PubMed Health⌕ Search

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 973 records · Page 54Linked to original sources
PubMed1987

Reconstitution of signaling in bacterial chemotaxis.

Strains missing several genes required for chemotaxis toward amino acids, peptides, and certain sugars were tethered and their rotational behavior was analyzed. Null strains (called gutted) were deleted for genes that code for the transducers Tsr, Tar, Tap, and Trg and for the cytoplasmic proteins CheA, CheW, CheR, CheB, CheY, and CheZ. Motor switch components were wild type, flaAII(cheC), or flaBII(cheV). Gutted cells with wild-type motors spun exclusively counterclockwise, while those with mutant motors changed their directions of rotation. CheY reduced the bias (the fraction of time that cells spun counterclockwise) in either case. CheZ offset the effect of CheY to an extent that varied with switch allele but did not change the bias when tested alone. Transducers also increased the bias in the presence of CheY but not when tested alone. However, cells containing transducers and CheY failed to respond to attractants or repellents normally detected in the periplasm. This sensitivity was restored by addition of CheA and CheW. Thus, CheY both enhances clockwise rotation and couples the transducers to the flagella. CheZ acts, at the level of the motor, as a CheY antagonist. CheA or CheW or both are required to complete the signal pathway. A model is presented that explains these results and is consistent with other data found in the literature.

Bacterial Proteins↗
PubMed1995

Lipoic acid metabolism in Escherichia coli: the lplA and lipB genes define redundant pathways for ligation of lipoyl groups to apoprotein.

Lipoic acid is a covalently bound disulfide-containing cofactor required for function of the pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, and glycine cleavage enzyme complexes of Escherichia coli. Recently we described the isolation of the lplA locus, the first gene known to encode a lipoyl-protein ligase for the attachment of lipoyl groups to lipoate-dependent apoenzymes (T. W. Morris, K. E. Reed, and J. E. Cronan, Jr., J. Biol. Chem. 269:16091-16100, 1994). Here, we report an unexpected redundancy between the functions of lplA and lipB, a gene previously identified as a putative lipoate biosynthetic locus. First, analysis of lplA null mutants revealed the existence of a second lipoyl ligase enzyme. We found that lplA null mutants displayed no growth defects unless combined with lipA (lipoate synthesis) or lipB mutations and that overexpression of wild-type LplA suppressed lipB null mutations. Assays of growth, transport, lipoyl-protein content, and apoprotein modification demonstrated that lplA encoded a ligase for the incorporation of exogenously supplied lipoate, whereas lipB was required for function of the second lipoyl ligase, which utilizes lipoyl groups generated via endogenous (lipA-mediated) biosynthesis. The lipB-dependent ligase was further shown to cause the accumulation of aberrantly modified octanoyl-proteins in lipoate-deficient cells. Lipoate uptake assays of strains that overproduced lipoate-accepting apoproteins also demonstrated coupling between transport and the subsequent ligation of lipoate to apoprotein by the LplA enzyme. Although mutations in two genes (fadD and fadL) involved in fatty acid failed to affect lipoate utilization, disruption of the smp gene severely decreased lipoate utilization. DNA sequencing of the previously identified slr1 selenolipoate resistance mutation (K. E. Reed, T. W. Morris, and J. E. Cronan, Jr., Proc. Natl. Acad. Sci. USA 91:3720-3724, 1994) showed this mutation (now called lplA1) to be a G76S substitution in the LplA ligase. When compared with the wild-type allele, the cloned lplA1 allele conferred a threefold increase in the ability to discriminate against the selenium-containing analog. These results support a two-pathway/two-ligase model of lipoate metabolism in E. coli.

Amino Acid Sequence↗
PubMed1995

Suppression of the pleiotropic effects of HisH and HisF overproduction identifies four novel loci on the Salmonella typhimurium chromosome: osmH, sfiW, sfiX, and sfiY.

Insertion mutations that suppress some or all the pleiotropic effects of HisH and HisF overproduction were obtained by using transposons Tn10dTet and Tn10dCam. All suppressor mutations proved to be recessive, indicating that their effects were caused by loss of function; thus, the suppressors identify genes that are necessary to trigger the pleiotropic response when HisH and HisF are overproduced. Genetic mapping of the suppressor mutations identifies four novel loci on the Salmonella typhimurium genetic map. Mutations in osmH (min 49) behave as general suppressors that abolish all manifestations of the pleiotropic response. Mutations in sfiY (min 83) suppress cell division inhibition and thermosensitivity but not osmosensitivity. Mutations that suppress only cell division inhibition define another locus, sfiX (min 44). A fourth novel locus, sfiW (min 19), is also involved in cell division inhibition. The phenotype of sfiW mutations is in turn pleiotropic: they suppress cell division inhibition, make S. typhimurium unable to grow in minimal media, and cause slow growth and abnormal colony and cell shape. The inability of sfiW mutants to grow in minimal medium cannot be relieved by any known nutritional requirement or by the use of carbon sources other than glucose. The hierarchy of suppressor phenotypes and the existence of epistatic effects among suppressor mutations suggest a pathway-like model for the Hisc pleiotropic response.

Alleles↗
PubMed2003

Role for the fission yeast RecQ helicase in DNA repair in G2.

Members of the RecQ helicase subfamily are mutated in several human genomic instability syndromes, such as Bloom, Werner, and Rothmund-Thomson syndromes. We show that Rqh1, the single Schizosaccharomyces pombe homologue, is a 3'-to-5' helicase and exists with Top3 in a high-molecular-weight complex. top3 deletion is inviable, and this is suppressed by concomitant loss of rqh1 helicase activity or loss of recombination functions. This is consistent with RecQ helicases in other systems. By using epistasis analysis of the UV radiation sensitivity and by analyzing the kinetics of Rhp51 (Rad51 homologue), Rqh1, and Top3 focus formation in response to UV in synchronized cells, we identify the first evidence of a function for Rqh1 and Top3 in the repair of UV-induced DNA damage in G(2). Our data provide evidence that Rqh1 functions after Rad51 focus formation during DNA repair. We also identify a function for Rqh1 upstream of recombination in an Rhp18-dependent (Rad18 homologue) pathway. The model that these data allow us to propose helps to reconcile different interpretations of RecQ family helicase function that have arisen between work based on the S. pombe system and models based on studies of Saccharomyces cerevisiae SGS1 suggesting that RecQ helicases act before Rad51.

Adenosine Triphosphatases↗
PubMed2006

WinBEST-KIT: Windows-based biochemical reaction simulator for metabolic pathways.

We have implemented an efficient, user-friendly biochemical reaction simulator called Web-based BEST-KIT (Biochemical Engineering System analyzing Tool-KIT) for analyzing large-scale nonlinear networks such as metabolic pathways. Users can easily design and analyze an arbitrary reaction scheme through the Internet and an efficient graphical user interface without considering the mathematical equations. The reaction scheme can include several reaction types, which are represented by both the mass action law (mass balance) and approximated velocity functions of enzyme kinetics at steady state, such as Michaelis-Menten, Hill cooperative, Competitive inhibition. However, since all modules in Web-based BEST-KIT have been developed in Java applet style, users cannot optionally make use of original mathematical equations in addition to the prepared equations. In the present study, we have developed a new version of BEST-KIT (for Microsoft Windows called WinBEST-KIT) to allow users to define original mathematical equations and to customize these equations very easily as user-defined reaction symbols. The following powerful system-analytical methods are prepared for system analysis: time-course calculation, parameter scanning, estimation of the values of unknown kinetic parameters based on experimentally observed time-course data of reactants, dynamic response of reactants against virtual external perturbations, and real-time simulation (Virtual Dry Lab).

Computational Biology↗
PubMed2005

Molecular physiology of legume seed development.

