SEARCH · PubMed Health

Results for “Functional potential”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 937 records · Page 52Linked to original sources

PubMed1982

Donnan potential measurements in extended hexagonal polyelectrolyte gels such as muscle.

In this paper we reconsider the theoretical and practical aspects of using KCl-filled microelectrodes in extended polyelectrolyte gels such as muscle to measure Donnan potentials, and then calculate protein fixed-charge concentrations. An analytical calculation of the electrical potential function between muscle filaments shows that whether the microelectrode averages the ionic concentration or the local potentials the results are indistinguishable in the practical regime. After consideration of this and other possible sources of error, we conclude that the charge-concentrations measurements that have appeared in the literature are legitimate.

Animals↗

PubMed2005

Endogenous extra-cellular heat shock protein 72: releasing signal(s) and function.

Exposure to acute physical and/or psychological stressors induces a cascade of physiological changes collectively termed the stress response. The stress response is demonstrable at the behavioural, neural, endocrine and cellular levels. Stimulation of the stress response functions to improve an organism's chance of survival during acute stressor challenge. The current review focuses on one ubiquitous cellular stress response, up-regulation of heat shock protein 72 (Hsp72). Although a great deal is known about the function of intra-cellular Hsp72 during exposure to acute stressors, little is understood about the potential function of endogenous extra-cellular Hsp72 (eHsp72). The current review will develop the hypothesis that eHsp72 release may be a previously unrecognized feature of the acute stress response and may function as an endogenous 'danger signal' for the immune system. Specifically, it is proposed that exposure to physical or psychological acute stressors stimulate the release of endogenous eHsp72 into the blood via an alpha1-adrenergic receptor-mediated mechanism and that elevated eHsp72 functions to facilitate innate immunity in the presence of bacterial challenge.

Animals↗

PubMed2002

Degeneracy of antigen recognition as the molecular basis for the high frequency of naive A2/Melan-a peptide multimer(+) CD8(+) T cells in humans.

In contrast with the low frequency of most single epitope reactive T cells in the preimmune repertoire, up to 1 of 1,000 naive CD8(+) T cells from A2(+) individuals specifically bind fluorescent A2/peptide multimers incorporating the A27L analogue of the immunodominant 26-35 peptide from the melanocyte differentiation and melanoma associated antigen Melan-A. This represents the only naive antigen-specific T cell repertoire accessible to direct analysis in humans up to date. To get insight into the molecular basis for the selection and maintenance of such an abundant repertoire, we analyzed the functional diversity of T cells composing this repertoire ex vivo at the clonal level. Surprisingly, we found a significant proportion of multimer(+) clonotypes that failed to recognize both Melan-A analogue and parental peptides in a functional assay but efficiently recognized peptides from proteins of self- or pathogen origin selected for their potential functional cross-reactivity with Melan-A. Consistent with these data, multimers incorporating some of the most frequently recognized peptides specifically stained a proportion of naive CD8(+) T cells similar to that observed with Melan-A multimers. Altogether these results indicate that the high frequency of Melan-A multimer(+) T cells can be explained by the existence of largely cross-reactive subsets of naive CD8(+) T cells displaying multiple specificities.

Amino Acid Sequence↗

PubMed2002

Osmotic pressure of charged colloidal suspensions: a unified approach to linearized Poisson-Boltzmann theory.

We study theoretically the equation of state of a fluid suspension of charged objects (e.g., colloids, polyelectrolytes, clay platelets, etc.) dialyzed against an electrolyte solution using the cell model and linear Poisson-Boltzmann (PB) theory. From the volume derivative of the grand potential functional of linear theory we obtain two expressions for the osmotic pressure in terms of the potential or ion profiles, neither of which coincides with the expression known from nonlinear PB theory, namely, the density of microions at the cell boundary. We show that the range of validity of linearization depends strongly on the linearization point and prove that expansion about the self-consistently determined average potential is optimal in several respects. For instance, screening inside the suspension is automatically described by the actual ionic strength, resulting in the correct asymptotics at high colloid concentration. Together with the analytical solution of the linear PB equation for cell models of arbitrary dimension and electrolyte composition, explicit and very general formulas for the osmotic pressure ensue. A comparison with nonlinear PB theory is provided. Our analysis also shows that whether or not linear theory predicts a phase separation depends crucially on the precise definition of the pressure, showing that depending on the choice, an artificial phase separation in systems as important as DNA in physiological salt solution may result.

