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At least 361 records · Page 20Linked to original sources
PubMed2002

Interactions between aromatase (estrogen synthase) and dopamine in the control of male sexual behavior in quail.

In male quail, like in other vertebrates including rodents, testosterone acting especially through its estrogenic metabolites is necessary for the activation of male sexual behavior. Also, the administration of dopamine agonists and antagonists profoundly influences male sexual behavior. How the steroid-sensitive neural network and dopamine interact physiologically, remains largely unknown. It is often implicitly assumed that testosterone or its metabolite estradiol, stimulates male sexual behavior via the modification of dopaminergic transmission. We have now identified in quail two possible ways in which dopamine could potentially affect sexual behavior by modulating the aromatization of testosterone into an estrogen. One is a long-acting mechanism that presumably involves the modification of dopaminergic transmission followed by the alteration of the genomic expression of aromatase. The other is a more rapid mechanism that does not appear to be dopamine receptor-mediated and may involve a direct interaction of dopamine with aromatase (possibly via substrate competition). We review here the experimental data supporting the existence of these controls of aromatase activity by dopamine and discuss the possible contribution of these controls to the activation of male sexual behavior.

Animals↗
PubMed2004

The mammalian basic helix-loop-helix/PAS family of transcriptional regulators.

Basic helix-loop-helix (bHLH)/PAS proteins are critical regulators of gene expression networks underlying many essential physiological and developmental processes. These include transcriptional responses to environmental pollutants and low oxygen tension, mediated by the aryl hydrocarbon (Dioxin) receptor and hypoxia inducible factors (HIF), respectively, and controlling aspects of neural development, mediated by the single minded (SIM) proteins. bHLH proteins must dimerise to form functional DNA binding complexes and bHLH/PAS proteins are distinguished from other members of the broader bHLH superfamily by the dimerisation specificity conferred by their PAS homology domains. bHLH/PAS proteins tend to be ubiquitous, latent signal-regulated transcription factors that often recognise variant forms of the classic E-box enhancer sequence bound by other bHLH proteins. Two closely related forms of each of the hypoxia inducible factors alpha and single minded proteins and the general partner protein, aryl hydrocarbon receptor nuclear translocator (ARNT), are present in many cell types. Despite high sequence conservation within their DNA binding and dimerisation domains, and having very similar DNA recognition specificities, the homologues are functionally non-redundant and biologically essential. While the mechanisms controlling partner choice and target gene activation that determine this functional specificity are poorly understood, interactions mediated by the PAS domains are essential. Information on structures and protein/protein interactions for members of the steroid hormone/nuclear receptor superfamily has contributed to our understanding of the way these receptors function and assisted the development of highly specific agonists and antagonists. Similarly, it is anticipated that developing a detailed mechanistic and structural understanding of bHLH/PAS proteins will ultimately facilitate drug design.

Animals↗
PubMed2005

The role of sex steroids in the complex physiology of the host-parasite relationship: the case of the larval cestode of Taenia crassiceps.

Sex steroids play a significant role in regulating the parasite load in experimental intraperitoneal Taenia crassiceps cysticercosis of male and female Balbc/anN mice. Briefly, oestrogens increase parasite loads and androgens decrease them (1) by acting directly on the parasite, favouring or hindering its reproduction, respectively, and (2) by biasing the hosts' immune response towards a parasite-permissive Th2 or a parasite-restrictive Th1 response. The infected male host also undergoes drastic endocrinological and behavioural changes that may impinge upon the course of infection, and the host's mating behaviour and its exposure to predators. In addition, at different times of infection, significant changes occur in the expression of c-fos in the host's hyppocampus, hypothalamus and preoptic area. Thus, the host's brain seems to sense and/ or react to intraperitoneal infection. The physiological domains of the network affected by the infection, which classically included the hypothalamus-pituitary-axis and the immune system, must now incorporate the host's sexual hormones and other areas of the brain. The network's complex circuitry and functions may help understand some basic questions of parasitology (i.e. the hosts' sexual dimorphism in parasite infections, host-parasite specificity, heterogeneity in the course and outcome of infections at different stages of parasite and host development). The plurality of elements and the complexity of the network that regulates the host-parasite relationship also point to additional strategies for the treatment and control of infections.

Animals↗
PubMedDate not supplied

Bioinformatical analysis of G-protein-coupled receptors.

