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At least 811 records · Page 45Linked to original sources

PubMed1995

Limitations of oxygen transport to the cell.

Perhaps the major points to be made from this review are the following: 1. Transport of O2 from the environment to the mitochondrion is accomplished in a well-described but not yet well-understood sequence of diffusive and convective steps that are highly interactive and thus integrative in their outcome. 2. Thus, under conditions of O2-supply limitation of VO2max in strenuous exercise in health, all transport steps affect the value of VO2max reached, but the sensitivity of VO2max (to changes in any step) is not the same for each step, and moreover, will vary with the quantitative conditions. It is time to abandon the very concept of a single limiting factor to VO2max. 3. O2 supply limitation of VO2 is seen under two very different conditions that in fact are at the opposite ends of the spectrum of metabolic scope: VO2max in strenuous exercise in health and basal VO2 in severe disease. Analysis of the latter using lessons learned from the former may be valuable. 4. We are currently greatly limited in our understanding of supply limitation in disease, mostly because of unavailability of methods to assess organ-specific cellular metabolism and its relation to O2 supply in patients, essentially noninvasively--a research direction that needs much support.

Blood Gas Analysis↗

PubMed1982

Interaction of spin-labeled local anesthetics with the sodium channel of squid axon membranes.

The effects of spin-labeled local anesthetics on sodium currents of internally perfused squid axons were studied using the voltage-clamp technique. Internal application (10 mum) of the most potent spin-labeled local anesthetic used in this study produced a small initial block of sodium currents. However, after sixty repetitive pulses (to + 80 mV) given at 1 Hz, the sodium currents were drastically reduced. In addition to this frequency-dependent phenomenon, the anesthetic effect on the sodium currents was also sensitive to the voltage of the pulses. Both the frequency- and voltage-dependent properties remained intact after removal of sodium inactivation with pronase. The recovery of sodium currents from this frequency-dependent anesthetic effect followed a single exponential curve with a surprisingly long time constant of about 10 min. Such a long recovery time, which is longer than any known sodium inactivation process, led us to suggest that the recovery process represents the dissociation of drug molecules from their binding sites. We have also found that increasing hydrophobic character of the homologues series of spin-labeled local anesthetics enhances the frequency- and voltage-dependent block of sodium currents. This effect strongly suggests that hydrophobic interaction is an integral component of the binding site. These probes with their selective effects on the sodium currents, are expected to be highly useful in studying the molecular structure of the sodium channels.

Action Potentials↗

PubMed1985

A model for red cell O2 uptake.

A computer model for red cell O2 uptake in the pulmonary capillary circulation is described. New features include the effect of hematocrit on blood viscosity and cardiac output and the precise modeling of the hemoglobin-O2 saturation curve as it varies with pH, the 2,3-DPG/Hb molar ratio, and PCO2 during oxygenation. The model is useful in the integration of many interacting physiologic variables that regulate O2 transport.

Adult↗

PubMed1999

Glucocorticoids, antioxidants and staurosporine modulate the adherence between monocytes and malaria infected erythrocytes.

OBJECTIVE AND DESIGN: Adherence interactions involving monocytes are important for cell-cell interaction as an integral component of immune function. The adherence of malaria parasitised red cells to monocytes was determined after monocytes were treated with dexamethasone, cortisol, ambroxol, danazol, probucol and staurosporine. MATERIALS: Human peripheral blood monocytes isolated by density gradient centrifugation and adherence to glass cover slips. METHODS: The adherence of malaria parasitised red cells to monocytes was determined after the monocytes were incubated for 24 h in the presence of each of the 6 drugs. RESULTS: The two glucocorticoids and staurosporine reduced the adherence of malaria infected erythrocytes to monocytes in a dose dependent manner at concentrations from 10(-10) M and above and ambroxol, danazol, and probucol at 10(-5) M. Staurosporine was the most effective of the drugs studied, completely abolishing adherence at 10(-6) M. CONCLUSION: The adherence of malaria infected erythrocytes to monocytes is reduced in response to glucocorticoids (dexamethasone and cortisol), anti-oxidants (probucol and ambroxol), danazol and staurosporine.

