Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Pathways”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

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

At least 1,603 records · Page 89Linked to original sources
PubMed1996

Wound care clinical pathway: a conceptual model.

A clinical pathway is a written sequence of clinical processes or events that guides a patient with a defined problem toward an expected outcome. Clinical pathways are tools to assist with the cost-effective management of clinical outcomes related to specific problems or disease processes. The primary obstacles to developing clinical pathways for wound care are the chronic natures of some wounds and the many variables that can delay healing. The pathway introduced in this article was modeled upon the three phases of tissue repair: inflammatory, proliferative, and maturation. This physiology-based model allows clinicians to identify and monitor outcomes based on observable and measurable clinical parameters. The pathway design, which also includes educational and behavioral outcomes, allows the clinician to individualize the expected timeframe for outcome achievement based on individual patient criteria and expert judgement. Integral to the pathway are the "4P's" which help standardize the clinical processes by wound type: Protocols, Policies, Procedures, and Patient education tools. Four categories into which variances are categorized based on the cause of the deviation from the norm are patient, process/system, practitioner, and planning/discharge. Additional research is warranted to support the value of this clinical pathway in the clinical arena.

Cost-Benefit Analysis↗
PubMedDate not supplied

Making the transition to critical pathways--a community behavioral health center's approach.

BACKGROUND: Shawnee Hills, Inc., formally began the transition to critical pathways in January 1996. The goal was to design and implement a service delivery model with clearly defined clinical paths and appropriate and functional technical support systems. No specific goal date for full implementation was designated; however, the intent was to move into the new system in a manner that allowed both consumer and employee participation in the planning process and to accommodate the organization's transition from a fee-for-service to a capitated model of contracting for services. The target date for completion of phase one, research and initial planning, was March 1, 1996. Although there were a number of benefits anticipated in adopting the critical paths method (CPM), the primary rationale was threefold: (1) standardizing the quality of care and treatment, (2) cost containment, and (3) better positioning of the organization for success within a capitated funding environment. A review of the publications indicated that the CPM had proved to be effective in other healthcare fields. In addition, the goals and approaches inherent within the CPM were consistent with the organization's total quality management (TQM) philosophy and operational practices. METHOD: By using the approach common to the organization since the adoption of the principles and practices of TQM in early 1992, a team was appointed with the mission of reengineering the clinical services delivery model. Unlike previous instances, however, this team was comprised largely of senior leadership, and two staff members were assigned on a full-time basis. A more detailed review of publications was conducted and, where possible, identification of critical pathways developed within the mental health field in other states were secured. Focus groups were used to address "best" or "preferred" practices for specific populations and age groups. Team members provided an orientation to the process, along with the opportunity to critique proposed pathways and models for service delivery as they were drafted to all employees through participation in ongoing staff development efforts. The center leadership was kept informed and was provided additional opportunities for input through regular presentations to the Quality Council that meets on a weekly basis. RESULTS: The first phase of the transition, research and initial planning, was completed on March 1, 1996. To date, the team has adopted or developed initial drafts of proposed clinical pathways for frequently occurring diagnoses within adult and child mental health, adult and child substance abuse, and specific to early childhood for the mental retarded or developmentally delayed. A model for clinical pathways was developed incorporating the JCAHO requirements to address assessment, care, and education at the major junctures of service delivery. In addition, the team formulated recommendations specific to priority areas for each major pathway and the approach to be taken in the transition from a fee-for-service to a capitated environment. A service delivery model built around acute care and continuing care was outlined, but remains a work-in-progress at this time. Finalizing the model and the completion of the clinical pathways for specific diagnostic groupings are two priorities for the second phase, product development-continued planning and transition, now underway. CONCLUSIONS: Although the effort is very much outcomes-oriented, data are not available at this early stage in the process. (ABSTRACT TRUNCATED)

Adult↗
PubMedDate not supplied

Determining the cost of care through clinical pathways.

Using the steps from the first approach, the costing of clinical pathways is useful to both the clinical and administrative teams. With knowledge of pathway cost, clinicians can plan cost-effective changes in the pathway or consider cost factors when deliberating on different approaches to care. Using the patient classification system to unbundle the nursing component and using the number of nursing hours per day of care provides an opportunity to describe the intensity of the pathway in its entirety, and by each day of care. One is provided with an opportunity to learn from the cost variances by reviewing the standardized costs for the pathway, and the actual cost of care of patients on the pathway provides an opportunity to learn from the cost variances. This learning, coupled with the clinical variance analysis, can suggest new opportunities for improving care and potential cost savings. Lastly, the cost associated with a pathway is useful knowledge in negotiating managed care contracts.$

Acute Disease↗
PubMed1997

Connections of the hippocampal formation in humans: II. The endfolial fiber pathway.