G-protein-coupled receptors play a key role in cellular signaling networks that regulate various physiological processes, such as vision, smell, taste, neurotransmission, secretion, inflammatory, immune responses, cellular metabolism, and cellular growth. These proteins are very important for understanding human physiology and disease. Many efforts in pharmaceutical research have been aimed at understanding their structure and function. Unfortunately, because they are difficult to crystallize and most of them will not dissolve in normal solvents, so far very few G-protein-coupled receptor structures have been determined. In contrast, more than 1000 G-protein-coupled receptor sequences are known, and many more are expected to become known soon. In view of the extremely unbalanced state, it would be very useful to develop a fast sequence-based method to identify their different types. This would no doubt have practical value for both basic research and drug discovery because the function or binding specificity of a G-protein coupled receptor is determined by the particular type it belongs to. To realize this, a statistical analysis has been performed for 566 G-protein-coupled receptors classified into seven different types. The results indicate that the types of G-protein-coupled receptors are predictable to a considerable accurate extent if a good training data set can be established for such a goal.

Algorithms↗
PubMed2005

The Cbl interactome and its functions.

Cbl proteins are ubiquitin ligases and multifunctional adaptor proteins that are implicated in the regulation of signal transduction in various cell types and in response to different stimuli. Cbl-associated proteins can assemble together at a given time or space inside the cell, and such an interactome can form signal competent networks that control many physiological processes. Dysregulation of spatial or temporal constraints in the Cbl interactome results in the development of human pathologies such as immune diseases, diabetes and cancer.

Actins↗
PubMed2005

Synergistic control of oscillations in the NF-kappaB signalling pathway.

In previous work, we studied the behaviour of a model of part of the NF-kappaB signalling pathway. The model displayed oscillations that varied both in number, amplitude and frequency when its parameters were varied. Sensitivity analysis showed that just nine of the 64 reaction parameters were mainly responsible for the control of the oscillations when these parameters were varied individually. However, the control of the properties of any complex system is distributed, and, as many of these reactions are highly non-linear, we expect that their interactions will be too. Pairwise modulation of these nine parameters gives a search space some 50 times smaller (81 against 4096) than that required for the pairwise modulation of all 64 reactions, and this permitted their study (which would otherwise have been effectively intractable). Strikingly synergistic effects were observed, in which the effect of one of the parameters was strongly (and even qualitatively) dependent on the values of another parameter. Regions of parameter space could be found in which the amplitude, but not the frequency (timing), of oscillations varied, and vice versa. Such modelling will permit the design and performance of experiments aimed at disentangling the role of the dynamics of oscillations, rather than simply their amplitude, in determining cell fate. Overall, the analyses reveal a level of complexity in these dynamic models that is not apparent from study of their individual parameters alone and point to the value of manipulating multiple elements of complex networks to achieve desired physiological effects.

Animals↗
PubMed1999

Impaired motor coordination and Purkinje cell excitability in mice lacking calretinin.

In the cerebellum, the parallel fiber-Purkinje cell synapse can undergo long-term synaptic plasticity suggested to underlie motor learning and resulting from variations in intracellular calcium concentration ([Ca2+]i). Ca2+ binding proteins are enriched in the cerebellum, but their role in information processing is not clear. Here, we show that mice deficient in calretinin (Cr-/-) are impaired in tests of motor coordination. An impairment in Ca2+ homeostasis in Cr-/- Purkinje cells was supported by the high Ca2+-saturation of calbindin-D28k in these cells. The firing behavior of Purkinje cells is severely affected in Cr-/- alert mice, with alterations of simple spike firing rate, complex spike duration, and simple spike pause. In contrast, in slices, transmission at parallel fiber- or climbing fiber-Purkinje cell synapses is unaltered, indicating that marked modifications of the firing behavior in vivo can be undetectable in slice. Thus, these results show that calretinin plays a major role at the network level in cerebellar physiology.

Aging↗
PubMedDate not supplied

Bovine primary chondrocyte culture in synthetic matrix metalloproteinase-sensitive poly(ethylene glycol)-based hydrogels as a scaffold for cartilage repair.

A poly(ethylene glycol) (PEG)-based hydrogel was used as a scaffold for chondrocyte culture. Branched PEG-vinylsulfone macromers were end-linked with thiol-bearing matrix metalloproteinase (MMP)-sensitive peptides (GCRDGPQGIWGQDRCG) to form a three-dimensional network in situ under physiologic conditions. Both four- and eight-armed PEG macromer building blocks were examined. Increasing the number of PEG arms increased the elastic modulus of the hydrogels from 4.5 to 13.5 kPa. PEG-dithiol was used to prepare hydrogels that were not sensitive to degradation by cell-derived MMPs. Primary bovine calf chondrocytes were cultured in both MMP-sensitive and MMP-insensitive hydrogels, formed from either four- or eight-armed PEG. Most (>90%) of the cells inside the gels were viable after 1 month of culture and formed cell clusters. Gel matrices with lower elastic modulus and sensitivity to MMP-based matrix remodeling demonstrated larger clusters and more diffuse, less cell surface-constrained cell-derived matrix in the chondron, as determined by light and electron microscopy. Gene expression experiments by real-time RT-PCR showed that the expression of type II collagen and aggrecan was increased in the MMP-sensitive hydrogels, whereas the expression level of MMP-13 was increased in the MMP-insensitive hydrogels. These results indicate that cellular activity can be modulated by the composition of the hydrogel. This study represents one of the first examples of chondrocyte culture in a bioactive synthetic material that can be remodeled by cellular protease activity.