Biophysical Phenomena↗

PubMed2000

Hadamard-based image decomposition and compression.

In this paper, we develop a general algorithm for decomposition and compression of grayscale images. The decomposition can be expressed as a functional relation between the original image and the Hadamard waveforms. The dynamic adaptive clustering procedure incorporates potential functions as a similarity measure for clustering as well as a reclustering phase. The latter is a multi-iteration, convergent procedure which divides the inputs into nonoverlapping clusters. These two techniques allow us to efficiently store and transmit a class of half-tone medical images such as magnetic resonance imaging (MRI) of the human brain. Due to the redundant image structure of MRI, obtained after the decomposition and clustering, almost half of the image can be omitted all together. Naturally, the compression rates for this specific type of grayscale image are increased greatly. A run-length coding is performed in order to compress further the retained information from the first two steps. Although all the techniques applied are simple, they represent an efficient way to compress grayscale images. The algorithm exhibits a performance which is competitive and often outperforming some of the methods reported in the literature.

Algorithms↗

PubMed2005

Ric-8 enhances G protein betagamma-dependent signaling in response to betagamma-binding peptides in intact cells.

Peptides derived from a random-peptide phage display screen with purified Gbeta(1)gamma(2) subunits as the target promote the dissociation of G protein heterotrimers in vitro and activate G protein signaling in intact cells. In vitro, one of these peptides (SIRKALNILGYPDYD; SIRK) promotes subunit dissociation by binding directly to Gbetagamma subunits and accelerating the dissociation of GalphaGDP without catalyzing nucleotide exchange. The experiments described here were designed to test whether the mechanism of SIRK action in vitro is in fact the mechanism of action in intact cells. We created a mutant of Gbeta(1) subunits (beta(1)W332A) that does not bind SIRK in vitro. Transfection of Gbeta(1)W332A mutant into Chinese hamster ovary cells blocked peptide-mediated activation of extracellular signal-regulated kinase (ERK), but it did not affect receptor-mediated Gbetagamma subunit-dependent ERK activation, indicating that Gbetagamma subunits are in fact the direct target in cells responsible for ERK activation. To determine whether free Galpha subunits were released from G protein heterotrimers upon peptide treatment, cells were transfected with Ric-8A, a guanine nucleotide exchange factor for free GalphaGDP, but not heterotrimeric G proteins. Ric-8A-transfected cells displayed enhanced myristoyl-SIRKALNILGYPDYD (mSIRK)-dependent inositol phosphate (IP) release and ERK activation. Ric-8A also enhanced ERK activation by the G(i)-linked G protein coupled receptor agonist lysophosphatidic acid. Inhibitors of Gbetagamma subunit function blocked Ric-8-enhanced activation of ERK and IP release. These results suggest that one potential function of Ric-8 in cells is to enhance G protein Gbetagamma subunit signaling. Overall, these experiments provide further support for the hypothesis that mSIRK promotes G protein subunit dissociation to release free betagamma subunits in intact cells.

Amino Acid Sequence↗

PubMed2004

Unintegrated lentivirus DNA persistence and accessibility to expression in nondividing cells: analysis with class I integrase mutants.