We investigated the anatomical connections of the pyramidal neurons located within the hilar region of the dentate gyrus of the human hippocampus, neurons which do not have a rodent equivalent. The myeloarchitectural patterns of the human hippocampus indicated the presence of a distinct fiber pathway, the endfolial fiber pathway, in the stratum oriens of the hilus and field CA3. By using the fluorescent lipophilic dye DiI in formalin-fixed human hippocampal tissue, we demonstrated that this is a continuous fiber pathway between the deep hilar region and CA2. This fiber pathway did not enter the fimbria or alveus along the entire distance of the traced pathway and ran exclusively in the stratum oriens of the hilus and CA3. Tracing studies with biocytin in in vitro human hippocampal slices indicated that the hilar and CA3 pyramidal neurons contributed to this pathway. Out distally in field CA3, the long transverse fibers became short and choppy, suggesting that they were beginning to move out of the plane of the tissue slice. Numerous fibers from this pathway were seen crossing the pyramidal layer. Based on comparative studies, we propose that the endfolial fiber system is a component of the hilar Schaffer collateral system in humans. The presence of a significant Schaffer collateral system from the pyramidal neurons in the hilar region would indicate that these neurons are anatomically related to the CA3 pyramidal neurons. Therefore, we suggest the inclusion of the human hilar pyramidal neurons within Lorente de No's field CA3 and, in particular, within subfield CA3c.

Adult↗
PubMed1996

Tyrosine kinase but not phospholipid/Ca2+ signaling pathway is involved in interferon-gamma stimulation of Ia expression in macrophages.

The specific signal transduction pathway(s) involved in the induction of the expression of the MHC class II molecule, Ia, on macrophages by interferon-gamma (IFN-gamma) is unclear. In this paper, we assessed the role of several signal transduction pathways including calcium mobilization, phospholipase C, protein kinase C and cyclic nucleotide-dependent protein kinase, and the tyrosine kinase pathways. IFN-gamma was unable to mobilize intracellular calcium, unlike platelet-activating factor, which stimulated a threefold increase in cytosolic Ca2+ concentration in macrophages. Inhibition of the phospholipase C pathway by U73122 or ET-180CH3 and of phosphatidic acid phosphohydrolase by propranolol did not suppress IFN-gamma-induced Ia expression. In addition, inhibition of protein kinase C by calphostin C or cyclic nucleotide-dependent protein kinase by HA1004 did not suppress Ia expression. However, IFN-gamma-induced Ia expression was significantly suppressed when the tyrosine kinase pathway was inhibited with herbimycin A and genestein. In addition, those two inhibitors suppressed tyrosine phosphorylation of several proteins in macrophages that may or may not be involved in the induction of Ia expression. Thus, IFN-gamma used only the tyrosine kinase signaling pathway, but not the phospholipid/Ca2+ signaling pathways, to induce Ia expression in macrophages.

Animals↗
PubMed2004

Fundamental Escherichia coli biochemical pathways for biomass and energy production: creation of overall flux states.

We have previously shown that the metabolism for most efficient cell growth can be realized by a combination of two types of elementary modes. One mode produces biomass while the second mode generates only energy. The identity of the four most efficient biomass and energy pathway pairs changes, depending on the degree of oxygen limitation. The identification of such pathway pairs for different growth conditions offers a pathway-based explanation of maintenance energy generation. For a given growth rate, experimental aerobic glucose consumption rates can be used to estimate the contribution of each pathway type to the overall metabolic flux pattern. All metabolic fluxes are then completely determined by the stoichiometries of involved pathways defining all nutrient consumption and metabolite secretion rates. We present here equations that permit computation of network fluxes on the basis of unique pathways for the case of optimal, glucose-limited Escherichia coli growth under varying levels of oxygen stress. Predicted glucose and oxygen uptake rates and some metabolite secretion rates are in remarkable agreement with experimental observations supporting the validity of the presented approach. The entire most efficient, steady-state, metabolic rate structure is explicitly defined by the developed equations without need for additional computer simulations. The approach should be generally useful for analyzing and interpreting genomic data by predicting concise, pathway-based metabolic rate structures.

