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421.
Weber CR Ginsburg KS Philipson KD Shannon TR Bers DM 《The Journal of general physiology》2001,117(2):119-131
The cardiac sarcolemmal Na-Ca exchanger (NCX) is allosterically regulated by [Ca](i) such that when [Ca](i) is low, NCX current (I(NCX)) deactivates. In this study, we used membrane potential (E(m)) and I(NCX) to control Ca entry into and Ca efflux from intact cardiac myocytes to investigate whether this allosteric regulation (Ca activation) occurs with [Ca](i) in the physiological range. In the absence of Ca activation, the electrochemical effect of increasing [Ca](i) would be to increase inward I(NCX) (Ca efflux) and to decrease outward I(NCX). On the other hand, Ca activation would increase I(NCX) in both directions. Thus, we attributed [Ca](i)-dependent increases in outward I(NCX) to allosteric regulation. Ca activation of I(NCX) was observed in ferret myocytes but not in wild-type mouse myocytes, suggesting that Ca regulation of NCX may be species dependent. We also studied transgenic mouse myocytes overexpressing either normal canine NCX or this same canine NCX lacking Ca regulation (Delta680-685). Animals with the normal canine NCX transgene showed Ca activation, whereas animals with the mutant transgene did not, confirming the role of this region in the process. In native ferret cells and in mice with expressed canine NCX, allosteric regulation by Ca occurs under physiological conditions (K(mCaAct) = 125 +/- 16 nM SEM approximately resting [Ca](i)). This, along with the observation that no delay was observed between measured [Ca](i) and activation of I(NCX) under our conditions, suggests that beat to beat changes in NCX function can occur in vivo. These changes in the I(NCX) activation state may influence SR Ca load and resting [Ca](i), helping to fine tune Ca influx and efflux from cells under both normal and pathophysiological conditions. Our failure to observe Ca activation in mouse myocytes may be due to either the extent of Ca regulation or to a difference in K(mCaAct) from other species. Model predictions for Ca activation, on which our estimates of K(mCaAct) are based, confirm that Ca activation strongly influences outward I(NCX), explaining why it increases rather than declines with increasing [Ca](i). 相似文献
422.
Isaac Ginsburg Milu Sadovnic James Varani Oren Tirosh Ron Kohen 《Free radical research》2013,47(2):79-91
The objective of the present communication is to describe the role played by combinations between diethydithiocarbamate (DDC) and divalent metals in hemolysis of human RBC. RBC which had been treated with DDC (10–50 μM) were moderately hemolyzed (about 50%) upon the addition of subtoxic amounts of Cu2+ (50 μM). However, a much stronger and a faster hemolysis occurred either if mixtures of RBC-DDC were immediately treated either by Co2+ (50 μM) or by a premixture of Cu2+ and Co2+ (Cu:Co) (50 μM).While Fe2+ and Ni2+, at 50 μM, initiated 30–50% hemolysis when combined with DDC (50 μM), on a molar basis, Cd2+ was at least 50 fold more efficient than any of the other metals in the initiation of hemolysis by DDC. On the other hand, neither Mn2+ nor Zn2+, had any hemolysis-initiating effects. Co2+ was the only metal which totally blocked hemolysis if added to DDC prior to the addition of the other metals.Hemolysis by mixtures of DDC + (Cu:Co) was strongly inhibited by anaerobiosis (flushing with nitrogen gas), by the reducing agents glutathione, N-acetyl cysteine, mercaptosuccinate, ascorbate, TEMPO, and α-tocopherol, by the PLA2 inhibitor bromophenacylbromide (BrPACBr), by tetracycline as well as by phosphatidyl choline, cholesterol and by trypan blue. However, TEMPO, BrPACBr and PC were the only agents which inhibited hemolysis induced by DDC:Cd2+ complexes.On the other hand, none of the classical scavengers of reactive oxygen species (ROS) employed e.g dimethylthiourea, catalase, histidine, mannitol, sodium benzoate, nor the metal chelators desferal and phenanthroline, had any appreciable inhibitory effects on hemolysis induced by DDC + (Cu:Co).DDC oxidized by H2O2 lost its capacity to act in concert either with Cu2+ or with Cd2+ to hemolyze RBC.While either heating RBC to temperatures greater than 37°C or exposure of the cells to glucose-oxidase-generated peroxide diminished their susceptibility to hemolysis, exposure to the peroxyl radical from AAPH, enhanced hemolysis by DDC + (Cu:Co).The cyclovoltammetry patterns of DDC were drastically changed either by Cu2+, Co2+ or by Cd2+ suggesting a strong interaction of the metals with DDC. Also, while the absorbance spectrum of DDC at 280 nm was decreased by 50% either by Co2+, Cd2+ or by H2O2, a 90% reduction in absorbance occurred if DDC + H2O2 mixtures were treated either by Cu2+ or by Co2+, but not by Cd2+.Taken together, it is suggested that DDC-metal chelates can induce hemolysis by affecting the stability and the integrity of the RBC membrane, and possibly also of the cytoskeleton and the role played by reducing agents as inhibitors might be related to their ability to deplete oxygen which is also supported by the inhibitory effects of anaeobiosis. 相似文献
423.
