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Current oscillations under voltage-clamp conditions: an interplay of series resistance and negative slope conductance.

Using the patch-clamp technique, we observed profound oscillations of the whole-vacuole outward current across the tonoplast of Mesembryanthemum crystallinum L. (common ice plant). These current oscillations showed a clear voltage dependence and appeared at membrane potentials more positive than 90-100 mV. This paper describes the oscillations in terms of two separate mechanisms. First, the Mesembryanthemum vacuolar membrane shows a negative slope conductance at membrane potentials more positive than 100-120 mV. The fact that the oscillations and the negative slope conductance show a similar threshold potential suggests that (part of) the same mechanism is involved in both phenomena. The second mechanism involved is the voltage drop across the series resistance. As a result, the potential actually experienced by the vacuolar membrane deviates from the command potential defined by the patch-clamp amplifier. This deviation depends in an Ohmic manner on the current magnitude. We suggest that the interplay of the negative slope conductance and the voltage drop across the series resistance can cause a positive feedback which is responsible for the current oscillations.

Electric Conductivity

Interplay between humans and infective agents: a population genetic study.

The genetic composition of present day human populations is determined largely by the interaction between the human host and infective agents. Therefore, theoretical analysis of the host-infective-agent system is required in order for us to be able to understand human evolution. Classical population genetics has been confined largely to analysing the interplay of various mechanisms, such as selection, mutation and drift, in one species at a time. Unfortunately, there have been few studies of such interactive systems. In the present investigation, these studies have been enlarged, with problems of human genetics in mind, by mathematical examination of a model in which a diploid host with three alleles interacts with a haploid infective agent with two alleles. The results are compared with those obtained from simpler models analysed in the past. The assumptions inherent in such "gene for gene" models and our results are discussed. An increase in the number of alleles appears to enhance the chances for the establishment of permanent genetic polymorphisms, improving genetic "elasticity" of a population for coping with changing challenges by various infective agents. Interaction between two haploid species leads to a loss of polymorphism in both of them and, hence, to a severe loss of evolutionary elasticity. The hypothesis that the evolution of diploidy might have been favoured by a selective advantage of diploid organisms interacting with environmental challenges, such as infective agents, is supported.

ABO Blood-Group System

High circulating levels of interleukin-6 in patients with septic shock: evolution during sepsis, prognostic value, and interplay with other cytokines. The Swiss-Dutch J5 Immunoglobulin Study Group.

PURPOSE AND PATIENTS: We measured the serum concentrations of interleukin-6 (IL-6) in 70 patients with established septic shock caused predominantly by gram-negative bacteria. The aims of the study were to determine whether and for how long IL-6 was detectable in the circulation of these patients, to assess whether IL-6 levels were associated with patients' outcomes, and, finally, to examine the interplay between IL-6, tumor necrosis factor (TNF), interleukin-1 beta (IL-1 beta), and interferon-gamma (IFN-gamma). RESULTS: IL-6 was detected in 64% of the patients at study entry but in only 18% on Day 1 and 2% on Day 10. Serum levels of IL-6 were higher (median: 3.5 ng/mL, range: less than 0.1 to 305 ng/mL) in patients dying of fulminant septic shock than in those surviving (median: 0.5 ng/mL, range: less than 0.1 to 135 ng/mL; p = 0.003) or in those with a transient reversal of shock but who ultimately died of a relapse of shock (median: less than 0.1 ng/mL, range: less than 0.1 to 12.5 ng/mL; p = 0.005). However, no cutoff values of IL-6 confidently predicted the outcome of an individual patient. The serum concentrations of IL-6 measured at study entry correlated with the duration of survival (r = -0.51, p = 0.004) and with the levels of TNF-alpha (r = 0.53; p less than 0.0001) but not with the levels of either IL-1 beta (r = 0.01, p = 0.90) or IFN-gamma (r = 0.06, p = 0.60). CONCLUSIONS: These results indicate that circulating levels of IL-6 are detectable in a majority of patients with gram-negative septic shock. Concentrations of IL-6 peaked near the onset of shock and rapidly decreased to undetectable levels within approximately 24 hours in most patients. Levels of IL-6 measured at study entry correlated with levels of TNF and with patients' outcomes. Yet, IL-6 does not appear to be a clinically useful laboratory test for predicting the outcome of an individual patient.

Adolescent

Interplay between lipoic acid and glutathione in the protection against microsomal lipid peroxidation.