Legume seed development is characterized by progressive differentiation of organs and tissues resulting in developmental gradients. The whole process is prone to metabolic control, and distinct metabolite profiles specify the differentiation state. Whereas early embryo growth is mainly maternally controlled, the transition into maturation implies a switch to filial control. A signaling network involving sugars, ABA, and SnRK1 kinases governs maturation. Processes of maturation are activated by changing oxygen/energy levels and/or a changing nutrient state, which trigger responses at the level of transcription and protein phosphorylation. This way seed metabolism becomes adapted to altering conditions. In maturing cotyledons photoheterotrophic metabolism improves internal oxygen supply and biosynthetic fluxes and influences assimilate partitioning. Transgenic legumes with changed metabolic pathways and seed composition provide suitable models to study pathway regulation and metabolic control. At the same time, desirable improvements of seed quality and yield may be achieved.

Energy Metabolism↗
PubMed1995

Novel model of integration of signaling pathways in rat pancreatic acinar cells.

Cholecystokinin (CCK) is the major pancreatic secretagogue and acinar cell mitogen. This study was performed to determine by which effector systems CCK regulates tyrosine kinases, phosphatidylinositol (PtdIns) 3-kinase, and phospholipase D (PLD) activities. Pancreatic acini loaded with [3H]myristic acid or [3H]inositol were used to assay PLD and PtdIns 3-kinase. G protein activation with NaF increased particulate and crude cytosolic tyrosine kinase and PLD activities. PLD activation was pertussis toxin sensitive. Inhibition of phospholipase C (PLC) slightly reduced caerulein-stimulated particulate tyrosine kinase and blocked crude cytosolic tyrosine kinase activity without affecting caerulein-induced PLD activity. Ca2+ is an important factor in caerulein stimulation of tyrosine kinase and PLD activities. Protein kinase C and tyrosine kinase inhibition abolished caerulein-activated particulate and crude cytosolic tyrosine kinase and PtdIns 3-kinase activities without any effect on PLD. Wortmannin inhibited PLD and PtdIns 3-kinase activation. Caerulein-induced amylase secretion was partially reduced by tyrosine kinase inhibition, with no effect from wortmannin. Caerulein can stimulate a pertussis toxin-insensitive G protein, leading to particulate tyrosine kinase activation and a Ca(2+)-sensitive cytosolic tyrosine kinase through PLC activation. However, PLD activation by caerulein is pertussis toxin sensitive, cytosolic Ca2+ sensitive, and independent of previous PLC and tyrosine kinase activation.

Androstadienes↗
PubMed1999

In vivo regulation of von willebrand factor synthesis: von Willebrand factor production in endothelial cells after lung transplantation between normal pigs and von Willebrand factor-deficient pigs.

To evaluate the regulation of plasma von Willebrand factor (vWF) and its in situ production by endothelial cells (ECs), 12 swine leukocyte antigen (SLA)-compatible left lung transplantations were performed. Normal lungs were transplanted into 10 pigs homozygous for von Willebrand disease and into 2 normal pigs. Additionally, 1 normal pig underwent pneumonectomy, and 1 SLA-incompatible lung transplantation between normal pigs was performed. None of the transplanted animals received immunosuppressive therapy. Plasma vWF level was evaluated by ELISA and multimeric pattern. EC vWF content was assessed by immunohistochemistry. Global hemostasis was assessed by standardized ear bleeding time. Six of 12 SLA-compatible lung transplantations and the incompatible transplantation were successful and were used for the study. The functions and the viability of ECs, reflected by their ability to produce vWF and normal multimeric plasma vWF pattern, were preserved in SLA-compatible and -incompatible lung transplantations. vWF production was preserved in ECs that initially synthesized it. EC constitutive and storage pathways are modulated differently according to transplantation compatibility and severity of rejection. In SLA-compatible lung transplantations without histological evidence of rejection, the production of vWF was preserved, whereas constitutive vWF secretion appeared to be altered in cases with minor histological signs of rejection. In pigs with von Willebrand disease that were transplanted with normal lungs without sign of rejection, plasma vWF was significantly increased in an amount expected from the estimated production of a normal lung. In the transplanted normal lung, there was no vWF overexpression by the ECs and no recruitment of ECs that initially did not express vWF. In SLA-incompatible transplantation, ECs were morphologically normal with increased and blurred vWF labeling, whereas plasma vWF levels remained normal, reflecting that EC activation is associated with an increased vWF production with probable diversion to storage pathway. This model depicts the changes of EC regulation of vWF secretion in pig lung transplants. However, this model cannot be directly extrapolated to human organ transplantation because animals did not receive any immunosuppressive therapy, which may be toxic to ECs.