Animals↗
PubMed2006

An algorithm for modularity analysis of directed and weighted biological networks based on edge-betweenness centrality.

MOTIVATION: Modularity analysis is a powerful tool for studying the design of biological networks, offering potential clues for relating the biochemical function(s) of a network with the 'wiring' of its components. Relatively little work has been done to examine whether the modularity of a network depends on the physiological perturbations that influence its biochemical state. Here, we present a novel modularity analysis algorithm based on edge-betweenness centrality, which facilitates the use of directional information and measurable biochemical data.

Algorithms↗
PubMed1996

Dialysis fluid cytotoxicity and inhibition of host defence in cultured human mesothelial cells are neutralized rapidly with incubation in the peritoneum.

BACKGROUND: A recent survey puts the global dialysis population at 535100; of those on peritoneal dialysis, 85% are on continuous ambulatory peritoneal dialysis. Current hyperosmolar dialysis fluids are toxic to peritoneal cells and inhibit certain host-defence functions. An alternative preparation, glucose polymer, has recently been developed. METHODS: Mesothelial cell viability, interleukin-6 and prostacyclin synthesis, after exposure to 7.5% glucose polymer, 1.36% glucose or 3.86% glucose peritoneal dialysis effluent solution was assessed. RESULTS: In its neat form, at an original pH of 5.4, glucose polymer was as toxic as hyperosmolar solutions (P < 0.01). Synthesis of interleukin-6 and prostacyclin were significantly inhibited by neat dialysis fluid, (P < 0.01). However, after an in vivo intraperitoneal incubation of only 15 min the toxicity of all solutions tested in vitro was lost. CONCLUSIONS: Despite rapid in situ neutralization of dialysis fluid toxicity, mesothelial injury and inhibition of host-defence function, early in the dialysis cycle, may affect peritoneal physiology given the complex network of pathways to which these cells contribute. Although recent trials indicate improved ultrafiltration is achievable with glucose polymer, it is not a biocompatible dialysis fluid in its current manufactured form.

6-Ketoprostaglandin F1 alpha↗
PubMed2006

Multiple feedback loop design in the tryptophan regulatory network of Escherichia coli suggests a paradigm for robust regulation of processes in series.

Biological networks have evolved through adaptation in uncertain environments. Of the different possible design paradigms, some may offer functional advantages over others. These designs can be quantified by the structure of the network resulting from molecular interactions and the parameter values. One may, therefore, like to identify the design motif present in the evolved network that makes it preferable over other alternatives. In this work, we focus on the regulatory networks characterized by serially arranged processes, which are regulated by multiple feedback loops. Specifically, we consider the tryptophan system present in Escherichia coli, which may be conceptualized as three processes in series, namely transcription, translation and tryptophan synthesis. The multiple feedback loop motif results from three distinct negative feedback loops, namely genetic repression, mRNA attenuation and enzyme inhibition. A framework is introduced to identify the key design components of this network responsible for its physiological performance. We demonstrate that the multiple feedback loop motif, as seen in the tryptophan system, enables robust performance to variations in system parameters while maintaining a rapid response to achieve homeostasis. Superior performance, if arising from a design principle, is intrinsic and, therefore, inherent to any similarly designed system, either natural or engineered. An experimental engineering implementation of the multiple feedback loop design on a two-tank system supports the generality of the robust attributes offered by the design.

Escherichia coli↗
PubMed2002

Modulation of network behaviour by changes in variance in interneuronal properties.

Interneurones are important regulators of neuronal networks. The conventional approach to interneurones is to focus on the mean values of various parameters. Here we tested the hypothesis that changes in the variance of interneuronal properties (e.g. in the degree of scattering of parameter values of individual cells around the population mean) may modify the behaviour of networks. Biophysically based multicompartmental models of principal cells and interneurones showed that changes in the variance in the electrophysiological and anatomical properties of interneurones significantly alter the input-output functions, rhythmicity and synchrony of principal cells, even if the mean values were unchanged. In most cases, increased heterogeneity in interneurones resulted in stronger inhibition of principal cell firing; however, there were parameter ranges where increased interneuronal variance decreased the inhibition of principal cells. Electrophysiological recordings showed that the variance in the resting membrane potential of CA1 stratum oriens interneurones persistently increased following experimental complex febrile seizures in developing rats, without a change in the mean resting membrane potential, indicating that lasting alterations in interneuronal heterogeneity can take place in real neuronal systems. These computational and experimental data demonstrate that modifications in interneuronal population variance influence the behaviour of neuronal networks, and suggest a physiological role for interneuronal diversity. Furthermore, the results indicate that interneuronal heterogeneity can change in neurological diseases, and raise the possibility that neuromodulators may act by regulating the variance of key parameters in interneuronal populations.

