SEARCH · PubMed Health

Results for “Pathway modelling”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 757 records · Page 42Linked to original sources

PubMed2004

Neuropeptidergic characterization of the leptin receptor mutated obese Koletsky rat.

Leptin regulates energy homeostasis and reproduction as evidenced by dysfunctions characterized in several genetic models of leptin pathway deficiency, such as the ob/ob and db/db mice and fa/fa Zucker rat. An additional model, the obese (f/f) Koletsky rat with a nonsense leptin receptor mutation has not been fully characterized. These rats are obese, hyperphagic, diabetic, and infertile; however, little else is known about the effects of the mutation. We have characterized alterations in hypothalamic appetite regulating neuropeptides as well as energy expenditure, metabolic hormones, and the reproductive axis of obese f/f rats. As expected, obese rats of both sexes were hyperinsulinemic, hyperglycemic, and hyperleptinemic. They exhibited reduced uncoupling protein-1 mRNA expression in brown fat, indicating reduced energy expenditure. In addition, hypothalamic expression of orexigenic neuropeptide Y and agouti-related peptide mRNA levels was upregulated while the anorexigenic cocaine and amphetamine regulated transcript and proopiomelanocortin mRNA levels were reduced. We also observed reproductive axis perturbations including reduced hypothalamic luteinizing hormone releasing hormone, serum estradiol and testosterone, and increased serum progesterone levels. In conclusion, obese Koletsky rats are phenotypically similar to other leptin pathway deficiency models with reduced energy expenditure and hypothalamic neuropeptidergic alterations that could account for their obesity and infertility.

Adipose Tissue, Brown↗

PubMed2002

The role of phosphatidic acid in the regulation of the Ras/MEK/Erk signaling cascade.

Phosphatidic acid (PA) is an important second messenger produced by the activation of numerous cell surface receptors. Recent data have suggested that PA regulates multiple cellular processes. This review addresses primarily the role of PA in the regulation of the Erk1/2 cascade pathway. A model for the regulation of Erk1/2 phosphorylation by cell surface receptors is presented. According to this model, agonists stimulate the binding of GTP to Ras and the activation of phospholipase D to generate phosphatidic acid. PA promotes the binding of cRaf-1 kinase to the membrane, where it interacts with Ras.GTP and other regulatory components of the pathway. Ras-Raf complexes remain bound to the surface of endosomes, where scaffolding complexes involving Ras, cRaf-1, MEK and Erk are formed. Complete activation and coupling of the cascade requires endocytosis, a process that is also modulated by PA.

Amino Acid Sequence↗

PubMed2006

Evidence of tumor necrosis factor receptor 1 signaling in human temporal lobe epilepsy.

Seizures, particularly when prolonged, may cause neuronal loss within vulnerable brain structures such as the hippocampus, in part by activating programmed (apoptotic) cell death pathways. Experimental modeling suggests that seizures activate tumor necrosis factor receptor 1 (TNFR1) and engage downstream pro- and anti-apoptotic signaling cascades. Whether such TNFR1-mediated signaling occurs in human temporal lobe epilepsy (TLE) is unknown. Presently, we examined this pathway in hippocampus surgically obtained from refractory TLE patients and contrasted findings to matched autopsy controls. Western blotting established that total protein levels of the TNFR1 proximal signaling adaptor TNFR-associated protein with death domain (TRADD), cleaved initiator caspase-8 and apoptosis signal-regulating kinase 1 (ASK1) were higher in TLE samples than controls. Intracellular distribution analyses revealed raised cytoplasmic levels of TNFR1, TRADD and the caspase-8 recruitment adaptor Fas-associated protein with death domain (FADD), and higher levels of TRADD and cleaved caspase-8 in the microsomal fraction, in TLE samples. Immunoprecipitation studies detected TRADD-FADD binding, and fluorescence microscopy revealed TRADD co-localization with FADD in TLE hippocampus. These data suggest that TNFR1 signaling is engaged in the hippocampus of patients with refractory temporal lobe epilepsy.

Adult↗

PubMed1997

Positive force feedback control of muscles.

