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Results for “Integrative interaction”

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PubMed1991

Significant efficiency findings while controlling for the frequent confounders of CAI research in the PlanAlyzer project's computer-based, self-paced, case-based programs in anemia and chest pain diagnosis.

Richard E. Clark in his widely published comprehensive studies and meta-analyses of the literature on computer assisted instruction (CAI) has decried the lack of carefully controlled research, challenging almost every study which shows the computer-based intervention to result in significant post-test proficiency gains over a non-computer-based intervention. We report on a randomized study in a medical school setting where the usual confounders found by Clark to plague most research, were carefully controlled. PlanAlyzer is a microcomputer-based, self-paced, case-based, event-driven system for medical education which was developed and used in carefully controlled trials in a second year medical school curriculum to test the hypothesis that students with access to the interactive programs could integrate their didactic knowledge more effectively and/or efficiently than with access only to traditional textual "nonintelligent" materials. PlanAlyzer presents cases, elicits and critiques a student's approach to the diagnosis of two common medical disorders: anemias and chest pain. PlanAlyzer uses text, hypertext, images and critiquing theory. Students were randomized, one half becoming the experimental group who received the interactive PlanAlyzer cases in anemia, the other half becoming the controls who received the exact same content material in a text format. Later in each year there was a crossover, the controls becoming the experimentals for a similar intervention with the cardiology PlanAlyzer cases. Preliminary results at the end of the first two full trials shows that the programs have achieved most of the proposed instructional objectives, plus some significant efficiency and economy gains. 96 faculty hours of classroom time were saved by using PlanAlyzer in their place, while maintaining high student achievement. In terms of student proficiency and efficiency, the 328 students in the trials over two years were able to accomplish the project's instructional objectives, and the experimentals accomplished this in 43% less time than the controls, achieving the same level of mastery. However, in spite of these significant efficiency findings, there have been no significant proficiency differences (as measured by current factual and higher order multiple choice post-tests) between the experimental and control groups. Very careful controls were used to avoid what Clark has found to be the most common confounders of CAI research. Accordingly, this research proved Clark's rival hypothesis, that the computer, in itself, does not appear to contribute to proficiency gains, at least as measured by our limited post-testing. Clark's position is that the computer is primarily a vehicle--as is either a pill or a hypodermic needle for delivering a drug.(ABSTRACT TRUNCATED AT 400 WORDS)

Anemia↗

PubMed1999

Noradrenergically mediated plasticity in a human attentional neuronal network.

Noradrenaline is implicated in the modulation of attention and arousal, but the neuroanatomical basis of this effect in humans is unknown. A previous functional neuroimaging study failed to find clear effects of clonidine (alpha2 adrenoceptor agonist) on activity of brain regions implicated in attention. Therefore, we now investigate whether clonidine affects the functional integration of a neuroanatomical attentional network, by modulating connectivity between brain regions rather than activity within discrete regions. Following infusion of either clonidine or placebo, positron emission tomography measurements of brain activity were collected in 13 normal subjects while they were either resting or performing an attentional task. Effective connectivity analysis showed that during rest, clonidine decreased the functional strength of connections both from frontal cortex to thalamus and in pathways to and from visual cortex. Conversely, during the attentional task, functional integration generally increased, with changes being centered on parietal cortex (increased connectivity from locus coeruleus to parietal cortex and from parietal cortex to thalamus and frontal cortex). A drug-induced increase in the modulatory effects of frontal cortex on projections from locus coeruleus to parietal cortex was also observed. Collectively, these results highlight cognitively dissociable effects of clonidine on interactions among functionally integrated brain regions and implicate the noradrenergic system in mediating the functional integration of attentional brain systems. The context-sensitive nature of the changes are consistent with observations that noradrenergic drugs have differential effects on brain processes depending on subjects' underlying arousal levels. More generally, the results illustrate the dynamic plasticity of cognitive brain systems following neurochemical challenge.