Reduced glutathione (GSH) delays microsomal lipid peroxidation via the reduction of vitamin E radicals, which is catalyzed by a free radical reductase (Haenen, G.R.M.M. et al. (1987) Arch. Biochem. Biophys. 259, 449-456). Lipoic acid exerts its therapeutic effect in pathologies in which free radicals are involved. We investigated the interplay between lipoic acid and glutathione in microsomal Fe2+ (10 microM)/ascorbate (0.2 mM)-induced lipid peroxidation. Neither reduced nor oxidized lipoic acid (0.5 mM) displayed protection against microsomal lipid peroxidation, measured as thiobarbituric acid-reactive material. Reduced lipoic acid even had a pro-oxidant activity, which is probably due to reduction of Fe3+. Notably, protection against lipid peroxidation was afforded by the combination of oxidized glutathione (GSSG) and reduced lipoic acid. It is shown that this effect can be ascribed completely to reduction of GSSG to GSH by reduced lipoic acid. This may provide a rationale for the therapeutic effectiveness of lipoic acid.

Animals

The regulation of GM-CSF is dependent on a complex interplay of multiple nuclear proteins.

GM-CSF is an important mediator of hematopoiesis and its dysregulation may play a role in neoplastic and inflammatory conditions. Previous studies have demonstrated that GM-CSF production depends upon the accumulation of specific mRNA, which occurs by transcriptional and post-transcriptional mechanisms. In order to dissect the cis-acting sequences responsible for its regulation, we performed an extensive mutagenesis study spanning 54 nucleotides 5' of the GM-CSF coding region. Our analysis suggests that the previously-described functional elements of the GM-CSF promoter, kappa B and a repetitive CATTT/A motif, the former co-exists with an overlapping 9 nucleotide site which silences promoter activity, and the CATTT/A complex binds multiple polypeptides which differentially contribute to basal and inducible promoter activity. These two sites interact to provide tissue-appropriate and stimulus-specific promoter function. Using DNA-protein cross-linking and co-transfection studies, we demonstrate that the c-rel-related proteins p65 and p50 bind to the GM-CSF promoter and that p65 binding is primarily responsible for the enhancing effects at this site. In addition, we show that the GM-CSF kappa B decanucleotide is inadequate to provide full binding affinity; mutation of nucleotides flanking this site affect promoter function by altering NF-kappa B binding affinity. Together these results suggest that the transcriptional response of GM-CSF is dependent on a complex interplay of multiple DNA binding proteins.

Base Sequence

Interplay of HIV-1 phenotype and neutralizing antibody response in pathogenesis of AIDS.

A majority of human immunodeficiency virus type 1 (HIV-1) infected individuals display a rapid loss of CD4+ lymphocytes with fast progression towards overt acquired immunodeficiency syndrome (AIDS). However, a small proportion of individuals infected by HIV-1 remain immunologically intact for many years. In order to identify factors that might influence the pathogenesis of HIV-1 infection, 21 Italian mothers and 11 Swedish homosexual men were studied for the presence of autologous neutralizing antibodies in serum, biological phenotype of virus isolates and envelope variable region 3 (V3) sequences. The results were compared to the risk of mother-to-child transmission and progression of the disease. The presence of a neutralizing antibody response to the autologous virus as well as a virus with slow replicative capacity were linked both to low risk of mother-to-child transmission and non-progression of the disease. Patients whose peripheral blood mononuclear cells contained a mutation in the tip of the V3 loop (Arg318 to serine, lysine or leucine) significantly more often had neutralizing antibodies to autologous virus isolates containing arginine at this position. Thus, it appears that the interplay and balance between neutralizing antibody response of the host and the biological phenotype of HIV-1 strongly influence pathogenesis.

Acquired Immunodeficiency Syndrome

Loneliness and alcohol abuse: a review of evidences of an interplay.

This report contains a review of the literature about the interplay between loneliness and the abuse of alcohol. A theoretical discussion based on clinical observations can be dated back to the 1950's. Systematic empirical studies, however, appear sparsely and have mainly been performed during the last decade. Thus, knowledge is still incomplete, but the review indicates that loneliness may be significant at all stages in the course of alcoholism: as a contributing and maintaining factor in the growth of abuse and as an encumbrance in attempts to give it up. Concordant reports demonstrate that alcoholics do feel more lonely than members of most other groups do. In advanced abusers, loneliness is obviously connected with a number of negative characteristics and, together with several of those, directly linked to a poor prognosis. There are, however, no obvious relations to the external social situation (i.e. network) or amount of drinking. Instead, the feeling of loneliness appears to be more connected with a general negative perception about oneself and one's relations to other people and also with a general dissatisfaction with most things in life. The lonely abuser seems likewise resigned and unable to bring himself to change his/her situation. There are also associations with a broad array of psychopathology. In comparison to people with other health problems, the supportive value of the social network of alcoholics appears to be more wavering.