Acute Disease↗
PubMed2004

Recent insights into the immunopathogenesis of psoriasis provide new therapeutic opportunities.

Chronic and excessive inflammation in skin and joints causes significant morbidity in psoriasis patients. As a prevalent T lymphocyte-mediated disorder, psoriasis, as well as the side effects associated with its treatment, affects patients globally. In this review, recent progress is discussed in the areas of genetics, the immunological synapse, the untangling of the cytokine web and signaling pathways, xenotransplantation models, and the growing use of selectively targeted therapies. Since psoriasis is currently incurable, new management strategies are proposed to replace previous serendipitous approaches. Such strategic transition from serendipity to the use of novel selective agents aimed at defined targets in psoriatic lesions is moving rapidly from research benches to the bedsides of patients with this chronic and debilitating disease.

Animals↗
PubMed2006

Tumor cell metabolism: the marriage of molecular genetics and proteomics with cellular intermediary metabolism; proceed with caution!

Metabolic transformations of malignant cells are essential to the development and progression of all cancers. The understanding of the pathogenesis and progression of cancer requires the establishment of the altered genetic/metabolic factors that are essential to the development, growth, and proliferation of the malignant cells. Recognition of this important relationship has resulted in a resurgence of interest in the intermediary metabolism of tumor cells. The role of molecular genetics and proteomics and the application of molecular technology in assessing altered cellular metabolism has become a major area of biomedical research. The contemporary generation of biomedical scientists is exceptionally well trained in all areas of molecular biology and molecular technology, which are now important tools to be applied to the regulation of cellular intermediary metabolism. Simultaneously, the didactic and methodological training associated with the principles and operation of metabolic pathways, enzymology, cellular enzyme activity, and associated biochemical implications has been diminished and often eliminated from the pre- and post-doctoral programs. Interpretations and conclusions of alterations in cellular enzyme activity and associated metabolic pathways based on genetic/proteomic changes can and will result in misrepresentation of important metabolic implications in malignancy and other diseases. It is essential that the genetic/proteomic studies be coupled to biochemical/metabolic cellular events to satisfy the axiom: "genetic transformations and proteomic alterations will have little relevancy to disease processes if the genetic/proteomic alterations are not manifested in altered and impaired cellular and metabolic function". The appropriate marriage of molecular genetics/proteomics with the regulation of cellular intermediary metabolism will provide new revelations and understanding of malignancy that could not be achieved in earlier generations.

Cell Transformation, Neoplastic↗
PubMed2004

Improved methods for the mathematically controlled comparison of biochemical systems.

The method of mathematically controlled comparison provides a structured approach for the comparison of alternative biochemical pathways with respect to selected functional effectiveness measures. Under this approach, alternative implementations of a biochemical pathway are modeled mathematically, forced to be equivalent through the application of selected constraints, and compared with respect to selected functional effectiveness measures. While the method has been applied successfully in a variety of studies, we offer recommendations for improvements to the method that (1) relax requirements for definition of constraints sufficient to remove all degrees of freedom in forming the equivalent alternative, (2) facilitate generalization of the results thus avoiding the need to condition those findings on the selected constraints, and (3) provide additional insights into the effect of selected constraints on the functional effectiveness measures. We present improvements to the method and related statistical models, apply the method to a previously conducted comparison of network regulation in the immune system, and compare our results to those previously reported.