Cell Division↗
PubMed1999

Irregularity of the ventricular rhythm during atrial fibrillation: effect of slow atrioventricular nodal pathway ablation.

BACKGROUND: The contribution of dual atrioventricular (AV) nodal pathway physiology to the irregularity of the ventricular rhythm during atrial fibrillation has not been clarified. HYPOTHESIS: This study was performed to assess the effects of slow AV nodal pathway ablation on the irregularity of the ventricular rhythm during atrial fibrillation. METHODS: Irregularity of the ventricular rhythm was quantified using analysis of heart rate variability. In 20 patients with AV nodal reentrant tachycardia, absolute heart rate variability during atrial fibrillation was quantified before and after slow AV nodal pathway ablation by the standard deviation of all NN intervals (SDNN). Relative heart rate variability was determined by computing the coefficient of variation, SDNN normalized for the standard deviation of the mean ventricular cycle length (MVCL-AF). RESULTS: The slope of the regression between MVCL-AF and SDNN was significantly more gradual after slow pathway ablation (slope 0.39 vs. 0.23, p < 0.001). Coefficient of variation increased in 12 patients with heart rates > 120 beats/min at baseline (18.6 +/- 3.9 vs. 22.1 +/- 2.7% MVCL-AF, p < 0.05), but decreased in 8 patients with heart rates < 120 beats/min at baseline (25.6 +/- 3.1 vs. 22.2 +/- 2.2% MVCL-AF, p = 0.05). Furthermore, coefficient of variation correlated with MVCL-AF only at baseline (slope 0.034, r = 0.66), but no relation was found after slow pathway ablation (slope 0, r = 0). CONCLUSIONS: Slow AV nodal pathway ablation alters the relation between absolute heart rate variability and mean ventricular rate during atrial fibrillation and eliminates cycle length dependency of relative heart rate variability. These data indicate that dual AV nodal pathway physiology contributes to the irregularity of the ventricular rhythm during atrial fibrillation.

Adult↗
PubMedDate not supplied

Glucose-stimulated signaling pathways in biphasic insulin secretion.

Glucose-stimulated biphasic insulin secretion involves at least two signaling pathways, the KATP channel-dependent and KATP channel-independent pathways, respectively. In the former, enhanced glucose metabolism increases the cellular adenosine triphosphate/adenosine diphosphate (ATP/ADP) ratio, closes KATP channels and depolarizes the cell. Activation of voltage-dependent Ca(2+) channels increases Ca(2+) entry and [Ca(2+)]i and stimulates insulin release. The KATP channel-independent pathways augment the response to increased [Ca(2+)]i by mechanisms that are currently unknown. However, they affect different pools of insulin-containing granules in a highly coordinated manner. The beta-cell granule pools can be minimally described as reserve, morphologically docked, readily and immediately releasable. Activation of the KATP channel-dependent pathway results in exocytosis of an immediately releasable pool that is responsible for the first phase of glucose-stimulated insulin release. Following glucose metabolism, the rate-limiting step for the first phase lies in the rate of signal transduction between sensing the rise in [Ca(2+)]i and exocytosis of the immediately releasable granules. The immediately releasable pool of granules can be enlarged by previous exposure to glucose (by time-dependent potentiation, TDP), and by second messengers such as cyclic adenosine monophosphate (cyclic AMP) and diacylglycerol (DAG). The second phase of glucose-stimulated insulin secretion is due mainly to the KATP channel-independent pathways acting in synergy with the KATP channel-dependent pathway. The rate-limiting step here is the conversion of readily releasable granules to the state of immediate releasability, following which, in an activated cell they will undergo exocytosis. In the rat and human beta-cell the KATP channel-independent pathways induce a time-dependent increase in the rate of this step that results in the typical rising second-phase response. In the mouse beta-cell the rate appears not to be changed much by glucose. Potential intermediates involved in controlling the rate-limiting step include increases in cytosolic long-chain acyl-CoA levels, adenosine triphosphate (ATP) and guanosine triphosphate (GTP), DAG binding proteins, including some isoforms of protein kinase (PKC), and protein acyl transferases. Agonists that can change the rate-limiting steps for both phases of insulin release include those like glucagon-like peptide 1 (GLP-1) that raise cyclic AMP levels and those like acetylcholine that act via DAG.

