Conduction of the cardiac impulse. 3. Characteristics of very slow conduction

The excitability of short segments (5–7 mm) of bundles of canine Purkinje fibers was depressed by exposure to 15–18 mM K⁺, to 15–18 mM K⁺ plus 5 x 10^-6 epinephrine or norepinephrine, to low K⁺, and to low Na⁺. The depressed segment was in the center chamber of a three-chamber bath; the ends of the bundle were exposed to normal Tyrode solution. Each method of depression resulted in slow and probably decremental conduction with an effective conduction velocity in the middle chamber of about 0.05 m/sec, or one-way block, or two-way block with summation of the graded responses in the depressed region. The action potential in the depressed segment (the slow response) differs from the normal action potential in its response to applied stimuli. A second active depolarization can be evoked by cathodal stimulation during much of the slow response. The response in the depressed segment is graded. The response of depressed fibers may depend on excitatory events similar to those responsible for the slow component of the cardiac action potential. It is suggested that the slow response can propagate, at least decrementally, in fibers in which the rapid, Na⁺-dependent upstroke is absent, and can cause reentrant excitation by so doing.     

Drift of large-core spiral waves in inhomogeneous excitable media

Spiral waves in excitable media may drift due to interaction with medium inhomogeneities. We describe this drift asymptotically, within the kinematic (eikonal) approximation.     

Plugging space into predator-prey models: an empirical approach

Extrapolating ecological processes from small-scale experimental systems to scales of natural populations usually entails a considerable increase in spatial heterogeneity, which may affect process rates and, ultimately, population dynamics. We demonstrate how information on the heterogeneity of natural populations can be taken into account when scaling up laboratory-derived process functions, using the technique of moment approximation. We apply moment approximation to a benthic crustacean predator-prey system, where a laboratory-derived functional response is made spatial by including correction terms for the variance in prey density and the covariance between prey and predator densities observed in the field. We also show how moment approximation may be used to incorporate spatial information into a dynamic model of the system. While the nonspatial model predicts stable dynamics, its spatial equivalent also produces bounded fluctuations, in agreement with observed dynamics. A detailed analysis shows that predator-prey covariance, but not prey variance, destabilizes the dynamics. We conclude that second-order moment approximation may provide a useful technique for including spatial information in population models. The main advantage of the method is its conceptual value: by providing explicit estimates of variance and covariance effects, it offers the possibility of understanding how heterogeneity affects ecological processes.     

New high-frequency catheter technique for His bundle ablation in dogs

A new method is presented for the production of complete atrioventricular heart block. It consists of a special catheter, which is inserted into the right atrium via a femoral vein and positioned in the region of the His bundle for His bundle potential recording. Production of heart block is achieved by a high frequency current pulse from an electrocautery unit.     

Signaling cascades as cellular devices for spatial computations

Signaling networks usually include protein-modification cycles. Cascades of such cycles are the backbones of multiple signaling pathways. Protein gradients emerge from the spatial separation of opposing enzymes, such as kinases and phosphatases, or guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs) for GTPase cycles. We show that different diffusivities of an active protein form and an inactive form leads to spatial gradients of protein abundance in the cytoplasm. For a cascade of cycles, using a discrete approximation of the space, we derive an analytical expression for the spatial gradients and show that it converges to an exact solution with decreasing the size of the quantization. Our results facilitate quantitative analysis of the dependence of spatial gradients on the network topology and reaction kinetics. We demonstrate how different cascade designs filter and process the input information to generate precise, complex spatial guidance for multiple GTPase effector processes. Thus, protein-modification cascades may serve as devices to compute complex spatial distributions of target proteins within intracellular space.     

Inhibition of hippocampal field potentials by GYKI 52466 in vitro and in vivo.

GYKI 52466 is a specific antagonist of the neuronal excitation mediated by the non-NMDA type excitatory amino acid receptors, at several sites in the central nervous system. The experiments presented here show that the drug has a dose-dependent, slowly developing, long-lasting and reversible inhibitory action on the field potentials recorded from the CA1 region of the rat hippocampus, in vitro. Its action is similar to that of the well-known non-NMDA receptor blocker, CNQX. When the stimulus intensity-dependence of the population spikes was investigated, both drugs shifted the input-output curves in a parallel manner, while the maximum responses were only slightly depressed at the doses applied. With i.v. application, GYKI 52466 also inhibited the hippocampal field potentials recorded from the CA1 region of anesthetized rats dose-dependently. The inhibition was relatively weak compared to the effect found in earlier studies in the spinal cord, by the same doses. Four mg/kg i.v., a doses which is able to block spinal reflexes completely, caused an only about 20% depression of the recorded responses in the hippocampal CA1 area.     

