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PubMed2001

New aspects of the glucose activation of the H(+)-ATPase in the yeast Saccharomyces cerevisiae.

The glucose-induced activation of plasma membrane ATPase from Saccharomyces cerevisiae was first described by Serrano in 1983. Many aspects of this signal transduction pathway are still obscure. In this paper, evidence is presented for the involvement of Snf3p as the glucose sensor related to this activation process. It is shown that, in addition to glucose detection by Snf3p, sugar transport is also necessary for activation of the ATPase. The participation of the G protein, Gpa2p, in transducing the internal signal (phosphorylated sugars) is also demonstrated. Moreover, the involvement of protein kinase C in the regulation of ATPase activity is confirmed. Finally, a model pathway is presented for sensing and transmission of the glucose activation signal of the yeast H(+)-ATPase.

Culture Media↗

PubMed2003

Prediction of human intestinal permeability using artificial membrane permeability.

The purpose of the present study was to examine a correlation between the human intestinal permeability (P(eff)) and the bio-mimetic artificial membrane permeability corrected by the paracellular pathway model based on the Renkin function (P(PAMPA-PP-RF)) and to construct a prediction scheme. The effect of the unstirred water layer was incorporated to the prediction scheme. Eighteen P(eff) values of passively absorbed drugs were employed for the analysis. The correlation coefficient (CC) between the predicted and observed logP(eff) was 0.91. P(eff) of furosemide, hydrochlorothiazide and creatinine were underestimated by P(PAMPA-PP-RF). When these compounds were excluded, CC was 0.97. Without the correction for the paracellular pathway, P(eff) of small, cationic and hydrophilic compounds were underestimated. Therefore, P(PAMPA-PP-RF) was found to be an adequate in vitro surrogate for P(eff).

Humans↗

PubMed2006

Tunneling through weak interactions: comparison of through-space-, H-bond-, and through-bond-mediated tunneling.

Results from ab initio electronic structure theory calculations on model systems allow for the detailed comparison of tunneling through covalently bonded contacts, hydrogen bonds, and van der Waals contacts. Considerable geometrical sensitivity as well as an exponential distance dependence of the tunneling is observed for tunneling through various nonbonded contacts. However, the fundamental result from the present study is that at most a modest difference is observed between tunneling mediated by H-bonds and tunneling mediated by van der Waals contacts at typical distances for each type of interaction. These results are considered in relation to the pathways model of Beratan and Onuchic, and implications for understanding long-range tunneling in biological systems are discussed.

Algorithms↗

PubMed2001

The Ste5p scaffold.

An emerging theme of mitogen-activated protein kinase (MAPK) cascades is that they form molecular assemblies within cells; the spatial organization of which is provided by scaffold proteins. Yeast Ste5p was the first MAPK cascade scaffold to be described. Early work demonstrated that Ste5p selectively tethers the MAPKKK, MAPKK and MAPK of the yeast mating pathway and is essential for efficient activation of the MAPK by the pheromone stimulus. Recent work indicates that Ste5p is not a passive scaffold but plays a direct role in the activation of the MAPKKK by a heterotrimeric G protein and PAK-type kinase. This activation event requires the formation of an active Ste5p oligomer and proper recruitment of Ste5p to a Gbetagamma dimer at the submembrane of the cell cortex, which suggests that Ste5p forms a stable Ste5p signalosome linked to a G protein. Additional studies underscore the importance of regulated localization of Ste5p to the plasma membrane and have revealed nuclear shuttling as a regulatory device that controls the access of Ste5p to the plasma membrane. A model that links Ste5p oligomerization with stable membrane recruitment is presented. In this model, pathway activation is coordinated with the conversion of a less active closed form of Ste5 containing a protected RING-H2 domain into an active Ste5p dimer that can bind to Gbetagamma and form a multimeric scaffold lattice upon which the MAPK cascade can assemble.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Smooth bistable S-systems.