The circumstances under which unintegrated lentivirus DNA can persist and be a functional template for transcription and protein expression are not clear. We constructed and validated the first class I (nonpleiotropic) integrase (IN) mutants for a non-human lentivirus (feline immunodeficiency virus [FIV]) and analyzed both these and known class I human immunodeficiency virus type 1 IN mutants. The FIV IN mutants (D66V and D66V/D118A) had class I properties: Gag/Pol precursor expression, proteolytic processing, particle formation, and reverse transcriptase (RT) production were normal, while the transduction of dividing fibroblasts was prevented and integration was blocked. When injected into rat retinas, the wild-type (WT) vector produced extensive, persistent transgene expression, compared with only rare positive neuronal cells for the IN mutant vector. In contrast, both WT and mutant vectors produced entirely equivalent, effective transduction levels of primary rat neurons (retinal ganglion cells). By testing the hypothesis that the unexpected retinal neuron transduction was related to cell cycle status, we found that when fibroblasts were growth arrested, transduction and internally promoted transgene expression were not inhibited at all by the class I FIV or HIV-1 IN mutations. Cells were then transduced under aphidicolin arrest and were released from the block 48 h later. Vector expression was stable and durable during repeated passaging in WT vector-transduced cells, while the release of cells transduced with equivalent RT units of class I IN mutant FIV or HIV vector resulted in a steady decline of expression, from 97 to 0% of cells by day 10. Southern blot and PCR analyses showed a lack of integration, irrespective of cell cycle, for the class I mutants and an increase in one- and two-long terminal repeat circular and linear unintegrated DNAs in growth-arrested cells. We conclude that if cell division is prevented, unintegrated FIV and HIV-1 vector DNAs can produce high-level internally promoted transgene expression equivalent to WT vectors. The expression correlates with the unintegrated DNA levels. These observations may facilitate the study of the roles of IN and other preintegration complex components in preintegration phases of infection by (i) providing an alternative way to monitor unintegrated nuclear cDNA forms, (ii) restricting ascertainment to the transcriptionally functional subset of unintegrated DNA, (iii) enabling analysis in individual, nondividing cells, and (iv) uncoupling other potential functions of IN from integration.

Amino Acid Sequence↗

PubMed2002

Regulation of vascular function by perivascular calcitonin gene-related peptide-containing nerves.

The rat mesenteric artery is innervated by nonadrenergic noncholinergic (NANC) vasodilator nerves in which calcitonin gene-related peptide (CGRP), a potent vasodilator peptide, acts as a vasodilator transmitter. The inhibition of CGRPergic nerve function potentiates a vasoconstrictor response mediated by the sympathetic adrenergic nerve, suggesting that CGRPergic nerves inhibit adrenergic function and play a role in the regulation of mesenteric vascular tone. In contrast, norepinephrine released from adrenergic nerves presynaptically inhibits neurotransmission of CGRPergic nerves. Thus, both nerves reciprocally control the vascular tone. Pathophysiological studies have shown that an age-related decrease in CGRPergic nerve-mediated vasodilation, neurogenic CGRP release and CGRP mRNA levels in the dorsal root ganglia are found in spontaneously hypertensive rats (SHR), indicating a reduced function of CGRPergic nerves. Long-term treatment with angiotensin converting enzyme inhibitor and angiotensin II-receptor antagonist restores the reduced function of CGRPergic nerves, suggesting the involvement of angiotensin II in the malfunction of CGRPergic nerves in SHR.

Animals↗

PubMedDate not supplied

[Theoretical conformational analysis of doulble-stranded polynucleotides].

Calculations of intramolecular interaction energy of two-stranded helical homopolynucleotide in the function of nine conformational variables have been carried out by the method of atom-atom potential functions. Four of these variables determine mutual position of base pairs, other four--deoxiribose ring conformation and other one--orientation of this ring with respect to the base. For this purpose an algorythm connecting dependent variables with independent ones has been developed. The investigation of energy function has shown that in the space of conformational parameters there are two valleys, which correspond to A-and B-families of conformations. Experimentaly determined conformations of two-stranded helical polynucleotides are located along the bottoms of these valleys. Along the bottom of each valley the intramolecular interaction energy changes rather little when conformational parameters change within a wide range. The valleys are separated by an energetical barrier.

Models, Chemical↗

PubMed1995

[Granulated CD56 lymphocytes of decidual tissue].