Anti-Inflammatory Agents↗

PubMed2006

A mechanism-based integrated pharmacokinetic enzyme model describing the time course and magnitude of phenobarbital-mediated enzyme induction in the rat.

PURPOSE: To characterize the magnitude, time course, and specificity of phenobarbital (PB)-mediated enzyme induction, and further, to develop an integrated pharmacokinetic (PK)-enzyme model describing the changes in the activities of CYP enzymes as well as in the PK of PB. METHODS: PB plasma concentrations and in vitro activities of several CYP enzymes were measured in rats treated with PB between 0 and 14 days. A PB PK-enzyme induction model was developed using the program NONMEM: . RESULTS: PB treatment both induces and reduces the activity of CYP enzymes by stimulating the enzymes' formation or elimination rates. Certain CYP enzymes affected the PB PK through autoinduction. The half-life of the induction process was estimated to be 2 days for CYP1A2, CYP3A1/2, and CYP2B1/2, and 3 days for androstenedione producing enzymes. The CYP2C11 activity was rapidly reduced by PB treatment. A lag time for the PB autoinduction was observed. This lag time is explained by the rate difference between induction and reduction in CYP activities. CONCLUSION: To our knowledge, this is the first example of an induction model that simultaneously describes plasma PK and in vitro data. It does so by integrating the bidirectional interaction between drug and enzymes in a mechanistic manner.

Animals↗

PubMed1997

A novel culture morphology resulting from applied mechanical strain.

To demonstrate that cells both perceive and respond to external force, a strain/relaxation regimen was applied to normal human fetal and aged dermal fibroblasts cultured as monolayers on flexible membranes. The precisely controlled protocol of stretch (20% elongation of the culture membrane) at 6.67 cycles/min caused a progressive change in the monolayers, such that the original randomly distributed pattern of cells became a symmetric, radial distribution as the cell bodies aligned parallel to the applied force. High cell density interfered with the success of re-alignment in the fetal cell cultures observed, which may reflect a preference in this cell strain for cell-cell over cell-matrix contacts. The chronologically aged cells observed did not demonstrate this feature, aligning efficiently at all seeding densities examined. The role of microfilaments in force perception and transmission was investigated through the addition of cytochalasin D in graded doses. Both intercellular interactions and cytoskeletal integrity mediate the morphological response to mechanical strain.

Actins↗

PubMed1989

Application of nonionic polyoxyethylene detergents in studies of phosphatidylinositol kinase.

Four commercial nonionic polyoxyethylene detergents were compared with Triton X-100 in terms of physicochemical properties and interaction with an integral membrane protein, phosphatidylinositol kinase. Tergitol 15-S-9, Tergitol TMN-10, polyoxyethylene 10 lauryl ether, and polyoxyethylene 10 tridecyl ether possess aliphatic hydrophobic moieties and therefore do not absorb significantly in the ultraviolet region. Like Triton X-100, these detergents have cloud points well above the physiological temperature range and partial specific volumes greater than 0.9 cm3/g. Critical micelle concentrations range from 0.02 to 0.03% with the exception of Tergitol TMN-10, for which the value is about 0.15%. All five detergents support activity of phosphatidylinositol kinase from rat liver in a mixed micellar assay and show similar ionic strength dependences for solubilization of the enzyme. Enzyme/detergent mixed micelles are somewhat smaller with Triton X-100 than for the other detergents. The data presented suggest that these detergents may be generally substituted for Triton X-100 in applications where uv invisibility is important.

1-Phosphatidylinositol 4-Kinase↗

PubMed1990

Studies on the sedimentation behavior of the Neurospora crassa plasma membrane H(+)-ATPase synthesized in vitro and integrated into homologous microsomal membranes.