Alcoholism

Interplay between chromatin structure and transcription.

Research on the interplay between chromatin and transcription has progressed along three lines during the past year. Evidence has been reported for disruption of nucleosomes by transcriptional regulatory proteins in cell-free systems; displacement of the histone octamer during transcription has been conclusively demonstrated; and insights into transcriptional repression by heterochromatin have been gained from studies of silent mating loci and telomeres in yeast.

Animals

The impact of metagenomic interplay on the mosquito redox homeostasis.

Mosquitoes are exposed to oxidative challenges throughout their life cycle. The primary challenge comes from a blood meal. The blood digestion turns the midgut into an oxidative environment, which imposes pressure not only on mosquito fecundity and other physiological traits but also on the microbiota in the midgut. During evolution, mosquitoes have developed numerous oxidative defense mechanisms to maintain redox homeostasis in the midgut. In addition to antioxidants, SOD, catalase, and glutathione system, sufficient supply of the reducing agent, NADPH, is vital for a successful defense against oxidative stress. Increasing evidence indicates that in response to oxidative stress, cells reconfigure metabolic pathways to increase the generation of NADPH through NADP-reducing networks including the pentose phosphate pathway and others. The microbial homeostasis is critical for the functional contributions to various host phenotypes. The symbiotic microbiota is regulated largely by the Duox-ROS pathway in Drosophila. In mosquitoes, Duox-ROS pathway, heme-mediated signaling, antimicrobial peptide production and C-type lectins work in concert to maintain the dynamic microbial community in the midgut. Microbial mechanisms against oxidative stress in this context are not well understood. Emerging evidence that microbial metabolites trigger host oxidative response warrants further study on the metagenomic interplay in an oxidative environment like mosquito gut ecosystem. Besides the classical Drosophila model, hematophagous insects like mosquitoes provide an alternative model system to study redox homeostasis in a symbiotic metagenomic context.

Animals

Kinetics of the interactions of a dicarboxylic porphyrin with unilamellar lipidic vesicles: interplay between bilayer thickness and pH in rate control.

The transfer of a dicarboxylic porphyrin from phosphatidylcholine fluid-phase unilamellar vesicles towards albumin is studied focusing on bilayer thickness and pH effects. The kinetics of this process yield the rate constants for the porphyrin flip-flop from the inner to the outer hemileaflet and its exit towards aqueous medium. Phospholipids with monounsaturated 14-22 carbon chains are used. Interplay between bilayer thickness and pH for the control of the rate constants is observed. This results in the amplification, at physiological pH, of the effect of membrane thickness on the flip-flop and exit rates as compared to pH 8.5 and 6.5. These data are explained by the degree of porphyrin burying within the bilayer resulting from a compromise between favorable hydrophobic interactions with the hydrocarbon phase and unfavorable penetration of the polar carboxylic chains. The balance between the two effects depends particularly on the neutralization of one carboxylic chain. Considering the bilayer hydrophobicity profile and the porphyrin size, the optimization of hydrophobic interactions appears dependent on the bilayer thickness. The flip-flop and the exit are governed by neutralization and deprotonation of the carboxylic chains, respectively, the rate of these proton exchanges being dependent on the porphyrin location within the bilayer.

Albumins

Adhesion-induced domain formation by interplay of long-range repulsion and short-range attraction force: a model membrane study.

We study the role of the interplay of specific and universal forces for the adhesion of giant vesicles on solid supported membranes. To model the situation of cell adhesion, we incorporated lipopolymers (phospholipids with polyethyleneoxide headgroups) as artificial glycocalix, whereas attractive lock-and-key forces are mimicked by incorporating biotinylated lipids into both membranes and by mediating the strong coupling through streptavidin. Adhesion is studied by quantitative reflection interference contrast microscopy (RICM), which enables visualization of the contact zone and reconstruction of the height profile of the membrane beyond the contact line (outside the contact zone) up to a height of 1 micron. We demonstrate that adhesion is accompanied by lateral phase separation, leading to the formation of domains of tight adhesion (adhesion plaques) separated by areas of weak adhesion exhibiting pronounced flickering. By analyzing the height profile S(x) near the contact line in terms of the tension equilibrium (Young equation) and the moment equilibrium, respectively, the adhesion energy and membrane tension can be approximately measured locally. We show that the adhesion energy is about three orders of magnitude larger for the adhesion plaques than for the weekly adhering regions. The adhesion is studied as a function of the excess area of the vesicle generated by temperature variation. A very remarkable finding is that increased excess area is not always stored in the contact area, but leads to the formation of microbuds (diameter approximately 2 microns).

