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PubMed1976

Simulation of network activity in stomatogastric ganglion of the spiny lobster, Panulirus.

We have compared experimental and model studies on the rhythmic activity of the lobster stomatogastric ganglion. Both the pyloric and gastric mill systems were simulated using a physiologically based network model. In the pyloric simulation the known synaptic connectivity of the 3 principal cell types in the pyloric rhythm was found to be sufficient to produce the correct sequence of cyclic bursting activity over a substantial range of parameter values, even though we did not simulate the known endogenous oscillatory driver potential of one of the cell types. It is not yet known whether the synaptic inhibition in the real system is in the right range to cause cyclic bursting in the absence of the driver potential, but the synaptic connectivity does appear to reinforce the cyclic pattern. Simulations were also done with alternative connectivity schemes to determine which synapses appear essential to generate the correct bursting sequence (in the absence of endogenous bursting activity). Other, more complex, systems simulated were: (1) all 5 cell groups of the pyloric system, and (2) the cells responsible for movement of the lateral teeth in the gastric mill. In both cases good qualitative agreement was achieved between model and real systems.

Action Potentials↗
PubMed1995

Prolactin receptors and the immune system.

The existence of a physiological immunoneuroendocrine network clearly contributing to homeostasis has now been demonstrated. In this context, nervous, endocrine, and immune systems communicate with each other, using common mediators and respective receptors. An interesting aspect of this network involves the interactions between prolactin (PRL) and the immune system. Prolactin plays a significant role in regulation of the humoral and cellular immune responses in physiological as well as pathological situations, such as autoimmune diseases. This role is exerted via the existence of specific receptors on cells on the immune system. Recently, using monoclonal antibodies (mAbs) raised against the extracellular domain of the rat liver PRL-receptor (PRL-R), we demonstrated by immunochemistry and molecular biology the presence of functional PRL receptors on thymic epithelial cells, one of the major components of the thymic microenvironment, which significantly influences early events in T-cell differentiation. Furthermore, using analytical fluocytometry, we showed that human and murine lymphoid cells also expressed PRL receptors. In both of the primary lymphoid organs, namely the thymus and bone marrow, more than 80% of cells expressed this receptor. In the periphery, all B cells and macrophages and 70% of T cells, with similar percentages of CD4+ and CD8+ cells, were PRL-R+. The density of receptors was lower on T cells than on B cells and macrophages, but this density was significantly enhanced following stimulation by T cell mitogens. These data, together with the demonstration of PRL production by thymocytes led to the hypothesis that, in addition to the classical endocrine pathway, autocrine and paracrine PRL/PRL-R interactions may exist in both central and peripheral lymphoid organs, and involve lymphocytes and microenvironmental cells.

Animals↗
PubMed2002

Thirteenth annual pezcoller symposium: focusing analytical tools on complexity in cancer.

The physiopathology of cancer cells is the result of very complex signaling networks that represent in many cases distortions of the orderly networks regulating the physiology of normal cells. These networks are the consequence of the expression of, or the lack of expression of, genes, mutated or not, which represent the genomic profile of different types of or of individual cancers. The complex signaling pathways, the cross-talks among them, and the redundancies existing for several of them mediate not only the transmission of signals from the cell environment to the nucleus but also that from the nucleus to the other cellular components whose function is involved in cell proliferation, apoptosis, or differentiation. Modern approaches to cancer therapy and also prevention are aimed at identifying new molecular targets, pivotal to the life of the cancer cell, which would provide for specific sites of intervention. In the face of the enormous complexity of the phenomena on which the life of cancer cells is based, it is both difficult to identify unique specific target for intervention and important to develop analytical tools and approaches capable to identify them for further exploitation. This was the main subject of the Symposium. Consideration was given to: (a) tumor genotypic analysis through expression array evaluation and definition of cancer transcriptomes in studies aimed at identifying determinants of specific characteristics of cancer cells; (b) approaches based on the knowledge gained in this analysis that would lead to the visualization of new targets exploitable for antitumor action; and (c) multifactorial analysis of the complex interactions regulating cancer cells and methods to comprehend the complexity of molecular models and validate their functional relevance.

