Dataset Information

Parameter adaptations during phenotype transitions in progressive diseases.

ABSTRACT:

Background

The study of phenotype transitions is important to understand progressive diseases, e.g., diabetes mellitus, metabolic syndrome, and cardiovascular diseases. A challenge remains to explain phenotype transitions in terms of adaptations in molecular components and interactions in underlying biological systems.

Results

Here, mathematical modeling is used to describe the different phenotypes by integrating experimental data on metabolic pools and fluxes. Subsequently, trajectories of parameter adaptations are identified that are essential for the phenotypical changes. These changes in parameters reflect progressive adaptations at the transcriptome and proteome level, which occur at larger timescales. The approach was employed to study the metabolic processes underlying liver X receptor induced hepatic steatosis. Model analysis predicts which molecular processes adapt in time after pharmacological activation of the liver X receptor. Our results show that hepatic triglyceride fluxes are increased and triglycerides are especially stored in cytosolic fractions, rather than in endoplasmic reticulum fractions. Furthermore, the model reveals several possible scenarios for adaptations in cholesterol metabolism. According to the analysis, the additional quantification of one cholesterol flux is sufficient to exclude many of these hypotheses.

Conclusions

We propose a generic computational approach to analyze biological systems evolving through various phenotypes and to predict which molecular processes are responsible for the transition. For the case of liver X receptor induced hepatic steatosis the novel approach yields information about the redistribution of fluxes and pools of triglycerides and cholesterols that was not directly apparent from the experimental data. Model analysis provides guidance which specific molecular processes to study in more detail to obtain further understanding of the underlying biological system.

SUBMITTER: Tiemann CA

PROVIDER: S-EPMC3354367 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Parameter adaptations during phenotype transitions in progressive diseases.

Tiemann Christian A CA Vanlier Joep J Hilbers Peter A J PA van Riel Natal A W NA

BMC systems biology 20111026

<h4>Background</h4>The study of phenotype transitions is important to understand progressive diseases, e.g., diabetes mellitus, metabolic syndrome, and cardiovascular diseases. A challenge remains to explain phenotype transitions in terms of adaptations in molecular components and interactions in underlying biological systems.<h4>Results</h4>Here, mathematical modeling is used to describe the different phenotypes by integrating experimental data on metabolic pools and fluxes. Subsequently, traje ...[more]

PMID: 22029623

Similar Datasets

Project description:Rationale: Honeycombing on chest computed tomography (CT) has been described in diverse forms of interstitial lung disease (ILD); however, its prevalence and association with mortality across the spectrum of ILD remains unclear. Objective: To determine the prevalence and prognostic value of CT honeycombing and characterize associated mortality patterns across diverse ILD subtypes in a multicenter cohort. Methods: This was an observational cohort study of adult participants with multidisciplinary or adjudicated ILD diagnosis and documentation of chest CT imaging at index diagnosis across five U.S. hospitals (one tertiary and four nontertiary medical centers). Participants were stratified based on presence or absence of CT honeycombing. Vital status was determined from review of medical records and social security death index. Transplant-free survival was analyzed using univariate and multivariable Cox regression. Results: The sample comprised 1,330 participants (mean age, 66.8 yr; 50% men) with 4,831 person-years of follow-up. The prevalences of CT honeycombing were 42.0%, 41.9%, 37.6%, and 28.6% in chronic hypersensitivity pneumonitis, connective tissue disease-related ILD (CTD-ILD), idiopathic pulmonary fibrosis (IPF), and unclassifiable/other ILDs, respectively. Among those with CT honeycombing, cumulative mortality hazards were similar across ILD subtypes, except for CTD-ILD, which had a lower mortality hazard. Overall, the mean survival time was shorter among those with CT honeycombing (107 mo; 95% confidence interval [CI], 92-122 mo) than those without CT honeycombing (161 mo; 95% CI, 147-174 mo). CT honeycombing was associated with an increased mortality rate (hazard ratio, 1.72; 95% CI, 1.38-2.14) even after adjustment for center, sex, age, forced vital capacity, diffusing capacity, ILD subtype, and use of immunosuppressive therapy (hazard ratio, 1.62; 95% CI, 1.29-2.02). CT honeycombing was associated with an increased mortality rate within non-IPF ILD subgroups (chronic hypersensitivity pneumonitis, CTD-ILD, and unclassifiable/other ILD). In IPF, however, mortality rates were similar between those with and without CT honeycombing. Conclusions: CT honeycombing is prevalent in diverse forms of ILD and uniquely identifies a progressive fibrotic ILD phenotype with a high mortality rate similar to IPF. CT honeycombing did not confer additional risk in IPF, which is already known to be a progressive fibrotic ILD phenotype regardless of the presence of CT honeycombing.