RNA transcripts that encoded the Neurospora crassa plasma membrane H(+)-ATPase (pma+), a polytopic integral membrane protein, and the pma+344, a truncated pma+ with the amino terminal 344 amino acids, were translated in a N. crassa in vitro system. The microsomal membranes integrated products were insensitive to extraction by Na2CO3 (pH 11.5). The velocity sedimentation behavior of the in vitro synthesized pma+ were examined under various conditions. The pma+ migrated on linear sucrose gradients as aggregates which were heterogeneous in size, in the regions of 9-13 S; whereas, these values were reduced when Triton X-100 was presence in the gradients. The formation of these aggregates is interpreted to suggest a mechanism that maintains this polytopic integral membrane protein in a soluble form until it is targeted to the membranes. The sedimentation coefficient of the Triton X-100 solubilized microsomal membranes integrated pma+ corresponded roughly to a monomer of the pma+. Furthermore, a comparison of the trypsin cleavage patterns of the in vitro synthesized pma+ and of the microsomal membranes integrated pma+ suggest that they have different tertiary, or quaternary, structures. The latter did not give the characteristic trypsin cleavage patterns that have been observed for the native pma+ in the presence of its ligands MgATP and vanadate (Addison, R. and Scarborough, G.A. (1982) J. Biol. Chem. 257, 10421-10426). This was interpreted to suggest that the microsomal membranes integrated pma+ cannot interact with its substrate, suggesting that it is catalytically inactive.

Cell Membrane↗

PubMed1983

The reversibility of the effects of ACTH and cytochalasin B on the ultrastructure and steroidogenic activity of adrenocortical tumor cells in vitro.

We have demonstrated previously that the steroidogenic activity of ACTH on cultured adrenal tumor cells is associated with cell rounding and a rearrangement of microfilaments. Cytochalasin B (CB) also induces cell rounding, but changes the conformation of microfilaments and severely inhibits steroidogenesis. ACTH and CB may have different modes of action on the contractile machinery which are related to their opposing actions on steroidogenesis. To investigate this possibility further, we have examined the reversibility of the morphological and functional effects of these agents. Cultures were incubated for 1 hr, with and without ACTH (10 microU/ml of media), or with CB (50 micrograms/ml), or with both agents simultaneously. After a media wash, the cultures were incubated for 1 hr, with and without ACTH. The steroid production of the cells during pre- and post-washout incubations was determined, and some cultures were fixed for electron microscopy at the end of both incubation periods. The three- to ten-fold increases in steroidogenic activity of ACTH-stimulated cells declined during recovery incubations, but remained well above basal values. These cells nearly reflattened and began to regain stress fibers which had been 'pulled apart'. The 'washed out' ACTH-stimulated cells were often refractory to restimulation. Cells recovering from CB also reflattened. Masses of filamentous felt induced by the drug disappeared from the cytoplasm, lost microvilli reappeared and stress fibers reformed. The 20-50% inhibition of basal steroidogenesis by CB was completely reversed. When ex-CB-treated cells were incubated with ACTH, their morphology and steroid production were typical of acutely stimulated cells. The recovery behavior of cells incubated with ACTH and CB simultaneously reflected the observation that there were cell-specific responses to one agent or the other during initial incubations. The persistence of heightened steroidogenic activity following a washout of ACTH and the rapid reversal of the effects of CB strongly support the concept that regulated actomyosin interactions are an integral part of the steroidogenic process.

Actomyosin↗

PubMed1991

Nucleus accumbens NMDA antagonist decreases locomotor activity produced by cocaine, heroin or accumbens dopamine, but not caffeine.