Animals↗
PubMed1996

Ultrastructural and immunohistochemical studies of intralobular fibroblasts in human submandibular gland: the recognition of a 'CD34 positive reticular network' connected by gap junctions.

In order to clarify the ultrastructural and immunophenotypic characteristics of intralobular stromal cells in the human submandibular gland, normal tissues were examined from 25 patients by conventional histology of wax sections, light microscope immunohistochemistry, conventional thin-sectioning transmission electron microscopy, immuno-electronmicroscopy (for the CD34 antigen) and scanning electron microscopy. Spindled stromal cells had abundant rough endoplasmic reticulum cisternae typical of fibroblasts. Some actin filaments and microtubules were seen, but the filaments lacked the focal densities of smooth-muscle, nor was a lamina present. Fibroblasts exhibited long slender processes which associated with other fibroblasts by means of gap junctions and with mononuclear cells (lymphocytes, plasma cells, macrophages) by means of close appositions of membrane. Immunoelectron microscopy for CD34 revealed positive staining over the fibroblast surfaces but not over the mononuclear cells. The novel observation of gap junctions suggests a tissue closely organized as a network in physical and perhaps physiological terms. This network also incorporates mononuclear cells. The possible role in immunosurveillance of this CD34-positive reticular network is discussed.

Adult↗
PubMed2002

Move to the rhythm: oscillations in the subthalamic nucleus-external globus pallidus network.

Recent anatomical, physiological and computer modeling studies have revealed that oscillatory processes at the levels of single neurons and neuronal networks in the subthalamic nucleus (STN) and external globus pallidus (GPe) are associated with the operation of the basal ganglia in health and in Parkinson's disease (PD). Autonomous oscillation of STN and GPe neurons underlies tonic activity and is important for synaptic integration, whereas abnormal low-frequency rhythmic bursting in the STN and GPe is characteristic of PD. These recent findings provide further support for the view that the basal ganglia use both the pattern and the rate of neuronal activity to encode information.

Animals↗
PubMed2006

Systems analysis of circadian time-dependent neuronal epidermal growth factor receptor signaling.

BACKGROUND: Identifying the gene regulatory networks governing physiological signal integration remains an important challenge in circadian biology. Epidermal growth factor receptor (EGFR) has been implicated in circadian function and is expressed in the suprachiasmatic nuclei (SCN), the core circadian pacemaker. The transcription networks downstream of EGFR in the SCN are unknown but, by analogy to other SCN inputs, we expect the response to EGFR activation to depend on circadian timing. RESULTS: We have undertaken a systems-level analysis of EGFR circadian time-dependent signaling in the SCN. We collected gene-expression profiles to study how the SCN response to EGFR activation depends on circadian timing. Mixed-model analysis of variance (ANOVA) was employed to identify genes with circadian time-dependent EGFR regulation. The expression data were integrated with transcription-factor binding predictions through gene group enrichment analyses to generate robust hypotheses about transcription-factors responsible for the circadian phase-dependent EGFR responses. CONCLUSION: The analysis results suggest that the transcriptional response to EGFR signaling in the SCN may be partly mediated by established transcription-factors regulated via EGFR transcription-factors (AP1, Ets1, C/EBP), transcription-factors involved in circadian clock entrainment (CREB), and by core clock transcription-factors (Ror alpha). Quantitative real-time PCR measurements of several transcription-factor expression levels support a model in which circadian time-dependent EGFR responses are partly achieved by circadian regulation of upstream signaling components. Our study suggests an important role for EGFR signaling in SCN function and provides an example for gaining physiological insights through systems-level analysis.

Animals↗
PubMed1995

Physiological activation of a cortical network during performance of the Wisconsin Card Sorting Test: a positron emission tomography study.

