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1.
Spin-echo NMR spectroscopy was shown to be a reliable technique for the monitoring of the in situ cleavage of gamma-Glu-Ala by gamma-glutamyl-amino acid cyclotransferase in whole erythrocytes and hemolysates. Of particular importance was the difference in chemical shifts between peptide resonances and those of the constituent amino acids. Using lysates of varying dilution, it was shown that the specific activity of the enzyme was not concentration-dependent, thus suggesting a lack of cytosolic low-molecular-weight-effectors or enzyme dissociation. Furthermore, the initial velocities of the reaction as a function of substrate concentration obeyed Michaelis-Menten kinetics with a Km = 2.0 +/- 0.3 mmol/l and Vmax = 137 +/- 7 mmol/h/l of cell water in 1H2O medium. Similar analysis in 2H2O medium revealed a solvent kinetic isotope effect of 1.9 +/- 0.4 at low substrate concentrations. The implications of this observation for the mechanism of the reaction are discussed. Cleavage of the peptide by a suspension of intact erythrocytes was at a rate 300 times less than the corresponding lysate flux, thus indicating the rate limitation by transport in the coupled system. 相似文献
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After 30 years of continuous research into the mechanisms of human hypertension, we summarize the results obtained by the members of the multidisciplinary research group on hypertension of the Clinical Research Institute of Montreal on the disturbances of minerlocorticoid activity in a rigorously selected group of patients with early, mild essential hypertension. We attempt to integrate these findings with those of many other groups working on other aspects of hypertensive cardiovascular diseases. On the assumption that the increased peripheral resistance responsible for hypertension results from an imbalance or a disturbance of the equilibrium between the sympathetic nervous system and norepinephrine on one hand, and the vascular tone, sensitivity and responsiveness of the arterial smooth muscle to norepinephrine and to angiotensin II on the other hand, three models that fit the experimental and clinical facts as known at present are described. 相似文献
5.
The activity and distribution of the selenium-containing enzyme, glutathione peroxidase, has been determined in muscle fractions in normal adult rats and sheep. Skeletal and cardiac muscle have been examined, and in both types of muscle the major proportion of the enzyme appeared in the cytosol fraction. Enzyme activity was higher in cardiac muscle than in skeletal muscle in both species, and based on total protein present in fractions, it appears that rat muscle contains more enzyme activity than sheep muscle. In tissues from lambs born to selenium-deprived ewes the levels of enzyme were significantly depressed. Two sampling periods were selected, the first when the lambs were 2-3 weeks of age and the second at slaughter when they were 10 weeks old. Muscle, plasma and erythrocyte levels of the enzyme indicated that the most sensitive measure of selenium deficiency is likely to be that of the erythrocyte enzyme level. 相似文献
6.
Elisabeth APM Romme Piet Geusens Willem F Lems Erica PA Rutten Frank WJM Smeenk Joop PW van den Bergh Peter ThW van Hal Emiel FM Wouters 《Respiratory research》2015,16(1)
Although osteoporosis and its related fractures are common in patients with COPD, patients at high risk of fracture are poorly identified, and consequently, undertreated. Since there are no fracture prevention guidelines available that focus on COPD patients, we developed a clinical approach to improve the identification and treatment of COPD patients at high risk of fracture. We organised a round-table discussion with 8 clinical experts in the field of COPD and fracture prevention in the Netherlands in December 2013. The clinical experts presented a review of the literature on COPD, osteoporosis and fracture prevention. Based on the Dutch fracture prevention guideline, they developed a 5-step clinical approach for fracture prevention in COPD. Thereby, they took into account both classical risk factors for fracture (low body mass index, older age, personal and family history of fracture, immobility, smoking, alcohol intake, use of glucocorticoids and increased fall risk) and COPD-specific risk factors for fracture (severe airflow obstruction, pulmonary exacerbations and oxygen therapy). Severe COPD (defined as postbronchodilator FEV1 < 50% predicted) was added as COPD-specific risk factor to the list of classical risk factors for fracture. The 5-step clinical approach starts with case finding using clinical risk factors, followed by risk evaluation (dual energy X-ray absorptiometry and imaging of the spine), differential diagnosis, treatment and follow-up. This systematic clinical approach, which is evidence-based and easy-to-use in daily practice by pulmonologists, should contribute to optimise fracture prevention in COPD patients at high risk of fracture. 相似文献
7.
Images of human erythrocytes from a healthy donor were recorded under differential interference contrast (DIC) microscopy;
they were acquired rapidly (~336 Hz) and the intensity of the centermost pixel of each cell was recorded for ~60 s (20,000
values). Various techniques were used to analyze the data, including detrended fluctuation analysis (DFA) and multiscale entropy
(MSE); however, power spectrum analysis was deemed the most appropriate for metrifying and comparing results. This analysis
was used to compare cells from young and old populations, and after perturbing normal conditions, with changes in temperature,
adenosine triphosphate (ATP) concentration (using NaF, an inhibitor of glycolysis, and α-toxin, a pore-forming molecule used
to permeabilize red cells to ATP), and water transport rates [using glycerol, and p-chloromercuriphenylsulfonic acid (pCMBS) to inhibit aquaporins, AQPs]. There were measurable differences in the membrane
fluctuation characteristics in populations of young and old cells, but there was no significant change in the flickering time
series on changing the temperature of an individual cell, by depleting it of ATP, or by competing with the minor water exchange
pathway via AQP3 using glycerol. However, pCMBS, which inhibits AQP1, the major water exchange pathway, inhibited flickering
in all cells, and yet it was restored by the membrane intercalating species dibutyl phthalate (DBP). We developed a computer
model to simulate acquired displacement spectral time courses and to evaluate various methods of data analysis, and showed
how the flexibility of the membrane, as defined in the model, affects the flickering time course. 相似文献
8.