Boumendil A Angus DC Guitonneau AL Menn AM Ginsburg C Takun K Davido A Masmoudi R Doumenc B Pateron D Garrouste-Orgeas M Somme D Simon T Aegerter P Guidet B;ICE-CUB study group 《PloS one》2012,7(4):e34387
Although increasing numbers of very elderly patients are requiring intensive care, few large sample studies have investigated ICU admission of very elderly patients. Data on pre triage by physicians from other specialities is limited. This observational cohort study aims at examining inter-hospital variability of ICU admission rates and its association with patients'' outcomes. All patients over 80 years possibly qualifying for ICU admission who presented to the emergency departments (ED) of 15 hospitals in the Paris (France) area during a one-year period were prospectively included in the study. Main outcome measures were ICU eligibility, as assessed by the ED and ICU physicians; in-hospital mortality; and vital and functional status 6 months after the ED visit. 2646 patients (median age 86; interquartile range 83–91) were included in the study. 94% of participants completed follow-up (n = 2495). 12.4% (n = 329) of participants were deemed eligible for ICU admission by ED physicians and intensivists. The overall in-hospital and 6-month mortality rates were respectively 27.2% (n = 717) and 50.7% (n = 1264). At six months, 57.5% (n = 1433) of patients had died or had a functional deterioration. Rates of patients deemed eligible for ICU admission ranged from 5.6% to 38.8% across the participating centers, and this variability persisted after adjustment for patients'' characteristics. Despite this variability, we found no association between level of ICU eligibility and either in-hospital death or six-month death or functional deterioration. In France, the likelihood that a very elderly person will be admitted to an ICU varies widely from one hospital to another. Influence of intensive care admission on patients'' outcome remains unclear.
Trial Registration
ClinicalTrials.gov NCT00912600相似文献424.
The Lagomerycidae, a small family of the Cervoidea, is known in France by the genera Lagomeryx, Ligeromeryx and Stephanocemas. Lagomeryx contains three species, the other two genera one species only. This family is known from MN3 to MN5. 相似文献
425.
Malaria parasites demonstrably increase the permeability of the membrane of the erythrocyte in which they develop and propagate. New permeability pathways (NPPs) generated by parasite activity and identified in the erythrocyte membrane are held responsible for these changes. Here, we present a novel analysis of hemolysis curves of infected cells in iso-osmotic solutions of solutes that penetrate selectively into infected cells, as a function of parasite development. The analysis yields three parameters: the t(1/2) of lysis (reciprocally related to permeability), the maximal lysis, and a parameter that expresses the variation of the cell population. Different developmental stages of the parasite were obtained either by sampling synchronized cultures with time or by the fractionation of asynchronous cultures on a Percoll-sorbitol density gradient. While the results confirm previous reports on the stage-dependent evolution of NPPs, they also reveal that the evolution of NPPs is not synchronous: NPPs evolve differentially throughout the ring stage and only at the mid-trophozoite stage they are fully deployed in the majority of the infected cells, but not in all. This leads to desynchronization in the culture and to less than the maximal possible rate of multiplication. 相似文献
426.