To determine the neural circuitry engaged by performance of the Wisconsin Card Sorting Test (WCST), a neuropsychological test traditionally considered to be sensitive to prefrontal lesions, regional cerebral blood flow was measured with oxygen-15 water and positron emission tomography (PET) while young normal subjects performed the test as well as while they performed a specially designed sensorimotor control task. To consider which of the various cognitive operations and other experiential phenomena involved in the WCST PET scan are critical for the pattern of physiological activation and to focus on the working memory component of the test, repeat WCST scans were also performed on nine of the subjects after instruction on the test and practice to criteria. We confirmed that performance of the WCST engages the frontal cortex and also produces activation of a complex network of regions consistently including the inferior parietal lobule but also involving the visual association and inferior temporal cortices as well as portions of the cerebellum. The WCST activation in the dorsolateral prefrontal cortex (DLPFC) remained significant even after training and practice on the test, suggesting that working memory may be largely responsible for the physiological response in DLPFC during the WCST and, conversely, that the DLPFC plays a major role in modulating working memory.

Adolescent↗
PubMed2006

Utilizing RNA aptamers to probe a physiologically important heme-regulated cellular network.

Broadly applicable strategies facilitating direct and selective modulation of the intracellular levels of physiologically important small molecules are essential for dissecting their integral and multiple roles in cellular processes. Therefore, we have been exploring the suitability of RNA aptamers for this purpose. Using the Escherichia coli heme biosynthetic pathway as a simple model of a negative feedback regulated process, we show that heme-binding RNA aptamers, developed in vitro and expressed intracellularly, induce a heme-dependent growth defect in an E. coli heme auxotroph defective in converting delta-aminolevulinic (delta-ALA) acid into downstream products. Relative to a control oligonucleotide, the aptamers also induce delta-ALA accumulation in cells grown under heme-limiting conditions. Increasing the concentration of heme in the media completely reverses both the growth defect and delta-ALA accumulation, except for two aptamers for which reversal is partial. Thus, these aptamers specifically target their cognate ligand in vivo and functionally modulate its intracellular concentration, demonstrating that RNA aptamers are useful tools for elucidating the role of heme and possibly other small molecules in regulating cellular networks.

Aptamers, Nucleotide↗
PubMed2002

Poincaré plot interpretation using a physiological model of HRV based on a network of oscillators.

In this paper, we develop a physiological oscillator model of which the output mimics the shape of the R-R interval Poincaré plot. To validate the model, simulations of various nervous conditions are compared with heart rate variability (HRV) data obtained from subjects under each prescribed condition. For a variety of sympathovagal balances, our model generates Poincaré plots that undergo alterations strongly resembling those of actual R-R intervals. By exploiting the oscillator basis of our model, we detail the way that low- and high-frequency modulation of the sinus node translates into R-R interval Poincaré plot shape by way of simulations and analytic results. With the use of our model, we establish that the length and width of a Poincaré plot are a weighted combination of low- and high-frequency power. This provides a theoretical link between frequency-domain spectral analysis techniques and time-domain Poincaré plot analysis. We ascertain the degree to which these principles apply to real R-R intervals by testing the mathematical relationships on a set of data and establish that the principles are clearly evident in actual HRV records.

Biological Clocks↗
PubMed2026

Integrative Multidimensional Profiling of Individuals Recovered from Mild COVID-19 Reveals Immune-Metabolic-Oxidative Network Interactions.

The COVID-19 pandemic underscored the need to better characterize immune and molecular responses following SARS-CoV-2 infection and vaccination. Beyond antibody and cellular immunity, COVID-19 involves oxidative stress and DNA damage, affecting repair mechanisms and metabolic adaptation linked to immune resilience. Here, we present a multidimensional analysis of 20 individuals who recovered from mild COVID-19, integrating clinical features with humoral and cellular immune responses, T cell and myeloid phenotypes, oxidative stress, DNA damage, and metabolomic and lipidomic profiles. Although most individual parameters fell within physiological ranges, network modeling revealed structured associations spanning multiple biological domains. A central finding was a coherent cluster organized around vaccine dose number, linking anti-Spike antibody titers, oxidative stress, bioenergetic signatures, and granulocyte activation. Higher vaccination was associated with stronger humoral responses, lower oxidative stress, and a more balanced myeloid-metabolic profile, suggesting a potential protective role extending beyond antibody induction. Additional associations linked symptom patterns to T cell differentiation states, anti-nucleocapsid responses to systemic inflammation, and anaerobic signatures to DNA damage markers, revealing interconnections between immunometabolism, clinical expression, and genomic stress. Despite the small sample size, these findings offer a preliminary systems-level perspective on mild COVID-19 recovery and illustrate the value of integrative exploratory frameworks in infectious disease research, laying the groundwork for validation in larger longitudinal cohorts.