Semiclassical approximations of stochastic epidemiological processes towards parameter estimation using as prime example the SIS system with import

In this paper we investigate several schemes to approximate the stationary distribution of the stochastic SIS system with import. We begin by presenting the model and analytically computing its stationary distribution. We then approximate this distribution using Kramers–Moyal approximation, van Kampen's system size expansion, and a semiclassical scheme, also called WKB or eikonal approximation depending on its different applications in physics. For the semiclassical scheme, done in the context of the Hamilton–Jacobi formalism, two approaches are taken. In the first approach we assume a semiclassical ansatz for the generating function, while in the second the solution of the master equation is approximated directly. The different schemes are compared and the semiclassical approximation, which performs better, is then used to analyse the time dependent solution of stochastic systems for which no analytical expression is known. Stochastic epidemiological models are studied in order to investigate how far such semiclassical approximations can be used for parameter estimation.     

Spatially implicit plankton population models: Transient spatial variability

Ocean plankton models are useful tools for understanding and predicting the behaviour of planktonic ecosystems. However, when the regions represented by the model grid cells are not well mixed, the population dynamics of grid cell averages may differ from those of smaller scales (such as the laboratory scale). Here, the ‘mean field approximation’ fails due to ‘biological Reynolds fluxes’ arising from nonlinearity in the fine-scale biological interactions and unresolved spatial variability. We investigate the domain-scale behaviour of two-component, 2D reaction-diffusion plankton models producing transient dynamics, with spatial variability resulting only from the initial conditions. Failure of the mean field approximation can be quite significant for sub grid-scale mixing rates applicable to practical ocean models. To improve the approximation of domain-scale dynamics, we investigate implicit spatial resolution methods such as spatial moment closure. For weak and moderate strengths of biological nonlinearity, spatial moment closure models generally yield significant improvements on the mean field approximation, especially at low mixing rates. However, they are less accurate given weaker transience and stronger nonlinearity. In the latter case, an alternative ‘two-spike’ approximation is accurate at low mixing rates. We argue that, after suitable extension, these methods may be useful for understanding and skillfully predicting the large-scale behaviour of marine ecosystems.     

Associations between chronotypes and psychological vulnerability factors of depression

Chronotypes have been associated with psychopathology. The eveningness chronotype has been consistently linked with depressed states or depressive disorder, but the underlying mechanism remains unclear. Prior studies have shown associations between chronotype and personality traits that are linked to depression (e.g. neuroticism), but other psychological vulnerability factors have not been previously investigated in relation to chronotypes. The aim of this study was to examine the association between chronotypes, depression and psychological risk factors of depression (namely, cognitive reactivity and worry), in a large cohort of depressed patients and healthy individuals. We used data from the Netherlands Study of Depression and Anxiety (n = 1654), which includes 1227 clinically diagnosed individuals with a lifetime diagnosis of depression and 427 healthy controls. We assessed cognitive reactivity (Leiden Index of Depression Sensitivity-Revised) and trait worry (Penn State Worry Questionnaire). We controlled for sociodemographic factors as well as for insomnia and neuroticism. We found that the evening type is associated with higher cognitive reactivity scores, especially with increased rumination. Cognitive reactivity also mediated the relationship between chronotype and depression status, even when controlling for neuroticism and insomnia. Trait worry was not associated with chronotype. Our findings show that depressogenic cognitions are more prevalent in evening types and perhaps mediate the association between chronotype and depression. Further prospective research is needed to determine the timeline of the association. Nevertheless, results imply that targeting depressogenic cognitive processes, perhaps in combination with chronotherapeutic treatments, may be particularly useful in evening types.     

Depression of mitochondrial respiration during daily torpor of the Djungarian hamster,Phodopus sungorus,is specific for liver and correlates with body temperature

Small mammals actively decrease metabolism during daily torpor and hibernation to save energy. Increasing evidence suggests depression of mitochondrial respiration during daily torpor of the Djungarian hamster but tissue-specificity and relation to torpor depth is unknown. We first confirmed a previous study by Brown and colleagues reporting on the depressed substrate oxidation in isolated liver mitochondria of the Djungarian hamster (Phodopus sungorus) during daily torpor. Next, we show that mitochondrial respiration is not depressed in kidneys, skeletal muscle and heart. In liver mitochondria, we found that state 3 and state 4 respirations correlate with body temperature, suggesting inhibition related to torpor depth and to metabolic rate. We conclude that molecular events leading to depression of mitochondrial respiration during daily torpor are specific to liver and linked to a decrease in body temperature. Different tissue-specificity of mitochondrial depression may assist to compare and identify the molecular nature of mitochondrial alterations during torpor.     

