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PubMed1977

Cutaneous cross-modal interactions: variations in punctate pressure sensitivity with skin surface temperature.

We determined the effects of adapting the skin surface to temperatures 3 degreees C, 8 degrees C, or 12 degrees C above and below physiological zero for 0, 2, 5, 10, 15, or 30 min on punctate pressure sensitivity. Temperatures above physiological zero reduced punctate pressure sensitivity and temperatures below physiological zero enhanced punctate pressure sensitivity. As the skin adapted to warmth, punctate pressure sensitivity increased suggesting a cross modal adaptation effect, however there was no indication of a decrease in punctate pressure sensitivity as the skin adapted to cooling. The results are considered to be consonant with a system of mechanoreceptors which also respond to temperature changes and a system in which there are points of convergence in the somesthetic pathways at which pressure and temperature information interact and are integrated.

Adaptation, Physiological↗

PubMed2003

A synthetic analysis of the Saccharomyces cerevisiae stress sensor Mid2p, and identification of a Mid2p-interacting protein, Zeo1p, that modulates the PKC1-MPK1 cell integrity pathway.

Mid2p is a plasma membrane protein that functions in Saccharomyces cerevisiae as a sensor of cell wall stress, activating the PKC1-MPK1 cell integrity pathway via the small GTPase Rho1p during exposure to mating pheromone, calcofluor white, and heat. To examine Mid2p signalling, a global synthetic interaction analysis of a mid2 mutant was performed; this identified 11 interacting genes. These include WSC1 and ROM2, upstream elements in cell integrity pathway signalling, and FKS1 and SMI1, required for 1,3-beta-glucan synthesis. These synthetic interactions indicate that the Wsc1p sensor acts through Rom2p to activate the Fks1p glucan synthase in a Mid2p-independent way. To further explore Mid2p signalling a two-hybrid screen was done using the cytoplasmic tail of Mid2p; this identified ZEO1 (YOL109w), encoding a 12 kDa peripheral membrane protein that localizes to the plasma membrane. Disruption of ZEO1 leads to resistance to calcofluor white and to a Mid2p-dependent constitutive phosphorylation of Mpk1p, supporting a role for Zeo1p in the cell integrity pathway. Consistent with this, zeo1-deficient cells suppress the growth defect of mutants in the Rho1p GDP-GTP exchange factor Rom2p, while exacerbating the growth defect of sac7delta mutants at 37 degrees C. In contrast, mid2delta mutants have opposing effects to zeo1delta mutants, being synthetically lethal with rom2delta, and suppressing an 18 degrees C growth defect of sac7delta, while overexpression of MID2 rescues a rom2delta 37 degrees C growth defect. Thus, MID2 and ZEO1 appear to play reciprocal roles in the modulation of the yeast PKC1-MPK1 cell integrity pathway.

Adaptor Proteins, Signal Transducing↗

PubMed1999

Evolutionary feedback: a new mechanism for stasis and punctuated evolutionary change based on integration of the organism.

This paper argues that organisms are integrated, holistic systems whose phenotypic traits and genes interact with each other and natural selection. More than this, organisms are feedback systems. I introduce the term integration of the organism to refer to this idea that organisms are such interacting systems. Integration of the organisms is a major reason why most mutations are deleterious, and why the larger a mutation's effect, the greater the probability that a mutation will be deleterious. Yet, it is also why macromutations can occasionally be adaptive. Such adaptive mutations of large effect, an example of which is neoteny, must be coordinated with the generic system and ontogeny of the organism. Integration of the organism and the ability of both the phenotype and genotype to influence and interact with natural selection means a species can undergo sequential evolution, a term I coin in this paper to refer to a change in a trait causing a change in selection on a second trait, which leads to a change in the second trait, which in turn causes a change in selection on a third trait, changing it, and so on. Sequential evolution can sometimes result in closed feedback loops, in which a trait farther down the sequence affects a trait earlier in the sequence of traits. I call this process evolutionary feedback. Both sequential evolution and evolutionary feedback can sometimes cause punctuated evolutionary change. Evolutionary feedback can also act as a mechanism for stasis. Hence, evolutionary feedback is a mechanism for punctuated equilibrium. I propose that species to a large extent influence, even drive, their own evolution. This, of course, is not to suggest they do so willfully or consciously. It is proposed that there are three mechanisms for punctuated evolutionary change; these are described. Examples of and evidence for sequential evolution and punctuated evolution by evolutionary feedback are presented.

