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PubMed2005

The trap-like relaxin-binding site of the leucine-rich G-protein-coupled receptor 7.

The pleated sheet region of the leucine-rich G-protein-coupled receptor 7 supports a relaxin-binding group of amino acids that perfectly matches the binding cassette of relaxin. Arginines B13 and B17 are each chelated by an aspartic acid/glutamic acid pair and by isoleucine B20, which, offset by a one-quarter helix turn from a straight line connecting the arginines, interacts with a cluster of hydrophobic amino acids. The binding cassette of relaxin cuts at an angle of approximately 45 degrees across five parallel leucine-rich repeats. The arginine residues 13 and 17, which evolve parallel from the B-chain alpha-helix of relaxin, neutralize the charge repulsion of the juxta-posed acidic groups on the receptor and thereby trigger closure of a hydrogen bonding network around the guanidinium groups. Thus, relaxin is bound by synchronized chelation of two arginines and stabilized by hydrophobic interaction of isoleucine B20 with tryptophan, isoleucine, and leucine in neighboring leucine-rich repeats of the receptor. Deletion of any one of the three features diminishes interaction to the level of nonspecific binding. This model explains the exquisite sensitivity of relaxin binding avidity to minute changes in the disposition of the guanidinium and the size dependence of the hydrophobic binding residue in position B20.

Amino Acid Sequence↗

PubMed1985

Indicator dilution approach to NMR signal-flow curves.

An indicator dilution model for the dependence of NMR signal on flow rate is presented. The model explains the enhancement in NMR signal observed at low flow rates and the reduction in NMR signal at high flow rates. It also produces an excellent fit to original NMR flow data, which are also presented.

Humans↗

PubMed2005

Differential improvement among countries in child stunting is associated with long-term development and specific interventions.

Stunting represents growth failure resulting from poor nutrition and health during the pre- and postnatal periods. Initiatives since 1980 have steadily reduced malnutrition and consequent retardation of child growth, but 1 of 3 preschool children worldwide remains stunted. Countries have varied substantially in progress achieved in reducing stunting. This study aimed to understand which underlying (i.e., proximal) and basic (i.e., distal) national factors have been most important in explaining this variation among countries, and the relation between the 2 sets of factors. Eighty-five developing countries with at least 2 surveys for stunting >4 y apart were included from the WHO Global Database on Child Growth. The analytic data set with independent variables from several sources was constructed to match closely by year for each country to initial and final stunting data. Full-information maximum likelihood estimated multiple linear regression models while accounting for missing data in independent variables. The final model explained 65.5% of the variance of change in stunting, and included both underlying and basic variables: initial and change in immunization rate, initial and change in safe water rate, initial female literacy rate, initial government consumption, initial income distribution, and the initial proportion of the economy devoted to agriculture. Although factors that were important for reducing stunting in the past may not necessarily be the ones that are important in the future, these results suggest that it possible for substantial progress to be made in reducing the current high prevalence of stunting by investing in both long-term development and in specific interventions.

Agriculture↗

PubMed2004

Efficiency of various lattices from hard ball to soft ball: theoretical study of thermodynamic properties of dendrimer liquid crystal from atomistic simulation.

Self-assembled supramolecular organic liquid crystal structures at nanoscale have potential applications in molecular electronics, photonics, and porous nanomaterials. Most of these structures are formed by aggregation of soft spherical supramolecules, which have soft coronas and overlap each other in the packing process. Our main focus here is to study the possible packing mechanisms via molecular dynamics simulations at the atomistic level. We consider the relative stability of various lattices packed by the soft dendrimer balls, first synthesized and characterized by Percec et al. (J. Am. Chem. Soc. 1997, 119, 1539) with different packing methods. The dendrons, which form the soft dendrimer balls, have the character of a hard aromatic region from the point of the cone to the edge with C(12) alkane "hair". After the dendrons pack into a sphere, the core of the sphere has the hard aromatic groups, while the surface is covered with the C(12) alkane "hair". In our studies, we propose three ways to organize the hair on the balls, Smooth/Valentino balls, Sticky/Einstein balls, and Asymmetric/Punk balls, which lead to three different packing mechanisms, Slippery, Sticky, and Anisotropic, respectively. We carry out a series of molecular dynamics (MD) studies on three plausible crystal structures (A15, FCC, and BCC) as a function of density and analyze the MD based on the vibrational density of state (DoS) method to extract the enthalpy, entropy, and free energies of these systems. We find that anisotropic packed A15 is favored over FCC, BCC lattices. Our predicted X-ray intensities of the best structures are in excellent agreement with experiment. "Anisotropic ball packing" proposed here plays an intermediate role between the enthalpy-favored "disk packing" and entropy-favored "isotropic ball packing", which explains the phase transitions at different temperatures. Free energies of various lattices at different densities are essentially the same, indicating that the preferred lattice is not determined during the packing process. Both enthalpy and entropy decrease as the density increases. Free energy change with volume shows two stable phases: the condensed phase and the isolated micelle phase. The interactions between the soft dendrimer balls are found to be lattice dependent when described by a two-body potential because the soft ball self-adjusts its shape and interaction in different lattices. The shape of the free energy potential is similar to that of the "square shoulder potential". A model explaining the packing efficiency of ideal soft balls in various lattices is proposed in terms of geometrical consideration.