Adolescent↗

PubMed2006

The debate over dopamine's role in reward: the case for incentive salience.

INTRODUCTION: Debate continues over the precise causal contribution made by mesolimbic dopamine systems to reward. There are three competing explanatory categories: 'liking', learning, and 'wanting'. Does dopamine mostly mediate the hedonic impact of reward ('liking')? Does it instead mediate learned predictions of future reward, prediction error teaching signals and stamp in associative links (learning)? Or does dopamine motivate the pursuit of rewards by attributing incentive salience to reward-related stimuli ('wanting')? Each hypothesis is evaluated here, and it is suggested that the incentive salience or 'wanting' hypothesis of dopamine function may be consistent with more evidence than either learning or 'liking'. In brief, recent evidence indicates that dopamine is neither necessary nor sufficient to mediate changes in hedonic 'liking' for sensory pleasures. Other recent evidence indicates that dopamine is not needed for new learning, and not sufficient to directly mediate learning by causing teaching or prediction signals. By contrast, growing evidence indicates that dopamine does contribute causally to incentive salience. Dopamine appears necessary for normal 'wanting', and dopamine activation can be sufficient to enhance cue-triggered incentive salience. Drugs of abuse that promote dopamine signals short circuit and sensitize dynamic mesolimbic mechanisms that evolved to attribute incentive salience to rewards. Such drugs interact with incentive salience integrations of Pavlovian associative information with physiological state signals. That interaction sets the stage to cause compulsive 'wanting' in addiction, but also provides opportunities for experiments to disentangle 'wanting', 'liking', and learning hypotheses. Results from studies that exploited those opportunities are described here. CONCLUSION: In short, dopamine's contribution appears to be chiefly to cause 'wanting' for hedonic rewards, more than 'liking' or learning for those rewards.

Animals↗

PubMed2001

[Rheumatoid arthritis. Recent findings and new pathogenic concepts].

The etiology of rheumatoid arthritis (RA) is still unknown, and many uncertainties regarding its pathogenetic mechanisms persist. During the past decade, various hypotheses have been advanced, yet none of these has been able to explain the complexity of the disease. In light of the most recent research, a sub-division of the pathogenesis of RA, in four phases, has been proposed. The first phase is that of tissue damage, induced by unknown infective or traumatic factors with the liberation of possible arthrogenic antigens that are presented to the immune system. In the second phase the immune and inflammatory mechanisms should begin to function and, if they are effective, they should determine the resolution of the process; the failure of these mechanisms would create a further amplification of the immuno-inflammation response (the third phase). The fourth phase would then be a chronic inflammatory with progressive articular destruction, as well as anatomical and functional damage. This evolution, in response to common pathogenic agents, is dependent upon a particular hereditary genetic asset (not only the HLA system) that is able to control the production of citokines and also upon the neuroendocrine system. The final outcome of the process is, therefore, determinated by multiple interference between the inflammatory/immune system and other systems that also interact with it (the integrated pathogenetic hypothesis). This hypothesis reflects the complexity of the immune/inflammatory system that must be considered to be an acting part of an integrated network of diverse systems. A better knowledge of these interactions needed for the discovery of potential new therapies for RA.

Arthritis, Rheumatoid↗

PubMed1997

Calculations of Double-Layer Electrostatic Interactions for the Sphere/Plane Geometry

A numerical scheme for solving the nonlinear Poisson-Boltzmann equation for the sphere/sphere and plane/sphere geometries has been developed. The method is based on an alternating direction overrelaxation procedure using the Newton-Raphson iteration to solve the nonlinear equation stemming from finite-difference discretization. The novelty of the algorithm consists in using the grid transforming functions that allow a more uniform distribution of mesh points in the vicinity of the particle. The method was used to perform extensive calculations for opposite surface potentials of the interface and the particle immersed in a symmetric electrolyte solution. The electric potential distribution (within and outside the sphere) was calculated, as well as the force and energy of interaction (from the integral of the force over separation distance), for the constant potential, the constant charge, and the mixed cases. The energy profiles calculated for various kappaa were compared with the analytical approximations derived using the Hogg-Healy-Fuerstenau method and the linear superposition approach (LSA). These calculations enabled us to conclude that the LSA can be used as a good estimate of interaction energy for a broad range of kappaa values at distances greater than kappa-1, i.e., for problems pertinent to colloid particle adsorption.