Adenosine Triphosphate↗
PubMed2004

Embryonic myogenesis pathways in muscle regeneration.

Embryonic myogenesis involves the staged induction of myogenic regulatory factors and positional cues that dictate cell determination, proliferation, and differentiation into adult muscle. Muscle is able to regenerate after damage, and muscle regeneration is generally thought to recapitulate myogenesis during embryogenesis. There has been considerable progress in the delineation of myogenesis pathways during embryogenesis, but it is not known whether the same signaling pathways are relevant to muscle regeneration in adults. Here, we defined the subset of embryogenesis pathways induced in muscle regeneration using a 27 time-point in vivo muscle regeneration series. The embryonic Wnt (Wnt1, 3a, 7a, 11), Shh pathway, and the BMP (BMP2, 4, 7) pathway were not induced during muscle regeneration. Moreover, antagonists of Wnt signaling, sFRP1, sFRP2, and sFRP4 (secreted frizzled-related proteins) were significantly up-regulated, suggesting active inhibition of the Wnt pathway. The pro-differentiation FGFR4 pathway was transiently expressed at day 3, commensurate with expression of MyoD, Myogenin, Myf5, and Pax7. Protein verification studies showed fibroblast growth factor receptor 4 (FGFR4) protein to be strongly expressed in differentiating myoblasts and newly formed myotubes. We present evidence that FGF6 is likely the key ligand for FGFR4 during muscle regeneration, and further suggest that FGF6 is released from necrotic myofibers where it is then sequestered by basal laminae. We also confirmed activation of Notch1 in the regenerating muscle. Finally, known MyoD coactivators (MEF2A, p/CIP, TCF12) and repressors (Twist, Id2) were strongly induced at appropriate time points. Taken together, our results suggest that embryonic positional signals (Wnt, Shh, and BMP) are not induced in postnatal muscle regeneration, whereas cell-autonomous factors (Pax7, MRFs, FGFR4) involving muscle precursor proliferation and differentiation are recapitulated by muscle regeneration.

Animals↗
PubMed2005

Effects of parathyroid hormone on Wnt signaling pathway in bone.

The Wnt signaling pathway has recently been demonstrated to play an important role in bone cell function. In previous studies using DNA microarray analyses, we observed a change in some of the molecular components of the canonical Wnt pathway namely, frizzled-1 (FZD-1) and axil, in response to continuous parathyroid hormone (PTH) treatment in rats. In the present study, we further explored other components of the Wnt signaling pathway in rat distal metaphyseal bone in vivo, and rat osteoblastic osteosarcoma cells (UMR 106) in culture. Several Wnt pathway components, including low-density lipoprotein-receptor-related protein 5 (LRP5), LRP6, FZD-1, Dickkopf-1 (Dkk-1), and Kremen-1 (KRM-1), were expressed in bone in vivo and in osteoblasts in vitro. Continuous exposure to PTH (1-38) both in vivo and in vitro upregulated the mRNA expression of LRP6 and FZD-1 and decreased LRP5 and Dkk-1. These effects in UMR 106 cells were associated with an increase in beta-catenin as measured by Western blots and resulted in functional activation (three to six-fold) of a downstream Wnt responsive TBE6-luciferase (TCF/LEF-binding element) reporter gene. Activation of the TBE6-luciferase reporter gene by PTH (1-38) in UMR 106 cells was inhibited by the protein kinase A (PKA) inhibitor, H89. Activation was mimicked by PTH (1-31), PTH-related protein (1-34), and forskolin, but both PTH (3-34) and (7-34) had no effect. These findings suggest that the effect of PTH on the canonical Wnt signaling pathway occurs at least in part via the cAMP-PKA pathway through the differential regulation of the receptor complex proteins (FZD-1/LRP5 or LRP6) and the antagonist (Dkk-1). Taken together, these results reveal a possible role for the Wnt signaling pathway in PTH actions in bone.

Animals↗
PubMed2006

Regulation of bone formation by adiponectin through autocrine/paracrine and endocrine pathways.