Computer Simulation↗

PubMed1982

The role of the adenine nucleotide translocator in oxidative phosphorylation. A theoretical investigation on the basis of a comprehensive rate law of the translocator.

A minimum model of adenine nucleotide exchange through the inner membrane of mitochondria is presented. The model is based on a sequential mechanism, which presumes ternary complexes formed by binding of metabolites from both sides of the membrane. The model explains the asymmetric kinetics of ADP-ATP exchange as a consequence of its electrogenic character. In energized mitochondria, a part of the membrane potential suppresses the binding of extramitochondrial ATP in competition with ADP. The remaining part of the potential difference inhibits the back exchange of internal ADP for external ATP. The assumption of particular energy-dependent conformational states of the translocator is not necessary. The model is not only compatible with the kinetic properties reported in the literature about the adenine nucleotide exchange, but it also correctly describes the response of mitochondrial respiration to the extramitochondrial ATP/ADP ratio under different conditions. The model computations reveal that the translocation step requires some loss of free energy as driving force. The size of the driving force depends depends on the flux rate as well as on the extra- and intramitochondrial ATP/ADP quotients. By both quotients the translocator control the export of ATP formed by oxidative phosphorylation in mitochondria.

Adenosine Diphosphate↗

PubMed1993

Beta gamma subunits of guanine nucleotide-binding proteins and regulation of spontaneous receptor activity: thermodynamic model for the interaction between receptors and guanine nucleotide-binding protein subunits.

We used a thermodynamic model to examine the interactions between receptor, guanine nucleotide-binding protein (G protein), and their ligands. The model describes the interactions as multiple equilibria occurring between three distinct protein species (receptor, G alpha subunit, and G beta gamma complex) and two small ligands, i.e., agonist (which interacts with receptor) and guanine nucleotide (which binds to G alpha). The equilibrium distribution of free and complexed species is determined by the total concentration of the components, the affinities that govern the biomolecular reactions, and the allosteric interactions that ligands exert on each other when they are simultaneously bound to the same species. These allosteric factors are given in terms of free energy coupling. The model explains a number of experimental observations, as follows. (i) Both GTP and GDP can reduce agonist affinity, whereas the agonist enhances the net binding of GTP and diminishes that of GDP. (ii) G beta gamma is more effective in reducing agonist-independent than agonist-dependent receptor activity. (iii) Removal of guanine nucleotides increases the ratio between agonist-independent and -dependent activation of G protein. The model leads to a number of interesting predictions. (i) Not only G alpha but also G beta gamma has effects on hormone binding. (ii) As long as the distribution of protein species is [G beta gamma] > [G alpha] > [receptor] (as often observed in the cell membrane), small changes in the concentration of G beta gamma do not alter the overall response induced by agonist. (iii) Agonist activity examined at low concentrations of guanine nucleotide is inevitably different from that observed at high concentrations, typical of intact systems. (iv) Differences in potencies and maximal effects for various guanine nucleotide analogues may reflect differences in their coupling constants that are experimentally measurable. The present model suggests several experimentally testable hypotheses that could be important in elucidating the activation mechanism and regulatory flexibility of G protein-dependent transduction systems.

Allosteric Regulation↗

PubMed2003

Exercise starts and ends in the brain.