This study was prompted by recent evidence for the existence of positive force feedback in feline locomotor control. Our aim was to establish some basic properties of positive force feedback in relation to load compensation, stability, intrinsic muscle properties, and interaction with displacement feedback. In human subjects, muscles acting about the wrist and ankle were activated by feedback-controlled electrical stimulation. The feedback signals were obtained from sensors monitoring force and displacement. The signals were filtered to mimic transduction by mammalian tendon organ and muscle spindle receptors. We found that when muscles under positive force feedback were loaded inertially, they responded in a stable manner with increased active force. The activation attenuated the muscle stretch (yield) that would otherwise occur in the absence of feedback. With enough positive force feedback gain, yield could actually reverse. This behavior, which we termed the affirming reaction, was reminiscent of the mammalian positive supporting reaction, a postural response elicited by contact of the foot with the ground. Muscles under positive force feedback remained stable, even when the loop gain (Gf) was set at levels of 2 or 3. In a linear system, if Gf > 1, instability occurs when the loop is closed. On further investigation, we found that Gf changed with joint angle: it declined as the load-bearing muscle actively shortened. We inferred that in closed-loop operation, the active muscles always shortened until Gf approached unity. In other words, the length-tension curve of active muscle ensures stability even when force-related excitation of motoneurons is very large. Concomitant negative displacement feedback reinforced and stabilized load compensation up to a certain gain, beyond which instability occurred. In further trials we included delays of up to 40 ms in the positive force feedback pathway, to model the delays recently described for tendon organ reflexes in cat locomotion. Contrary to expectations, this did not destabilize the loop. Indeed, when instability was deliberately evoked by setting displacement feedback gain high, delays in the positive force feedback pathway actually stabilized control. The stabilization of positive force feedback by inherent properties of the neuromuscular system increases the functional scope to be expected of feedback from force receptors in biological motor control. Our results provide a rationale for the delayed excitatory action of Ib heteronymous input on extensor motoneurons in cat locomotion.

Adult↗

PubMed1991

Internodal pathways in the human atria: a model study.

An electrophysical/anatomical computer model of human atrial excitation was used to investigate the controversy over specialized internodal pathways. The only atrial pathways that have been thoroughly described in the literature are those that connect the sinoatrial (SA) and atrioventricular (AV) nodes, and the right and left atria. By incorporating pathways of rapid propagation representing the internodal and interatrial tracts, anisotropy was introduced into an otherwise isotropic atrial model. Simulated epicardial isochrone maps, heart vector loops, and electrograms were calculated for both the isotropic and anisotropic atrial models, and the simulations were compared with observed normal data. Although the simulations using the anisotropic model compare more favorably with real data, the results suggest that there are more pathways of rapid propagation in the atria than those described and that a global anisotropy based on morphology and fiber direction is a more likely explanation than rapid propagation confined to a few specialized pathways.

Anisotropy↗

PubMed2005

Pathways to suicidal behaviour among adolescent girls in Nicaragua.

Adolescent girls are the most frequent suicide attempters worldwide. However, there is little knowledge about pathways leading to suicidal behaviour among young people, in particular in low-income countries. This study explores the motives and processes related to suicidal behaviour among young girls in Nicaragua. Individual in-depth interviews were conducted with eight girls aged between 12 and 19 admitted to hospital after attempting suicide. The audio-taped interviews lasted 2-4 h and were transcribed, translated into English and coded for content. Grounded theory and content analysis were used to construct a theory of the mechanisms behind their suicidal behaviour. A tentative model exploring pathways to suicidal behaviour is described with four main categories: structuring conditions, triggering events, emotions and actions taken. The model illustrates the dialectic interplay between structure and actions taken. Actions taken were categorized as problem solving or various forms of escape where failure with either of these strategies resulted in a suicide attempt. Dysfunctional families, absent fathers and lack of integration into society were some of the structuring conditions that lead to emotional distress. Abuse, deaths in the family, break-up with boyfriends or suicide among friends acted as triggering events. A striking finding was the obvious narrative competence of the girls. Our findings indicate that suicide prevention programmes for young people must offer support from professionals, independent of their family and social networks. Institutions in the community in contact with young people with suicidal behaviour must develop communicative skills to offer a trusting environment mobilising the resources that young people have.

Adolescent↗

PubMed1998

EGF receptor regulation of cell motility: EGF induces disassembly of focal adhesions independently of the motility-associated PLCgamma signaling pathway.