Adaptation, Physiological↗

PubMed2001

Immune-endocrine interactions of the hypothalamus-pituitary-thyroid axis: integration, communication and homeostasis.

The immune and neuroendocrine systems are two essential physiological components of mammalian organisms. Although each is primarily committed to a set of tasks involved, on the one hand, in the protection from infection and disease, and on the other hand, in the regulation of metabolism and other physiological activities, there is also evidence indicating that active and dynamic collaborations exist between those systems in the execution of their designated functions. These interactions occur at many stages of embryonic and neonatal development, and they are a continual part of the normal homeostatic balance needed to maintain health. The present review discusses various historical and contemporary perspectives of immune-endocrine interactions involving the hypothalamus-pituitary-thyroid axis, and offers a hypothesis of how this aspect of the neuroendocrine system participates directly in the immune response to antigenic challenge, infection and disease.

Animals↗

PubMedDate not supplied

GA-binding protein transcription factor: a review of GABP as an integrator of intracellular signaling and protein-protein interactions.

GA-binding protein (GABP) is an ets transcription factor that controls gene expression in several important biological settings. It is unique among ets factors, since the transcriptionally active complex is an obligate heterotetramer that is composed of two distinct proteins. GABPalpha includes an ets DNA binding domain (DBD), while a distinct protein, GABPbeta, contains ankyrin repeats and the transcriptional activation domain (TAD). GABP was first identified as a regulator of viral genes and nuclear respiratory factors. However, GABP is now recognized to be a key transcriptional regulator of dynamically regulated, lineage-restricted genes, especially in myeloid cells and at the neuromuscular junction. Furthermore, it regulates genes that are intimately involved in cell cycle control, protein synthesis, and cellular metabolism. GABP acts as an integrator of cellular signaling pathways by regulating key hormones and transmembrane receptors. In addition, GABP itself, is a target of phosphorylation events that lie downstream of signal transduction pathways. The physical and functional interactions of GABPalpha and GABPbeta with each other and with other transcription factors and co-activators are key to its ability to regulate gene expression. Its role in regulating genes involved in fundamental cellular processes places GABP at the nexus of key cellular pathways and functions.

DNA-Binding Proteins↗

PubMed2005

Enamel matrix protein interactions.

UNLABELLED: The recognized structural proteins of the enamel matrix are amelogenin, ameloblastin, and enamelin. While a large volume of data exists showing that amelogenin self-assembles into multimeric units referred to as nanospheres, other reports of enamel matrix protein-protein interactions are scant. We believe that each of these enamel matrix proteins must interact with other organic components of ameloblasts and the enamel matrix. Likely protein partners would include integral membrane proteins and additional secreted proteins. INTRODUCTION: The purpose of this study was to identify and catalog additional proteins that play a significant role in enamel formation. MATERIALS AND METHODS: We used the yeast two-hybrid assay to identify protein partners for amelogenin, ameloblastin, and enamelin. Once identified, RT-PCR was used to assess gene transcription of these newly identified and potential "enamel" proteins in ameloblast-like LS8 cells. RESULTS: In the context of this yeast assay, we identified a number of secreted proteins and integral membrane proteins that interact with amelogenin, ameloblastin, and enamelin. Additionally, proteins whose functions range from the inhibition of soft tissue mineralization, calcium ion transport, and phosphorylation events have been identified as protein partners to these enamel matrix proteins. For each protein identified using this screening strategy, future studies are planned to confirm this physiological relationship to biomineralization in vivo. CONCLUSION: Identifying integral membrane proteins of the secretory surface of ameloblast cells (Tomes' processes) and additional enamel matrix proteins, based on their abilities to interact with the most abundant enamel matrix proteins, will better define the molecular mechanisms of enamel formation at its most rudimentary level.

Ameloblasts↗

PubMed2002

Calcium homeostasis and parturient hypocalcemia: an integral feedback perspective.

Calcium is tightly regulated in mammals because of the critical role of calcium ion concentrations in many physiological functions. In this work, we develop a model for calcium homeostasis and identify integral feedback control as a functional module that maintains this homeostasis. We argue that maintaining calcium concentrations in a narrow range and perfect adaptation seen when the calcium homeostatic mechanism is subjected to extreme disturbances are the result of a feedback control system implementing integral control through specific interactions of the regulating hormones. Based on the constraints imposed by the suggested integral control, we arrive at a simple dynamical model for calcium homeostasis. We show that the model is biologically plausible and is consistent with known physiology. Furthermore, the utility of the integral-feedback model is revealed by examining an extreme calcium perturbation, parturient paresis in dairy cows.