Classically the limit to endurance of exercise is explained in terms of metabolic capacity. Cardio-respiratory capacity and muscle fatigue are thought to set the limit and the majority of studies on factors limiting endurance exercise discuss issues such as maximal oxygen uptake (VO2max), aerobic enzyme capacity, cardiac output, glycogen stores, etc. However, this paradigm does not explain the limitation to endurance exercise with large muscle groups at altitude, when at exhaustion exercise is ended without limb locomotor muscle fatigue and with sub-maximal cardiac output. A simple fact provides a basis for an explanation. Voluntary exercise starts and ends in the brain. It starts with spatial and temporal recruitment of motor units and ends with their de-recruitment. A conscious decision precedes a voluntary effort. The end of effort is again volitional and a forced conscious decision to stop precedes it, but it is unknown what forces the off-switch of recruitment at exhaustion although sensation of exertion certainly plays a role. An alternative model explaining the limitation of exercise endurance thus proposes that the central nervous system integrates input from various sources all related to the exercise and limits the intensity and duration of recruitment of limb skeletal muscle to prevent jeopardizing the integrity of the organism. This model acknowledges the cardio-respiratory and muscle metabolic capacities as prime actors on the performance scene, while crediting the central nervous system for its pivotal role as the ultimate site where exercise starts and ends.

Adolescent↗

PubMed2003

CD28 signaling in neutrophil induces T-cell chemotactic factor(s) modulating T-cell response.

We previously reported that human peripheral blood neutrophils express CD28 and interact with macrophage B7 to generate CD28 signaling through PI-3 kinase. Here, we demonstrate that crosslinking of CD28 on neutrophils results in the release of IFN-gamma, which restricts amastigote growth and modulates CD4+ T cells cytokine secretion. CD28 crosslinking also induces a T-cell chemotactic factor (TCF) that induces chemotactic migration of CD4+ T cells. Based on our previous and the current set of data, we propose an operational model explaining how neutrophils are involved in Leishmania infection and how the reported effect of neutrophils on the control of infection is mediated by alteration of T-cell function.

Animals↗

PubMed2004

Communication between ClpX and ClpP during substrate processing and degradation.

In the ClpXP compartmental protease, ring hexamers of the AAA(+) ClpX ATPase bind, denature and then translocate protein substrates into the degradation chamber of the double-ring ClpP(14) peptidase. A key question is the extent to which functional communication between ClpX and ClpP occurs and is regulated during substrate processing. Here, we show that ClpX-ClpP affinity varies with the protein-processing task of ClpX and with the catalytic engagement of the active sites of ClpP. Functional communication between symmetry-mismatched ClpXP rings depends on the ATPase activity of ClpX and seems to be transmitted through structural changes in its IGF loops, which contact ClpP. A conserved arginine in the sensor II helix of ClpX links the nucleotide state of ClpX to the binding of ClpP and protein substrates. A simple model explains the observed relationships between ATP binding, ATP hydrolysis and functional interactions between ClpX, protein substrates and ClpP.

ATPases Associated with Diverse Cellular Activitie↗

PubMed1989

Predictions of structural elements for the binding of Hin recombinase with the hix site of DNA.

Molecular dynamics simulations were coupled with experimental data from biochemistry and genetics to generate a theoretical structure for the binding domain of Hin recombinase complexed with the hix site of DNA. The theoretical model explains the observed sequence specificity of Hin recombinase and leads to a number of testable predictions concerning altered sequence selectivity for various mutants of protein and DNA.

Amino Acid Sequence↗

PubMedDate not supplied

Alternate models of positive health practices in adolescents.

The purpose of this study was to develop and test two alternate causal models of positive health practices in adolescents, which built on a modification of the original theoretical formulation previously tested in adolescents by Yarcheski and Mahon (1989). The sample consisted of 202 adolescents, aged 15 to 21. In classroom settings they responded to instruments and a demographic data sheet measuring variables in both models (age, gender, self-esteem, social support, and positive health practices), and to additional variables in Model 1 (future time perspective) and Model 2 (perceived health status). Both causal models were tested by the LISREL 7 program. By all indicators used in the study, there was a very good fit of both models with their data, there were no specification errors in either model, and neither model required modification. Visual inspection of the indicators suggested that Model 1 had a slightly better fit than did Model 2 with their respective data. These results suggested that causal models explaining positive health practices should include endogenous variables that share a common orientation, such as those with a psychosocial focus versus those with a health-related focus.

