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1.
Maintenance of paroxysmal atrial fibrillation (AF) by fast rotors in the left atrium (LA) or at the pulmonary veins (PVs) is not fully understood. To gain insight into this dynamic and complex process, we studied the role of the heterogeneous distribution of transmembrane currents in the PVs and LA junction (PV-LAJ) in the localization of rotors in the PVs. We also investigated whether simple pacing protocols could be used to predict rotor drift in the PV-LAJ. Experimentally observed heterogeneities in IK1, IKs, IKr, Ito, and ICaL in the PV-LAJ were incorporated into two- and pseudo three-dimensional models of Courtemanche-Ramirez-Nattel-Kneller human atrial kinetics to simulate various conditions and investigate rotor drifting mechanisms. Spatial gradients in the currents resulted in shorter action potential duration, minimum diastolic potential that was less negative, and slower upstroke and conduction velocity for rotors in the PV region than in the LA. Rotors under such conditions drifted toward the PV and stabilized at the shortest action potential duration and less-excitable region, consistent with drift direction under intercellular coupling heterogeneities and regardless of the geometrical constraint in the PVs. Simulations with various IK1 gradient conditions and current-voltage relationships substantiated its major role in the rotor drift. In our 1:1 pacing protocol, we found that among various action potential properties, only the minimum diastolic potential gradient was a rate-independent predictor of rotor drift direction. Consistent with experimental and clinical AF studies, simulations in an electrophysiologically heterogeneous model of the PV-LAJ showed rotor attraction toward the PV. Our simulations suggest that IK1 heterogeneity is dominant compared to other currents in determining the drift direction through its impact on the excitability gradient. These results provide a believed novel framework for understanding the complex dynamics of rotors in AF.  相似文献   

2.
A simple method has been developed for the rapid screening of potential effectors on enzymatic reactions. Use is made of the linear relationship between the inhibitor concentration I and the corresponding value I(I ? P), where P is the fraction of inhibition given by I. This mode of representation permits the evaluation of half-inhibitory doses (I50) and the calculation of their standard deviations SI50. Theoretically, these parameters can be determined from the results of measurements carried out at a single inhibitor concentration. The method proved useful when applied to the study of a number of potential effectors of adrenal cortex cyclic AMP phosphodiesterase activity. This model system was used to assess the advantages and limitations of the procedure. This approach should be of value when dealing with the usual types of enzyme inhibition mechanisms and may be of interest in other biochemical fields, such as in the study of hormone-receptor interaction, provided that the biological and statistical limitations of the method are not overlooked.  相似文献   

3.
4.
Excitability (action potential and refractory period) has been described by A. Finkelstein in the depolarizing region of the current-voltage (I-V) curve of the isolated frog skin. Recently Fishman and Macey interpreted this phenomenon as a consequence of a region with negative resistance that confers to the I-V curve an N shape. We have studied the I-V relation of the isolated frog skin in the hyperpolarizing region with a current-ramp system. It was found that in Na2SO4 Ringer's, the resistance continuously increases in the hyperpolarizing direction. When hyperpolarization reaches 300 mv an electrical breakdown occurs, occasionally followed by a region of negative resistance. In NaCl Ringer's the breakdown was also found although the I-V relation was reasonably linear. Unidirectional Na+ outflux was measured at different levels of voltage clamping across the skin and with different Na+ concentrations in the solutions. The Na+ outflux was found to be relatively independent of these parameters. Based on these results a Na+ rectifying structure is postulated. An electrical model for active Na+ transport including a diode and an oscillator is proposed. The effects of CO2, nitrogen, amiloride, and ouabain on the I-V relation are described.  相似文献   