Journal Article↗

PubMed2006

Monitoring regulated protein-protein interactions using split TEV.

Signaling cascades integrate extracellular stimuli primarily through regulated protein-protein interactions (PPIs). Intracellular signal transduction strictly depends on PPIs occurring at the membrane and in the cytosol. To monitor constitutive and regulated protein interactions within living mammalian cells, we have developed a biological assay termed split TEV. We engineered inactive fragments of the NIa protease from the tobacco etch virus (TEV protease) that regain activity only when coexpressed as fusion constructs with interacting proteins. Functional reconstitution of TEV protease fragments can be monitored with 'proteolysis-only' reporters, which can be previously silent fluorescent and luminescent reporter proteins. Additionally, proteolytically cleavable inactive transcription factors can be combined with any downstream reporter gene of choice to yield 'transcription-coupled' reporter systems. Thus, split TEV combines the advantages of split enzyme- and reporter gene-mediated assays, and provides full flexibility with regard to the final readout. In a first biological application, we monitored neuregulin-induced ErbB2/ErbB4 receptor tyrosine kinase heterodimerization.

Cell Physiological Phenomena↗

PubMedDate not supplied

A practical approach to spectral volume rendering.

To make a spectral representation of color practicable for volume rendering, a new low-dimensional subspace method is used to act as the carrier of spectral information. With that model, spectral light material interaction can be integrated into existing volume rendering methods at almost no penalty. In addition, slow rendering methods can profit from the new technique of postillumination-generating spectral images in real-time for arbitrary light spectra under a fixed viewpoint. Thus, the capability of spectral rendering to create distinct impressions of a scene under different lighting conditions is established as a method of real-time interaction. Although we use an achromatic opacity in our rendering, we show how spectral rendering permits different data set features to be emphasized or hidden as long as they have not been entirely obscured. The use of postillumination is an order of magnitude faster than changing the transfer function and repeating the projection step. To put the user in control of the spectral visualization, we devise a new widget, a "light-dial," for interactively changing the illumination and include a usability study of this new light space exploration tool. Applied to spectral transfer functions, different lights bring out or hide specific qualities of the data. In conjunction with postillumination, this provides a new means for preparing data for visualization and forms a new degree of freedom for guided exploration of volumetric data sets.

Algorithms↗

PubMed1989

Inhibition of synaptosome membrane-bound integral enzymes by organic solvents.

The possible mechanism of the depressive effect of organic solvents on the central nervous system (CNS) was studied with synaptosome membranes as a model. The changes in the activities of the membrane-bound integral enzymes acetylcholinesterase, total adenosinetriphosphatase, and magnesium-activated adenosinetriphosphatase were determined after treatment with different concentrations of organic solvents in vitro. Aromatic hydrocarbons and chlorinated aliphatic hydrocarbons inhibited all the enzyme activities concentration dependently. Alcohols had no significant effect at the same dose levels. The results of the present study suggest that the CNS depressive effect of organic solvents may be based on their interaction with membrane integral proteins.

Acetylcholinesterase↗

PubMed2005

FtsY, the bacterial signal-recognition particle receptor, interacts functionally and physically with the SecYEG translocon.