Since interaction between bone and lipid metabolism has been suggested, this study investigated the regulation of bone metabolism by adiponectin, a representative adipokine, by analyzing deficient and overexpressing transgenic mice. We initially confirmed that adiponectin and its receptors were expressed in osteoblastic and osteoclastic cells, indicating that adiponectin can act on bone not only through an endocrine pathway as a hormone secreted from fat tissue, but also through an autocrine/paracrine pathway. There was no abnormality in bone mass or turnover of adiponectin-deficient (Ad-/-) mice, possibly due to an equivalent balance of the two pathways. In the culture of bone marrow cells from the Ad-/- mice, osteogenesis was decreased compared to the wild-type (WT) cell culture, indicating a positive effect of endogenous adiponectin through the autocrine/paracrine pathway. To examine the endocrine action of adiponectin, we analyzed transgenic mice overexpressing adiponectin in the liver, and found no abnormality in the bone. Addition of recombinant adiponectin in cultured osteoprogenitor cells suppressed osteogenesis, suggesting that the direct action of circulating adiponectin was negative for bone formation. In the presence of insulin, however, this suppression was blunted, and adiponectin enhanced the insulin-induced phosphorylations of the main downstream molecule insulin receptor substrate-1 and Akt. These lines of results suggest three distinct adiponectin actions on bone formation: a positive action through the autocrine/paracrine pathway by locally produced adiponectin, a negative action through the direct pathway by circulating adiponectin, and a positive action through the indirect pathway by circulating adiponectin via enhancement of the insulin signaling.

Adiponectin↗
PubMed1982

Stimulation of the hexosemonophosphate-pentose pathway by pyrroline-5-carboxylate in cultured cells.

delta 1-Pyrroline-5-carboxylic acid, an intermediate in the interconversions of proline, ornithine, and glutamate, is a potent stimulator of glucose oxidation through the hexosemonophosphate-pentose pathway. The effect is observed in cultured human fibroblasts, Chinese hamster ovary cells (CHO-K1), and rabbit kidney cells (LLC-RK1). In human fibroblasts, the magnitude of the stimulation of the hexosemonophosphate-pentose pathway is dependent on the concentration of added pyrroline-5-carboxylate and the effect is observed over a wide range of glucose concentrations. The mechanism of the effect is related to the generation of oxidizing potential in the form of NADP+ by pyrroline-5-carboxylate reductase concomitant with the conversion of pyrroline-5-carboxylate to proline. In LLC-RK1 cells, a cell line unique in having proline oxidase activity, proline also stimulated hexosemonophosphate-pentose pathway activity. Although pyrroline-5-carboxylate markedly stimulated the hexosemonophosphate-pentose pathway, it has no effect on glucose metabolism in the Embden-Meyerhof pathway or the tricarboxylic acid cycle. Since the hexosemonophosphate-pentose pathway is a source of ribose-5-phosphate, the precursor of phosphoribosyl pyrophosphate, the effect of pyrroline-5-carboxylate on the hexosemonophosphate-pentose pathway may link amino acid and nucleic acid metabolism.

Animals↗
PubMed1991

Multiple pathways for ligand internalization in rat hepatocytes. II: Effect of hyperosmolarity and contribution of fluid-phase endocytosis.

In a companion report (Moss and Ward: J. Cell. Physiol 149:313-318, 1991) evidence was presented for multiple pathways for insulin internalization based on differences between the internalization of insulin and that of two other ligands, asialofetuin (Afet) and epidermal growth factor (EGF), in the presence of several perturbations of endocytosis. In the present study we have explored the characteristics of three internalization pathways and the contribution of each to overall insulin uptake. Freshly isolated hepatocytes were incubated with radiolabeled ligands in the presence of hyperosmolar sucrose, treatment that is thought to inhibit the coated pit pathway of endocytosis. Insulin internalization was decreased approximately 39%, but much greater decreases were observed with Afet (86%) and EGF (62%). Competition between uptake of radiolabeled and unlabeled insulin was observed in hyperosmolar-treated cells, suggestive of endocytosis by a receptor-mediated noncoated-pit pathway. Uptake of radiolabeled insulin that persisted in the presence of hyperosmolarity and high concentrations of unlabeled insulin suggested a third uptake pathway: fluid-phase endocytosis. A rate of fluid-phase endocytosis of 7.2 microL/hr/10(6) cells was determined from the uptake of the fluid-phase marker lucifer yellow. At high insulin concentrations (greater than or equal to 250 ng/ml), fluid-phase endocytosis appears to be the predominant pathway for insulin uptake, but at lower insulin concentrations (physiological) the coated pit and noncoated pit pathways are the primary routes for insulin internalization.

