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101.
102.
Rudenko IN Kaganovich A Hauser DN Beylina A Chia R Ding J Maric D Jaffe H Cookson MR 《The Biochemical journal》2012,446(1):99-111
Autosomal-dominant missense mutations in LRRK2 (leucine-rich repeat kinase 2) are a common genetic cause of PD (Parkinson's disease). LRRK2 is a multidomain protein with kinase and GTPase activities. Dominant mutations are found in the domains that have these two enzyme activities, including the common G2019S mutation that increases kinase activity 2-3-fold. However, there is also a genetic variant in some populations, G2385R, that lies in a C-terminal WD40 domain of LRRK2 and acts as a risk factor for PD. In the present study we show that the G2385R mutation causes a partial loss of the kinase function of LRRK2 and deletion of the C-terminus completely abolishes kinase activity. This effect is strong enough to overcome the kinase-activating effects of the G2019S mutation in the kinase domain. Hsp90 (heat-shock protein of 90 kDa) has an increased affinity for the G2385R variant compared with WT (wild-type) LRRK2, and inhibition of the chaperone binding combined with proteasome inhibition leads to association of mutant LRRK2 with high molecular mass native fractions that probably represent proteasome degradation pathways. The loss-of-function of G2385R correlates with several cellular phenotypes that have been proposed to be kinase-dependent. These results suggest that the C-terminus of LRRK2 plays an important role in maintaining enzymatic function of the protein and that G2385R may be associated with PD in a way that is different from kinase-activating mutations. These results may be important in understanding the differing mechanism(s) by which mutations in LRRK2 act and may also have implications for therapeutic strategies for PD. 相似文献
103.
Marinkovic D Tucci FC Tran JA Fleck BA Wen J Chen C 《Bioorganic & medicinal chemistry letters》2008,18(17):4817-4822
A series of piperazinebenzylalcohols were prepared and studied to compare with their ketone and amine analogs as MC4R antagonists. Several benzylalcohols such as 14a and 14g displayed low nanomolar binding affinities (Ki < 10 nM), and high selectivities over other melanocortin receptor subtypes. 相似文献
104.
105.
Mirjana Ruml Ana Vuković Dragan Milatović 《International journal of biometeorology》2010,54(4):411-422
The aim of this study was to examine different methods for determining growing degree-day (GDD) threshold temperatures for two phenological stages (full bloom and harvest) and select the optimal thresholds for a greater number of apricot (Prunus armeniaca L.) cultivars grown in the Belgrade region. A 10-year data series were used to conduct the study. Several commonly used methods to determine the threshold temperatures from field observation were evaluated: (1) the least standard deviation in GDD; (2) the least standard deviation in days; (3) the least coefficient of variation in GDD; (4) regression coefficient; (5) the least standard deviation in days with a mean temperature above the threshold; (6) the least coefficient of variation in days with a mean temperature above the threshold; and (7) the smallest root mean square error between the observed and predicted number of days. In addition, two methods for calculating daily GDD, and two methods for calculating daily mean air temperatures were tested to emphasize the differences that can arise by different interpretations of basic GDD equation. The best agreement with observations was attained by method (7). The lower threshold temperature obtained by this method differed among cultivars from −5.6 to −1.7°C for full bloom, and from −0.5 to 6.6°C for harvest. However, the “Null” method (lower threshold set to 0°C) and “Fixed Value” method (lower threshold set to −2°C for full bloom and to 3°C for harvest) gave very good results. The limitations of the widely used method (1) and methods (5) and (6), which generally performed worst, are discussed in the paper. 相似文献
106.
Cubrilo D Djordjevic D Zivkovic V Djuric D Blagojevic D Spasic M Jakovljevic V 《Molecular and cellular biochemistry》2011,355(1-2):273-279
Maximal workload in elite athletes induces increased generation of reactive oxygen/nitrogen species (RONS) and oxidative stress, but the dynamics of RONS production are not fully explored. The aim of our study was to examine the effects of long-term engagement in sports with different energy requirements (aerobic, anaerobic, and aerobic/anaerobic) on oxidative stress parameters during progressive exercise test. Concentrations of lactates, nitric oxide (NO) measured through stabile end product-nitrites (NO2 ?), superoxide anion radical (O2 ??), and thiobarbituric reactive substances (TBARS) as index of lipid peroxidation were determined in rest, after maximal workload, and at 4 and 10th min of recovery in blood plasma of top level competitors in rowing, cycling, and taekwondo. Results showed that sportmen had similar concentrations of lactates and O2 ?? in rest. Nitrite concentrations in rest were the lowest in taekwondo fighters, while rowers had the highest levels among examined groups. The order of magnitude for TBARS level in the rest was bicycling > taekwondo > rowing. During exercise at maximal intensity, the concentration of lactate significantly elevated to similar levels in all tested sportsmen and they were persistently elevated during recovery period of 4 and 10 min. There were no significant changes in O2 ??, nitrite, and TBARS levels neither at the maximum intensity of exercise nor during the recovery period comparing to the rest period in examined individuals. Our results showed that long term different training strategies establish different basal nitrites and lipid peroxidation levels in sportmen. However, progressive exercise does not influence basal nitrite and oxidative stress parameters level neither at maximal load nor during the first 10 min of recovery in sportmen studied. 相似文献
107.