Animals↗
PubMed1999

Human health risk assessment: A case study involving heavy metal soil contamination after the flooding of the river Meuse during the winter of 1993-1994.

At the end of December 1993 and also at the end of January 1995, the river Meuse, one of the major rivers in Europe, flooded and river banks were inundated. We investigated the possible health risks of exposure to heavy metal concentrations in river bank soils resulting from the flooding of the river Meuse at the end of 1993. Soil and deposit samples and corresponding aerable and fodder crops were collected and analyzed for heavy metals. Although the soils of the floodplain of the river Meuse appeared severely polluted mainly by Cd and Zn, the heavy metal concentrations in the crops grown on these soils were within background ranges. Incidentally, the legal standard for Cd as endorsed by the Commodities Act was exceeded in wheat crops. The main exposure pathways for the general population were through the consumption of food crops grown on the river banks and through the direct ingestion of contaminated soils. For estimating potential human exposure in relation to soil pollution, we used a multiple pathway exposure model. For estimating the actual risk, we determined metal contents of vegetables grown in six experimental gardens. From this study, it can be concluded that there is a potential health risk for the river bank inhabitants as a consequence of Pb and Cd contaminations of the floodplain soils of the river Meuse, which are frequently inundated (averaged flooding frequency once every 2 years).

Adult↗
PubMed2006

Understanding intracellular transport processes pertinent to synthetic gene delivery via stochastic simulations and sensitivity analyses.

A major challenge in synthetic gene delivery is to quantitatively predict the optimal design of polymer-based gene carriers (polyplexes). Here, we report a consistent, integrated, and fundamentally grounded computational methodology to address this challenge. This is achieved by accurately representing the spatio-temporal dynamics of intracellular structures and by describing the interactions between gene carriers and cellular components at a discrete, nanoscale level. This enables the applications of systems tools such as optimization and sensitivity analysis to search for the best combination of systems parameters. We validate the approach using DNA delivery by polyethylenimine as an example. We show that the cell topology (e.g., size, circularity, and dimensionality) strongly influences the spatiotemporal distribution of gene carriers, and consequently, their optimal intracellular pathways. The model shows that there exists an upper limit on polyplexes' intracellular delivery efficiency due to their inability to protect DNA until nuclear entry. The model predicts that even for optimally designed polyethylenimine vectors, only approximately 1% of total DNA is delivered to the nucleus. Based on comparison with gene delivery by viruses, the model suggests possible strategies to significantly improve transfection efficiencies of synthetic gene vectors.

Biological Transport, Active↗
PubMed1998

Output signals of the SCN.

The suprachiasmatic nucleus (SCN) of the hypothalamus controls circadian rhythmicity in mammals (for reviews, see Refs. 33 and 59). Responses modulated by the SCN are numerous and include rhythms in sleep/wake cycles, locomotor, gnawing and general activity, temperature, ingestive behavior, and rhythms of hormonal and peptide secretions. Though a great deal is known about the neuroanatomical organization of the SCN, many elements of the structure-function relationships remain to be discovered. For example, it is not known which cellular components of the SCN function as driving pacemakers or which output signal(s) of these pacemakers are important for each of its functions. While some signals from pacemaker cells reach target regions by neural efferents, there is also evidence that rhythmic responses can be controlled by diffusible signals. This article reviews output signals from the SCN. The data available suggest that neural efferents are not necessary for the control of locomotor activity rhythms. Evidence that a diffusible signal is sufficient to restore activity rhythms in SCN-lesioned animals is described. Finally, possible physiological mechanisms for diffusible signals are suggested.

Animals↗
PubMed2003

IL-13 is sufficient for respiratory syncytial virus G glycoprotein-induced eosinophilia after respiratory syncytial virus challenge.