Animals↗
PubMed2002

Generation of free radicals and induction of DNA adducts by activation of heterocyclic aromatic amines via different metabolic pathways in vitro.

Food-derived heterocyclic aromatic amines (HCAs) have proved to be carcinogenic in both rodents and nonhuman primates. Two different metabolic pathways are suggested for the metabolic activation of HCA. The hepatic pathway proceeds via a two-step process involving N-hydroxylation by cytochrome P4501A2 and subsequent O-acetylation by N-acetyltransferase-2. An alternative pathway may be of particular interest in extrahepatic tissues and proceeds via one-electron oxidation catalyzed by prostaglandin H synthase (PHS), rendering free-radical metabolites. In this study, we investigated the metabolic activation of two HCAs, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), by two different enzyme systems in vitro, generating different primary and secondary reactive metabolites. Rat liver S9 mix and PHS were used as the activating system and represent the hepatic and extrahepatic pathways, respectively. Electron-spin resonance spectroscopy showed that both IQ and PhIP exerted inhibiting effects on PHS-mediated formation of hydroxyl radicals during the conversion of arachidonic acid to prostaglandins. Evidence for the formation of HCA free radicals was presented in an indirect way by the formation of glutathione-derived thiyl radicals, with purified PHS as the activating system. Activation by S9 mix did not result in the formation of detectable radical metabolites, showing that the two metabolic routes primarily led to the formation of different metabolites. In all electron-spin resonance experiments, IQ appeared to be more effective than PhIP. In contrasts, DNA adduct analysis by means of (32)P-postlabeling showed similar adduct patterns for S9 and PHS in single-stranded and double-stranded salmon testes DNA after incubation with PhIP, indicating the ultimate formation of a common reactive intermediate. For IQ, activation by PHS led to an additional adduct spot that was not present after S9 activation. Furthermore, activation of IQ resulted in higher adduct levels compared with PhIP for both activation pathways. Overall, adduct levels were higher in single-stranded DNA than double-stranded DNA. Our results showed that the hepatic and extrahepatic pathways resulted in different primary metabolites, while the ultimate formation of a similar reactive intermediate for PhIP, possibly an arylnitrenium ion, suggested that both pathways could play an important role in the onset of carcinogenesis.

Amines↗
PubMed1995

Dynamics and organization of MAP kinase signal pathways.

In the budding yeast, Saccharomyces cerevisiae, four separate but structurally related mitogen-activated protein kinase (MAPK) activation pathways are known. The best understood of these regulates mating. Pheromone binding to receptor informs cells of the proximity of a mating partner and induces differentiation to a mating competent state. The MAPK activation cascade mediating this signal is made up of Ste11 (a MEK kinase [MEKK]), Ste7 (a MAPK/ERK kinase [MEK]), and the redundant MAPK-related Fus3 and Kss1 enzymes. Another MAPK activation pathway is important for cell integrity and regulates cell wall construction. This cascade consists of Bck1 (a MEKK), the redundant Mkk1 and Mkk2 enzymes (MEKs), and Mpk1 (a MAPK). We exploited these two pathways to learn about the coordination and signal transmission fidelity of MAPK activation cascades. Two lines of evidence suggest that the activities of the mating and cell integrity pathways are coordinated during mating differentiation. First, cells deficient in Mpk1 are susceptible to lysis when they make a mating projection in response to pheromone. Second, Mpk1 activation during pheromone induction coincides with projection formation. The mechanism underlying this coordination is still unknown to us. Our working model is that projection formation generates a mobile second messenger for activation of the cell integrity pathway. Analysis of a STE7 mutation gave us some unanticipated but important insights into parameters important for fidelity of signal transmission. The Ste7 variant has a serine to proline substitution at position 368. Ste7-P368 has higher basal activity than the wild-type enzyme but still requires Ste11 for its function. Additionally, the proline substitution enables the variant to transmit the signal from mammalian Raf expressed in yeast. This novel activity suggests that Ste7-P368 is inherently more permissive than Ste7 in its interactions with MEKKs. Yet, Ste7-P368 cross function in the cell integrity pathway occurs only when it is highly overproduced or when Ste5 is missing. This behavior suggests that Ste5, which has been proposed to be a tether for the kinases in the mating pathway, contributes to Ste7 specificity and fidelity of signal transmission.

