Mechanism of PP2A-mediated IKKβ dephosphorylation: a systems biological approach

BACKGROUND: Biological effects of nuclear factor-kappaB (NF kappaB) can differ tremendously depending on the cellular context. For example, NF kappaB induced by interleukin-1 (IL-1) is converted from an inhibitor of death receptor induced apoptosis into a promoter of ultraviolet-B radiation (UVB)-induced apoptosis. This conversion requires prolonged NF kappaB activation and is facilitated by IL-1 + UVB-induced abrogation of the negative feedback loop for NF kappaB, involving a lack of inhibitor of kappaB (I kappaB alpha) protein reappearance. Permanent activation of the upstream kinase IKK beta results from UVB-induced inhibition of the catalytic subunit of Ser-Thr phosphatase PP2A (PP2Ac), leading to immediate phosphorylation and degradation of newly synthesized I kappaB alpha. RESULTS: To investigate the mechanism underlying the general PP2A-mediated tuning of IKK beta phosphorylation upon IL-1 stimulation, we have developed a strictly reduced mathematical model based on ordinary differential equations which includes the essential processes concerning the IL-1 receptor, IKK beta and PP2A. Combining experimental and modelling approaches we demonstrate that constitutively active, but not post-stimulation activated PP2A, tunes out IKK beta phosphorylation thus allowing for I kappaB alpha resynthesis in response to IL-1. Identifiability analysis and determination of confidence intervals reveal that the model allows reliable predictions regarding the dynamics of PP2A deactivation and IKK beta phosphorylation. Additionally, scenario analysis is used to scrutinize several hypotheses regarding the mode of UVB-induced PP2Ac inhibition. The model suggests that down regulation of PP2Ac activity, which results in prevention of I kappaB alpha reappearance, is not a direct UVB action but requires instrumentality. CONCLUSION: The model developed here can be used as a reliable building block of larger NF kappa B models and offers comprehensive simplification potential for future modeling of NF kappa B signaling. It gives more insight into the newly discovered mechanisms for IKK deactivation and allows for substantiated predictions and investigation of different hypotheses. The evidence of constitutive activity of PP2Ac at the IKK complex provides new insights into the feedback regulation of NF kappa B, which is crucial for the development of new anti-cancer strategies

Evaluation of a Workplace Disability Prevention Intervention in Canada: Examining Differing Perceptions of Stakeholders

Introduction Workplace disability prevention is important, but stakeholders can differ in their appreciation of such interventions. We present a responsive evaluation of a workplace disability prevention intervention in a Canadian healthcare organization. Three groups of stakeholders were included: designers of the intervention, deliverers, and workers. The aim was to examine the appreciation of this intervention by analyzing the discrepancies with respect to what these various stakeholders see as the causes of work disability, what the intervention should aim at to address this problem, and to what extent the intervention works in practice. Methods A qualitative research method was used, including data-triangulation: (a) documentary materials; (b) semi-structured interviews with the deliverers and workers (n = 14); (c) participatory observations of group meetings (n = 6); (d) member-checking meetings (n = 3); (e) focus-group meetings (n = 2). A grounded theory approach, including some ethnographic methodology, was used for the data-analysis. Results Stakeholders’ perceptions of causes for work disability differ, as do preferred strategies for prevention. Designers proposed work-directed measures to change the workplace and work organizations, and individual-directed measures to change workers’ behaviour. Deliverers targeted individual-directed measures, however, workers were mostly seeking work-directed measures. To assess how the intervention was working, designers sought a wide range of outcome measures. Deliverers focused on measurable outcomes targeted at reducing work time-loss. Workers perceived that this intervention offered short-term benefits yet fell short in ensuring sustainable return-to-work. Conclusion This study provides understanding of where discrepancies between stakeholders’ perceptions about interventions come from. Our findings have implications for workplace disability prevention intervention development, implementation and evaluation criteria

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Implementing Team-Based Innovation in Primary Health Care in British Columbia

Improving health services integration for patients with complex needs is a national priority in Canada. Health systems in all provinces grapple with the rising complexity of patients and the services they need. Team-based primary health care (PHC) models have been implemented in diverse ways to improve patients' experiences, increase the coordination of care, improve population health and reduce costs. While some provinces have more than two decades of experience with PHC teams, others such as British Colombia (BC) have made changes more recently. We conducted an in-depth analysis of 12 provincial policy documents produced since 2011 to study the evolution of interprofessional models in PHC. BC has integrated team-based care through overarching policy support and funding from the provincial government. Structural practice changes to support team-based care, such as Primary Care Networks (PCNs), were designed to address the quadruple aim, a framework designed to improve health system performance through integrated primary care. Policies have addressed the vision and goals of team-based care, but discussion of processes that support teams, such as a strategy for capitation-based funding and team composition, were non-specific. Finally, there is a significant need for a provincial strategy for continuous quality improvement and evaluation of reforms. Améliorer l'intégration des services de santé pour les patients ayant des besoins complexes est une priorité au Canada. Les systèmes de santé de toutes les provinces sont aux prises avec une augmentation du nombre des patients qui nécessitant des services complexes. Différents modèles variés de services de première ligne ont été mis en œuvre afin d'améliorer l'expérience des patients améliorer la coordination des services, améliorer la santé de la population ainsi que de  réduire les coûts. Si certaines provinces ont plus de vingt ans d'expérience dans la mise en place d'équipes de première ligne interdisciplinaires, d'autres provinces comme la Colombie-Britannique (CB) n'innovent que depuis peu. Nous avons mené une analyse approfondie de 12 politiques provinciales mise en place depuis 2011 pour étudier l'évolution des modèles interprofessionnels de première ligne. La CB a intégré des équipes de première ligne interdisciplinaires grâce à des politiques et des financements du gouvernement provincial. Les changements structurels pour soutenir le travail en équipe, comme les Réseaux de soins primaires (PCN), ont été conçus pour répondre au « quadruple objectif », qui est un cadre conceptuel pour améliorer la performance des systèmes de santé, par le biais de services de première ligne intégrés. Les politiques ont détaillé  les visions et objectifs des équipes de première ligne, mais les discussions sur les processus qui soutiennent ces équipes comme les stratégies de financement par capitation et la composition des équipes n’ont pas été explicitées. Enfin, il existe un besoin important d'une stratégie provinciale pour l'amélioration continue de la qualité et l'évaluation des réformes