Although well studied in settings of helminth infection and allergen sensitization, the combined contributions of IL-4 and IL-13 and their signaling pathways in models of viral pathogenesis have not been reported. Using a murine model of respiratory syncytial virus (RSV) infection, we evaluated the contribution of IL-13, alone and in conjunction with IL-4, during immunization with recombinant vaccinia virus expressing RSV G glycoprotein (vvGs) or with formalin-inactivated RSV (FI-RSV). We showed that both IL-4 and IL-13 activity must be inhibited to modulate G-specific responses resulting in severe RSV-induced disease. Inhibition of IL-4 or IL-13 activity alone had minimal impact on disease in vvGs-immunized mice. However, treatment of IL-4-deficient mice with IL-13Ra during vvGs immunization reduced IL-5, IL-13, and eotaxin production and pulmonary eosinophilia after RSV challenge. In contrast, FI-RSV-induced immune responses were diminished when either IL-4 or IL-13 activity was blocked. After RSV challenge, these type 2 T cell responses were also diminished in vvGs-primed IL-4Ralpha-deficient mice. Our data suggest that secreted vvGs uses mechanisms requiring signaling through the IL-4Ralpha-chain by either IL-4 or IL-13 for induction of eosinophilia and is the first description of the relative contributions of IL-4, IL-13, and their receptors in viral pathogenesis.

Animals↗
PubMed1998

Tiagabine: a new therapeutic option for people with intellectual disability and partial epilepsy.

Tiagabine exerts its antiepileptic drug (AED) activity by selectively inhibiting the uptake of gamma-aminobutyric acid (GABA) onto the transporter molecules, and thus, increasing extracellular concentrations of GABA in the brain. The absorption and elimination of tiagabine follow linear pharmacokinetics. Tiagabine is metabolized by hepatic cytochrome P450 enzymes and enzyme-inducing AEDs increase tiagabine clearance by 50-65%. Tiagabine has shown no clinically important interactions with other drugs, including oral contraceptives. In the perforant pathway stimulation model of status epilepticus, tiagabine reduced the seizure number and severity, and also prevented the loss of pyramidal cells in the hippocampus as well as alleviated impairment of the spatial memory impairment associated with hippocampal damage. Tiagabine has both antiepileptogenic and anticonvulsant effects in the kindling model of epilepsy. Based on the data from the short- and long-term add-on studies, tiagabine is effective adjunctive therapy for all partial seizure types in adolescents and adults. Conversion to tiagabine monotherapy has been also possible in substantial amount of patients with partial seizures in three trials. Tiagabine is generally well-tolerated. The most common adverse events in controlled studies involve the central nervous system; for example, dizziness, asthenia, nervousness, tremor, depressed mood and emotional lability. Special safety analyses with formal neuropsychological testing suggest that tiagabine does not adversely affect cognition or mood. Tiagabine represents an important new therapeutic option for patients with treatment-refractory partial seizures. The role of tiagabine in the management of partial epilepsy of patients with intellectual disability is especially emphasized since tiagabine has a low side-effect profile in the cognitive area.

Adult↗
PubMed1998

Evaluating and improving the delivery of heart care: the University of Michigan experience.

With increasing pressure to curb escalating costs in medical care, there is particular emphasis on the delivery of cardiovascular services, which account for a substantial portion of the current healthcare dollar spent in the United States. A variety of tools were used to improve performance at the University of Michigan Health System, one of the oldest university-affiliated hospitals in the United States. The tools included initiatives to understand outcomes after coronary bypass operations and coronary angioplasty through use of proper risk-adjusted models. Critical pathways and guidelines were implemented to streamline care and improve quality in interventional cardiology, management of myocardial infarction, and preoperative assessment of patients undergoing vascular operations. Strategies to curb unnecessary costs included competitive bidding of vendors for expensive cardiac commodities, pharmacy cost reductions, and changes in nursing staff. Methods were instituted to improve guest services and partnerships with the community in disease prevention and health promotion.

Cardiology Service, Hospital↗