Calcium-Calmodulin-Dependent Protein Kinases↗
PubMed2006

Development pathways in learning to be a physiotherapist.

BACKGROUND AND PURPOSE: Few studies have examined the experiences of students' professional socialization in physiotherapy. This international longitudinal study aimed to study experiences of situated learning and change in a student cohort during a physiotherapy education programme. METHOD: A phenomenographic design with semi-structured interviews was carried out with a cohort of physiotherapy students from two sites, strategically selected for variation in gender, age, educational background, work experience and academic level. Interviews were carried out after each of the first five semesters in the programme by a team of researchers. Seventy-six interviews explored students' learning experiences. Analysis identified the variation in experiences seen as important to becoming a physiotherapist. RESULTS: Distinct perceptions of professional growth and progression are identified in four pathways of development: 'Reflecting on Practice'; 'Communicating with Others'; 'Performing Skills'; and 'Searching Evidence'. These pathways demonstrate qualitative differences in the focus of learning experiences and preferred learning context, and include learning in a context which supports reflection, learning as agreed by others in a context with patients and other professionals, learning physiotherapy skills in a practice context and learning formal knowledge in a context where theory can be linked with practice. CONCLUSIONS: In a cohort of students professional growth can be seen in a variety of development pathways. Each shows progress of professional growth in the 'what' as changes in experiences and the 'how' as ways of learning from them. In addition, the pattern of pathways in a cohort may change from one semester to another suggesting individuals may adopt different learning pathways throughout their education. Teaching staff are challenged to consider how they recognize a variation in development pathways in their student cohorts and how they purposefully ensure experiences to guide students through different learning pathways in socialization to become a physiotherapist.

Clinical Competence↗
PubMed2005

Water dynamics simulation as a tool for probing proton transfer pathways in a heptahelical membrane protein.

The proton transfer pathway in a heptahelical membrane protein, the light-driven proton pump bacteriorhodopsin (BR), is probed by a combined approach of structural analysis of recent X-ray models and molecular dynamics (MD) simulations that provide the diffusion pathways of internal and external water molecules. Analyzing the hydrogen-bond contact frequencies of the water molecules with protein groups, the complete proton pathway through the protein is probed. Beside the well-known proton binding sites in the protein interior-the protonated Schiff base, Asp85 and Asp96, and the H(5)O(2) (+) complex stabilized by Glu204 and Glu194-the proton release and uptake pathways to the protein surfaces are described in great detail. Further residues were identified, by mutation of which the proposed pathways can be verified. In addition the diffusion pathway of water 502 from Lys216 to Asp96 is shown to cover the positions of the intruding waters 503 and 504 in the N-intermediate. The transiently established water chain in the N-state provides a proton pathway from Asp96 to the Schiff base in the M- to N-transition in a Grotthus-like mechanism, as concluded earlier from time-resolved Fourier transform infrared experiments [le Coutre et al., Proc Nat Acad Sci USA 1995;92:4962-4966].

Aspartic Acid↗
PubMed2006

Computational exploration of the activated pathways associated with DNA damage response in breast cancer.

Molecular signaling events regulate cellular activity. Cancer stimulating signals trigger cellular responses that evade the regulatory control of cell development. To understand the mechanism of signaling regulation in cancer, it is necessary to identify the activated pathways in cancer. We have developed RepairPATH, a computational algorithm that explores the activated signaling pathways in cancer. The RepairPATH integrates RepairNET, an assembled protein interaction network associated with DNA damage response, with the gene expression profiles derived from the microarray data. Based on the observation that cofunctional proteins often exhibit correlated gene expression profiles, it identifies the activated signaling pathways in cancer by systematically searching the RepairNET for proteins with significantly correlated gene expression profiles. Analyzing the gene expression profiles of breast cancer, we found distinct similarities and differences in the activated signaling pathways between the samples from the patients who developed metastases and the samples from the patients who were disease free within 5 years. The cellular pathways associated with the various DNA repair mechanisms and the cell-cycle checkpoint controls are found to be activated in both sample groups. One of the most intriguing findings is that the pathways associated with different cellular processes are functionally coordinated through BRCA1 in the disease-free sample group, whereas such functional coordination is absent in the samples from patients who developed metastases. Our analysis revealed the potential cellular pathways that regulate the signaling events in breast cancer.

Algorithms↗