The reproduction is a complex mechanism wich is subtly immunoregulated since the semiallogenic fetus is not rejected by the mother. At the feto-maternal tissue interface, where fundamental mechanisms of tolerance occur, a large and unusual lymphocytes population takes place. These cells recruited during the earlier stages of pregnancy are very granulated and express brightly the N-CAM molecule (or CD56) with numerous adhesion and activation molecules. Nevertheless, they seem fonctionnally inactivated. They phenotypically belong to the peripheral blood minor fraction of NK cells which are CD56++CD16-CD3-. Although their function in the establishment of the gestation is not clearly known, because of their phenotypical heterogeneity, they may have two distinct functions: cytotoxicity and suppression. Their cytokine pattern, preferentially of the Th1 type, inform us about their potential functions and their interactions with other cells populations in this tissue, allowing us to understand the main mechanism in the establishment of the pregnancy.

Abortion, Spontaneous↗

PubMed1990

[Correlation between late potentials, left ventricular function and coronary heart disease].

By signal averaging it is possible to registrate late, fragmented low amplitude signals (late potentials, LP's) from the bodysurface 26 patients (21 males, 5 females) with a mean age of 57 years were investigated by signal averaging, Holter-monitoring and cardiac catheterization. 11 patients had a dilative cardiomyopathy (group A), 10 patients a coronary heart disease (group B), 5 of them with an ejection fraction greater than 50%, 5 of them with a reduced ejection fraction, whereas the control-group with 5 patients (group C) showed no coronary stenosis or reduced ventricular function, 6 out of 11 patients with dilative cardiomyopathy showed LP's; all of these with Lown IVb had LP's. In 2 patients with coronary heart disease and good left ventricular function late potentials were found, and in all 5 patients with disturbed left ventricular function. The control-group revealed no late potentials although 4 patients had Lown IVa or more in Holter-ECG. In conclusion, late potentials show a good correlation to malignant ventricular ectopic beats in patients with dilative cardiomyopathy and coronary heart disease, especially when the left ventricular function is reduced.

Adult↗

PubMed2000

Different roles of the CD2 and LFA-1 T-cell co-receptors for regulating cytotoxic, proliferative, and cytokine responses of human V gamma 9/V delta 2 T cells.

BACKGROUND: Human V gamma 9/V delta 2 T lymphocytes recognize nonpeptidic antigens in a manner distinct from the classical antigen recognition by alpha beta T cells. The apparent lack of major histocompatibility (MHC) restriction and antigen processing allows very fast responses against pathogenic insults. To address the potential functional requirement for accessory molecules, we investigated the roles of the CD2 and lymphocyte function-associated antigen (LFA)-1 T-cell co-receptors in antigen-induced activities of human V gamma 9/V delta 2 T-cell clones. MATERIALS AND METHODS: Human peripheral blood V gamma 9/V delta 2 T lymphocytes were cloned and their cytotoxicity against Daudi lymphoma was measured by a standard 51Cr-release assay. The responses of V gamma 9/V delta 2 T lymphocytes to nonpeptidic antigens were assessed using DNA synthesis and cytokine ELISA assays. Monoclonal antibodies specific for various molecules with potential T-cell accessory functions were utilized in blocking assays. RESULTS: All of our V gamma 9/V delta 2 T-cell clones displayed the Th1 phenotype. The anti-LFA-1 antibody strongly inhibited the cytotoxicity of V gamma 9/V delta 2 T cells against Daudi B-cell lymphoma; whereas, it had no influence on the antigen-induced cytokine release or proliferation. In contrast, antibodies against CD2 and LFA-3 had no effect on the lytic activity of V gamma 9/V delta 2 T cells, but strongly inhibited the cytokine release and proliferation. However, the CD2-LFA-3 interaction was not an absolute requirement for the cytokine release and the DNA synthetic activity of antigen-stimulated V gamma 9/V delta 2 T cells, since the inhibitory effect could be reversed by addition of exogenous interleukin 2 (IL-2). CONCLUSIONS: These novel observations indicate that the signals generated by different accessory molecules and IL-2 can contribute in an integrated fashion to the regulation of V gamma 9/V delta 2 T cells. These interactions may be important for the effectiveness of V gamma 9/V delta 2 T-cell responses.