S-systems have been used as models of biochemical systems for over 30 years. One of their hallmarks is that, although they are highly non-linear, their steady states are characterised by linear equations. This allows streamlined analyses of stability, sensitivities and gains as well as objective, mathematically controlled comparisons of similar model designs. Regular S-systems have a unique steady state at which none of the system variables is zero. This makes it difficult to represent switching phenomena, as they occur, for instance, in the expression of genes, cell cycle phenomena and signal transduction. Previously, two strategies were proposed to account for switches. One was based on a technique called recasting, which permits the modelling of any differentiable non-linearities, including bistability, but typically does not allow steady-state analyses based on linear equations. The second strategy formulated the switching system in a piece-wise fashion, where each piece consisted of a regular S-system. A representation gleaned from a simplified form of recasting is proposed and it is possible to divide the characterisation of the steady states into two phases, the first of which is linear, whereas the other is non-linear, but easy to execute. The article discusses a representative pathway with two stable states and one unstable state. The pathway model exhibits strong separation between the stable states as well as hysteresis.

Cell Physiological Phenomena↗

PubMed1994

Synthesis of surface sphingomyelin in the plasma membrane recycling pathway of BHK cells.

Sphingomyelin, which has been degraded at the BHK cell surface by exogenous sphingomyelinase, is converted back into sphingomyelin with kinetics similar to those of plasma membrane recycling. Resynthesis of sphingomyelin under these conditions proceeds at a rate about 4-fold higher than normal biosynthesis of sphingomyelin. Neither resynthesis of sphingomyelin nor its return to the surface is inhibited by brefeldin A (BFA), which is a potent blocker of vesicular transport through the Golgi but has no effect on plasma membrane recycling. However, resynthesis of plasma membrane sphingomyelin is greatly decreased in cells undergoing mitosis or energy depletion, where endocytosis is inhibited. We conclude that the main site of surface sphingomyelin synthesis in BHK cells could be in recycling endosomes and not in the Golgi apparatus as proposed previously. We also suggest a model pathway by which cholesterol may reach the plasma membrane via recycling endosomes.

Animals↗

PubMed2006

Adolescent violence screening in the ED.

Youth violence is widely recognized as a major public health problem. Adolescent suicidality (ideation, behavior, or both) is disturbingly common in the United States, and homicide remains one of the leading causes of death for young people aged 10 to 24 years. Assessing youth suicidality and homicidality in the emergency department (ED) is a complex and challenging task. Evidence about the value of available ED risk assessments is not encouraging. Attempts to develop models that predict violence have in part been unsuccessful from the fact that ideation is common and the value of depression is hard to determine. The current study presents an empirically based assessment (adolescent and child urgent threat evaluation) and algorithm (violence ideation and suicidality treatment algorithm) evaluating the impact of ideation and nonideation states on attempt among clinical samples, such as serotonin reuptake inhibitor akathisia and acute adjustment disorders. The authors suggest important time-related factors and easy-to-administer procedures when assessing near-future youth violence. A validated suicide-homicide final common pathway model is discussed.

Adolescent↗

PubMedDate not supplied

Telephone prescreening enhancing a model for proactive healthcare practice.

PURPOSE: This article explicates the process of developing and implementing a contemporary, innovative program using the telephone as a tool for prescreening newly diagnosed cancer patients before their arrival at the cancer center. As another element of existing models of psychosocial care, this service lays the foundation for the efficient delivery of clinical social work services. DESCRIPTION OF PROGRAM: In the Surgical Oncology Clinic of the M.D. Anderson Cancer Center in Houston, Tex, 28 patients were contacted as part of a telephone prescreening model of a practice program from February 1, 1995 through March 31, 1995. Using a structured telephone interview format, two clinic social workers contacted patients and provided information on social work services. Patients needing resource assistance were provided with community referrals. Using the information from the telephone call, a brief outpatient assessment was completed for each patient before his or her arrival at the clinic. During the initial clinic visit, each new patient was met by the social worker to conduct a qualitative interview and address specific treatment-related concerns. OUTCOME OF PROGRAM: The patients expressed their appreciation of the interest of the social work staff and their satisfaction with the information provided. In addition, obtaining patient information and identifying patient needs before the initial visit allowed social workers to use clinic time more efficiently. Because of restructuring, the Surgical Oncology Clinic was eliminated and use of the intervention suspended. Based on the encouraging results of the telephone prescreening model of care program, reinstating the program in the future would include expanding its hours of operation to reach individuals who are not at home during the hours of 8:00 am 25:00 pm and including language assistance to address the needs of the increasingly multicultural population. CLINICAL IMPLICATIONS: Telephone prescreening is one strategy for personalizing psychosocial assessment. In this era of outpatient day surgery and cost-controlled managed healthcare, the benefits of prescreening are empowerment for both patients and multidisciplinary team members. The future holds promise for telephone prescreening to become part of the collaborative clinical pathways model of the disease-site centers concept.