Co-translational membrane targeting of proteins by the bacterial signal-recognition particle (SRP) requires the specific interaction of the SRP-ribosome nascent chain complex with FtsY, the bacterial SRP receptor (SR). FtsY is homologous to the SRalpha-subunit of the eukaryotic SR, which is tethered to the endoplasmic-reticulum membrane by its interaction with the integral SRbeta-subunit. In contrast to SRalpha, FtsY is partly membrane associated and partly located in the cytosol. However, the mechanisms by which FtsY associates with the membrane are unclear. No gene encoding an SRbeta homologue has been found in bacterial genomes, and the presence of an FtsY-specific membrane receptor has not been shown so far. We now provide evidence for the direct interaction between FtsY and the SecY translocon. This interaction offers an explanation of how the bacterial SRP cycle is regulated in response to available translocation channels.

Bacterial Proteins↗

PubMed2006

Regulation of cell adhesion by protein-tyrosine phosphatases: II. Cell-cell adhesion.

Cell-cell adhesion is critical to the development and maintenance of multicellular organisms. The stability of many adhesions is regulated by protein tyrosine phosphorylation of cell adhesion molecules and their associated components, with high levels of phosphorylation promoting disassembly. The level of tyrosine phosphorylation reflects the balance between protein-tyrosine kinase and protein-tyrosine phosphatase activity. Many protein-tyrosine phosphatases associate with the cadherin-catenin complex, directly regulating the phosphorylation of these proteins, thereby affecting their interactions and the integrity of cell-cell junctions. Tyrosine phosphatases can also affect cell-cell adhesions indirectly by regulating the signaling pathways that control the activities of Rho family G proteins. In addition, receptor-type tyrosine phosphatases can mediate outside-in signaling through both ligand binding and dimerization of their extracellular domains. This review will discuss the role of protein-tyrosine phosphatases in cell-cell interactions, with an emphasis on cadherin-mediated adhesions.

Animals↗

PubMed1991

The identification of proteins in the proximity of signal-anchor sequences during their targeting to and insertion into the membrane of the ER.

Using a photocross-linking approach we have investigated the cytosolic and membrane components involved in the targeting and insertion of signal-anchor proteins into the membrane of the ER. The nascent chains of both type I and type II signal-anchor proteins can be cross-linked to the 54-kD subunit of the signal recognition particle. Upon addition of rough microsomes the type I and type II signal-anchor proteins interact with a number of components. Both types of protein interact with an integral membrane protein, the signal sequence receptor, previously identified by its proximity to preprolactin during its translocation (Wiedmann, M., T.V. Kurzchalia, E. Hartmann, and T.A. Rapoport. 1987. Nature [Lond.] 328:830-833). Three proteins, previously unidentified, were found to be cross-linked to the nascent chains of the signal-anchor proteins. Among them was a 37-kD protein that was found to be the main component interacting with the type I SA protein used. These proteins were not seen in the absence of membranes suggesting they are components of the ER. The ability of the nascent chains to be cross-linked to these identified proteins was shown to be abolished by prior treatment with agents known to disrupt translocation intermediates or ribosomes. We propose that the newly identified proteins function either in the membrane insertion of only a subset of proteins or only at a specific stage of insertion.

Amino Acid Sequence↗

PubMed1997

The lumenal domain of Sec63p stimulates the ATPase activity of BiP and mediates BiP recruitment to the translocon in Saccharomyces cerevisiae.

We studied the molecular nature of the interaction between the integral membrane protein Sec63p and the lumenal Hsp70 BiP to elucidate their role in the process of precursor transit into the ER of Saccharomyces cerevisiae. A lumenal stretch of Sec63p with homology to the Escherichia coli protein DnaJ is the likely region of interface between Sec63p and BiP. This domain, purified as a fusion protein (63Jp) with glutathione S-transferase (GST), mediated a stable ATP-dependent binding interaction between 63Jp and BiP and stimulated the ATPase activity of BiP. The interaction was highly selective because only BiP was retained on immobilized 63Jp when detergent-solubilized microsomes were mixed with ATP and the fusion protein. GST alone was inactive in these assays. Additionally, a GST fusion containing a point mutation in the lumenal domain of Sec63p did not interact with BiP. Finally, we found that the soluble Sec63p lumenal domain inhibited efficient precursor import into proteoliposomes reconstituted so as to incorporate both BiP and the fusion protein. We conclude that the lumenal domain of Sec63p is sufficient to mediate enzymatic interaction with BiP and that this interaction positioned at the translocation apparatus or translocon at the lumenal face of the ER is vital for protein translocation into the ER.