Adolescent↗

PubMed2002

Job stress, fatigue, and job dissatisfaction in Dutch lorry drivers: towards an occupation specific model of job demands and control.

OBJECTIVES: Building on Karasek's model of job demands and control (JD-C model), this study examined the effects of job control, quantitative workload, and two occupation specific job demands (physical demands and supervisor demands) on fatigue and job dissatisfaction in Dutch lorry drivers. METHODS: From 1181 lorry drivers (adjusted response 63%) self reported information was gathered by questionnaire on the independent variables (job control, quantitative workload, physical demands, and supervisor demands) and the dependent variables (fatigue and job dissatisfaction). Stepwise multiple regression analyses were performed to examine the main effects of job demands and job control and the interaction effect between job control and job demands on fatigue and job dissatisfaction. RESULTS: The inclusion of physical and supervisor demands in the JD-C model explained a significant amount of variance in fatigue (3%) and job dissatisfaction (7%) over and above job control and quantitative workload. Moreover, in accordance with Karasek's interaction hypothesis, job control buffered the positive relation between quantitative workload and job dissatisfaction. CONCLUSIONS: Despite methodological limitations, the results suggest that the inclusion of (occupation) specific job control and job demand measures is a fruitful elaboration of the JD-C model. The occupation specific JD-C model gives occupational stress researchers better insight into the relation between the psychosocial work environment and wellbeing. Moreover, the occupation specific JD-C model may give practitioners more concrete and useful information about risk factors in the psychosocial work environment. Therefore, this model may provide points of departure for effective stress reducing interventions at work.

Adult↗

PubMed1983

The maintenance of polymorphisms at two loci in house mouse (Mus musculus) populations.

To determine the roles of mutation, migration, and selection in maintaining genetic variability in populations of house mice (Mus musculus), stochastic models based on characteristics of mouse populations inhabiting corn cribs in southwestern Ontario and the t allele were developed. Two sets of models were examined. One involved selection against t/t mice and a migration rate of 0.05 to 0.10 (low migration model) whereas the other involved selection against both t/t and +/t genotypes and a migration rate of 0.33 (high migration model). Both models could account for the t allele frequencies observed in natural populations. Similarly both models explain the frequencies observed at a second polymorphic locus, the Hbb locus which controls the beta chain of the hemoglobin molecule, provided strong selection favoring the Hbb heterozygotes is incorporated. Without such selection pressure rapid extinction of one of the alleles at this locus occurred. A stabilizing force such as selection is considered necessary for the hemoglobin polymorphism observed in the populations under consideration. Evidence supporting the high migration model as the more realistic is also presented.

Alleles↗

PubMed1996

The nursing practice environment, staff retention, and quality of care.

The effects of key factors in the nursing practice environment--management style, group cohesion, job stress, organizational job satisfaction, and professional job satisfaction--on staff nurse retention and process aspects of quality of care were examined. Hinshaw and Atwood's (1985) anticipated turnover model was modified and expanded to include relevant antecedent and outcome variables. The four-stage theoretical model was tested using data from 50 nursing units at four acute care hospitals in the southeast. The model explained 49% of the variance in staff nurse retention and 39% of the variance in process aspects of quality of nursing care. Study findings warrant careful consideration in light of recent practice environment changes: experience on the unit and professional job satisfaction were predictors of staff nurse retention; job stress and clinical service were predictors of quality of care. The variable contributing the most to indirect, and in turn, total model effects, was that of management style. These results substantiate the belief that aspects of the practice environment affect staff nurse retention, and most importantly, the quality of care delivered on hospital nursing units.

Analysis of Variance↗

PubMed2006

Response times seen as decompression times in Boolean concept use.