Adult↗

PubMed2003

The application of a facet scale job satisfaction model for environmental health officers in Australia and Scotland.

The direction provided from published research emphasises that job satisfaction is multi-dimensional, and the associations with work related and non-work related predictor variables as being complex. The isolation of the discrete influence of individual predictor variables is therefore difficult. The application of multivariate analysis incorporating hierarchical stepdown protocols and interaction effects offers one approach that provides for the discrimination between the explanatory characteristics of these variables. Principal Axis Factoring with oblimin rotation and Structural Equations Modelling were applied to survey data to develop a Measurement Model comprising six latent constructs that characterised the job satisfaction of Environmental Health Officers (EHOs) in Australia. The model was successfully applied to data from the EHOs in Scotland. This paper presents the application of the Measurement Model to examine the association between selected work content and the demographic aspects of the EHOs in Australia and in Scotland, and their job satisfaction. The analysis protocol included Canonical Correlation, Multiple Linear Regression and Factorial Manova and Mancova. The unique variance explained by the work content factors and the demographic aspects of the job were similar. The linear representation of model pathways provided more comprehensive explanatory power than the curvilinear association. The presentation of evidence of multidimensional complexity, including interaction effects, underscored the need for caution before generalising on the influence of individual factors on job satisfaction. The analysis protocol presented in this paper can be applied to other situations in environmental health involving multivariate complexity.

Australia↗

PubMed2001

Failure to overcome 'innate' fear: a developmental test of the non-associative model of fear acquisition.

The non-associative, Darwinian theory of fear acquisition proposes that some individuals fail to overcome biologically-relevant fears (e.g. height) because they (1) do not have sufficient safe exposure to the relevant stimuli early in life or (2) are poor habituators who have difficulty 'learning not to fear'. These two hypotheses were tested in a longitudinal birth cohort study. Study 1 found evidence for reduced exposure to height stimuli in childhood for individuals with a fear of heights compared to study members without fear. Study 2 found evidence for higher levels of stress reactivity (a proxy for habituation) in childhood and adolescence among 18-year-old height phobics compared to study members with dental phobia and those with no fear. The results were discussed in relation to recent findings suggesting that some evolutionary-relevant fears may appear in the absence of traumatic 'learning' experiences. The merits of adding a fourth, non-associative pathway to Rachman's [Rachman, S. (1977)]. The conditioning theory of fear acquisition: a critical examination. Behaviour Research and Therapy, 15, 375-387) three pathways model of fear acquisition were briefly considered.

Adolescent↗

PubMed2003

Electron transfer through a prenucleated bimetalated alanine-based peptide helix.