Adenosine Triphosphatases↗

PubMed2001

New tools for studying integration and modularity.

The study of phenotypic integration concerns the modular nature of organismal phenotypes. The concept provides a rationale for why certain subsets of phenotypic traits show particularly high levels of association over development and/or evolution. The techniques detailed in this report facilitate the generation and testing of hypotheses of phenotypic integration and trait interaction. The approach advocated for exploring patterns of interaction among traits is based on the statistical notion of conditional independence, incorporated in a technique known as graphical modeling. The use of graphical models is illustrated with an application to a well-known biological dataset of fowl skeletal measurements, previously analyzed by Sewall Wright. A definition of phenotypic modularity is given, based on a notion of mutual information, which provides a consistent criterion for recognizing and delimiting integrated subsets of traits and which can be related to standard models of multivariate selection.

Analysis of Variance↗

PubMed2026

Bridging Organ-on-a-Chip and Omics: A Multi-Dimensional Frontier in Biomedical Research.

Organ-on-a-Chip (OOC) technology offers a powerful platform for replicating human tissue-specific microenvironments, thereby narrowing the translational gap between conventional biomedical models and actual human physiology. Concurrently, omics technologies deliver comprehensive molecular-level insights into biological systems. This review highlights the transformative potential of integrating OOC platforms with high-throughput omics methodologies. We systematically examine the classification, structural configurations, and engineering principles underlying OOC systems, alongside the defining attributes of key omics domains-genomics, transcriptomics, proteomics, and metabolomics. The convergence of dynamic OOC models with advanced omics technologies enables high-resolution, multi-dimensional analyses across numerous biomedical applications, including drug metabolism, disease mechanisms, environmental toxicity assessments, and host-microbiome interactions. This interdisciplinary integration is driving a paradigm shift in precision and translational medicine. However, several challenges remain to be addressed, such as the development of whole-organ mimetics, adaptation of sample collection techniques, and real-time artificial intelligence-based integration of biosensor data with multi-omics datasets. Addressing these hurdles will be vital for unlocking the full potential of this technological synergy in biomedical science.

Multiomics↗

PubMed1999

Cysteine-directed cross-linking demonstrates that helix 3 of SecE is close to helix 2 of SecY and helix 3 of a neighboring SecE.

Preprotein translocation in Escherichia coli is mediated by translocase, a multimeric membrane protein complex with SecA as the peripheral ATPase and SecYEG as the translocation pore. Unique cysteines were introduced into transmembrane segment (TMS) 2 of SecY and TMS 3 of SecE to probe possible sites of interaction between the integral membrane subunits. The SecY and SecE single-Cys mutants were cloned individually and in pairs into a secYEG expression vector and functionally overexpressed. Oxidation of the single-Cys pairs revealed periodic contacts between SecY and SecE that are confined to a specific alpha-helical face of TMS 2 and 3, respectively. A Cys at the opposite alpha-helical face of TMS 3 of SecE was found to interact with a neighboring SecE molecule. Formation of this SecE dimer did not affect the high-affinity binding of SecA to SecYEG and ATP hydrolysis, but blocked preprotein translocation and thus uncouples the SecA ATPase activity from translocation. Conditions that prevent membrane deinsertion of SecA markedly stimulated the interhelical contact between the SecE molecules. The latter demonstrates a SecA-mediated modulation of the protein translocation channel that is sensed by SecE.

Adenosine Triphosphatases↗

PubMed2004

Superoxide: a key player in hypertension.