Bacterial Proteins

Insulin receptor-deficient cells as a new tool for dissecting complex interplay in insulin and insulin-like growth factors.

Cell systems derived from knockout mice for the insulin receptor (IR) or the IGF-1 receptor (IGF-1R) represent unique tools for dissecting complex interplay in the actions of insulin and insulin-like growth factors through their cognate versus non-cognate receptor. In this study, we used a fibroblast cell line derived from IR-deficient mice to investigate metabolic and mitogenic effects of IGF-1 and insulin. IGF-1 was able to stimulate glucose uptake, glucose incorporation into glycogen and thymidine incorporation in such cells. Phosphatidylinositol 3-kinase and mitogen-activated protein kinase, two enzymes of major metabolic-mitogenic signaling pathways, were activated upon stimulating these cells with IGF-1. All these effects were also achieved when IR-deficient cells were stimulated with insulin. Thus, IGF-1R can represent an alternative receptor through which insulin might exert some of its effects.

Animals

High-performance liquid chromatography of substituted p-benzoquinones and p-hydroquinones. I. Interplay of on-column redox reaction and the chromatographic retention process.

Chromatograms exhibiting unusual elution profiles were obtained in the reversed-phase chromatography of methoxy-substituted hydroquinones with hydro-organic mobile phases. The dependence of the elution profiles on the flow-rate and the mass of injected sample indicated that peaks were caused by the interplay of the chromatographic retention process and the concomitant oxidation of hydroquinones in the chromatographic column. The reaction was first investigated in free solution and the first-order rate constants and equilibrium constants were estimated for the oxidation of 2-methoxy-, 2,5-dimethoxy-, 2,6-dimethoxy-, 2,3,5-trimethoxy- and 2,3,5,6-tetramethoxyhydroquinones. The effect of Fe3+ and Cu2+ on the oxidation of 2,6-dimethoxyhydroquinone was also examined and it was found that Fe3+ caused a ten-fold increase in the reaction rate. The oxidation of 2-methoxy- and 2,6-dimethoxyhydroquinones in the chromatographic column showed first-order and zerothorder kinetic behavior at low and high sample loads, respectively. Such change in reaction order is typical for heterogeneous reactions that follow Langmuir-Hinshelwood kinetics and suggests the existence of catalytically active sites on the silica. Upon purging the columns with EDTA, on-column oxidation of the hydroquinones was attenuated so that no reaction zones appeared on the chromatogram. Subsequent loading of the column with Fe3+, however, gave rise to broad reaction zones and possibly to total conversion of the hydroquinones to benzoquinones in the column. In all cases investigated the rate of oxidation was much higher in the column than in free solution. On the basis of the results obtained here, heavy mental-catalyzed reaction at the stationary phase surface is proposed to be the dominant mechanism for the oxidation reaction examined here.

Benzoquinones

L-arginine modulates aggregation and intracellular cyclic 3,5-guanosine monophosphate levels in human platelets: direct effect and interplay with antioxidative thiol agent.

Platelet nitric oxide is involved in the control of aggregability via cyclic 3',5'-guanosine monophosphate synthesis. Since L-arginine provides a guanidino nitrogen group for nitric oxide synthesis through nitric oxide synthase activity, we tried to clarify whether an increased availability of this amino acid can directly modulate the response of human platelets. In our conditions, L-arginine (at 100-6000 micromol/L) was able to influence the response of human platelets stimulated with adenosine 5-diphosphate and collagen both in PRP and in whole blood. The anti-aggregating effect was not present when D-arginine was used. Permeabilized platelets exhibited an increased sensitivity to L-arginine. Also, an increased availability of Ca2+ enhanced L-arginine effect. L-arginine (at 120-500 micromol/L) increased cyclic 3',5'-guanosine monophosphate levels in resting platelets; the amino acid also determined an increase of cyclic 3',5'-guanosine monophosphate in platelets at the end of adenosine 5-diphosphate-induced aggregation. Nitric oxide synthase inhibitor N(G)-monomethyl-L-arginine prevented L-arginine effects on aggregation and cyclic 3',5'-guanosine monophosphate synthesis. Phosphodiesterase III inhibitor milrinone and antioxidative thiol N-acetyl-L-cysteine enhanced the effect of L-arginine on cyclic 3',5'-guanosine monophosphate. In conclusion, L-arginine exerts inhibitory effects on human platelet response through a nitric oxide-dependent synthesis of cyclic 3',5'-guanosine monophosphate. A positive interplay on platelet response between L-arginine and milrinone or antioxidative thiol N-acetyl-L-cysteine was evidenced.