Fredrick M Mobegi Sacha AFT van Hijum Peter Burghout Hester J Bootsma Stefan PW de Vries Christa E van der Gaast-de Jongh Elles Simonetti Jeroen D Langereis Peter WM Hermans Marien I de Jonge Aldert Zomer 《BMC genomics》2014,15(1)
Background
Bacterial respiratory tract infections, mainly caused by Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis are among the leading causes of global mortality and morbidity. Increased resistance of these pathogens to existing antibiotics necessitates the search for novel targets to develop potent antimicrobials.Result
Here, we report a proof of concept study for the reliable identification of potential drug targets in these human respiratory pathogens by combining high-density transposon mutagenesis, high-throughput sequencing, and integrative genomics. Approximately 20% of all genes in these three species were essential for growth and viability, including 128 essential and conserved genes, part of 47 metabolic pathways. By comparing these essential genes to the human genome, and a database of genes from commensal human gut microbiota, we identified and excluded potential drug targets in respiratory tract pathogens that will have off-target effects in the host, or disrupt the natural host microbiota. We propose 249 potential drug targets, 67 of which are targets for 75 FDA-approved antimicrobials and 35 other researched small molecule inhibitors. Two out of four selected novel targets were experimentally validated, proofing the concept.Conclusion
Here we have pioneered an attempt in systematically combining the power of high-density transposon mutagenesis, high-throughput sequencing, and integrative genomics to discover potential drug targets at genome-scale. By circumventing the time-consuming and expensive laboratory screens traditionally used to select potential drug targets, our approach provides an attractive alternative that could accelerate the much needed discovery of novel antimicrobials.Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-15-958) contains supplementary material, which is available to authorized users. 相似文献9.
Max Puckeridge Bogdan E. Chapman Arthur D. Conigrave Philip W. Kuchel 《European biophysics journal : EBJ》2014,43(4-5):169-177
Recent studies suggest a link between adenosine triphosphate (ATP) concentration and the amplitude of cell membrane flickering (CMF) in the human erythrocyte (red blood cell; RBC). Potentially, the origin of this phenomenon and the unique discocyte shape could be active processes that account for some of the ATP turnover in the RBC. Active flickering could depend on several factors, including pH, osmolality, enzymatic rates and metabolic fluxes. In the present work, we applied the data analysis described in the previous article to study time courses of flickering RBCs acquired using differential interference contrast light microscopy in the presence of selected effectors. We also recorded images of air bubbles in aqueous detergent solutions and oil droplets in water, both of which showed rapid fluctuations in image intensity, the former showing the same type of spectral envelope (relative frequency composition) to RBCs. We conclude that CMF is not directly an active process, but that ATP affects the elastic properties of the membrane that flickers in response to molecular bombardment in a manner that is described mathematically by a constrained random walk. 相似文献
10.
A. R. Waldeck A. S.-L. Xu Basil D. Roufogalis P. W. Kuchel 《European biophysics journal : EBJ》1998,27(3):247-254
NMR-based assays for measuring the fluxes of Ca2+, H+, and ATP in liposomal systems are presented. The 19F NMR Ca2+-chelating molecule 5,5-difluoro-1,2-bis(o-amino-phenoxy)ethane-N,N,N′,N′-tetraacetic acid (5FBAPTA) was trapped inside large unilamellar vesicles and used to monitor
passive and A23187-mediated Ca2+ transport into them. The data were analyzed using progress curves of the transport reaction. They demonstrated the general
applicability of 5FBAPTA as a 19F NMR probe of active Ca2+ transport. 31P NMR time-courses were used to monitor simultaneously the ATP hydrolysing activity of the reconstituted human erythrocyte Ca2+-ATPase and the concomitant acidification of the reaction medium in a suspension of small unilamellar vesicles. Using an estimate
of the extraliposomal buffering capacity, the H+/ATP coupling stoichiometry, in the presence of A23187, was estimated from the NMR-derived data at steady state; it amounted
to 1.4±0.3. This result is discussed with respect to the issue of molecular `slip' in the context of a non-equilibrium thermodynamics
model of the pump (accompanying paper in this issue). Importantly, NMR, in contrast to optical detection methods, can potentially
register all fluxes and (electro)chemical gradients involved in the Ca2+-ATPase-mediated H+/Ca2+counterport, in a single experiment.
Received: 19 June 1997 / Accepted: 3 December 1997 相似文献