Humans↗
PubMed2001

PHOTOSYSTEM I: Function and Physiology.

Photosystem I is the light-driven plastocyanin-ferredoxin oxidoreductase in the thylakoid membranes of cyanobacteria and chloroplasts. In recent years, sophisticated spectroscopy, molecular genetics, and biochemistry have been used to understand the light conversion and electron transport functions of photosystem I. The light-harvesting complexes and internal antenna of photosystem I absorb photons and transfer the excitation energy to P700, the primary electron donor. The subsequent charge separation and electron transport leads to the reduction of ferredoxin. The photosystem I proteins are responsible for the precise arrangement of cofactors and determine redox properties of the electron transfer centers. With the availability of genomic information and the structure of photosystem I, one can now probe the functions of photosystem I proteins and cofactors. The strong reductant produced by photosystem I has a central role in chloroplast metabolism, and thus photosystem I has a critical role in the metabolic networks and physiological responses in plants.

Journal Article↗
PubMed2005

Integrative re-organization mechanism for reducing tremor in Parkinson's disease patients.

A special movement therapy, called coordination dynamics therapy, has been reported to have the potential to improve central nervous system (CNS) functioning in Parkinson's disease patients. Electromyography using surface electrodes (sEMG) showed that the rhythmic muscle activity leading to Parkinsonian tremor was generated in the patients by the impairment of two kinds of inhibition. First, some premotor spinal oscillators organized themselves in the CNS neuronal networks without strong adequate input and second, the oscillators synchronized their firing to give rise to rhythmic muscle activity and tremor. In this paper it will be shown that highly coordinated arm and leg movements, generated when exercising on a special coordination dynamics therapy device, can reduce Parkinsonian tremor in amplitude and frequency and improve CNS functioning in the short-term memory. sEMG measurements showed upon exercising on the special coordination dynamics therapy device that the motor program improved in the short-term memory and tremor muscle activity became coordinated with the volitional motor program and reduced in size and frequency. Higher load exercising seemed to better reduce tremor muscle activity, probably because the physiologic CNS organization was more integrative then and could 'bind' stronger simultaneous pathologic tremor activity. Moreover, the rhythmic synchronized motor unit firing in different arm and leg muscles was synchronized or coordinated and changed in frequency and amplitude. It is concluded that the integrative re-organization mechanism to reduce Parkinsonian tremor is the phase and frequency coordination between neuron firing of the physiologic neuronal network state, generated by the highly coordinated arm and leg movements, and the simultaneous pathologic tremor network state, generated by the uninhibited neurons, firing synchronized oscillatory.

Aged↗
PubMed2006

Integrating genetic and gene expression data: application to cardiovascular and metabolic traits in mice.

The millions of common DNA variations that occur in the human population, or among inbred strains of mice and rats, perturb the expression (transcript levels) of a large fraction of the genes expressed in a particular tissue. The hundreds or thousands of common cis-acting variations that occur in the population may in turn affect the expression of thousands of other genes by affecting transcription factors, signaling molecules, RNA processing, and other processes that act in trans. The levels of transcripts are conveniently quantitated using expression arrays, and the cis- and trans-acting loci can be mapped using quantitative trait locus (QTL) analysis, in the same manner as loci for physiologic or clinical traits. Thousands of such expression QTL (eQTL) have been mapped in various crosses in mice, as well as other experimental organisms, and less detailed maps have been produced in studies of cells from human pedigrees. Such an integrative genetics approach (sometimes referred to as "genetical genomics") is proving useful for identifying genes and pathways that contribute to complex clinical traits. The coincidence of clinical trait QTL and eQTL can help in the prioritization of positional candidate genes. More importantly, mathematical modeling of correlations between levels of transcripts and clinical traits in genetic crosses can allow prediction of causal interactions and the identification of "key driver" genes. An important objective of such studies will be to model biological networks in physiologic processes. When combined with high-density single nucleotide polymorphism (SNP) mapping, it should be feasible to identify genes that contribute to transcript levels using association analysis in outbred populations. In this review we discuss the basic concepts and applications of this integrative genomic approach to cardiovascular and metabolic diseases.