We have synthesized a 22 residue alanine-based peptide with a tris(bipyridyl)ruthenium(II) amino acid near the middle of the peptide which can act as a photoinducible electron donor. Two histidines spaced i, i + 4 near the C-terminus of the peptide were then cross-linked with a tetraammineruthenium(III) moiety to prenucleate the helix and provide an electron acceptor site. Introduction of the cross-link enhances the average helix content from 67% to 84% at 0 degrees C, as judged by circular dichroism spectroscopy. The temperature dependence of the mean molar residue ellipticity at 222 nm, [THETAV;](222), for the bimetalated peptide was fit to a modified Lifson-Roig helix-coil model to permit extraction of the population of helical conformation at each residue separating the electron donor and acceptor. On average, the residues between the donor and acceptor are 92% helical. Photoinduced electron transfer with a driving force of -1.0 eV and an estimated reorganization energy of 0.82 eV was measured by fluorescence quenching methods in H(2)O and D(2)O, yielding rate constants, k(ET), of 7 +/- 3 x 10(6) s(-)(1) and 5 +/- 1 x 10(6) s(-)(1) at 0 degrees C. Calculation of the electronic coupling matrix element, H(ab), with the Marcus equation yields a value of 0.19 +/- 0.4 cm(-)(1). Analysis in terms of the pathway model for electronic coupling indicates that this magnitude of H(ab) is consistent with the participation of hydrogen bonds in electronic coupling for an isolated alpha-helix.

Alanine↗

PubMed2002

A twin study of genetic relationships between psychotic symptoms.

OBJECTIVE: Biometrical model fitting was applied to clinical data from twins to investigate whether operationally defined schizophrenic, schizoaffective, and manic syndromes share genetic risk factors. METHOD: Seventy-seven monozygotic and 89 same-sex dizygotic twin pairs in which the proband met the Research Diagnostic Criteria (RDC) for lifetime-ever schizophrenic, schizoaffective, or manic syndrome were ascertained from the Maudsley Twin Register in London. The syndromes were defined non-hierarchically. Correlations in liability were calculated for each syndrome in the monozygotic and dizygotic pairs and across the three pairings of schizophrenic-manic, schizophrenic-schizoaffective, and schizoaffective-manic syndromes both within probands and within pairs. For the three syndromes considered together, an independent pathway model was fitted. RESULTS: The model fitting showed significant genetic correlations between all three syndromes. There was evidence of both common and syndrome-specific genetic contributions to the variance in liability to the schizophrenic and manic syndromes, but the genetic liability to the schizoaffective syndrome was entirely shared in common with the other two syndromes. In contrast, environmental liability to the schizoaffective syndrome was not shared with the other syndromes. CONCLUSIONS: If diagnostic hierarchies are relaxed, there is a degree of overlap in the genes contributing to RDC schizophrenic, schizoaffective, and manic syndromes. Supplementing the traditional approach of assigning a single main lifetime diagnosis with information on within-person comorbidity of psychotic syndromes may provide valuable information about the familial aggregation of psychotic symptoms.

Adolescent↗

PubMed1982

Erythrocyte permeability to lipophilic solutes changes with temperature.

Studies of permeability coefficients of biological barriers to members of homologous series can provide information of value in assessing barrier characteristics. To this end, we have determined the linear diffusion coefficients of tracer water (THO), [14C]antipyrine, [14C]acetamide, and n-[14C]alcohols over the range of 10-37 degrees C for dog erythrocytes (D), hemoglobin (D2), and plasma (D1). Permeability coefficients (Po) calculated with the series-parallel pathway model are higher than Po for water at 37 degrees C for all the alcohols except hexanol. Po for acetamide and antipyrine are considerably lower than Po for water at 37 degrees C. The apparent activation energies (Ea) for Po of acetamide and the C1, C2, and C3 alcohols are 10.5 kcal.mol-1, similar to the values obtained with epithelial or lipid bilayers. The Ea's for the larger alcohols are 2-4 kcal.mol-1. The Ea for Po of water is 5.3 kcal.mol-1, similar to the Ea for self-diffusion of water; Ea for antipyrine is 25 kcal.mol-1. We interpret these results to indicate heterogeneity of membrane-solute interactions or of membrane pathways in the erythrocyte for lipid-soluble molecules that is related to both lipid solubility and solute size, as we have suggested in an earlier study and confirmed experimentally in the present one.

