The role of mig6 in pancreas development and diabetes

Indiana University-Purdue University Indianapolis (IUPUI)Diabetes occurs as a result of the failure of pancreatic insulin-producing β cells. The preservation or renewal of β cells is a strategy that can prevent diabetes by targeted manipulation of mechanisms associated with autoimmune β cell destruction or β cell regeneration. ErbB signaling, specifically epidermal growth factor receptor (EGFR) signaling, is associated with cell survival, growth, and proliferation. Thus, we investigated the role of the ErbB inhibitor, mitogen-inducible gene 6 (mig6), in pancreas development and in the progression to diabetes. Using morpholino knockdown in a zebrafish model of development, we discovered that mig6 is required for the generation of α and β cells as well as the formation of the exocrine pancreas. We suspect that the loss of mig6 function causes premature differentiation of ductal progenitor cells, and acts as a switch between progenitor differentiation and endocrine transdifferentiation. Furthermore, we established a pancreas-specific mig6 knockout mouse that maintained glucose tolerance and had a higher β cell mass after chemically-induced β cell injury by way of increased β cell proliferation. Our data suggests that mig6 is required during pancreas development and may be employed as a switch to direct the production of new β cells, but that during adulthood, it is detrimental to the recovery of β cell mass, making it a therapeutic target for β cell preservation after the onset of diabetes

SEED: A framework for integrating ecological stoichiometry and eco‐evolutionary dynamics

Characterising the extent and sources of intraspecific variation and their ecological consequences is a central challenge in the study of eco‐evolutionary dynamics. Ecological stoichiometry, which uses elemental variation of organisms and their environment to understand ecosystem patterns and processes, can be a powerful framework for characterising eco‐evolutionary dynamics. However, the current emphasis on the relative content of elements in the body (i.e. organismal stoichiometry) has constrained its application. Intraspecific variation in the rates at which elements are acquired, assimilated, allocated or lost is often greater than the variation in organismal stoichiometry. There is much to gain from studying these traits together as components of an ‘elemental phenotype’. Furthermore, each of these traits can have distinct ecological effects that are underappreciated in the current literature. We propose a conceptual framework that explores how microevolutionary change in the elemental phenotype occurs, how its components interact with each other and with other traits, and how its changes can affect a wide range of ecological processes. We demonstrate how the framework can be used to generate novel hypotheses and outline pathways for future research that enhance our ability to explain, analyse and predict eco‐evolutionary dynamics

Neuroligin1: a cell adhesion molecule that recruits PSD-95 and NMDA receptors by distinct mechanisms during synaptogenesis

<p>Abstract</p> <p>Background</p> <p>The cell adhesion molecule pair neuroligin1 (Nlg1) and β-neurexin (β-NRX) is a powerful inducer of postsynaptic differentiation of glutamatergic synapses <it>in vitro</it>. Because Nlg1 induces accumulation of two essential components of the postsynaptic density (PSD) – PSD-95 and NMDA receptors (NMDARs) – and can physically bind PSD-95 and NMDARs at mature synapses, it has been proposed that Nlg1 recruits NMDARs to synapses through its interaction with PSD-95. However, PSD-95 and NMDARs are recruited to nascent synapses independently and it is not known if Nlg1 accumulates at synapses before these PSD proteins. Here, we investigate how a single type of cell adhesion molecule can recruit multiple types of synaptic proteins to new synapses with distinct mechanisms and time courses.</p> <p>Results</p> <p>Nlg1 was present in young cortical neurons in two distinct pools before synaptogenesis, diffuse and clustered. Time-lapse imaging revealed that the diffuse Nlg1 aggregated at, and the clustered Nlg1 moved to, sites of axodendritic contact with a rapid time course. Using a patching assay that artificially induced clusters of Nlg, the time course and mechanisms of recruitment of PSD-95 and NMDARs to those Nlg clusters were characterized. Patching Nlg induced clustering of PSD-95 via a slow palmitoylation-dependent step. In contrast, NMDARs directly associated with clusters of Nlg1 during trafficking. Nlg1 and NMDARs were highly colocalized in dendrites before synaptogenesis and they became enriched with a similar time course at synapses with age. Patching of Nlg1 dramatically decreased the mobility of NMDAR transport packets. Finally, Nlg1 was biochemically associated with NMDAR transport packets, presumably through binding of NMDARs to MAGUK proteins that, in turn, bind Nlg1. This interaction was essential for colocalization and co-transport of Nlg1 with NMDARs.</p> <p>Conclusion</p> <p>Our results suggest that axodendritic contact leads to rapid accumulation of Nlg1, recruitment of NMDARs co-transported with Nlg1 soon thereafter, followed by a slower, independent recruitment of PSD-95 to those nascent synapses.</p