Project description:BACKGROUND:KARS encodes lysyl- transfer ribonucleic acid (tRNA) synthetase, which catalyzes the aminoacylation of tRNA-Lys in the cytoplasm and mitochondria. Eleven families/sporadic patients and 16 different mutations in KARS have been reported to date. The associated clinical phenotype is heterogeneous ranging from early onset encephalopathy to isolated peripheral neuropathy or nonsyndromic hearing impairment. Recently additional presentations including leukoencephalopathy as predominant cerebral involvement or cardiomyopathy, isolated or associated with muscular and cerebral involvement, have been reported. A progressive Leukoencephalopathy with brainstem and spinal cord calcifications was previously described in a singleton patient and in two siblings, without the identification of the genetic cause. We reported here about a new severe phenotype associated with biallelic KARS mutations and sharing some common points with the other already reported phenotypes, but with a distinct clinical and neuroimaging picture. Review of KARS mutant patients published to date will be also discussed. RESULTS:Herein, we report the clinical, biochemical and molecular findings of 2 unreported Italian patients affected by developmental delay, acquired microcephaly, spastic tetraparesis, epilepsy, sensory-neural hypoacusia, visual impairment, microcytic hypochromic anaemia and signs of hepatic dysfunction. MRI pattern in our patients was characterized by progressive diffuse leukoencephalopathy and calcifications extending in cerebral, brainstem and cerebellar white matter, with spinal cord involvement. Genetic analysis performed on these 2 patients and in one subject previously described with similar MRI pattern revealed the presence of biallelic mutations in KARS in all 3 subjects. CONCLUSIONS:With our report we define the molecular basis of the previously described Leukoencephalopathy with Brainstem and Spinal cord Calcification widening the spectrum of KARS related disorders, particularly in childhood onset disease suggestive for mitochondrial impairment. The review of previous cases does not suggest a strict and univocal genotype/phenotype correlation for this highly heterogeneous entity. Moreover, our cases confirm the usefulness of search for common brain and spine MR imaging pattern and of broad genetic screening, in syndromes clinically resembling mitochondrial disorders in spite of normal biochemical assay.

Project description:BackgroundTinnitus is a common condition, especially prevalent among military Veterans. Progressive Tinnitus Management (PTM) is an interdisciplinary, structured, stepped-care approach to providing clinical services, including teaching coping skills, to people bothered by tinnitus. PTM has been shown to be effective at reducing functional distress, but implementation of the intervention outside of a research setting has not been studied, even though dissemination is underway within the Veterans Health Administration (VHA) system in the United States. This study was designed to address a gap in knowledge of PTM clinical implementation to date, with a focus on factors facilitating or hindering implementation in VHA audiology and mental health clinic contexts, and whether implementing sites had developed intervention adaptations.MethodsQualitative interviews were conducted with 21 audiology and mental health clinicians and service chiefs across a regional service network. Interviews were transcribed and coded using a hybrid inductive-deductive analytic approach guided by existing implementation research frameworks and then iteratively developed for emergent themes.ResultsPTM prioritization was rare overall, with providers across disciplines challenged by lack of capacity for implementation, but with differences by discipline in challenges to prioritization. Where PTM was prioritized and delivered, this was facilitated by perception of unique value, provider's own experience of tinnitus, observation/experience with PTM delivery, intervention fit with provider's skills, and an environment with supportive leadership and adaptive reserve. PTM was frequently adapted to local contexts to address delivery challenges and diversify patient options. Adaptations included shifting from group to individual formats, reducing or combining sessions, and employing novel therapeutic approaches.ConclusionsExisting adaptations highlight the need to better understand mechanisms underlying PTM's effectiveness, and research on the impact of adaptations on patient outcomes is an important next step. Prioritization of PTM is a key barrier to the scale up and spread of this evidence-based intervention. Developing clinician champions may facilitate dissemination, especially if accompanied by signals of systemic prioritization. Novel approaches exposing clinicians and administrators to PTM may identify and develop clinical champions. Acknowledging the potential for PTM adaptations may make delivery more feasible in the context of existing system constraints and priorities.

Dataset Information

Parameter adaptations during phenotype transitions in progressive diseases.

Background

Results

Conclusions

Publications

Parameter adaptations during phenotype transitions in progressive diseases.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets