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Interaction among primary afferents, corticofugal fibers, and intrinsic elements allows for sensorimotor integration at the dorsal column nuclei. The interneurons permit the spatial localization, the recurrent collaterals synchronize the activity of projecting cells with overlapping receptive fields, and the corticofugal fibers induce a central zone of activity surrounded by a peripheral zone of inhibition.
Integration of biochemical and biophysical data on the lactose permease of Escherichia coli has culminated in a molecular model that predicts substrate-protein proximities which include interaction of a hydroxyl group in the galactopyranosyl ring with Glu269. In order to test this hypothesis, we studied covalent modification of carboxyl groups with carbodiimides using electrospray ionization mass spectrometry (ESI-MS) and demonstrate that substrate protects the permease against carbodiimide reactivity. Further more, a significant proportion of the decrease in carbodiimide reactivity occurs specifically in a nanopeptide containing Glu269. In contrast, carbodiimide reactivity of mutant Glu269-->Asp that exhibits lower affinity is unaffected by substrate. By monitoring the ability of different substrate analogs to protect against carbodiimide modification of Glu269, it is suggested that the C-3 OH group of the galactopyranosyl ring may play an important role in specificity, possibly by H-bonding with Glu269. The approach demonstrates that mass spectrometry can provide a powerful means of analyzing ligand interactions with integral membrane proteins.
Identification, selection, validation and prioritization of targets for therapeutic intervention requires understanding of the biological role of individual proteins in cellular pathways. Unraveling the ways in which proteins interact with each other appears to be crucial in achieving that goal. A number of recently described high-throughput approaches for analyzing cellular protein-protein interactions and previously proposed prediction procedures are compared in this review. The relative advantages of each method are discussed in relation to reproducibility, comprehensiveness and biological significance. It is concluded that only a combination of complementary biochemical technologies supported by reliable algorithms, will provide exhaustive maps of protein interactions for a cellular interactome.
The RGD1 gene was identified during systematic genome sequencing of Saccharomyces cerevisiae. To further understand Rgd1p function, we set up a synthetic lethal screen for genes interacting with RGD1. Study of one lethal mutant made it possible to identify the SLG1 and MID2 genes. The gene SLG1/HCS77/WSC1 was mutated in the original synthetic lethal strain, whereas MID2/SMS1 acted as a monocopy suppressor. The SLG1 gene has been described to be an upstream component in the yeast PKC pathway and encodes a putative cell surface sensor for the activation of cell integrity signalling. First identified by viability loss of shmoos after pheromone exposure, and since found in different genetic screens, MID2 was recently reported as also encoding an upstream activator of the PKC pathway. The RGD1 gene showed genetic interactions with both sensors of cell integrity pathway. The rgd1 slg1 synthetic lethality was rescued by osmotic stabilization, as expected for mutants altered in cell wall integrity. The slight viability defect of rgd1 in minimal medium, which was exacerbated by mid2, was not osmoremediated. As for mutants altered in PKC pathway, the accumulation of small-budded dead cells in slg1, rgd1 and mid2 after heat shock was prevented by 1 M sorbitol. In addition, the rgd1 strain also displayed dead shmoos after pheromone treatment, like mid2. Taken together, the present results indicate close functional links between RGD1, MID2 and SLG1 and suggest that RGD1 and MID2 interact in a cell integrity signalling functionally linked to the PKC pathway.
To evaluate expectations derived from ego-identity theory and symbolic-interaction theories about the association between self-concept and peer-group affiliations in adolescence, we examined the self-esteem of 221 7th through 12th graders associated by peers with one of five major school crowds and 106 students relatively unknown by classmates and not associated with any school crowd. Among crowd members, self-esteem was directly related to the position of one's crowd in the peer-group status hierarchy (based on both peer-rated and self-perceived crowd affiliation). Outsiders' self-esteem differed in relation to the accuracy of their reflected appraisal of and the salience they attached to crowd affiliation. Crowd members as a whole exhibited higher self-esteem than outsiders as a whole. Differences, however, were mediated by crowd status, salience of crowd affiliation, and the accuracy of reflected appraisals. An adequate interpretation of the findings required an integration of Festinger's (1954, 1957) social comparisons and cognitive-dissonance theories, Cooley's (1902) notions of reflected appraisal, and Newman and Newman's (1976) extrapolations from ego-identity theory.