Glutamatergic afferents to the nucleus accumbens (NAC) have been suggested to modulate psychostimulant-induced locomotor activation. The purpose of this study was 1) to determine the importance of nucleus accumbens N-methyl-D-aspartate (NMDA) glutamate receptors in the control of psychostimulant-induced locomotion, 2) to determine whether NMDA receptor modulation of psychostimulant-induced locomotion occurs presynaptic to or postsynaptic to NAC dopamine terminals, and 3) to determine whether NMDA receptors also modulate opiate- and caffeine-induced locomotor activation. For this purpose, rats treated with cocaine (10 mg/kg IP), dopamine (20 micrograms directly into the NAC), heroin (0.5 mg/kg SC), or caffeine (10 mg/kg SC) were challenged with intra-NAC microinfusion of 2-amino-5-phosphonovaleric acid (APV), a selective NMDA receptor antagonist. APV reduced locomotor activation induced by cocaine, heroin and intra-NAC dopamine, but not caffeine. These results suggest that NAC glutamate modulates psychomotor stimulation at the level of the NAC through an interaction with the integrated output of this region.

2-Amino-5-phosphonovalerate↗

PubMed1994

Planning the health sciences library: a new building for information services.

Planning for a new Health Sciences Library at the University of Maryland at Baltimore extended over more than 15 years. The program plan was created through an interactive process with the architects, involving all the staff from the library and computing/communications groups, now together in a umbrella organization known as Information Services. The layout for the new building was developed to promote interactions and to integrate staff and services on each floor.

Architecture↗

PubMed1994

Marginal topography of neurons expressing the substance P receptor in the rat suprachiasmatic nucleus.

Neurons expressing the substance P (SP) receptor (NK1 receptor) in the suprachiasmatic nucleus of the hypothalamus (SCN) have been topographically identified using radioactive in situ hybridization histochemistry. In the anterior hypothalamic area, clustered labeled neurons of small size and exhibiting low levels of gene expression are observed exclusively at the dorsolateral margin of the SCN, straddling cytoarchitectural boundaries of the nucleus. The marginal topography of neurons putative target of a SP-containing retinal input to the ventral SCN indicates that their dendrites bearing the receptor extend towards the retinorecipient part of the nucleus, where they can be modulated by overlapping inputs from the intergeniculate leaflet and the raphe. Eventual interactions between glutamatergic and putative tachykininergic retinal pathways for a coherent photic control of circadian rhythms may therefore occur mainly via intrinsic neuronal connections between their distinct target populations. In addition, since glutamate and SP induce electrophysiological responses in ventrolateral neurons with no interactive effect, neurons integrating both chemical signals, subsequently to their modulation by several influences, may be not located within the ventrolateral SCN. Alternatively but not exclusively, marginal neurons could be a target of SP-containing neurons within the SCN or nearby the nucleus, or from ascending projections from the raphé where serotonin and SP colocalize. The marginal topography of neurons expressing the SP receptor supports the view of the involvement of neurons located in the vicinity of the nucleus in the regulation of circadian rhythms.

Animals↗

PubMed1994

Specificity and regulation of a synaptic vesicle docking complex.

Synaptic vesicles are proposed to dock at the presynaptic plasma membrane through the interaction of two integral membrane proteins of synaptic vesicles, VAMP and synaptotagmin, and two plasma membrane proteins, syntaxin and SNAP-25. We have characterized the binding properties of these proteins and observed SNAP-25 potentiation of VAMP 2 binding to syntaxins 1a and 4 but not syntaxins 2 or 3. n-sec1, a neuron-specific syntaxin-binding protein, bound syntaxin with nanomolar affinity, forming a complex that is distinct from the previously identified 7S and 20S syntaxin-containing complexes. This suggests that syntaxin exists in at least three states: bound to n-sec1, in a 7S particle, and in a 20S particle. Recombinant n-sec1 inhibited VAMP or SNAP-25 binding to syntaxin. We propose that the specific associations of VAMP, SNAP-25, and syntaxin mediate vesicle docking and that a syntaxin/n-sec1 complex precedes and/or regulates formation of these complexes.

Amino Acid Sequence↗

PubMed2004

Renal protection strategies in the perioperative period.