5.
The rapidly activating, voltage gated Na+ current, INa, has recently been measured in mammalian nonmyelinated axons. Those results have been incorporated in simulations of the action potential, results that demonstrate a significant separation in time during the spike between INa and the repolarizing K+ current, IK. The original Hodgkin and Huxley (1952) model of Na+ channel gating, m3h, where m and h are channel activation and inactivation, respectively, has been used in this analysis. This model was originally developed for invertebrate nonmyelinated axons, squid giant axons in particular. The model has not survived challenges based on results from invertebrate preparations using a double-step voltage clamp protocol and measurements of gating currents, results that demonstrate a kinetic link between activation and inactivation leading to a delayed onset of inactivation following a voltage step. These processes are independent of each other in the Hodgkin and Huxley (1952) model. Application of the double-step protocol to the m3h model for mammalian INa results reveals a surprising prediction, an apparent delay in onset of inactivation even though activation and inactivation are uncoupled in the model. Other results, most notably gating currents, will be required to demonstrate such a link, if indeed it exists for mammalian Na+ channels. The information obtained will be significant in determining the way in which the Na+ channel is sequestered away from its open state during repolarization, thereby allowing for a separation in time between INa and IK during a spike, an energetically efficient mechanism of neuronal signaling in the mammalian brain.  相似文献   

6.
Detailed understanding of IKs gating complexity may provide clues regarding the mechanisms of repolarization instability and the resulting arrhythmias. We developed and tested a kinetic model to interpret physiologically relevant IKs properties, including pause-dependence and modulation by β-adrenergic receptors (β-AR). IKs gating was evaluated in guinea-pig ventricular myocytes at 36°C in control and during β-AR stimulation (0.1 μmol/L isoprenaline (ISO)). We tested voltage dependence of steady-state conductance (Gss), voltage dependence of activation and deactivation time constants (τact, τdeact), and pause-dependence of τact during repetitive activations (τreact). The IKs model was developed from the Silva and Rudy formulation. Parameters were optimized on control and ISO experimental data, respectively. ISO strongly increased Gss and its voltage dependence, changed the voltage dependence of τact and τdeact, and modified the pause-dependence of τreact. A single set of model parameters reproduced all experimental data in control. Modification of only three transition rates led to a second set of parameters suitable to fit all ISO data. Channel unitary conductance and density were unchanged in the model, thus implying increased open probability as the mechanism of ISO-induced Gss enhancement. The new IKs model was applied to analyze ISO effect on repolarization rate-dependence. IKs kinetics and its β-AR modulation were entirely reproduced by a single Markov chain of transitions (for each channel monomer). Model-based analysis suggests that complete opening of IKs channels within a physiological range of potentials requires concomitant β-AR stimulation. Transient redistribution of state occupancy, in addition to direct modulation of transition rates, may underlie β-AR modulation of IKs time dependence.  相似文献   

7.
The binding affinity of Fe(III) to methioninehydroxamate (MX) has been studied spectrophotometrically at I=0.15 M NaCl and T=25 °C. Equilibrium data have been assessed by the program SQUAD(II) in the wavelength range 400–550 nm and in the pH range 1.5–5.0. Five formation constants were determined for the species Fe(MX)(H)3+, Fe(MX)2+, Fe(MX)2(H)23+, Fe(MX)2(H)2+ and Fe2(MX)33+. The stopped-flow kinetic data studied at 470 nm and in the pH range 1.0–3.0 is collectively expressed by the following rate equation at a given pH Rate=(A + BTMX)TMX where TMX=the analytical connection of MX and the parameters A and B are both functions of pH in the range 1.7–3.0, but only A in the range 1.2– 1.7. A proposed mechanism was discussed, based on the equilibrium study, where the role of the chloro species of Fe(OH)2+ and Fe(OH)2+ in the complex formation of Fe(III) with MX has been emphasized. Correlation of the results with pertinent systems has also been discussed.  相似文献   

8.
9.
Experimental evidence suggests that regional differences in action potential (AP) morphology can provide a substrate for initiation and maintenance of reentrant arrhythmias in the right atrium (RA), but the relationships between the complex electrophysiological and anatomical organization of the RA and the genesis of reentry are unclear. In this study, a biophysically detailed three-dimensional computer model of the right atrial tissue was constructed to study the role of tissue heterogeneity and anisotropy in arrhythmogenesis. The model of Lindblad et al. for a rabbit atrial cell was modified to incorporate experimental data on regional differences in several ionic currents (primarily, INa, ICaL, IK1, Ito, and Isus) between the crista terminalis and pectinate muscle cells. The modified model was validated by its ability to reproduce the AP properties measured experimentally. The anatomical model of the rabbit RA (including tissue geometry and fiber orientation) was based on a recent histological reconstruction. Simulations with the resultant electrophysiologically and anatomically detailed three-dimensional model show that complex organization of the RA tissue causes breakdown of regular AP conduction patterns at high pacing rates (>11.75 Hz): as the AP in the crista terminalis cells is longer, and electrotonic coupling transverse to fibers of the crista terminalis is weak, high-frequency pacing at the border between the crista terminalis and pectinate muscles results in a unidirectional conduction block toward the crista terminalis and generation of reentry. Contributions of the tissue heterogeneity and anisotropy to reentry initiation mechanisms are quantified by measuring action potential duration (APD) gradients at the border between the crista terminalis and pectinate muscles: the APD gradients are high in areas where both heterogeneity and anisotropy are high, such that intrinsic APD differences are not diminished by electrotonic interactions. Thus, our detailed computer model reconstructs complex electrical activity in the RA, and provides new insights into the mechanisms of transition from focal atrial tachycardia into reentry.  相似文献   

10.
The aim of this work was to determine the concentrations and properties of free radicals in piperacillin, ampicillin, and crystalline penicillin after gamma irradiation. The radicals were studied by electron paramagnetic resonance (EPR) spectroscopy using an X-band spectrometer (9.3 GHz). Gamma irradiation was performed at a dose of 25 kGy. One- and two-exponential functions were fitted to the experimental data, in order to assess the influence of the antibiotics’ storage time on the measured EPR lines. After gamma irradiation, complex EPR lines were recorded confirming the presence of a large number of free radicals formed during the irradiation. For all tested antibiotics, concentrations of free radicals and parameters of EPR spectra changed with storage time. The results obtained demonstrate that concentration of free radicals and other spectroscopic parameters can be used to select the optimal parameters of radiation sterilization of β-lactam antibiotics. The most important parameters are the constants τ (τ 1(A),(I) and τ 2(A),(I)) and K (K 0(A),(I), K 1(A),(I), K 2(A),(I)) of the exponential functions that describe free radicals decay during samples storage.  相似文献   

11.
Inherited dilated cardiomyopathy (DCM) is characterized by dilatation and dysfunction of the ventricles, and often results in sudden death or heart failure (HF). Although angiotensin receptor blockers (ARBs) have been used for the treatment of HF, little is known about the effects on postulated electrical remodeling that occurs in inherited DCM. The aim of this study was to examine the effects of candesartan, one of the ARBs, on cardiac function and electrical remodeling in the hearts of inherited DCM model mice (TNNT2 ΔK210). DCM mice were treated with candesartan in drinking water for 2 months from 1 month of age. Control, non-treated DCM mice showed an enlargement of the heart with prolongation of QRS and QT intervals, and died at t1/2 of 70 days. Candesartan dramatically extended the lifespan of DCM mice, suppressed cardiac dilatation, and improved the functional parameters of the myocardium. It also greatly suppressed prolongation of QRS and QT intervals and action potential duration (APD) in the left ventricular myocardium and occurrence of ventricular arrhythmia. Expression analysis revealed that down-regulation of Kv4.2 (Ito channel protein), KChIP2 (auxiliary subunit of Kv4.2), and Kv1.5 (IKur channel protein) in DCM was partially reversed by candesartan administration. Interestingly, non-treated DCM heart had both normal-sized myocytes with moderately decreased Ito and IKur and enlarged cells with greatly reduced K+ currents (Ito, IKur IK1 and Iss). Treatment with candesartan completely abrogated the emergence of the enlarged cells but did not reverse the Ito, and IKur in normal-sized cells in DCM hearts. Our results indicate that candesartan treatment suppresses structural remodeling to prevent severe electrical remodeling in inherited DCM.  相似文献   