A current model of growth factor-induced cell motility invokes integration of diverse biophysical processes required for cell motility, including dynamic formation and disruption of cell/substratum attachments along with extension of membrane protrusions. To define how these biophysical events are actuated by biochemical signaling pathways, we investigate here whether epidermal growth factor (EGF) induces disruption of focal adhesions in fibroblasts. We find that EGF treatment of NR6 fibroblasts presenting full-length WT EGF receptors (EGFR) reduces the fraction of cells presenting focal adhesions from approximately 60% to approximately 30% within 10 minutes. The dose dependency of focal adhesion disassembly mirrors that for EGF-enhanced cell motility, being noted at 0.1 nM EGF. EGFR kinase activity is required as cells expressing two kinase-defective EGFR constructs retain their focal adhesions in the presence of EGF. The short-term (30 minutes) disassembly of focal adhesions is reflected in decreased adhesiveness of EGF-treated cells to substratum. We further examine here known motility-associated pathways to determine whether these contribute to EGF-induced effects. We have previously demonstrated that phospholipase C(gamma) (PLCgamma) activation and mobilization of gelsolin from a plasma membrane-bound state are required for EGFR-mediated cell motility. In contrast, we find here that short-term focal adhesion disassembly is induced by a signaling-restricted truncated EGFR (c'973) which fails to activate PLCgamma or mobilize gelsolin. The PLC inhibitor U73122 has no effect on this process, nor is the actin severing capacity of gelsolin required as EGF treatment reduces focal adhesions in gelsolin-devoid fibroblasts, further supporting the contention that focal adhesion disassembly is signaled by a pathway distinct from that involving PLCgamma. Because both WT and c'973 EGFR activate the erk MAP kinase pathway, we additionally explore here this signaling pathway, not previously associated with growth factor-induced cell motility. Levels of the MEK inhibitor PD98059 that block EGF-induced mitogenesis and MAP kinase phosphorylation also abrogate EGF-induced focal adhesion disassembly and cell motility. In summary, we characterize for the first time the ability of EGFR kinase activity to directly stimulate focal adhesion disassembly and cell/substratum detachment, in relation to its ability to stimulate migration. Furthermore, we propose a model of EGF-induced motogenic cell responses in which the PLCgamma pathway stimulating cell motility is distinct from the MAP kinase-dependent signaling pathway leading to disassembly and reorganization of cell-substratum adhesion.

Animals↗

PubMed2002

A design of two simple models to predict PCDD/F concentrations in vegetation and soils.

The vegetation and soil levels of the 17 polychlorinated dibenzo-p-dioxin and dibenzofuran (PCDD/F) toxic congeners were calculated by means of a vegetation and a soil model, respectively. Both models predicted the levels of the 17 PCDD/F congeners in quite good agreement with the observed results although the soil model was more accurate than the vegetation model. Four different pathways of contribution to the vegetation concentrations were taken into account: vapour-phase absorption, dry particle deposition, wet particle deposition and uptake by root. The most important pathway was the vapour-phase absorption and the less was the uptake by root. In the soils model four pathways were considered: background soil concentration, dry particle deposition, wet particle deposition and uptake by root. After the background concentration, the most important pathway was the wet deposition.

Absorption↗

PubMedDate not supplied

Cybernetic modeling and regulation of metabolic pathways in multiple steady states of hybridoma cells.

Hybridoma cells utilize a pair of complementary and partially substitutable substrates, glucose and glutamine, for growth. It has been shown that cellular metabolism shifts under different culture conditions. When those cultures at different metabolic states are switched to a continuous mode, they reach different steady states under the same operating conditions. A cybernetic model was constructed to describe the complementary and partial substitutable nature of substrate utilization. The model successfully predicted the metabolic shift and multiple steady-state behavior. The results are consistent with the experimental observation that the history of the culture affects the resulting steady state.

Cell Culture Techniques↗

PubMed2005

Candidate gene analysis in human neural tube defects.

Biochemical and developmental pathways, mouse models, and positional evidence have provided numerous candidate genes for the study of human neural tube defects. In a survey of 80 studies on 38 candidate genes, few found significant results in human populations through case-control or family-based association studies. While the folate pathway has been explored extensively, only the MTHFR 677C > T polymorphism was significant, and only in an Irish population. Developmental pathways such as the Wnt signaling pathway and Hox genes have also been explored without positive results. More than 90 mouse candidates have been identified through spontaneous and knockout mutations, but only the T locus (mouse Brachyury gene) showed association in an initial study that was not confirmed on follow-up. Positional candidates have been derived from cytogenetic evidence, but preliminary genomic screens have limited power due to small sample sizes. Future studies would increase their power to detect association by using more samples. In addition a clarification of the phenotype would be beneficial as many studies used different inclusion criteria. Incorporating several types of data could highlight better candidates, as would looking beyond the traditional sources for candidate genes. Recent studies of an energy metabolism gene (UCP2) and vitamin B metabolism (Transcoalbumin) have produced promising results. Utilizing other model organisms may also be beneficial, as in a recent study from a chick model of NTDs in NCAM1. New approaches combined with traditional methods and increased sample sizes will help prioritize human NTD candidate genes and clarify the complex etiology of this condition.

Animals↗

PubMed1991

A simulated human fovea: the L-type cells of the magnocellular pathway.