We have applied the systems approach, to the analysis of mechanisms whereby connective tissue (CT) is integrated into one functional system. The primary CT functions in health and in disease (biomechanical, trophic, protective, reparative, and morphogenetic) are carried out by means of cell-cell, cell-matrix and intertissue interactions based on feedback between these components. Both CT as a whole and its cellular and extracellular elements exhibit structural and functional heterogeneity which increases the capacity of CT for adaptation. The intercellular interactions take place via soluble and insoluble mediators, direct cellular contacts, and cell/matrix degradation products. Results of this study support the concept of internal "network" regulation of the CT composition, functions and growth through intercellular interactions at different structural levels. Feedback mechanisms between degradation and production of collagen and interactions between collagen, macrophages and fibroblasts play a special role in the self-regulation of reparative CT growth. Collagen restores an impaired self-regulation and exerts a marked therapeutic effect on wounds, burns, trophic ulcers, and other lesions. A similar function may be performed by other matrix components and degradation/secretion products of macrophages and fibroblasts.
Integration of the central nervous system is an expression of cerebral homeostasis that is essential for the internal ability of the organism to adapt to its changing environment throughout life. It is generally accepted that neurons undergo no further division after differentiation, whereas glial cells continue to proliferate throughout life. The increase in glial cells with advanced age may reflect a compensatory process of the brain to overcome neuronal loss or neuronal functional changes that may occur with age. Therefore, these neuronal-glial interactions during development and aging may play a key role in the integrative capacity of the brain. One of the mechanisms contributing to brain stability is the blood-brain barrier, which regulates the neuronal-glial microenvironment in the mature organism. Neuronal intercommunication is mediated via neurotransmitter substances and a shift may occur from excitation to inhibition and vice versa in some CNS areas with aging. Studies of some aspects of cholinergic, monoaminergic and amino acid neurotransmission show that their maturational patterns are CNS-area specific and that some neurotransmitter processes decline with advanced age. Glial cells, besides participating in the regulation of extraneuronal environment, are also proposed to be involved in neurotransmission mechanisms in the adult and aging CNS and since they are the major CNS cellular compartment that changes with age they may thus contribute significantly to the maintenance of CNS integrative ability and adaptation with age.
The structural and thermodynamical properties of classical fluids orientationally ordered by an external field are investigated by means of integral equation theories. A general theoretical framework for handling these theories is developed and detailed for the particular case of separable interactions between fluid particles. This approach is then illustrated for the case of two (off lattice) models: the ferromagnetic Heisenberg model and a simple liquid crystal model, for which the numerical solution of integral equations such as the Percus-Yevick, the hypernetted chain, and the reference hypernetted chain closure equations are presented and compared with Monte Carlo simulation results and the analytical solution of the mean spherical approximation. The zero-field case is also examined, and the spontaneous ordering is analyzed in detail, mainly in what concerns the appearance of infinite wavelength singularity in the Ornstein-Zernike equation and the relation with the one-body closure equations and the long range orientational ordering that occurs. In particular, it is shown that the Wertheim one-body closure equation appears as a sum rule compatible with the Ornstein-Zernike equation. The relation between the elastic constant and the long range tail of the pair correlation function is made explicit. In particular, the long range behavior of the various terms in the expansion of the pair correlation function is depicted. The numerical investigation of the two models shows that it is not possible to discriminate between the four integral equations, as to which one would be the most accurate in all cases. The general trends in the thermodynamical and structural properties seem to indicate that the Percus-Yevick approximation is generally better in the strong ordering case, whereas the reference hypernetted chain approximation might be better suited to the study of the isotropic phase and the low ordering regimes.
The CNS and PNS interact and form an integrated system which mediates adaptive gill withdrawal reflex behaviors evoked by tactile stimulation of the siphon. The CNS exerts suppressive and facilitatory control over the PNS in the mediation of these behaviors. It was found that in Aplysia the CNS's supressive control over the PNS was significantly greater than in nonsatiated control animals. In the controls, the evoked gill reflex met a mimimal response amplitute criterion with the CNS and PNS present, while in the satiated group the reflex did not meet this criterion. In the control group, the relflex amplitute and the subsequent habituation were the same following removal of the CNS, while in satiated animals the reflex amplitude was larger and the rate of habituation slower with only the PNS intact. Satiation had no effect on young Aplysia since CNS control was not yet operable. It is thus of prime importance to take the "state" of the preparation into consideration in the analysis of the neural mechanisms that underlie adaptive gill reflex behaviors. The gill withdrawal reflex and its subsequent habituation evoked by repeated tactile stimulation of the siphon in Aplysia has been studied extensively in an attempt to gain an understanding of the neuronal mechanisms that underlie adaptive behavior (Jacklet and Lukowiak, 1975; Kandel, 1976). It has been found that the central (CNS) and peripheral(PNS) nervous systems in Aplysia interact and form an integrated system which normally mediates both the reflex and its subsequent habituation (Peretz, Jacklet, and Lukowaik, 1976; Lukowiak and Peretz, 1977). Further, it was found that in the integrated system the CNS exerted both suppressive and facilitatory control over the PNS in the mediation of gills reflex behaviors (Lukowiak, 1977a). Removal of only the CNS's suppressive control over the PNS, while leaving intact its facilitatory influence, resulted in a significant reduction in reflex latency, a significant increase in reflex amplitude, and a reflex that is resistant to habituation with repeated stimulation (Lukowiak, 1977a). In addition, it was found that an identifiable neuron, Ld9, could modulate the ability of the reflex to habituate (Lukowiak, 1979a). With induced tonic low-level activity in L9 the reflex evoked by repeated siphon stimulation did not habituate even though the synaptic decremental process which occurs in gill motor neurons such as L7 and accompanies gill reflex habituation (Castellucci et al., 1970) continued to occur. The neurons in abdominal ganglion, which by their activity exert control over the PNS and thus the reflex, have not yet been identified but it is known that these same neutrons apparently exert control over the synaptic input received by gill motor neurons such as L7 from the central sensory neurons (Byrne, Castellucci, and Kandel, 1974) as a result of siphon stimulation (Peretz and Lukowiak, 1975; Lukowiak and Peretz, 1980).
We have developed an approach using Bayesian networks to predict protein-protein interactions genome-wide in yeast. Our method naturally weights and combines into reliable predictions genomic features only weakly associated with interaction (e.g., messenger RNAcoexpression, coessentiality, and colocalization). In addition to de novo predictions, it can integrate often noisy, experimental interaction data sets. We observe that at given levels of sensitivity, our predictions are more accurate than the existing high-throughput experimental data sets. We validate our predictions with TAP (tandem affinity purification) tagging experiments. Our analysis, which gives a comprehensive view of yeast interactions, is available at genecensus.org/intint.
Ca2+/calmodulin-sensitive adenylyl cyclase plays a role in several forms of synaptic plasticity and learning. To understand how cellular signals from neuronal activity during behavioral stimuli might be integrated by adenylyl cyclase, we have characterized the response of type I adenylyl cyclase to transient Ca2+ stimuli. Stimulation by a several second Ca2+ stimulus is delayed, rising to a peak after the Ca2+ stimulus has ended. We attempted to identify the site of the persistent Ca2+ signal that enabled adenylyl cyclase stimulation to increase after free Ca2+ had declined. Free calmodulin itself displayed no persistent activation by Ca2+ and was unable to activate adenylyl cyclase if exposed to low Ca2+ solution <1 s before reaching adenylyl cyclase. In contrast, activation of the calmodulin-adenylyl cyclase complex persisted for seconds after Ca2+ stimulus. Activation decayed with a time constant of 6 or 13 s depending on assay conditions. These results suggest that the calmodulin-adenylyl cyclase complex can serve as a site of cellular memory for a Ca2+ transient that has ended even before adenylyl cyclase is fully activated.
Using an integrable Gardner equation as an example, a perturbation theory is developed for systems in which limiting-amplitude solitons exist in the form of a pair of distanced kinks. Approximate equations describing multisoliton interactions are derived and further used for modeling the evolution of an arbitrary set of solitons. The results are compared with an exact solution and numerical results. The theory is applied to data from observation of a train of strongly nonlinear internal waves in the ocean.
