μm(3)), while the diameter of the parental cells was 12.7 μm (1100 μm(3)). The respiration rate of mitochondria in situ was measured by oxygen consumption in intact and digitonin-permeabilized NK/Ly cells. Endogenous respiration of intact giant NK/Ly cells was three times higher compared to the parental ones, roughly in agreement with the volume change. The giant NK/Ly cells were far more resistant to permeabilization with digitonin than the parental cells, as shown by Trypan Blue and LDH (lactate dehydrogenase) release tests. After digitonin permeabilization, oxygen consumption was reduced to a minimal level (0.06 ng atom O/(s × 106 cells) in both types of cells. Addition of α-ketoglutarate or succinate to the incubation medium increased oxygen consumption in the parental cells by 46 and 164% respectively. In the giant NK/Ly cells, the corresponding increases were 164 and 276%. Addition of ADP to α-ketoglutarate- or succinate-supplemented medium further stimulated oxygen consumption of the permeabilized NK/Ly cells; however, the effect of ADP was more pronounced in the giant cells. In addition, indices of respiratory control were significantly higher in the giant cells. Oligomycin suppressed considerably the respiration of the intact giant cells but had a much weaker effect on parental cells. Thus, giant NK/Ly cells possess much higher respiration rates and show tighter coupling between the respiration and oxidative phosphorylation compared with parental cells. 相似文献
129.
130.
Maxwell CA Benítez J Gómez-Baldó L Osorio A Bonifaci N Fernández-Ramires R Costes SV Guinó E Chen H Evans GJ Mohan P Català I Petit A Aguilar H Villanueva A Aytes A Serra-Musach J Rennert G Lejbkowicz F Peterlongo P Manoukian S Peissel B Ripamonti CB Bonanni B Viel A Allavena A Bernard L Radice P Friedman E Kaufman B Laitman Y Dubrovsky M Milgrom R Jakubowska A Cybulski C Gorski B Jaworska K Durda K Sukiennicki G Lubiński J Shugart YY Domchek SM Letrero R Weber BL Hogervorst FB Rookus MA 《PLoS biology》2011,9(11):e1001199
Differentiated mammary epithelium shows apicobasal polarity, and loss of tissue organization is an early hallmark of breast carcinogenesis. In BRCA1 mutation carriers, accumulation of stem and progenitor cells in normal breast tissue and increased risk of developing tumors of basal-like type suggest that BRCA1 regulates stem/progenitor cell proliferation and differentiation. However, the function of BRCA1 in this process and its link to carcinogenesis remain unknown. Here we depict a molecular mechanism involving BRCA1 and RHAMM that regulates apicobasal polarity and, when perturbed, may increase risk of breast cancer. Starting from complementary genetic analyses across families and populations, we identified common genetic variation at the low-penetrance susceptibility HMMR locus (encoding for RHAMM) that modifies breast cancer risk among BRCA1, but probably not BRCA2, mutation carriers: n = 7,584, weighted hazard ratio (wHR) = 1.09 (95% CI 1.02–1.16), ptrend = 0.017; and n = 3,965, wHR = 1.04 (95% CI 0.94–1.16), ptrend = 0.43; respectively. Subsequently, studies of MCF10A apicobasal polarization revealed a central role for BRCA1 and RHAMM, together with AURKA and TPX2, in essential reorganization of microtubules. Mechanistically, reorganization is facilitated by BRCA1 and impaired by AURKA, which is regulated by negative feedback involving RHAMM and TPX2. Taken together, our data provide fundamental insight into apicobasal polarization through BRCA1 function, which may explain the expanded cell subsets and characteristic tumor type accompanying BRCA1 mutation, while also linking this process to sporadic breast cancer through perturbation of HMMR/RHAMM. 相似文献