Acetylcysteine

Ca2+ signalling in rat chromaffin cells: interplay between Ca2+ release from intracellular stores and membrane potential.

Cytosolic Ca2+ oscillations are physiologically important in a range of excitable and non-excitable cells. The combined techniques of whole-cell patch clamp and photometric measurement of cytosolic Ca2+ has enabled us to identify the components of Ca2+ spiking in rat chromaffin cells. We show that Ca2+ oscillations continue at a fixed membrane potential and that infusion of the InsP3 receptor antagonist, heparin, substantially blocked the cytosolic Ca2+ spikes. However, even in the presence of heparin we observed spikes of membrane potential depolarization due to the repetitive activation of a transient inward cation current. We conclude that Ca2+ oscillations are dependent on Ca2+ release from heparin sensitive Ca2+ stores and possibly on Ca2+ entry associated with the repetitive activation of a transient cation current. The depolarizing action of the cation current would, in turn, recruit voltage-sensitive Ca2+ channels and further Ca2+ entry would augment the cytosolic Ca2+ spikes. Our results demonstrate that Ca2+ oscillations in rat chromaffin cells are due to a complex interplay of Ca2+ entry and Ca2+ release.

Adrenal Medulla

Interplay of causation between suppliers and consumers in evolutionary trophic dynamics.

Natural selection, conceived as the process of small causes making small effects on the level of molecular evolutionary dynamics of a population, can yield global effects on the level of evolutionary trophic dynamics of populations, including those of mass extinctions. Occurrence of mass extinctions is due to the interplay of causation between suppliers and consumers in trophic dynamics. If the case of supplier causation is available such that resource exploitation by consumers on the upper trophic level follows in time resource presentation by suppliers on the lower, instead of resource exploitation followed by resource presentation, mass extinctions could be a norm of the evolutionary trophic dynamics.

Biological Evolution

Functional interplay between gelatinases and hyperalgesia in endotoxin-induced localized inflammatory pain.

The role of ECM-degrading proteinases in normal developmental processes and in pathological conditions is extensively studied. However, few reports describe the role ECM-degrading proteinases play in modulating hyperalgesia. The goal of this study is to describe the regulation of gelatinases during endotoxin mediated local inflammation, induced by intra plantar endotoxin (ET; 1.25 microg/50 microl) injection in Balb/c mice, and to correlate that with hyperalgesia. ET injections induced hyperalgesia, as determined by hot plate and paw pressure tests, which peaked by 24 h and recovered by 48 h post-injection. Contralateral paw of ET injected mice and saline injected paws in control mice elicited no hyperalgesia. Zymography showed that ET and saline injected paws elicited increased gelatinase activity by 9 h after injection. However, only the former maintained high levels of expression of a 90 kD gelatinase up to at least 96 h post ET injection, while in the latter gelatinase expression was down regulated by 24 h. Interestingly, the 90-kD gelatinase was upregulated in the contralateral paw of the ET-injected mice beyond 48 h post injection. Saline injection in that paw, during a time when gelatinases are upregulated, induced hyperalgesia. Intraperitoneal injection of either ZnCl(2) (100 microM), thymulin (5 microg/100 microl), or morphine (2 mg/kg/100 microl) reversed the ET-induced hyperalgesia and suppressed gelatinase activity. Furthermore, intraperitoneal injection of MPI, an ECM-degrading proteinase inhibitor, reversed ET induced hyperalgesia. Taken together, the above suggests that a functional interplay exists between gelatinase upregulation triggered by ET injections and hyperalgesia. The exact mechanism underlying such correlation remains to be determined.

Animals

The dynamic interplay of malignant and benign T cells in cutaneous T-cell lymphoma.

Cutaneous T-cell lymphoma is a malignancy of functional, tissue-specific T cells. Many characteristics of the disease can be explained by virtue of the ability of the malignant cell population to actively participate in the host's immunologic network. Various aspects of this dynamic interplay between malignant and benign T cells are discussed, including impact on diagnosis, staging, and therapy.

Diagnosis, Differential