A static model of the human fovea is used to study the properties of L-type amacrine cells (L-AC) that link the cones with the magnocellular pathway. Sine and square wave gratings are used to obtain response spectra of L-ACs and C-type bipolar cells (C-BC); these two types of cells are compared in both central fovea, where there are no blue-sensitive cones and parafovea, where the blue-sensitive cones 12% of the population. Three dispersion conditions are used: no, aberration-free, and chromatic dispersions. The abilities of L- and C-type cells to resolve a two-bar image are also compared. The findings are consistent with the magnocellular pathway having higher contrast luminance and chromatic sensitivity gains than those of the parvocellular pathways, but under specified conditions. And under specified conditions the findings are also consistent with both pathways being involved in the detection of chromatic and achromatic signals. Nevertheless when all factors are considered the parvocellular pathway appears to be involved with fine spatial and chromatic tuning while the magnocellular pathway appears to deal with coarser tuning.

Color Perception↗

PubMed2006

Metabolic networks in motion: 13C-based flux analysis.

Many properties of complex networks cannot be understood from monitoring the components--not even when comprehensively monitoring all protein or metabolite concentrations--unless such information is connected and integrated through mathematical models. The reason is that static component concentrations, albeit extremely informative, do not contain functional information per se. The functional behavior of a network emerges only through the nonlinear gene, protein, and metabolite interactions across multiple metabolic and regulatory layers. I argue here that intracellular reaction rates are the functional end points of these interactions in metabolic networks, hence are highly relevant for systems biology. Methods for experimental determination of metabolic fluxes differ fundamentally from component concentration measurements; that is, intracellular reaction rates cannot be detected directly, but must be estimated through computer model-based interpretation of stable isotope patterns in products of metabolism.

Animals↗

PubMed2006

Hold your horses: a dynamic computational role for the subthalamic nucleus in decision making.

The basal ganglia (BG) coordinate decision making processes by facilitating adaptive frontal motor commands while suppressing others. In previous work, neural network simulations accounted for response selection deficits associated with BG dopamine depletion in Parkinson's disease. Novel predictions from this model have been subsequently confirmed in Parkinson patients and in healthy participants under pharmacological challenge. Nevertheless, one clear limitation of that model is in its omission of the subthalamic nucleus (STN), a key BG structure that participates in both motor and cognitive processes. The present model incorporates the STN and shows that by modulating when a response is executed, the STN reduces premature responding and therefore has substantial effects on which response is ultimately selected, particularly when there are multiple competing responses. Increased cortical response conflict leads to dynamic adjustments in response thresholds via cortico-subthalamic-pallidal pathways. The model accurately captures the dynamics of activity in various BG areas during response selection. Simulated dopamine depletion results in emergent oscillatory activity in BG structures, which has been linked with Parkinson's tremor. Finally, the model accounts for the beneficial effects of STN lesions on these oscillations, but suggests that this benefit may come at the expense of impaired decision making.

Action Potentials↗

PubMed2004

Top-down approaches to the study of natural variation in complex physiological pathways using the white-footed mouse (Peromyscus leucopus) as a model.

Variation in complex physiological pathways has important effects on human function and medical treatment. Complex pathways involve cells at multiple locations, which serve different functions regulated by many genes and include complex neuroendocrine pathways that regulate physiological function. One of two competing hypotheses regarding the effects of selection on complex pathways predicts that variability should be common within complex pathways. If this hypothesis is correct, then we should expect wide variation in neuroendocrine function to be typical within natural populations. To test this hypothesis, a complex neuroendocrine pathway that regulates photoperiod-dependent changes in fertility in a natural population of white-footed mice (Peromyscus leucopus) was used to test for natural genetic variability in multiple components of the pathway. After testing only six elements in the photoperiod pathway in P. leucopus, genetic variation in the following four of these elements was evident: the circadian clock, melatonin receptor abundance or affinity, sensitivity of the reproductive axis to steroid negative feedback, and gonadotropin-releasing hormone neuronal activity. If this result can be extended to humans, the prediction would be that significant variation at multiple loci in complex neuroendocrine pathways is common among humans, and that variation would exist even in human populations from a common genetic background. This finding could only be drawn from an "exotic" animal model derived from a natural source population, confirming the continuing importance of nontraditional models alongside the standard laboratory species.

Animal Husbandry↗

PubMed2006

A kinetic model of calcium mass balance during dialysis therapy.