Animals↗

PubMed2005

Processing of viral DNA ends channels the HIV-1 integration reaction to concerted integration.

Retroviral DNA made by reverse transcription is blunt-ended, and the viral integrase protein must remove two nucleotides from each 3' end prior to integration into chromosomal DNA. Under most reaction conditions for integration in vitro, the majority of the reaction products are "half-site" products that result from integration of only one viral DNA end into one strand of the target DNA. Preprocessed DNA substrates are more efficient substrates for half-site reactions than are blunt-ended substrates, which require the removal of two nucleotides prior to integration. In contrast, we find that blunt-ended DNA is a better substrate for the biologically relevant reaction of concerted integration of pairs of viral DNA ends. The reaction pathway is channeled to concerted integration, and half-site integration products are reduced with blunt-ended DNA substrate that must first be processed by integrase. In addition, the terminal nucleotide requirements for concerted integration are more stringent than for the half-site reaction. Longer DNA is more efficient for the concerted reaction than is shorter DNA that is capable of efficient half-site integration. This suggests that nonspecific interactions of integrase with viral DNA distant from the termini contribute to the assembly of a complex that is competent for concerted integration. Finally, differential effects of mutation of a residue in the C-terminal domain of integrase on concerted versus half-site integration implicate protein-protein interactions involving this domain as important for concerted integration.

DNA↗

PubMed2006

Modulating target site selection during human immunodeficiency virus DNA integration in vitro with an engineered tethering factor.

The mechanisms controlling retroviral integration have been the topic of intense interest, in part because of adverse clinical events that occurred during retrovirus-mediated human gene therapy. Here we investigate the use of artificial tethering interactions to constrain retroviral integration site selection in an in vitro model. During normal infection, HIV DNA integration is favored in active cellular transcription units. One component of the targeting mechanism is the cellular LEDGF/p75 protein. LEDGF/p75 binds tightly to HIV integrase (IN) protein, and depletion of LEDGF/p75 from target cells results in reduced integration in transcription units, suggesting integration targeting by a tethering mechanism. We constructed and analyzed fusions of LEDGF/p75 or its IN-binding domain (IBD) to the DNA-binding domain of phage lambda repressor protein (lambdaR). In the presence of the lambdaR-LEDGF/p75 fusions, increased strand transfer by IN was seen in target DNA near lambdaR-binding sites in vitro . These data support the idea that a direct interaction between LEDGF/p75 and IN can mediate targeting via a tethering mechanism, and provide proof of concept for the idea that protein-protein interactions might be engineered to constrain integration site selection during human gene therapy.

Base Sequence↗

PubMed1995

Characterization of the interaction between the lambda intasome and attB.

Bacteriophage lambda DNA integrates into the chromosome of Escherichia coli by first forming an intasome at the phage attachment site on the phage DNA with the integrase Int and integration host factor. This intasome searches the host chromosome for the bacterial attachment site (attB) and then orchestrates two sequential strand exchange reactions to achieve integration. This study characterizes the weak interaction of the intasome and attB. The hypothesis that all of the proteins necessary for integration are brought to the reaction site by the intasome is given additional support by showing that the concentration of phage attachment site and not attB determines the optimal concentration of proteins for integration. The value of the dissociation constant of the complex formed between the intasome and attB is determined in two different ways. First, the rate of the integration reaction is measured as a function of the attB DNA concentration. The saturation constant reflects the dissociation constant of the complex. Second, a recombination reaction is inhibited by the introduction of varying amounts of a second attB with a sequence change that blocks recombination with this site. The inhibition constant reflects the dissociation constant of the intasome and altered attB in this experiment. The two methods agree and give a dissociation constant of approximately 300 nM. attB contains two core binding sites for the intasome; it is shown that both are necessary for efficient capture. The value of the dissociation constants are considerably lower when a mutant integrase, IntE174K, is used. This increased affinity for core sites can explain how IntE174K can function in the absence of integration host factor. The inhibition constants also show dependence on the exact sequence of the inhibiting attB. Possible implications of this dependence are discussed.

Bacterial Proteins↗

PubMed2001

Proteins interacting with the mammalian estrogen receptor: proposal for an integrated model for estrogen receptor mediated regulation of transcription.

Two forms of estrogen receptor (ER) that exist in the mammalian uterus have been examined in this review. (1) ERalpha, or the classical estrogen receptor that is considered to influence the transcriptional process; (2) the non-activated estrogen receptor (naER), an alternative form of ER with no DNA binding function, localized in the plasma membrane. An integrated model is being proposed to highlight the functional roles of both receptors in transcriptional regulation. The proteins with which ER interacts during various stages of its existence are being examined. These stages include: (1) transport from the cytoplasm to the nucleus; (2) interaction with the nuclear transcription machinery; (3) involvement in post-transcriptional control mechanisms; and (4) degradation through ubiquitination. The proteins with which naER interacts during its plasma membrane-to-nucleus movement have also been identified; the results have not yet been published. Within the nucleus it dimerizes with a DNA-binding protein, the estrogen receptor activation factor (E-RAF). It is being proposed that the purpose behind the dimerization between naER and E-RAF is to transport E-RAF to the transcription initiation site as the naER in the heterodimer is a RNA-polymerase binding protein. Deglycosylated naER fails to dimerize with the E-RAF. Deglycosylation of the naER therefore dissociates the heterodimer and this transformed naER is now identified as nuclear estrogen receptor II (nER II). The dissociated E-RAF is free either to destabilize (E-RAF II) or stabilize (E-RAF I) the DNA while the naER remains bound to the RNA polymerase II. nER II phosphorylates certain subunits in RNA polymerase; the functional significance of this phosphorylation remains to be known.

Animals↗

PubMed2000

Narrative and interactional process for preventing harmful struggle in therapy: an integrative empirical model.

Resistance or struggle in therapy looms large as a predictor of treatment outcomes. This study organizes the significant empirical data on struggle into a coherent, operational framework for use by therapists in preventing and/or ameliorating harmful struggle in therapy. First, we review the prevalence and significance of struggle. Second, we offer a historical and conceptual overview, with emphasis on a contemporary interactional/systemic perspective on struggle. Third, we provide a synthesis of peer-reviewed research, profiling struggle at speech-act and episode levels of interaction process and across assessment/joining, intervention, and integration-consolidation phases of therapy. Fourth, based upon this review, we propose a three-factor model--consisting of eliciting dialogue, enactments, and accommodation--for successful therapy process relative to the occurrence of struggle.

Behavior Therapy↗

PubMed2005

Untangling the web of functional and physical interactions in yeast.

An analysis of an integrated network of over 150,000 functional and physical interactions in yeast suggests that the network can be hierarchically decomposed into themes and thematic maps. This decomposition can be used to explore the organizational principles of integrated biological networks within cells.

Gene Expression Regulation, Fungal↗

PubMed2005

Cingulate control of fronto-temporal integration reflects linguistic demands: a three-way interaction in functional connectivity.

In a recent fMRI language comprehension study, we asked participants to listen to word-pairs and to make same/different judgments for regularly and irregularly inflected word forms [Tyler, L.K., Stamatakis, E.A., Post, B., Randall, B., Marslen-Wilson, W.D., in press. Temporal and frontal systems in speech comprehension: an fMRI study of past tense processing. Neuropsychologia, available online.]. We found that a fronto-temporal network, including the anterior cingulate cortex (ACC), left inferior frontal gyrus (LIFG), bilateral superior temporal gyrus (STG) and middle temporal gyrus (MTG), is preferentially activated for regularly inflected words. We report a complementary re-analysis of the data seeking to understand the behavior of this network in terms of inter-regional covariances, which are taken as an index of functional connectivity. We identified regions in which activity was predicted by ACC and LIFG activity, and critically, by the interaction between these two regions. Furthermore, we determined the extent to which these inter-regional correlations were influenced differentially by the experimental context (i.e. regularly or irregularly inflected words). We found that functional connectivity between LIFG and left MTG is positively modulated by activity in the ACC and that this effect is significantly greater for regulars than irregulars. These findings suggest a monitoring role for the ACC which, in the context of processing regular inflected words, is associated with greater engagement of an integrated fronto-temporal language system.

Acoustic Stimulation↗

PubMed2026

Integrative multi-omics analysis of metabolite-protein interaction networks across different stages of coronary heart disease.