Animals↗
PubMed2005

WW domains provide a platform for the assembly of multiprotein networks.

WW domains are protein modules that mediate protein-protein interactions through recognition of proline-rich peptide motifs and phosphorylated serine/threonine-proline sites. To pursue the functional properties of WW domains, we employed mass spectrometry to identify 148 proteins that associate with 10 human WW domains. Many of these proteins represent novel WW domain-binding partners and are components of multiprotein complexes involved in molecular processes, such as transcription, RNA processing, and cytoskeletal regulation. We validated one complex in detail, showing that WW domains of the AIP4 E3 protein-ubiquitin ligase bind directly to a PPXY motif in the p68 subunit of pre-mRNA cleavage and polyadenylation factor Im in a manner that promotes p68 ubiquitylation. The tested WW domains fall into three broad groups on the basis of hierarchical clustering with respect to their associated proteins; each such cluster of bound proteins displayed a distinct set of WW domain-binding motifs. We also found that separate WW domains from the same protein or closely related proteins can have different specificities for protein ligands and also demonstrated that a single polypeptide can bind multiple classes of WW domains through separate proline-rich motifs. These data suggest that WW domains provide a versatile platform to link individual proteins into physiologically important networks.

Amino Acid Motifs↗
PubMed1993

Analysis of striatal dynamics: the existence of two modes of behaviour.

The qualitative dynamical behaviour of a neural model based on the mammalian neostriatum was analyzed. The neostriatum was modelled as a mutually inhibitory network of physiological neurones, which was driven by excitatory afferents from the cerebral cortex. The analysis defined the conditions under which the system would enter into one of two dynamic modes, competition or co-activation, in terms of the parameters defining receptor-operated and voltage-sensitive channels in the neuronal membrane. We have previously argued that the mode of co-activation in the neostriatum may correspond to the state of muscular rigidity which occurs as a symptom of Parkinson's disease. The present work extends a preliminary analysis of a two-neurone system to a system of arbitrary size. An explicit prediction is made of the conditions under which a transition from co-activation to competition will occur, which is testable experimentally. The wavelength of a non-uniform activity pattern produced by small departures from uniform afferent drive is determined for one- and two-dimensional arrays of neurones. Two mild assumptions about the connectivity of the network were used to simplify the analysis, namely that the network was symmetric and homogeneous. The implications of departures from these assumptions for understanding the disordered movement seen in Huntington's disease are also considered.

Animals↗
PubMed2003

Physiology of the alveolar surface network.

The alveolar surface network (ASN) is the totally fluid intraacinar conformation of the alveolar surface liquid (ASL) continuum circulating, both in series and in parallel, through ultrathin (to <7 nm) molecular conduits formed by appositions of unit bubbles of alveolar gas. The ASN is the analogue of foam in vitro. Appositions of unit bubble films, namely foam films, include (a) bubble-to-bubble at the alveolar entrance, across alveolar ducts, and at pores of Kohn ('classical foam films'); (b) bubble-to-epithelial cell surface ('cell-surface foam film'); and (c) bubble-to-open surface liquid layer of the terminal conducting airways ('surface foam film'). These appositions of monolayer bubble films create (a) 'macrochannels' ('pressure points', 'reservoirs') that modulate ASL transfers, volume and flow throughout the acinus and between acinar surface and both the interstitium and the terminal conducting airways surfaces, and (b) 'microchannels' along the broadest surfaces of the appositions. 'Microchannels', which are expectedly bilayer, serve several functions, including (a) virtually frictionless orientation of unit bubbles and ASL to fill the acinar air space; (b) virtually unrestricted diffusion of respiratory gases; (c) architectural support ('infrastructure') against the 'mass' and 'recoil' force of the interstitium; and (d) provision of 'gate' and 'bridge' dynamics that further modulate and direct ASL circulation. The physiological and anatomical boundary between acinar ASN and the bubble-free open liquid surfaces of the conducting airways is marked by the surface foam film. The ASN operates as outlined above in all regions of the lung, at all lung volumes, beginning at the onset of air-breathing at birth and continuing throughout life. Reports of its discovery (Pulmonary Physiology of the Fetus, Newborn and Child (1975) 116; Pediatr. Res. 12 (1978) 1070) and subsequent confirmatory research including the adult lung are summarized in this review by progressive development of each function. These functions, which are normal for a relatively dry foam such as the ASN (where gas:liquid volume ratio is >99:1) cannot be duplicated by the conventional theories and models of an open 'alveolar lining layer'. The unfortunate research technologies upon which these theories and models have been formulated have, indeed, obfuscated recognition of the ASN in vivo. They are also presented and critiqued in this review.