Variance-mean analysis in the presence of a rapid antagonist indicates vesicle depletion underlies depression at the climbing fiber synapse

Many types of synapses throughout the nervous system are transiently depressed during high-frequency stimulation. Several mechanisms have been proposed to account for this depression, including depletion of release-ready vesicles. However, numerous studies have raised doubts about the importance of depletion in depression of central synapses and have implicated alternative mechanisms, such as decreased release probability. We use variance-mean analysis to determine the mechanism of depression at the climbing fiber to Purkinje cell synapse. We find that postsynaptic receptor saturation makes it difficult to distinguish between a decrease in available vesicles and a reduction in release probability. When AMPA receptor saturation is relieved with a low-affinity antagonist, variance-mean analysis reveals that depression arises from a decrease in the number of release-ready vesicles. Vesicle depletion is prominent, despite numerous docked vesicles at each release site, due to multivesicular release. We conclude that vesicle depletion can contribute significantly to depression of central synapses.     

Steric accessibility of the HIV-1 gp41 N-trimer region

During human immunodeficiency virus entry, gp41 undergoes a series of conformational changes that induce membrane fusion. Immediately prior to fusion, gp41 exists in a prehairpin intermediate in which the N- and C-peptide regions of gp41 are exposed. Rearrangement of this intermediate into a six-helix bundle composed of a trimeric coiled coil from the N-peptide region (N-trimer) surrounded by three peptides from the C-peptide region provides the driving force for membrane fusion, whereas prevention of six-helix bundle formation inhibits viral entry. Because of its central role in mediating viral entry, the N-trimer region of gp41 is a key vaccine target. Extensive efforts to discover potent and broadly neutralizing antibodies (Abs) against the N-trimer region have, thus far, been unsuccessful. In this study, we attached a potent C-peptide inhibitor that binds to the N-trimer region to cargo proteins of various sizes to examine the steric accessibility of the N-trimer during fusion. These inhibitors show a progressive loss of potency with increasing cargo size. Extension of the cargo/C-peptide linker partially restores inhibitory potency. These results demonstrate that the human immunodeficiency virus defends its critical hairpin-forming machinery by steric exclusion of large proteins and may explain the current dearth of neutralizing Abs against the N-trimer. In contrast, previous results suggest the C-peptide region is freely accessible during fusion, demonstrating that the N- and C-peptide regions are in structurally distinct environments. Based on these results, we also propose new strategies for the generation of neutralizing Abs that overcome this steric block.     

Spatial instabilities and local oscillations in a lattice gas Lotka–Volterra model

 We analyze the evolution of spatially inhomogeneous perturbations in a lattice gas model for a prey-predator population. Starting with the master equation of the model, decoupled by means of a mean field approximation, spatial instabilities are seen to take place in a region of the phase diagram. This is in qualitative agreement with local oscillations already observed in computer simulations. We determine the transition line that separates the homogeneous region from the inhomogeneous region and we study the spatio-temporal self-organized structures that appear inside the inhomogeneous region. Received 3 November 1995; received in revised form 26 January 1996     

Functional disability of rat splenocytes provoked to lipid peroxidation by cumene hydroperoxide

Rat splenocytes were provoked to lipid peroxidation in a dose-dependent manner by cumene hydroperoxide. After exposure to cumene hydroperoxide, formation of high molecular weight protein, presumably through cross-linking of lower molecular weight protein, was stimulated in splenocytes as well as in erythrocyte ghosts. The mitogenic response to concanavalin A of splenocytes was remarkably depressed by addition of cumene hydroperoxide to cultures. This depression was due rather to failures of splenocytes in responding to concanavalin A than deactivation of concanavalin A molecules. It is notworthy that the viability of splenocytes was unaffected by cumene hydroperoxide under the culture conditions where the mitogenic response was depressed. The addition of alpha-tocopherol or thiourea could block the depression of mitogenic response by cumene hydroperoxide, indicating that the depressed response to concanavalin A was related to radical formation. Overall evidence suggests that the function of immunocompetent cells can be depressed through lipid peroxidation-associated mechanisms without suffering from lethal damage.     