M Ginsburg J Hochman H Eyal-Giladi 《The International journal of developmental biology》1989,33(3):389-395
An antiserum against quail 7 day gonadal germ cells was found to react specifically with gonadal germ cells of both sexes. Transverse sections from a range of early quail developmental stages were submitted to the antibody PAP reaction. Blastodiscs from the earliest uterine stages (II to X E.G. & K) reacted very strongly, while the overall reaction gradually decreased in older blastoderms. At stage XIII both epiblast and hypoblast were weakly stained, but some large, PGC-like cells stained intensively. During gastrulation (PS formation) the reaction of the epiblast disappears quicker than that of the hypoblast. The newly formed mesoderm and entoderm do not react at all and the reaction gradually becomes limited mainly to the PGCs and somewhat to the primary hypoblast which is moving into the germinal crescent. The widely spread reaction at the early stages is thus gradually being restricted to the PGCs. 相似文献
427.
Lawrence DA Olson ST Muhammad S Day DE Kvassman JO Ginsburg D Shore JD 《The Journal of biological chemistry》2000,275(8):5839-5844
The serpin family of serine proteinase inhibitors is a mechanistically unique class of naturally occurring proteinase inhibitors that trap target enzymes as stable covalent acyl-enzyme complexes. This mechanism appears to require both cleavage of the serpin reactive center loop (RCL) by the proteinase and a significant conformational change in the serpin structure involving rapid insertion of the RCL into the center of an existing beta-sheet, serpin beta-sheet A. The present study demonstrates that partitioning between inhibitor and substrate modes of reaction can be altered by varying either the rates of RCL insertion or deacylation using a library of serpin RCL mutants substituted in the critical P(14) hinge residue and three different proteinases. We further correlate the changes in partitioning with the actual rates of RCL insertion for several of the variants upon reaction with the different proteinases as determined by fluorescence spectroscopy of specific RCL-labeled inhibitor mutants. These data demonstrate that the serpin mechanism follows a branched pathway, and that the formation of a stable inhibited complex is dependent upon both the rate of the RCL conformational change and the rate of enzyme deacylation. 相似文献
428.
Inactivation of L-type Ca channels (LTCC) is regulated by both Ca and voltage-dependent processes (CDI and VDI). To differentiate VDI and CDI, several experimental and theoretical studies have considered the inactivation of Ba current through LTCC (IBa) as a measure of VDI. However, there is evidence that Ba can weakly mimic Ca, such that IBa inactivation is still a mixture of CDI and VDI. To avoid this complication, some have used the monovalent cation current through LTCC (INS), which can be measured when divalent cation concentrations are very low. Notably, INS inactivation rate does not depend on current amplitude, and hence may reflect purely VDI. However, based on analysis of existent and new data, and modeling, we find that INS can inactivate more rapidly and completely than IBa, especially at physiological temperature. Thus VDI that occurs during IBa (or ICa) must differ intrinsically from VDI during INS. To account for this, we have extended a previously published LTCC mathematical model of VDI and CDI into an excitation-contraction coupling model, and assessed whether and how experimental IBa inactivation results (traditionally used in VDI experiments and models) could be recapitulated by modifying CDI to account for Ba-dependent inactivation. Thus, the view of a slow and incomplete INS inactivation should be revised, and INS inactivation is a poor measure of VDI during ICa or IBa. This complicates VDI analysis experimentally, but raises intriguing new questions about how the molecular mechanisms of VDI differ for divalent and monovalent currents through LTCCs. 相似文献
429.
Twelve domestic chickens showed virtually no immobility reactions until the age of 9 days when tested repeatedly on a flat surface. However, twelve chicks did show pronounced immobility reactions as early as 1 day of age when tested repeatedly on a cloth surface which slightly contoured the chick's body. It was suggested that previous failures to observe immobility reactions in chicks less than 7 days old were due to inappropriate testing conditions and not to the absence of fear (a presumed substrate of the reaction), insufficient hormonal functioning, or non-functioning ‘releasing nervous mechanisms’. Young chicks do indeed become immobile if effector disruption is prevented and/or if increased physical contact during induction augments fear or produces a ‘prolonged zero’ in the animal's defensive distance. 相似文献
430.