12.
The Bergman’s minimal model of glucose and insulin plasma levels is commonly used to analyse the results of glucose tolerance tests in humans. In this paper, we present the modified minimal model with plasma insulin compartment under the assumption that if the plasma glucose compartment drops below the basal glucose levels, the rate of insulin entering the plasma glucose compartment is zero. Insulin is cleared from the plasma insulin compartment at a rate proportional to the amount of insulin in the plasma insulin compartment. The modified minimal model was used to study the effect of physical exercise via parameters of a mathematical model to qualitative the magnitude of changes in insulin sensitivity (S I) and glucose effectiveness (S G) in response to exercise in type 2 diabetes and healthy human. The short-term effects of physical exercise in type 2 diabetes did not improve S G, but markedly improved the low S I values found in type 2 diabetes, indicating that the effects of exercise on S I are quantitatively important in the interpretation of training-related S I changes and may even be therapeutically useful in type 2 diabetes patients. Physical exercise is indicated either to prevent or delay the onset of type 2 diabetes or to assure a good control of type 2 diabetes by increasing insulin sensitivity.  相似文献   

13.
Depolarization-induced automaticity (DIA) of cardiomyocytes is the property of those cells to generate pacemaker cell-like spontaneous electrical activity when subjected to a depolarizing current. This property provides a candidate mechanism for generation of pathogenic ectopy in cardiac tissue. The purpose of this study was to determine the biophysical mechanism of DIA in terms of the ion conductance properties of the cardiomyocyte membrane. First, we determined, by use of the conventional whole-cell patch-clamp technique, the membrane conductance and DIA properties of ventricular cardiomyocytes isolated from adult rat heart. Second, we reproduced and analysed DIA properties by using an adapted version of the experimentally based mathematical cardiomyocyte model of Pandit et al. (Biophys J 81:3029–3051 2001, Biophys J 84:832–841 2003) and Padmala and Demir (J Cardiovasc Electrophysiol 14:990–995 2003). DIA in 23 rat cardiomyocytes was a damped membrane potential oscillation with a variable number of action potentials and/or waves, depending on the strength of the depolarizing current and the particular cell. The adapted model was used to reconstruct the DIA properties of a particular cardiomyocyte from its whole-cell voltage-clamp currents. The main currents involved in DIA were an L-type calcium current (I CaL) and a slowly activating and inactivating Kv current (I ss), with linear (I B) and inward rectifier (I K1) currents acting as background currents and I Na and I t as modulators. Essential for DIA is a sufficiently large window current of a slowly inactivating I CaL combined with a critically sized repolarizing current I ss. Slow inactivation of I ss makes DIA transient. In conclusion, we established a membrane mechanism of DIA primarily based on I CaL, I ss and inward rectifier properties; this may be helpful in understanding cardiac ectopy and its treatment.  相似文献   

14.
During digestion, dietary proteins cleaved in di and tri-peptides are translocated from the intestinal lumen into the enterocytes via PepT1 (SLC15A1) using an inwardly directed proton electrochemical gradient. The kinetic properties in various PepT1 orthologs (Dicentrarchus labrax, Oryctolagus cuniculus, Danio rerio) have been explored to determine the transport efficiency of different combinations of lysine, methionine, and glycine. Species-specific differences were observed. Lys-Met resulted the best substrate at all tested potentials in sea bass and rabbit PepT1, whereas in the zebrafish transporter all tested dipeptides (except Gly-Lys) elicited similar currents independently on the charge position or amino acid composition. For the sea bass and rabbit PepT1, kinetic parameters, K0.5 and Imax and their ratio, show the importance of the position of the charged lysine in the peptide. The PepT1 transporter of these species has very low affinity for Lys-Lys and Gly-Lys; this reduces the transport efficiency which is instead higher for Lys-Met and Lys-Gly. PepT1 from zebrafish showed relatively high affinity and excellent transport efficiency for Met-Lys and Lys-Met. These data led us to speculate about the structural determinants involved in substrate interaction according to the model proposed for this transporter.  相似文献   