The development of acute renal failure (ARF) in the perioperative period continues to be a vexing condition associated with high morbidity and mortality rates which have been unchanged for several decades. In this article I briefly review recent research categorizing pathogenesis of ARF and mechanisms of recovery. Once ARF is established, its maintenance phase is dependent on several mechanisms that interact with cellular integrity. The main focus of the article is on assessing clinical and experimental interventions to prevent ARF. Unfortunately, existing pharmacological and other interventions show a rather limited efficacy in preventing ARF.

Acute Kidney Injury↗

PubMed2004

Membrane targeting: getting Arl to the Golgi.

Post-translational modification with myristoyl or prenyl groups is essential for membrane association of many small GTPases in the Ras superfamily. Two recent papers show that, rather than myristoylation, amino-terminal acetylation of the Arf-like protein Arl3p is required for Golgi targeting via an interaction with an integral membrane protein called Sys1.

ADP-Ribosylation Factors↗

PubMed2005

Elastic properties, Young's modulus determination and structural stability of the tropocollagen molecule: a computational study by steered molecular dynamics.

The aim of this report is to investigate at microscopic level the elastic properties of a tropocollagen-like molecule submitted to linear traction along its longitudinal axis. For this purpose, we performed steered molecular dynamics (SMD) simulations for a wide range of spring constants in order to test the molecular response based on a two-spring model connected in series. An elastic behavior was observed in an elongation range of 2.5-4% of the molecular length, estimating an "effective molecular elastic constant" of 1.02+/-0.20 kcal/mol A2 in this region. Accordingly, a Young's modulus for the tropocollagen molecule of Y=4.8+/-1.0 GPa was calculated. The complex hydrogen bond network was traced along molecular dynamics (MD) and SMD simulations revealing a rearrangement of these interactions preserving the integrity of the molecular structure when submitted to traction. No evidence of the significant role attributed to water bridges for structural stability was detected, on the contrary facts pointed out that the hydrogen bond network might be the responsible.

Computer Simulation↗

PubMed2005

Dimerisation of myomesin: implications for the structure of the sarcomeric M-band.

The sarcomeric M-band is thought to provide a link between the thick and the elastic filament systems. So far, relatively little is known about its structural components and their three-dimensional organisation. Myomesin seems to be an essential component of the M-band, since it is expressed in all types of vertebrate striated muscle fibres investigated and can be found in its mature localisation pattern as soon as the first myofibrils are assembled. Previous work has shown that the N-terminal and central part of myomesin harbour binding sites for myosin, titin and muscle creatine kinase. Intrigued by the highly conserved domain layout of the C-terminal half, we screened for new interaction partners by yeast two-hybrid analysis. This revealed a strong interaction of myomesin with itself. This finding was confirmed by several biochemical assays. Our data suggest that myomesin can form antiparallel dimers via a binding site residing in its C-terminal domain 13. We suggest that, similar to alpha-actinin in the Z-disc, the myomesin dimers cross-link the contractile filaments in the M-band. The new and the already previously identified myomesin interaction sites are integrated into the first three-dimensional model of the sarcomeric M-band on a molecular basis.

Animals↗

PubMed2005

Did protein kinase regulatory mechanisms evolve through elaboration of a simple structural component?

Statistical analysis of the functional constraints acting on eukaryotic protein kinases (EPKs) and on distantly related kinases suggests that EPK regulatory mechanisms evolved around an ancient structural component whose most distinctive features include the HxD-motif adjoining the catalytic loop, the F-helix, an F-helix aspartate, and the DFG-motif adjoined to the activation loop. The HxD-histidine constitutes a convergence point for signal integration, as conserved interactions link it to key catalytic residues, to the F-helix aspartate, and to both ends of the DFG-motif. These and other conserved features appear to be associated with DFG conformational changes and with coordinated movements possibly associated with phosphate transfer and ADP release. The EPKs have acquired structural features that link this core component to likely substrate-interacting regions at either end of the F-helix (most notably involving an F-helix tryptophan) and to three regions undergoing conformational changes upon kinase activation: the activation segment, the C-helix, and the nucleotide-binding pocket.

Adenosine Diphosphate↗