Alcohols↗

PubMed2003

TGF-beta down-regulates IL-6 signaling in intestinal epithelial cells: critical role of SMAD-2.

Interleukin-6 (IL-6) is a pro-inflammatory cytokine that plays an important role in the pathogenesis of inflammatory bowel disease. TGF-beta, a multifunctional cytokine, is a potent negative regulator of mucosal inflammation in the intestine. The aim of the present study is to determine possible cross-talk between IL-6 and TGF-beta signaling pathways. Model intestinal epithelial cell lines, Caco2-BBE were used. We show that TGF-beta receptor Type II is predominantly present in the basolateral membrane of intestinal epithelial cells. TGF-beta1 induces a time-dependent phosphorylation of Smad2 and co-immunoprecipitation of SMAD-2 with Smad-4 and its subsequently translocation to the nucleus. We show that pretreatment of cells with TGF-beta1 is associated with a down-regulation of IL-6 induced tyrosine phosphorylation of STAT1 and STAT3 and suppression of ICAM-1 expression. Furthermore, TGF-beta1 pretreatment resulted in a significant inhibition of IL-6 induced ICAM-1 promoter activity. TGF-beta mediated inhibition of IL-6 induced ICAM-1 expression was reversed by transfection with dominant negative Smad2 constructs. In conclusion, we show that: 1) TGF-beta receptor Type II is predominantly located on basolateral membrane and receptor stimulation activates Smad pathway; 2) TGF-beta1 down-regulates IL-6-induced tyrosine phoshorylation of STAT1 and STAT3 and ICAM-1 expression; and 3) Smad2 is required for the down-regulation of IL-6 signaling by TGF-beta. Collectively, our data demonstrate a cross-talk between TGF-beta and IL-6, and TGF-beta may play a role in the negative regulation of IL-6 signaling in intestinal epithelial cells.

Active Transport, Cell Nucleus↗

PubMed1998

Necessity of acetylcholine for retinal directionally selective responses to drifting gratings in rabbit.

1. A model for retinal directional selectivity postulates that GABAergic inhibition of responses to motions in the null (anti-preferred) direction underlies this selectivity. An alternative model postulates that besides this inhibition, there exists an asymmetric, nicotinic acetylcholine (ACh) input from starburst amacrine cells. It is possible for the latter but not the former model that stimuli could exist such that nicotinic blockade eliminates directional selectivity. Such stimuli would drive the cholinergic but not the GABAergic system well. 2. So far, attempts to eliminate directional selectivity with nicotinic blockade have failed, but they always used isolated, moving bars as the stimulus. We confirmed this failure for On-Off directionally selective (DS) ganglion cells in our preparation of the rabbit's retina. 3. However, while recording from these cells, we discovered that nicotinic blockade eliminated directional selectivity to drifting, low spatial frequency sine- and square-wave gratings. 4. This effect was not just due to the smallness of the responses under nicotinic blockade. NMDA blockade caused even smaller responses, but no loss of directional selectivity. 5. This result is consistent with a two-asymmetric-pathways model of directional selectivity, but inconsistent with an asymmetric-GABA-only model. 6. We conclude that asymmetric nicotinic inputs extend the range of stimuli that can elicit directional selectivity to include moving textures, that is, those with multiple peaks in their spatial luminance profile.

Acetylcholine↗

PubMed2002

Substrate regulation of calcium binding in Ca2+-ATPase molecules of the sarcoplasmic reticulum. I. Effect of ATP.