15.
Galantamine is widely used for the treatment of Alzheimer’s disease. According to the generally accepted viewpoint, its therapeutic effect is based on inhibition of acetylcholinesterase (AChE) and potentiation of nicotinic receptors. Alternative molecular targets for galanatamine, namely, voltage-gated Ca2+ and K+ channels of the neuronal membrane, are also widely discussed in the current literature. The present study is devoted to the analysis of effects of galantamine on high-threshold Ca2+ currents (I Ca) and three different kinds of highthreshold K+ current, viz.: Ca2+-dependent K+ current (I C), delayed rectifier (I DR), and fast-inactivating K+ current (I Adepol). Experiments were conducted on molluscan neurons with the help of two-microelectrode voltageclamp technique. It was found that galantamine caused a fast, reversible and dose-dependent suppression of all types of high-threshold ionic currents. The maximal blocking effect of the alkaloid for I Ca, I C, and I DR, was 100%, while for I Adepol the maximal suppression was only 60%. The mean values of IC 50 for I C, I DR, I Adepol, and I Ca were 109, 237, 66, and 515 μ M, respectively, i.e., substantially higher than the corresponding values for the alkaloid-induced inhibition of AChE and potentiation of nicotinic receptors. It is concluded that the blockade of Ca2+ and K+ channels has little or no contribution to the therapeutic activity of galantamine.  相似文献   

16.
The hyperpolarization-activated current, Ih, is carried by members of the Hcn channel family and contributes to resting potential and firing properties in excitable cells of various systems, including the auditory system. Ih has been identified in spiral ganglion neurons (SGNs); however, its molecular correlates and their functional contributions have not been well characterized. To investigate the molecular composition of the channels that carry Ih in SGNs, we examined Hcn mRNA harvested from spiral ganglia of neonatal and adult mice using quantitative RT-PCR. The data indicate expression of Hcn1, Hcn2, and Hcn4 subunits in SGNs, with Hcn1 being the most highly expressed at both stages. To investigate the functional contributions of HCN subunits, we used the whole-cell, tight-seal technique to record from wild-type SGNs and those deficient in Hcn1, Hcn2, or both. We found that HCN1 is the most prominent subunit contributing to Ih in SGNs. Deletion of Hcn1 resulted in reduced conductance (Gh), slower activation kinetics (τfast), and hyperpolarized half-activation (V1/2) potentials. We demonstrate that Ih contributes to SGN function with depolarized resting potentials, depolarized sag and rebound potentials, accelerated rebound spikes after hyperpolarization, and minimized jitter in spike latency for small depolarizing stimuli. Auditory brainstem responses of Hcn1-deficient mice showed longer latencies, suggesting that HCN1-mediated Ih is critical for synchronized spike timing in SGNs. Together, our data indicate that Ih contributes to SGN membrane properties and plays a role in temporal aspects of signal transmission between the cochlea and the brain, which are critical for normal auditory function.  相似文献   

17.
Trichoderma reesei cellobiohydrolase I (TrCel7A) is a molecular motor that directly hydrolyzes crystalline celluloses into water-soluble cellobioses. It has recently drawn attention as a tool that could be used to convert cellulosic materials into biofuel. However, detailed mechanisms of action, including elementary reaction steps such as binding, processive hydrolysis, and dissociation, have not been thoroughly explored because of the inherent challenges associated with monitoring reactions occurring at the solid/liquid interface. The crystalline cellulose Iα and IIII were previously reported as substrates with different crystalline forms and different susceptibilities to hydrolysis by TrCel7A. In this study, we observed that different susceptibilities of cellulose Iα and IIII are highly dependent on enzyme concentration, and at nanomolar enzyme concentration, TrCel7A shows similar rates of hydrolysis against cellulose Iα and IIII. Using single-molecule fluorescence microscopy and high speed atomic force microscopy, we also determined kinetic constants of the elementary reaction steps for TrCel7A against cellulose Iα and IIII. These measurements were performed at picomolar enzyme concentration in which density of TrCel7A on crystalline cellulose was very low. Under this condition, TrCel7A displayed similar binding and dissociation rate constants for cellulose Iα and IIII and similar fractions of productive binding on cellulose Iα and IIII. Furthermore, once productively bound, TrCel7A processively hydrolyzes and moves along cellulose Iα and IIII with similar translational rates. With structural models of cellulose Iα and IIII, we propose that different susceptibilities at high TrCel7A concentration arise from surface properties of substrate, including ratio of hydrophobic surface and number of available lanes.  相似文献   