微电泳给予回苏灵对家兔小脑皮层单位放电的影响

文献报道呼吸复苏剂回苏灵(dimefline,DIM)的作用可能是阻断 GABA 受体。本工作选择 GABA 受体密集的小脑皮层用微电泳方法对此加以验证。用五管玻璃微电极记录了16只家兔小脑皮层100个自发放电单位。除8个单位对 GABA、DIM 均不敏感外,有92个单位对 GABA 敏感。微电泳给予 DIM 能使这些单位的放电出现兴奋,阻遏及先兴奋后阻遏等不同效应。在75个 GABA 敏感的单位中,有71个单位 DIM 能对抗 GABA 的阻遏效应或使该单位对 GABA 的敏感性下降,未能对抗 GABA 作用的单位只有4个。静脉注射 DIM 能产生相似的结果。在35个 GABA 敏感的单位中,比较了荷包牡丹碱(bicuculline,BIC)与DIM 对 GABA 阻遏效应的影响。其中两者均能对抗 GABA 效应的有21个,两者都不能对抗的有3个,还有11个单位则 BIC 不能对抗而 DIM 能对抗。本工作提示,DIN 能对抗GABA 的阻遏效应,可作为 GABA 受体的阻断剂。     

Local Explanations of Landscape Patterns: Can Analytical Approaches Approximate Simulation Models of Spatial Processes?

Research over the last 100 years has demonstrated the importance of space for ecological processes. Given this importance, it may seem natural to start investigations into broad-scale ecological processes with a comprehensive, broad-scale spatial map. Here we argue that it may sometimes be possible to answer important questions about spatial processes using crude spatial information obtained when a comprehensive map is not available. To present our argument, we first develop a simple simulation model for a perennial plant reproducing and dying on a landscape with different arrangements of suitable and unsuitable sites. We then develop a simple, analytical approximation to predict the fraction of suitable sites that are occupied by the simulated plants. The analytical approximation summarizes the spatial map by using a single parameter that gives the probability that a site adjacent to a suitable site is suitable. Comparing the predictions of both approaches highlights three points: (a) The role of the spatial environment in ecological processes may play out at the local scale. Therefore, studying the local-scale processes may provide insights into landscape patterns. (b) The predictions from the analytical approximation fail noticeably when suitable sites are rare and are distributed randomly (rather than clumped) on the map. In these situations, patches of interconnected suitable sites are very small, and populations within small patches may go extinct via demographic stochasticity. This illustrates how analytical approximations can be used to identify cases when local-scale spatial processes are not sufficient to understand the ecological consequences of space. (c) For many natural systems, constructing the appropriate environmental map needed to study ecological processes is difficult or impossible. However, summary characteristics such as those employed by the analytical approximation may be estimated directly in nature. Therefore, even in the absence of an explicitly spatial broad-scale map, it may be possible to study spatial processes by understanding which local-scale characteristics of space are important. Received 5 May 1997; accepted 31 July 1997.     

Depression is associated with an increase in the expression of the platelet adhesion receptor glycoprotein Ib

There is a significant association between cardiovascular disease and depression. Previous studies have documented changes in platelets in depression. It is unknown if depression causes functional changes in platelet surface receptors. Therefore, we analyzed (1) the surface expression of glycoprotein (GP)Ib and the integrin receptor _IIbβ_IIIa, receptors involved in platelet adhesion and aggregation, (2) CD62 (P-selectin) and CD63, integral granule proteins translocated during platelet activation, (3) platelet aggregation in response to ADP and (4) plasma levels of glycocalicin and von Willebrand factor (vWF), in depressed patients compared to healthy volunteers. Fifteen depressed patients with a Hamilton depression score of at least 22 and fifteen control subjects were studied. Platelets were assessed for surface expression levels of GPIb, _IIbβ_IIIa, CD62 and CD63 by flow cytometry. Genomic DNA was isolated to investigate a recently described polymorphism in the 5’ untranslated region of the GPIb gene. The number of GPIb receptors was significantly increased on the surface of platelets from patients with depression compared to control subjects. Surface expression of CD62 was also significantly increased in the depressed patients versus control subjects. There was no significant difference between depressed patients and healthy volunteers in the surface expression of _IIbβ_IIIa or CD63, or in glycocalicin or vWF plasma concentration, or ADP-induced aggregation. There was no difference in allele frequency of the Kozak region polymorphism of the GPIb gene, which can affect GPIb expression. The results of this study demonstrate that the number of GPIb receptors on platelets are increased in depression and suggest a novel risk factor for thrombosis in patients with depression.