Trajectories of self-rated health in people with diabetes: Associations with functioning in a prospective community sample

© 2013 Schmitz et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Background: Self-rated health (SRH) is a single-item measure that is one of the most widely used measures of general health in population health research. Relatively little is known about changes and the trajectories of SRH in people with chronic medical conditions. The aims of the present study were to identify and describe longitudinal trajectories of self-rated health (SRH) status in people with diabetes. Methods: A prospective community study was carried out between 2008 and 2011. SRH was assessed at baseline and yearly at follow-ups (n=1288). Analysis was carried out through trajectory modeling. The trajectory groups were subsequently compared at 4 years follow-up with respect to functioning. Results: Four distinct trajectories of SRH were identified: 1) 72.2% of the participants were assigned to a persistently good SRH trajectory; 2) 10.1% were assigned to a persistently poor SRH trajectory; 3) mean SRH scores changed from good to poor for one group (7.3%); while 4) mean SRH scores changed from poor to medium/good for another group (10.4%). Those with a persistently poor perception of health status were at higher risk for poor functioning at 4 years follow-up than those whose SRH scores decreased from good to poor. Conclusions: SRH is an important predictor for poor functioning in diabetes, but the trajectory of SRH seems to be even more important. Health professionals should pay attention to not only SRH per se, but also changes in SRH over time.This work was supported by Operating Grant MOP-84574 from the Canadian Institutes of Health Research (CIHR). GG was supported by a doctoral fellowship from the CIHR. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Assessment of the Variability in Influenza A(H1N1) Vaccine Effectiveness Estimates Dependent on Outcome and Methodological Approach

Estimation of Influenza vaccine effectiveness (VE) varies with study design, clinical outcome 10 considered and statistical methodology used. By estimating VE using differing outcomes and 11 statistical methods on the same cohort of individuals the variability in the estimates produced can 12 be better understood. The Pandemic Influenza Primary Care Reporting (PIPeR) cohort of approximately 193,000 individuals 14 was used to estimate pandemic VE in Scotland during season 2009-10. VE results for three 15 outcomes; influenza related consultations, virological confirmed influenza and death were 16 considered. Use of individualised records allowed all models to be adjusted for age, sex, 17 deprivation, risk status relating to chronic illnesses, seasonal vaccination status and a marker of the 18 individual’s propensity to consult. For the consultation and death outcomes, VE was calculated by 19 comparing consultation rates in the unvaccinated and vaccinated groups, adjusted for the listed 20 factors, using both Cox and Poisson regression models. For the consultation outcome, the 21 unvaccinated group was split into individuals before vaccination and those never vaccinated to allow 22 for potential differences in the health seeking behaviour of these groups. For the virology outcome 23 estimates were calculated using a generalised additive logistic regression model. All models were 24 adjusted for time. Vaccine effect was demonstrated for the influenza-like illness consultation outcome using the Cox 26 model (VE=49% 95% CI (19%, 67%)) with lower estimates from the model splitting the before and 27 never vaccinated groups (VE=34.2% with 95% CI (-0.5%, 58.9%)). Vaccine effect was also illustrated 28 for overall mortality (VE=40% (95% CI 18%, 56%)) and a virological confirmed subset of symptomatic 29 individuals (VE=60% (95% CI -38%, 89%))

Hypothalamic and brainstem glucose-dependent insulinotropic polypeptide receptor neurons employ distinct mechanisms to affect feeding

Central glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) signaling is critical in GIP-based therapeutics’ ability to lower body weight, but pathways leveraged by GIPR pharmacology in the brain remain incompletely understood. We explored the role of Gipr neurons in the hypothalamus and dorsal vagal complex (DVC) — brain regions critical to the control of energy balance. Hypothalamic Gipr expression was not necessary for the synergistic effect of GIPR/GLP-1R coagonism on body weight. While chemogenetic stimulation of both hypothalamic and DVC Gipr neurons suppressed food intake, activation of DVC Gipr neurons reduced ambulatory activity and induced conditioned taste avoidance, while there was no effect of a short-acting GIPR agonist (GIPRA). Within the DVC, Gipr neurons of the nucleus tractus solitarius (NTS), but not the area postrema (AP), projected to distal brain regions and were transcriptomically distinct. Peripherally dosed fluorescent GIPRAs revealed that access was restricted to circumventricular organs in the CNS. These data demonstrate that Gipr neurons in the hypothalamus, AP, and NTS differ in their connectivity, transcriptomic profile, peripheral accessibility, and appetite-controlling mechanisms. These results highlight the heterogeneity of the central GIPR signaling axis and suggest that studies into the effects of GIP pharmacology on feeding behavior should consider the interplay of multiple regulatory pathways

The transverse aortic constriction heart failure animal model: a systematic review and meta-analysis