Antigen-Presenting Cells↗

PubMed1999

Binding, partial agonism, and potentiation of alpha(1)-adrenergic receptor function by benzodiazepines: A potential site of allosteric modulation.

Benzodiazepines, a class of drugs commonly used to induce anesthesia and sedation, can attenuate intracellular calcium oscillations evoked by alpha(1)-adrenergic receptor (alpha(1)-AR) stimulation in pulmonary artery smooth muscle cells. We postulated a direct action of benzodiazepines in modulating alpha(1)-AR function at the receptor level. Benzodiazepines bound to each of the cloned alpha(1)-AR subtypes (alpha(1a)-, alpha(1b)-, or alpha(1d)-AR) on COS-1 cell membranes transiently transfected to express a single population of alpha(1)-AR subtype. The ability of benzodiazepines to alter alpha(1)-AR signal transduction was investigated by measuring total inositol phosphate generation in rat-1 fibroblast cells, stably transfected to express a single alpha(1)-AR subtype. By themselves, benzodiazepines displayed partial agonism. At alpha(1b)-ARs and alpha(1d)-ARs, the maximal inositol phosphate response to phenylephrine was potentiated almost 2-fold by either midazolam or lorazepam (100 microM). At alpha(1a)-ARs, diazepam, lorazepam, and midazolam all increased the maximal response of the partial agonist clonidine at these receptors, whereas the response to the full agonist phenylephrine was unaltered or inhibited. The potentiating actions of midazolam and its partial agonism at alpha(1)-ARs was blocked by the addition of 1 microM prazosin, an alpha(1)-AR antagonist, and not by a gamma-aminobutyric acid(A)-receptor antagonist. These studies show that benzodiazepines modulate the function of alpha(1)-ARs in vitro, and this is the first report of a potential allosteric site on alpha(1)-ARs that may be therapeutically useful for drug design.

Adrenergic alpha-Agonists↗

PubMed1998

Reaching the global minimum in docking simulations: a Monte Carlo energy minimization approach using Bezier splines.

The docking problem faces two major challenges: the global optimization of a multivariable function, such as the energy, and the ability to discriminate between true and false positive results, i.e., native from nonnative structures based on the input energy function. Among all energy evaluation tools, only a local energy-minimization method using an accurate enough potential function is able to discriminate between native and nonnative structures. To meet these requirements, a Monte Carlo with energy-minimization method has been incorporated into a new ECEPP/3 docking program. The efficiency of the simulation results from the use of an energy-grid technique based on Bezier splines and from a simplification of the receptor by switching on the energy of only important residues of the active site. Simulations of a thrombin-inhibitor complex show that the global minimum of the energy function was reached in every independent run within less than 3 min of time on an IBM RX 6000 computer. For comparison, 10 standard independent Monte Carlo simulations with 10(6) steps in each were carried out. Only three of them led to a conformation close to the x-ray structure. The latter simulations required an average of 24 min and about 10 hr with and without the grid, respectively. Another important result is that the Bezier spline technique not only speeds up the calculation by reducing the number of operations during the energy evaluation but also helps in reaching the global minimum by smoothing out the potential energy surface.

Animals↗

PubMed2005

Identification of steroid derivatives that function as potent antiandrogens.

We have hypothesized that some steroid derivatives bind to the androgen receptor (AR) with very low androgenic activity and therefore potentially function as better AR antagonists than clinically used antiandrogens, such as flutamide. Indeed, we previously found such a compound, 3beta-acetoxyandrosta-1,5-diene-17-one ethylene ketal (ADEK), with some estrogenic activity. Here we report the identification of 2 additional steroid derivatives, 3beta-hydroxyandrosta-5,16-diene (HAD) and androsta-1,4-diene-3,17-dione-17-ethylene ketal (OAK), as new potent antiandrogens. Like ADEK, HAD and OAK could interrupt androgen binding to the AR and suppress both dihydrotestosterone- and androstenediol-induced transactivations of wild-type and mutant ARs in prostate cancer cells. These 2 compounds also inhibited prostate-specific antigen expression in LNCaP as well as growth of different AR-positive prostate cancer cell lines stimulated by androgen. Significantly, HAD and OAK had only marginal agonist effects, as compared to hydroxyflutamide. More importantly, in contrast to ADEK, OAK was shown to possess marginal estrogenic activity. These results strengthen our hypothesis and suggest that selective steroid derivatives could be potent antiandrogenic drugs with less unfavorable effects for the treatment of prostate cancer.