To elucidate the molecular characteristics of synergistic interactions across the clinical stages of coronary heart disease (CHD)-specifically stable angina pectoris (SAP), unstable angina pectoris (UAP), and acute myocardial infarction (AMI)-through integrated metabolomic and proteomic analyses. Based on a cohort including SAP, UAP, AMI, and healthy controls, metabolomic and proteomic analyses were performed to identify differentially expressed molecules, followed by KEGG pathway enrichment analysis. Pathways co-enriched across both omics platforms were selected to construct metabolite-protein interaction networks. The number of pathways co-enriched in both metabolomic and proteomic analyses increased markedly with disease stage. Only two pathways (histidine metabolism and arginine and proline metabolism) were identified in the SAP stage; this number increased to five in the UAP stage (including ferroptosis and efferocytosis) and expanded to 25 in the AMI stage, encompassing three major functional modules: immune inflammation, metabolic reprogramming, and cell signaling. The core network exhibited a stepwise increase in connectivity, shifting from a sparse structure in the SAP stage to a highly interconnected architecture in the AMI stage, with L-glutamate and KNG1 identified as the central hubs in this cross-sectional network. In addition, CNDP1 exhibited a stage-dependent functional transition, shifting from downregulation in SAP to upregulation in AMI. In this cross-sectional analysis, metabolic dysregulation and immune activation exhibited stepwise increases in interconnectivity across the SAP, UAP, and AMI groups, with the most extensive crosstalk observed in the AMI stage-a network configuration consistent with a tightly coupled "molecular storm". These findings provide novel insights into stage-associated molecular signatures of CHD and identify candidate hub molecules for stage-oriented therapeutic investigation.

Humans↗

PubMed2004

Synaptic integration in electrically coupled neurons.

Interactions among chemical and electrical synapses regulate the patterns of electrical activity of vertebrate and invertebrate neurons. In this investigation we studied how electrical coupling influences the integration of excitatory postsynaptic potentials (EPSPs). Pairs of Retzius neurons of the leech are coupled by a nonrectifying electrical synapse by which chemically induced synaptic currents flow from one neuron to the other. Results from electrophysiology and modeling suggest that chemical synaptic inputs are located on the coupled neurites, at 7.5 microm from the electrical synapses. We also showed that the space constant of the coupled neurites was 100 microm, approximately twice their length, allowing the efficient spread of synaptic currents all along both coupled neurites. Based on this cytoarchitecture, our main finding was that the degree of electrical coupling modulates the amplitude of EPSPs in the driving neurite by regulating the leak of synaptic current to the coupled neurite, so that the amplitude of EPSPs in the driving neurite was proportional to the value of the coupling resistance. In contrast, synaptic currents arriving at the coupled neurite through the electrical synapse produced EPSPs of constant amplitude. This was because the coupling resistance value had inverse effects on the amount of current arriving and on the impedance of the neurite. We propose that by modulating the amplitude of EPSPs, electrical synapses could regulate the firing frequency of neurons.

Action Potentials↗

PubMed2004

Application of the split-ubiquitin membrane yeast two-hybrid system to investigate membrane protein interactions.

The characterization of protein-protein interactions provides the foundation for further studies concerning protein complex function and regulation. Since the advent of the yeast two-hybrid assay, many additional genetic systems based upon the principle of protein fragment complementation have been designed. One such system, the split-ubiquitin membrane yeast two-hybrid system (MbYTH), is able to analyze the interaction status between two integral membrane proteins. This ability of the MbYTH system augments genetic analysis of protein interactions by covering for the inherent limitation of the yeast two-hybrid system when studying membrane protein interactions. Herein, we provide a description of the MbYTH method and detailed protocols in order to monitor protein interactions and discover novel interacting partners using the MbYTH system.

DNA, Complementary↗

PubMed2005

Beta1 integrins regulate mammary gland proliferation and maintain the integrity of mammary alveoli.

Integrin-extracellular matrix interactions play important roles in the coordinated integration of external and internal cues that are essential for proper development. To study the role of beta1 integrin in the mammary gland, Itgbeta1(flox/flox) mice were crossed with WAPiCre transgenic mice, which led to specific ablation of beta1 integrin in luminal alveolar epithelial cells. In the beta1 integrin mutant mammary gland, individual alveoli were disorganized resulting from alterations in cell-basement membrane associations. Activity of focal adhesion kinase (FAK) was also decreased in mutant mammary glands. Luminal cell proliferation was strongly inhibited in beta1 integrin mutant glands, which correlated with a specific increase of p21 Cip1 expression. In a p21 Cip1 null background, there was a partial rescue of BrdU incorporation, providing in vivo evidence linking p21 Cip1 to the proliferative defect observed in beta1 integrin mutant glands. A connection between p21 Cip1 and beta1 integrin as well as FAK was also established in primary mammary cells. These results point to the essential role of beta1 integrin signaling in mammary epithelial cell proliferation.

Animals↗