The transverse aortic constriction (TAC) model is frequently used to study adverse cardiac remodeling upon pressure overload. We set out to define the most important characteristics that define the degree of cardiac remodeling in this model. A systematic review and meta-analyses were performed on studies using the TAC mouse/rat model and reporting echocardiographic outcome parameters. We included all animal studies in which a constriction around the transverse aorta and at least one of the predefined echocardiography or MRI outcome parameters were assessed. A total of 502 articles and > 3000 wild-type, untreated animals undergoing TAC were included in this study and referenced to a control group. The duration of aortic constriction correlated to the degree of adverse remodeling. However, the mouse data is strongly biased by the preferential use of male C57Bl/6 mice (66% of studies). Furthermore, mostly ketamine/xylazine anesthetics, 27G needle constriction, and silk sutures are used. Nonetheless, despite the homogeneity in experimental design, the model contained a substantial degree of heterogeneity in the functional outcome measures. When looking at study quality, only 12% reported randomization, 23% mentioned any sort of blinding, 25% adequately addressed the outcomes, and an amazingly low percentage (2%) showed sample size calculation. Meta-analyses did not detect specific study characteristics that explained the heterogeneity in the reported outcome measures, however this might be related to the strong bias towards the use of specific mouse lines, sex as well as age or to poor reporting of characteristics of study quality

The forgotten population? A call to invest in adolescent well-being in humanitarian and fragile settings

Adolescents are disproportionately affected in humanitarian and fragile settings, where they will often find themselves in high-risk situations and may be forced to take on adult roles within their families and communities. They are also more likely to have poor well-being outcomes related to disrupted or no access to optimum nutrition, health services and protection, as well as opportunities for education, training, and employment. Our paper aims to provide an overview of current interventions focusing on adolescent well-being and to provide a set of policy and programmatic recommendations to prevent long-term consequences of crisis and conflict on adolescents’ lives. According to the UN H6+ Technical Working Group on Adolescent Health and Well-beings’ framework for adolescent well-being, this article analyses adolescents’ backgrounds and interventions oriented to them within humanitarian and fragile settings. In this sense, we refer to five domains that include: good health and optimum nutrition; connectedness, positive values and contribution to society; safety and a supportive environment; learning, competence, education, skills and employability; and agency and resilience

Perceptions of Teachers’ Interpersonal Styles and Well-Being and Ill-Being in Secondary School Physical Education Students: The Role of Need Satisfaction and Need Frustration

This study examined the associations among physical education students’ perceptions of their teachers’ autonomy-supportive and controlling interpersonal styles, need satisfaction and need frustration, and indices of psychological well-being (subjective vitality) and ill-being (negative affect). The results from 591 Chinese secondary school students in Hong Kong indicated that the relationship between students’ perceptions of autonomy-supportive teaching behaviors and subjective vitality was primarily mediated by need satisfaction, whereas the relationship between perceived controlling teaching behaviors and negative affect was primarily mediated by need frustration. The results obtained from the multi-group structural equation model also suggested that these relationships were invariant across sex

A Prospective Multicenter Study Evaluating Learning Curves and Competence in Endoscopic Ultrasound and Endoscopic Retrograde Cholangiopancreatography Among Advanced Endoscopy Trainees: The Rapid Assessment of Trainee Endoscopy Skills (RATES) Study

Background and aims Based on the Next Accreditation System, trainee assessment should occur on a continuous basis with individualized feedback. We aimed to validate endoscopic ultrasound (EUS) and endoscopic retrograde cholangiopancreatography (ERCP) learning curves among advanced endoscopy trainees (AETs) using a large national sample of training programs and to develop a centralized database that allows assessment of performance in relation to peers. Methods ASGE recognized training programs were invited to participate and AETs were graded on ERCP and EUS exams using a validated competency assessment tool that assesses technical and cognitive competence in a continuous fashion. Grading for each skill was done using a 4-point scoring system and a comprehensive data collection and reporting system was built to create learning curves using cumulative sum analysis. Individual results and benchmarking to peers were shared with AETs and trainers quarterly. Results Of the 62 programs invited, 20 programs and 22 AETs participated in this study. At the end of training, median number of EUS and ERCP performed/AET was 300 (range 155-650) and 350 (125-500). Overall, 3786 exams were graded (EUS:1137; ERCP–biliary 2280, pancreatic 369). Learning curves for individual endpoints, and overall technical/cognitive aspects in EUS and ERCP demonstrated substantial variability and were successfully shared with all programs. The majority of trainees achieved overall technical (EUS: 82%; ERCP: 60%) and cognitive (EUS: 76%; ERCP: 100%) competence at conclusion of training. Conclusions These results demonstrate the feasibility of establishing a centralized database to report individualized learning curves and confirm the substantial variability in time to achieve competence among AETs in EUS and ERCP