Androgen Antagonists↗

PubMed2006

Impact of complex genetic variation in COMT on human brain function.

Catechol-O-methyltransferase (COMT) has been shown to be critical for prefrontal dopamine flux, prefrontal cortex-dependent cognition and activation. Several potentially functional variants in the gene have been identified, but considerable controversy exists regarding the contribution of individual alleles and haplotypes to risk for schizophrenia, partly because clinical phenotypes are ill-defined and preclinical studies are limited by lack of adequate models. Here, we propose a neuroimaging approach to overcome these limitations by characterizing the functional impact of ambiguous haplotypes on a neural system-level intermediate phenotype in humans. Studying 126 healthy control subjects during a working-memory paradigm, we find that a previously described risk variant in a functional Val158Met (rs4680) polymorphism interacts with a P2 promoter region SNP (rs2097603) and an SNP in the 3' region (rs165599) in predicting inefficient prefrontal working memory response. We report evidence that the nonlinear response of prefrontal neurons to dopaminergic stimulation is a neural mechanism underlying these nonadditive genetic effects. This work provides an in vivo approach to functional validation in brain of the biological impact of complex genetic variations within a gene that may be critical for its clinical association.

Adult↗

PubMed1999

Modularity and homology: modelling of the type II module family from titin.

We report the homology modelling of the structures of the 162 type II modules from the giant multi-domain protein titin (also known as connectin). The package MODELLER was used and implemented in an automated fashion using four experimentally determined structures as templates. Validation of the models was assessed in terms of divergence from the templates and consensus of the alignments. The homology within the whole family of type II modules as well as with the templates is relatively high (20-35% identity and ca 50% similarity). Comparison between the models of domains for which an NMR structure has been solved and the experimental solution gives an estimate of the quality of the modelling. Our results allow us to distinguish between a set of structurally relevant residues, which are conserved throughout the whole family and buried in the hydrophobic core, from the residues that are conserved and exposed. These latter residues are potentially functionally important. Comparison of exposed conserved patches for modules in different regions of the titin molecule suggests potential interaction surfaces. Our results may be tested directly for those modules whose binding partner is known.

Amino Acid Sequence↗

PubMed1991

COSMIC(90): an improved molecular mechanics treatment of hydrocarbons and conjugated systems.

Four modifications to the COSMIC molecular mechanics force field are described, which greatly increase both its versatility and the accuracy of calculated conformational energies. The Hill non-bonded van der Waals potential function has been replaced by a two-parameter Morse curve and a new H-H potential, similar to that in MM3, incorporated. Hydrocarbon energies in particular are much improved. A simple iterative Hückel pi-electron molecular orbital calculation allows modelling of conjugated systems. Calculated bond lengths and rotational barriers for a series of conjugated hydrocarbons and nitrogen heterocycles are shown to be as accurate as those determined by the MM2 SCF method. Explicit hydrogen-bonding potentials for H-bond acceptor-donor atom pairs have been included to give better hydrogen bond energies and lengths. The van der Waals radii of protonic hydrogens are reduced to 0.5 A and the energy well depth is increased to 1.0 kcal mol-1. Two new general atom types, N+sp2 and O-sp3, have been introduced which allow a wide variety of charged conjugated systems to be studied. A minimum of parameterisation is required, as the new types are easily included in the Hückel scheme which automatically adjusts bond and torsional parameters according to the defined bond-order relationships.

Computer Simulation↗