This paper reports a study of a multi-agent model of working memory (WM) in the context of Boolean concept learning. The model aims to assess the compressibility of information processed in WM. Concept complexity is described as a function of communication resources (i.e., the number of agents and the structure of communication between agents) required in WM to learn a target concept. This model has been successfully applied in measuring learning times for three-dimensional (3D) concepts (Mathy and Bradmetz in Curr Psychol Cognit 22(1):41-82, 2004). In this previous study, learning time was found to be a function of compression time. To assess the effect of decompression time, this paper presents an extended intra-conceptual study of response times for two- and 3D concepts. Response times are measured in recognition phases. The model explains why the time required to compress a sample of examples into a rule is directly linked to the time to decompress this rule when categorizing examples. Three experiments were conducted with 65, 49, and 84 undergraduate students who were given Boolean concept learning tasks in two and three dimensions (also called rule-based classification tasks). The results corroborate the metric of decompression given by the multi-agent model, especially when the model is parameterized following static serial processing of information. Also, this static serial model better fits the patterns of response times than an exemplar-based model.

Adolescent↗

PubMed1998

Structural and theoretical studies suggest domain movement produces an active conformation of thymidine phosphorylase.

Two new crystal forms of Escherichia coli thymidine phosphorylase (EC 2.4.2.4) have been found; a monoclinic form (space group P21) and an orthorhombic form (space group I222). These structures have been solved and compared to the previously determined tetragonal form (space group P43212). This comparison provides evidence of domain movement of the alpha (residues 1 to 65, 163 to 193) and alpha/beta (residues 80 to 154, 197 to 440) domains, which is thought to be critical for enzymatic activity by closing the active site cleft. Three hinge regions apparently allow the alpha and alpha/beta-domains to move relative to each other. The monoclinic model is the most open of the three models while the tetragonal model is the most closed. Phosphate binding induces formation of a hydrogen bond between His119 and Gly208, which helps to order the 115 to 120 loop that is disordered prior to phosphate binding. The formation of this hydrogen bond also appears to play a key role in the domain movement. The alpha-domain moves as a rigid body, while the alpha/beta-domain has some non-rigid body movement that is associated with the formation of the His119-Gly208 hydrogen bond. The 8 A distance between the two substrates reported for the tetragonal form indicates that it is probably not in an active conformation. However, the structural data for these two new crystal forms suggest that closing the interdomain cleft around the substrates may generate a functional active site. Molecular modeling and dynamics simulation techniques have been used to generate a hypothetical closed conformation of the enzyme. Analysis of this model suggests several residues of possible catalytic importance. The model explains observed kinetic results and satisfies requirements for efficient enzyme catalysis, most notably through the exclusion of water from the enzyme's active site.

Binding Sites↗

PubMed1982

Photolytic studies on the carbon monoxide complex of sulphaemoglobin.

The CO complex of sulphaemoglobin was found to be photolytically dissociable at pH 6.0 and pH 8.5. The recombination kinetics of the CO complex after flash photolysis show two phases, which differ in rate by approximately 20-fold. At both pH 6.0 and pH 8.5 the two phases show an identical linear dependence on CO concentration, with associated second-order rate constants of 6.0 x 10(3) M-1 . s-1 and 1.2 x 10(5) M-1 . s-1 respectively. The percentage contribution of each of the two phases to the total absorbance change is independent of the CO concentration employed, but is a function of the protein concentration used. The percentage of the faster phase increases with protein dilution. These results taken together with computer simulation suggest the existence of appreciable amounts of monomeric species in solution at both pH 6.0 and pH 8.5 at low concentration of liganded protein. Estimates of the dissociation constants for the dimer in equilibrium monomer equilibrium yield values of 8 microM and 3.5 microM at pH 6.0 and pH 8.5 respectively. Stopped-flow delayed-flash-photolysis studies show that the liganded dimer decays to the liganded monomer with a half-life of approx. 0.5 s. Constant-illumination experiments allow an estimation of the half-life for the combination of deoxy monomers to deoxy dimers of 22 s. A model explaining the range of CO recombination kinetics seen for sulphaemoglobin does not require the existence of a photolytically produced high-activity form, even at high pH, in contrast with the case for normal haemoglobin.

Carbon Monoxide↗

PubMed1987

Life satisfaction and quality of life among disabled elderly adults.

This paper investigates predictors of life satisfaction and quality of life among severely disabled elderly adults. Markides and Martin's (1979) path analysis model was adapted specifically to elderly persons with severe disabilities. The study group comprised 97 patients discharged from three medical rehabilitation facilities in metropolitan Boston during 1984. The adapted model explained about 40% of the variance in quality of life among both men and women, with functional capacity being the most important predictor.

Aged↗