18.
The taxonomic attribution of isolated hominin distal humeri has been a matter of uncertainty and disagreement notwithstanding their relative abundance in the fossil record. Four taxonomically-based morphotypes, respectively representing Pboisei, Probustus, non-erectus early Homo and Herectus, have been identified based on the cross-sectional outer shape variation of an assemblage of Plio-Pleistocene eastern and southern African specimens (Lague, 2015). However, the existence of possible differences between Paranthropus and Homo in the inner structural organisation at this skeletal site remains unexplored. We used noninvasive imaging techniques to tentatively characterize the endostructural organization of five early Pleistocene distal humeri from South Africa (TM 1517g, SK 24600, SKX 10924, SKX 34805) and Ethiopia (Gombore IB), which have been variably attributed to Paranthropus or Homo. While the investigated specimens reveal diverse degrees of inner preservation related to their taphonomic and diagenetic history, in all but SK 24600 from Swartkrans we could comparatively assess some geometric properties at the most distal cross-sectional level (%CA, Ix/Iy, Imax/Imin) and quantify cortical bone thickness topographic variation across the preserved shaft portions by means of a 2-3D Relative Cortical Thickness index. Whenever possible, we also provided details about the site-specific organization of the cancellous network and measured the same parameters in a comparative sample of twelve adult extant humans. For most features, our results indicate two main patterns: the first includes the specimens TM 1517g, SKX 10924 and SKX 34805, while the second endostructural morphotype sets apart the robust Homo aff. erectus Gombore IB specimen from Melka Kunture, which more closely resembles the condition displayed by our comparative human sample. Notably, marked differences in the amount and pattern of proximodistal cortical bone distribution have been detected between Gombore IB and SKX 34805 from Swartkrans. Given its discordant outer and inner signatures, we conclude that the taxonomic status of SKX 34805 deserves further investigations.  相似文献   

19.
Fast urbanization and industrialization in developing countries result in significant stormwater runoff pollution, due to drastic changes in land-use, from rural to urban. A three-year study on the stormwater runoff pollutant loading distributions of industrial, parking lot and mixed commercial and residential catchments was conducted in the Tongsha reservoir watershed of Dongguan city, a typical, rapidly industrialized urban area in China. This study presents the changes in concentration during rainfall events, event mean concentrations (EMCs) and event pollution loads per unit area (EPLs). The first flush criterion, namely the mass first flush ratio (MFFn), was used to identify the first flush effects. The impacts of rainfall and catchment characterization on EMCs and pollutant loads percentage transported by the first 40% of runoff volume (FF40) were evaluated. The results indicated that the pollutant wash-off process of runoff during the rainfall events has significant temporal and spatial variations. The mean rainfall intensity (I), the impervious rate (IMR) and max 5-min intensity (Imax5) are the critical parameters of EMCs, while Imax5, antecedent dry days (ADD) and rainfall depth (RD) are the critical parameters of FF40. Intercepting the first 40% of runoff volume can remove 55% of TSS load, 53% of COD load, 58% of TN load, and 61% of TP load, respectively, according to all the storm events. These results may be helpful in mitigating stormwater runoff pollution for many other urban areas in developing countries.  相似文献   

20.
The compounds [Ni(L)(MeCN)]I8 (1) and [Ni(L)(MeCN)]I12 (2) have been obtained from the reactions of the complexes [Ni(L)(L)][BF4](2 + n) {L=2,5,8-trithia[9](2,9)-1,10-phenanthrolinophane; L=MeCN, Cl, Br, I; n=charge of L} with an excess of I2 (molar ratios of 6, 10 and 20 have been used), in the presence of the stoichiometric amount of I (as Bu4nNI) necessary to balance the charge of the complex cation [Ni(L)(L)](2 + n)+. An X-ray diffraction analysis shows that, independently of the nature of L, both 1 and 2 contain the complex cation [Ni(L)(MeCN)]2+, which is therefore capable of templating two different polyiodide networks based on interacting I3/I5 and I5/I7 units, respectively. The solid state FT-Raman spectra of 1 and 2 are discussed based on their structural features.  相似文献   

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