Animals↗
PubMed1993

Isolation of the physiological regulation component of the arterial pressure time variation after postural stresses in by a model of the gravitational and arterial kinking effects.

Prompt active postural manoeuvres induce an immediate arterial pressure variation followed by a period of regulation. For the squatting manoeuvre, initial hypertension was explained by a rise of cardiac filling pressure due to "squeezing blood out of the veins of the legs", leading to an increase in stroke output by Frank-Starling mechanism. For a minor part, it was also explained by "kinking" of the femoral arteries. O'Donnel and Mc Ilroy observed an increase in central blood volume and accepted the idea of a rise of cardiac filling. However, they did not observe so consistent circulatory variations when postural changes were realized in a water tank. Therefore, they concluded that kinking of the arteries and veins of the legs could not be very important. Moreover, the immediate pressure variations, most often appearing in the first beat succeeding the postural manoeuvres cannot be easily explained by the previously invoked modifications of cardiac filling pressures. When Hoffman et al lifted dogs until they stood erect, the right ventricular stroke volume usually fell in the first beat after the postural change, but the left ventricular stroke volume did not fall for another 1-3 beats. When the dogs were rapidly lowered to standing on four legs again, a delay of 2-3 beats was also observed. Thus, another interpretation of immediate hypotension must be added. It should especially take into account the natural gravitational fluid mechanics phenomena imposed to the arterial blood. Besides, to allow the investigation of the orthostatic regulation of arterial blood pressure, it would be necessary to separate the cardiovascular regulation component of the arterial pressure time course from the pressure evolution that would naturally appear in the network without physiological contribution. It is the aim of this study.

Blood Pressure↗
PubMedDate not supplied

Model of global spontaneous activity and local structured activity during delay periods in the cerebral cortex.

We investigate self-sustaining stable states (attractors) in networks of integrate-and-fire neurons. First, we study the stability of spontaneous activity in an unstructured network. It is shown that the stochastic background activity, of 1-5 spikes/s, is unstable if all neurons are excitatory. On the other hand, spontaneous activity becomes self-stabilizing in presence of local inhibition, given reasonable values of the parameters of the network. Second, in a network sustaining physiological spontaneous rates, we study the effect of learning in a local module, expressed in synaptic modifications in specific populations of synapses. We find that if the average synaptic potentiation (LTP) is too low, no stimulus specific activity manifests itself in the delay period. Instead, following the presentation and removal of any stimulus there is, in the local module, a delay activity in which all neurons selective (responding visually) to any of the stimuli presented for learning have rates which gradually increase with the amplitude of synaptic potentiation. When the average LTP increases beyond a critical value, specific local attractors (stable states) appear abruptly against the background of the global uniform spontaneous attractor. In this case the local module has two available types of collective delay activity: if the stimulus is unfamiliar, the activity is spontaneous; if it is similar to a learned stimulus, delay activity is selective. These new attractors reflect the synaptic structure developed during learning. In each of them a small population of neurons have elevated rates, which depend on the strength of LTP. The remaining neurons of the module have their activity at spontaneous rates. The predictions made in this paper could be checked by single unit recordings in delayed response experiments.

Cerebral Cortex↗