A kinetic model of Ca mass balance during dialysis has been developed. It is a single-compartment, variable-volume model to compute Ca mass balance during dialysis in its volume of distribution, the extracellular fluid. The model was used to analyze literature data which were suitable for the assessment of Ca mass balance over the course of dialysis. The modeled analyses predicted the serial plasma Ca concentrations very well. The mass balance analyses revealed a pool of rapidly diffusible Ca beyond the extracellular fluid distribution volume where Ca could be mobilized (M+(Ca)) or sequestered (M-(Ca)) very rapidly at rate equal but opposite in sign to dialyzer flux and thus effectively maintain near constant plasma Ca in the face of dialyzer Ca concentration gradients. This pool is likely the large pool of diffusible (miscible) Ca in connective tissue and on bone surfaces. Analysis of net Ca flux during dialysis with Cdi(Ca) = 2.50 mEq/l suggests that 80% of patients are in positive Ca balance during dialysis. Further studies are required to verify the model and to develop a model of interdialytic Ca mass balance.

Calcium↗

PubMed2004

An animal model for cochlear implants.

OBJECTIVE: To test the feasibility of using the deaf white cat model of early-onset deafness. We studied the neuronal effects of prosthetic intervention with a clinical, "off-the-shelf" multichannel cochlear implant. METHODS: We placed cochlear implants in 5 deaf white kittens at age 12 and 24 weeks. The devices were activated and stimulated in the laboratory using a clinical speech processor programmed with a high-resolution continuous interleaved sampling (CIS) strategy for 8 to 24 weeks. Stimulus parameters were guided by electrically evoked brainstem responses and intracochlear-evoked potentials. Kittens were assessed with respect to their tolerance and general behavior in response to speech, music, and environmental sounds. RESULTS: Surgical complications were minimal, and kittens tolerated the experimental procedures well. Subjects were able to detect and respond to a specific sound played from a computer speaker. Electrophysiologic responses were reliably attainable and showed consistency with observed behavioral responses to sound. This experimental paradigm, using clinical devices, can be used in a practical research setting in cats. CONCLUSIONS: Deafness and other variations in neural activity result in many distinct changes to the central auditory pathways. Animal models will facilitate assessment of the reversibility of deafness-associated changes at the level of the neuron and its connections. Our observations of the feasibility of using clinical devices in animal models will enable us to simulate clinical conditions in addressing questions about the effects of "replacement" activity on the structure and function within the central auditory pathways in deafness.

Animals↗

PubMed1997

The response of subthalamic nucleus neurons to dopamine receptor stimulation in a rodent model of Parkinson's disease.

Overactivity in the subthalamic nucleus (STN) is believed to contribute to the pathophysiology of Parkinson's disease. It is hypothesized that dopamine receptor agonists reduce neuronal output from the STN. The present study tests this hypothesis by using in vivo extracellular single unit recording techniques to measure neuronal activity in the STN of rats with 6-hydroxydopamine-induced lesions of the nigrostriatal pathway (a model of Parkinson's disease). As predicted, firing rates of STN neurons in lesioned rats were tonically elevated under basal conditions and were decreased by the nonselective dopamine receptor agonists apomorphine and L-3, 4-dihydroxyphenylalanine (L-DOPA). STN firing rates were also decreased by the D2 receptor agonist quinpirole when administered after the D1 receptor agonist (+/-)- 1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol (SKF 38393). Results of the present study challenge the prediction that dopaminergic agonists reduce STN activity predominantly through actions at striatal dopamine D2 receptors. Firing rates of STN neurons were not altered by selective stimulation of D2 receptors and were increased by selective stimulation of D1 receptors. Moreover, there was a striking difference between the responses of the STN to D1/D2 receptor stimulation in the lesioned and intact rat; apomorphine inhibited STN firing in the lesioned rat and increased STN firing in the intact rat. These findings support the premise that therapeutic efficacy in the treatment of Parkinson's disease is associated with a decrease in the activity of the STN, but challenge assumptions about the roles of D1 and D2 receptors in the regulation of neuronal activity of the STN in both the intact and dopamine-depleted states.

Animals↗

PubMed2006

Systems biology of the human red blood cell.

While the potential possibilities of systems biology appear to hold great promise, there are still many challenges to overcome, notably lack of complete characterization of biological components and their interactions and ways to measure these changes experimentally. The comparative simplicity of the human red cell sidesteps much of these challenges. Detailed models of human red cell metabolism have been developed for the last quarter century and continued development of these models has resulted in the ability to make functional phenotype predictions, in silico. Additionally, existing experimental proteomic and metabolomic technologies now provide the capability to perform individualized characterization of erythrocytes. While an experimentally testable systems biology model of most human cells is presently out of reach, it may be achievable with the red cell.

Computational Biology↗