Animals↗
PubMed2001

Fear as the main feature of epileptic seizures.

OBJECTIVES: There are circumstances in which partial seizures may be misdiagnosed as acute psychiatric disturbances. In particular, when fear is the prominent feature the patient may be considered for years as having panic attacks. Eight patients in whom fear was the main symptom of the seizures are reported on. Patients who had a proved lack of consciousness during the fits and patients in whom fear was just fear of having a seizure were excluded. The ictal involvement of temporal limbic and frontal structures in those patients with fear of particular intensity was studied. METHODS: The localisation of the epileptogenic zone was assessed by prolonged interictal EEG recordings as well as ictal video-EEG recording of at least one seizure in every patient; five had ictal SPECT and four had chronic stereotactic implantation of depth electrodes (SEEG). In six patients, a cortical resection was performed with an Engel's class 1 outcome (minimum 28 months follow up, except for two patients). RESULTS: Localisations of primary epileptogenic zones were right temporal in three patients, left temporal in three, bitemporal in one, and frontal in one. In all cases, diagnosis of epileptic seizures could be clinically evoked because of the stereotypy of fits and of associated symptoms. The association of a fear sensation, autonomic symptoms, and coordinated behaviour suggests disturbance of a particular system. The SEEG data argue for temporolimbic and prefrontal lobe involvement in the expression of ictal fear. CONCLUSIONS: In intense ictal fear, with coordinated behaviour and autonomic features, the discharge may involve or interfere with a physiological complex information processing network. This network involves orbitoprefrontal, anterior cingulate, and temporal limbic cortices.

Adolescent↗
PubMed2002

Gene expression studies using microarrays: principles, problems, and prospects.

A number of mammalian genomes having been sequenced, an important next step is to catalog the expression patterns of all transcription units in health and disease by use of microarrays. Such discovery programs are crucial to our understanding of the gene networks that control developmental, physiological, and pathological processes. However, despite the excitement, the full promise of microarray technology has yet to be realized, as the superficial simplicity of the concept belies considerable problems. Microarray technology is very new; methodologies are still evolving, common standards have yet to be established, and many problems with experimental design and variability have still to be fully understood and overcome. This review will describe the time course of a microarray experiment-RNA isolation from sample, target preparation, hybridization to the microarray probe, data capture, and bioinformatic analysis. For each stage, the advantages and disadvantages of competing techniques are compared, and inherent sources of error are identified and discussed.

Animals↗
PubMed2000

Segregation of nociceptive and non-nociceptive networks in the squirrel monkey somatosensory thalamus.

The somatosensory thalamus (here we examine neurons in the caudal cutaneous portion of ventral posterior lateral nucleus, VPL) is composed of a somatotopic arrangement of anteroposteriorly oriented rods. Each rod is a collection of neurons with homogeneous properties that relay sensory information to specific cortical columns. We developed a multi-electrode recording technique, using fixed-geometry four-tip electrodes that allow simultaneous recordings from small populations of neurons (4-11), in a approximately 150 x 150 x 150 micrometer(3) volume of brain tissue (i.e., the approximate diameter of rods) and study of their spatiotemporal interactions. Due to the fixed geometry of the four-tip electrodes, the relative locations of these neurons can be determined, and due to the simultaneity of the recordings, their spike-timing coordination can be calculated. With this method, we demonstrate the existence of two distinct functional networks: nociceptive and non-nociceptive networks. The population dynamics of these two types of networks are different: cross-correlations in each type of network were different in direction and strength, were a function of the distance between neurons, had an opponent organization for nociceptive networks and a non-opponent organization for non-nociceptive networks, and rapidly changed under different stimulus conditions independent of changes in firing rates. A simple neural network model mimicked these physiological findings, demonstrating the necessity of inhibitory interneurons and different amounts of afferent input synchronization. Based on these results, we conclude that the somatosensory thalamus is composed of two modules, nociceptive and non-nociceptive rods, and that the response dynamics differences between these modules are due to spatiotemporal differences of their afferent inputs.

Action Potentials↗