Superoxide is increased in the vessel wall of spontaneously hypertensive rats (SHR) where, if "blocked," potentiates endothelium-dependent vasodilation. The purpose of this study was to determine the role of superoxide anion in hypertension and its interaction with nitric oxide (NO). For this purpose we used a low molecular weight synthetic superoxide dismutase mimetic (M40403), known to remove selectively superoxide anion. Baseline mean arterial pressure (MAP) was significantly elevated in the SHR compared with its normal counterpart, Wistar Kyoto (WKY). M40403 at a dose (2 mg x kg(-1) x h(-1)), which had no effect in the WKY, significantly decreased MAP in SHR rats. To determine whether superoxide anion increases MAP by inactivating NO, NO synthesis was blocked with N(G) nitro-arginine methyl ester (L-NAME, 3 mg/kg i.v.), a nonselective nitric oxide synthase inhibitor. L-NAME (3 mg/kg, i.v) blocked the anti-hypertensive effect of M40403 (2 mg/kg over 30 min). When used at a dose that yielded similar increases in MAP, norepinephrine (2.1 microg/kg) failed to alter the anti-hypertensive effects of M40403 in the SHR. To investigate whether the anti-hypertensive effect of M40403 was associated with an improvement of the alterations in vascular reactivity, a separate group of experiments was carried out ex vivo. Endothelium-dependent vasorelaxation to acetylcholine (10 nM-10 microM), an index of endothelial function, was reduced in aortic rings taken from SHR rats when compared with WKY rats. In vivo treatment with M40403 caused an improvement of the degree of the endothelial dysfunction in SHR rats. Furthermore, immunohistochemical analysis for nitrotyrosine (the product formed from the interaction of nitric oxide with superoxide) revealed a positive staining in aorta from SHR rats. The degree of staining for nitrotyrosine was markedly reduced in tissue sections obtained from SHR rats treated with M40403. Our data suggest that overt production of superoxide in SHR couples with nitric oxide, reducing its function and leading to a loss of blood vessel tone and hypertension. Another important effect appears to be at the level of endothelial cellular integrity, where by interacting with nitric oxide, superoxide anion forms peroxynitrite and subsequent endothelial cell dysfunction. By removing superoxide, M40403 restores blood pressure to near-to-normal values.

Animals↗

PubMed1994

Classwide peer tutoring: an integration strategy to improve reading skills and promote peer interactions among students with autism and general education peers.

A multiple baseline design across subjects with a reversal was used to examine the effects of classwide peer tutoring relative to traditional reading instruction on reading skills and social interaction time for 3 high-functioning students with autism and their typical peers in integrated, general education classrooms. Traditional reading instruction consisted largely of teacher-led instruction with individual student participation and seat work. Classwide peer tutoring consisted of 25 to 30 min of well-specified instruction in which tutor-learner pairs worked together on a classwide basis on reading fluency and comprehension skills. All students participated in 15- to 20-min unstructured free-time activities immediately following reading instruction. Results of reading assessments demonstrated that classwide peer tutoring increased reading fluency and correct responses to reading comprehension questions for students with autism and their peers. The procedure further increased the total duration of free-time social interactions for students with autism and typical peers, with individual variation in performance.

Autistic Disorder↗

PubMedDate not supplied

Striatal mechanism of action of corticoliberin on behavior in dogs in conditions of dopamine deficiency.

This report describes studies of the interaction of the integrative dopaminergic and corticoliberin systems in the neostriatum during performance of situational food-related conditioned reflexes. Studies were performed in dogs with chemotrodes implanted in the substantia nigra and the head of the caudate nucleus. 6-Hydroxydopamine was injected into the substantia nigra at a dose of 50 microg, and 10 microg of corticoliberin was injected into the caudate nucleus. Blood cortisol and catecholamine levels were determined. Analysis of the result showed that an interaction takes place in the neostriatum between the corticoliberin and dopaminergic systems, and that in conditions in which dopaminergic structures are excluded, the efficacy of corticoliberin in the performance of behavioral acts decreases by 30-40%, i.e., complete expression of its regulatory role of motor situational conditioned reflexes is lost.

Animals↗