Dragan AI Casas-Finet JR Bishop ES Strouse RJ Schenerman MA Geddes CD 《Biophysical journal》2010,99(9):3010-3019
PicoGreen is a fluorescent probe that binds dsDNA and forms a highly luminescent complex when compared to the free dye in solution. This unique probe is widely used in DNA quantitation assays but has limited application in biophysical analysis of DNA and DNA-protein systems due to limited knowledge pertaining to its physical properties and characteristics of DNA binding. Here we have investigated PicoGreen binding to DNA to reveal the origin and mode of PicoGreen/DNA interactions, in particular the role of electrostatic and nonelectrostatic interactions in formation of the complex, as well as demonstrating minor groove binding specificity. Analysis of the fluorescence properties of free PicoGreen, the diffusion properties of PG/DNA complexes, and the excited-state lifetime changes upon DNA binding and change in solvent polarity, as well as the viscosity, reveal that quenching of PicoGreen in the free state results from its intramolecular dynamic fluctuations. On binding to DNA, intercalation and electrostatic interactions immobilize the dye molecule, resulting in a >1000-fold enhancement in its fluorescence. Based on the results of this study, a model of PicoGreen/DNA complex formation is proposed. 相似文献
108.
Firozi PF Vulimiri SV Rajaniemi H Hemminki K Dragan Y Pitot HC DiGiovanni J Zhu YH Li D 《Chemico-biological interactions》2000,126(1):33-43
Our previous study has shown that chronic exposure to tamoxifen (TAM) induced formation of high levels of DNA adducts in the liver, the target tissue of TAM-induced carcinogenesis in rats. One of the major DNA adducts (spot 1), as detected by 32P-postlabeling, accounted for 53% of the total adducts. To characterize this major adduct, the current study has compared spot 1 with two previously identified TAM-DNA adducts, i.e. alpha-TAM-N2-deoxyguanine (alpha-TAM-N2-dG) and alpha-N-desmethyl TAM-N2-deoxyguanine (alpha-N-dmTAM-N2-dG) by various rechromatography methods. It was found that spot 1 was further resolved into two fractions during rechromatography analysis, one fraction co-migrated with the alpha-TAM-N2-dG and the other fraction co-migrated with the alpha-N-dmTAM-N2-dG. These findings have demonstrated that chronic exposure to tamoxifen induced the same major DNA adducts, i.e. alpha-TAM-N2-dG and alpha-N-dmTAM-N2-dG as those detected in acutely exposed rats. 相似文献
109.
Pontillo J Marinkovic D Tran JA Arellano M Fleck BA Wen J Tucci FC Nelson J Saunders J Foster AC Chen C 《Bioorganic & medicinal chemistry letters》2005,15(20):4615-4618
Piperazinebenzylamines bearing a small N-(1-methoxy-2-propyl) side chain were found to be potent and selective antagonists of the human melanocortin-4 (MC4) receptor. Compound 7b, having K(i) values of 6.9 and 2800 nM at the human MC4 and MC3 receptors, respectively, has moderate oral bioavailability in mice, which is improved relative to the arylethyl analogues. 相似文献
110.
Tucci FC White NS Markison S Joppa M Tran JA Fleck BA Madan A Dyck BP Parker J Pontillo J Arellano LM Marinkovic D Jiang W Chen CW Gogas KR Goodfellow VS Saunders J Foster AC Chen C 《Bioorganic & medicinal chemistry letters》2005,15(19):4389-4395
The melanocortin-4 receptor (MC4R) plays an important role in the regulation of energy homeostasis. Recent studies have shown that blockade of the MC4R reverses tumor-induced weight loss in mice. Herein, we describe the synthesis and identification of potent and selective non-peptide antagonists of the human MC4R from a series of 2-ethoxycarbonylcyclohexyl-piperazines. Compound 12i was found to possess low nanomolar affinity for the MC4R, and exhibit oral bioavailability in rats. More importantly, when administered orally to mice (10 mg/kg), it led to statistically significant increases in food intake over a 24-h period. 相似文献