Rheb is a recently described member of the Ras family that was originally identified as an immediate-early gene in brain but is also widely expressed in other tissues. Here we demonstrate that Rheb interacts with and appears to regulate Raf-1 kinase, an essential component of the H-Ras signaling pathway. In direct contrast to H-Ras, however, the interaction of Rheb with Raf-1 is potentiated by growth factors in combination with agents that increase cyclic AMP (cAMP) levels. Protein kinase A-dependent phosphorylation of serine 43 within the regulatory domain of Raf-1 reciprocally potentiates its interaction with Rheb and decreases its interaction with H-Ras. A single amino acid in the G2 effector domain is critical for the differential properties of Rheb. Since Rheb is an immediate-early gene, our studies suggest that Rheb functions in concert with H-Ras to dynamically integrate cAMP and growth factor signaling.
MOTIVATION: Complex biological functions emerge from interactions between proteins in stable supra-molecular assemblies and/or through transitory contacts. Most of the time protein partners of the assemblies are composed of one or several domains which exhibit different biochemical functions. Thus the study of cellular process requires the identification of different functional units and their integration in an interaction network; such complexes are referred to as integrated systems. In order to exploit with optimum efficiency the increased release of data, automated bioinformatics strategies are needed to identify, reconstruct and model such systems. For that purpose, we have developed a knowledge warehouse dedicated to the representation and acquisition of bacterial integrated systems involved in the exchange of the bacterial cell with its environment. RESULTS: ISYMOD is a knowledge warehouse that consistently integrates in the same environment the data and the methods used for their acquisition. This is achieved through the construction of (1) a domain knowledge base (DKB) devoted to the storage of the knowledge about the systems, their functional specificities, their partners and how they are related and (2) a methodological knowledge base (MKB) which depicts the task layout used to identify and reconstruct functional integrated systems. Instantiation of the DKB is obtained by solving the tasks of the MKB, whereas some tasks need instances of the DKB to be solved. AROM, an object-based knowledge representation system, has been used to design the DKB, and its task manager, AROMTasks, for developing the MKB. In this study two integrated systems, ABC transporters and two component systems, both involved in adaptation processes of a bacterial cell to its biotope, have been used to evaluate the feasibility of the approach.
A statistical mechanical treatment of biological macromolecules is presented that includes the sequence information as an internal coordinate. Using a path integral representation, the canonical partition function can be represented as a product of a polymer configurational path integral and a sequence walk path integral. In most biological instances, the sequence composition influences the potential energy of intersubunit interaction. Consequently, the two path integrals are not separable, but rather "interact" via a sequence-dependent configurational potential. In proteins and RNA, the sequence walk occurs in dimensions greater than three and, therefore, will be an ideal "polymer." The Markovian nature of this walk can be exploited to show that all the structural information is contained in the sequence. This latter effect is a result of the dimensionality of the sequence walk and is not necessarily a result of biological optimization of the system.
Conventional electron spin resonance (ESR) of spin-labelled lipids and saturation transfer ESR of spin-labelled proteins are used to study lipid-protein interactions and the mobility of integral proteins, respectively, both in biological membranes and in reconstituted lipid-protein systems. Conventional ESR spectra reveal two spin-labelled lipid populations, the mobility of one of which is hindered by direct interaction with the integral membrane proteins. The proportion of the latter component increases with increasing protein content and with increasing selectivity of the lipid species for the protein. The two-component spectra are quantitated by spectral subtraction and addition, and by simulation using the exchange-coupled Bloch equations. Lipid exchange rates at the protein interface obtained by simulation are found to be consistent with fast exchange found by 2H NMR on similar systems and to reflect the lipid selectivity observed by ESR. Protein-reactive covalent spin labels have been used to study the rotational diffusion and aggregation states of membrane proteins via saturation transfer ESR. The integral protein rotation is uniaxial to the first approximation and the anisotropic motion is analyzed to obtain the principal component of the diffusion tensor. The latter is sensitively dependent on the cross-sectional dimensions of the protein in the membrane, and hence on its state of assembly. A variety of new experiments based on the power saturation properties of the spin-labelled components are also used to determine lipid exchange rates, protein translational diffusion rates, and the location and penetration of proteins in membranes.
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