The effect of ATP on calcium binding of the Ca2+-ATPase of the sarcoplasmic reticulum has not been clarified. By comparing the calcium dependence of the ATPase activity and of phosphorylation of the ATPase molecules with that of calcium binding in the absence of ATP, we show the existence of two types of regulatory site of the enzyme molecules at which ATP binding variously improves the calcium binding performance of the molecules depending on the aggregation state of the molecules and pH; the two regulatory sites bind ATP at submillimolar (0.25 mm) and millimolar (5 mm) ATP, respectively. The results are discussed based on a model of two conformational variants (A and B forms) of the chemically equivalent ATPase molecules (Nakamura, J., and Furukohri, T. (1994) J. Biol. Chem. 269, 30818-30821). For example, in the sarcoplasmic reticulum membrane at pH 7.40, submillimolar ATP converted the calcium binding manner of the A form from noncooperative (Hill number (n(H)) of approximately 1) to cooperative (n(H) approximately 2), concurrent with a decrease in the apparent calcium affinity (K(0.5)) from 2-6 to 0.1-0.3 microm. The binding of the A form became almost the same as that of the B form (n(H) approximately 2, K(0.5) approximately 0.2 microm), which was not affected by ATP. Millimolar ATP further decreased the K(0.5) of the cooperative binding of the two forms to approximately 0.05 microm. Regulation of the calcium binding performance by ATP is discussed in terms of monomeric and oligomeric pathway models.

Animals↗

PubMed2003

Docking and electron transfer studies between rubredoxin and rubredoxin:oxygen oxidoreductase.

The interaction and electron transfer (ET) between rubredoxin (Rd) and rubredoxin:oxygen oxidoreductase (ROO) from Desulfovibrio gigas is studied by molecular modelling techniques. Experimental kinetic assays using recombinant proteins show that the Rd reoxidation by ROO displays a bell-shaped dependence on ionic strength, suggesting a non-trivial electrostatic dependence of the interaction between these two proteins. Rigid docking studies reveal a prevalence for Rd to interact, in a very specific way, with the surface of the ROO dimer near its FMN cofactors. The optimization of the lowest energy complexes, using molecular dynamics simulation, shows a very tight interaction between the surface of the two proteins, with a high probability for Rd residues (but not the iron centre directly) to be in direct contact with the FMN cofactors of ROO. Both electrostatics and van der Waals interactions contribute to the final energy of the complex. In these complexes, the major contributions for complex formation are polar interactions between acidic residues of Rd and basic residues of ROO, plus substantial non-polar interactions between different groups. Important residues for this process are identified. ET estimates (using the Pathways model), in the optimized lowest energy complexes, suggest that these configurations are efficient for transferring electrons. The experimental bell-shaped dependence of kinetics on ionic strength is analysed in view of the molecular modelling results, and hypotheses for the molecular basis of this phenomenon are discussed.

Amino Acid Sequence↗

PubMed2006

Child ADHD and personality/temperament traits of reactive and effortful control, resiliency, and emotionality.

BACKGROUND: Models of attention-deficit/hyperactivity disorder (ADHD) suggest developmental influences may feed into components of the disorder separately from associated disruptive behavior problems. We investigated this in terms of key personality/temperament traits of Reactive and Effortful Control, Resiliency, and Emotionality. METHODS: A sample of 179 children (age 6-12, 63% boys), of whom 92 had ADHD, 52 were Controls, and 35 were borderline or not otherwise specified cases of ADHD, were examined. Dispositional trait scores were derived from parent-completed California Q-sort and the Early Adolescent Temperament Questionnaire. Child ADHD symptoms were evaluated using maternal structured diagnostic interview and teacher-completed symptom ratings. RESULTS: Traits were differentially associated with symptoms. Reactive Control was related to hyperactivity-impulsivity as rated by both parents and teachers. Negative Emotionality was related to oppositional-defiance. Resiliency was primarily related to inattention-disorganization as rated by both parents and teachers; Effortful Control was related uniquely to inattention in parent but not teacher data. A moderation effect emerged; the relationship between parent-rated Negative Emotionality and teacher-rated ADHD symptoms was stronger for children with high levels of both Reactive and Effortful Control. CONCLUSIONS: Results are interpreted in relation to a two-pathway model of ADHD; regulation problems contribute to the emergence of symptoms of inattention-disorganization, reactive or motivational control problems to the emergence of hyperactivity-impulsivity, and these are distinct from negative affectivity. Children with regulation deficits and a reactive motivational style are especially at risk for the development of ADHD.

Adaptation, Psychological↗