An insulin receptor mutant (Asp707 → Ala), involved in leprechaunism, is processed and transported to the cell surface but unable to bind insulin

We have identified a homozygous mutation near the carboxyl terminus of the insulin receptor (IR) α subunit from a leprechaun patient, changing Asp707 into Ala. Fibroblasts from this patient had no high affinity insulin binding sites. To examine the effect of the mutation on IR properties, the mutant IR was stably expressed in Chinese hamster ovary cells. Western blot analysis and metabolic labeling showed a normal processing of the mutant receptor to α and β subunits. No increase in high affinity insulin binding sites was observed on Chinese hamster ovary cells expressing the mutant receptor, and also, affinity cross-linking of 125I- labeled insulin by disuccinimidyl suberate to these cells failed to label the mutant α subunit. Biotinylation of cell surface proteins by biotin succinimidyl ester resulted in efficient biotinylation of the mutant IR α and β subunits, showing its presence on the cell surface. On solubilization of the mutant insulin receptor in Triton X. 100-containing buffers, 125I- insulin was efficiently cross-linked to the receptor a subunit by disuccinimidyl suberate. These studies demonstrate that Ala707 IR is normally processed and transported to the cell surface and that the mutation distorts the insulin binding site. Detergent restores this site. This is an example of a naturally occurring mutation in the insulin receptor that affects insulin binding without affecting receptor transport and processing. This mutation points to a major contribution of the a subunit carboxyl terminus to insulin binding

Dynamic Interactive Social Cognition Training in Virtual Reality (DiSCoVR) versus Virtual Reality Relaxation (VRelax) for People With a Psychotic Disorder:A Single-Blind Multicenter Randomized Controlled Trial

BACKGROUND AND HYPOTHESIS: Social cognition training (SCT), an intervention for social cognition and social functioning, might be improved by using virtual reality (VR), because VR may offer better opportunities to practice in a potentially more realistic environment. To date, no controlled studies have investigated VR-SCT. This study investigated a VR-SCT, "DiSCoVR". We hypothesized that DiSCoVR would improve social cognition and social functioning. STUDY DESIGN: Participants were randomized to DiSCoVR (n = 41) or VR relaxation ('VRelax', n = 40), an active control condition, and completed 16 twice-weekly sessions. Three assessments (baseline, posttreatment, and 3-month follow-up) were performed by blinded assessors. The primary outcome was social cognition (emotion perception and theory of mind). Secondary outcomes included social functioning (measured with an interview and experience sampling), psychiatric symptoms, information processing, and self-esteem. Data were analyzed using mixed-models regression analysis. Treatment effects were evaluated by the time by condition interaction terms. STUDY RESULTS: No significant time by condition interactions were found for any of the outcome variables, indicating an absence of treatment effects. Between-group effect sizes ranged from negligible to moderate (Cohen's d < |0.53|). Main effects of time were found for several outcomes. CONCLUSIONS: These results suggest that DiSCoVR was not effective, possibly because of inadequate simulation of emotional expressions in VR. This lack of efficacy may indicate that current SCT protocols are relatively unsuitable for improving social functioning. Previous studies showed small to moderate effects on higher order social cognition, but the SCT approach may need critical reevaluation, as it may not sufficiently lead to functional improvement

Mutation in human CLPX elevates levels of δ-aminolevulinate synthase and protoporphyrin IX to promote erythropoietic protoporphyria

Loss-of-function mutations in genes for heme biosynthetic enzymes can give rise to congenital porphyrias, eight forms of which have been described. The genetic penetrance of the porphyrias is clinically variable, underscoring the role of additional causative, contributing, and modifier genes. We previously discovered that the mitochondrial AAA+ unfoldase ClpX promotes heme biosynthesis by activation of δ-aminolevulinate synthase (ALAS), which catalyzes the first step of heme synthesis. CLPX has also been reported to mediate heme-induced turnover of ALAS. Here we report a dominant mutation in the ATPase active site of human CLPX, p.Gly298Asp, that results in pathological accumulation of the heme biosynthesis intermediate protoporphyrin IX (PPIX). Amassing of PPIX in erythroid cells promotes erythropoietic protoporphyria (EPP) in the affected family. The mutation in CLPX inactivates its ATPase activity, resulting in coassembly of mutant and WT protomers to form an enzyme with reduced activity. The presence of low-activity CLPX increases the posttranslational stability of ALAS, causing increased ALAS protein and ALA levels, leading to abnormal accumulation of PPIX. Our results thus identify an additional molecular mechanism underlying the development of EPP and further our understanding of the multiple mechanisms by which CLPX controls heme metabolism. Keywords: heme biosynthesis; porphyria; ALAS; protein unfoldases; AAA+ ATPaseNational Institutes of Health (U.S.) (Grant F32 DK095726)National Institutes of Health (U.S.) (Grant R01 GM049224

Ageism and Dementia

This chapter explores the relationship between ageism and dementia. Although dementia is not an unavoidable consequence of ageing, increasing age is the biggest risk factor for having this disease. The prevalence of dementia increases exponentially with age and 95% of those with Alzheimer's Disease, the most common form of dementia, are aged 65 or over. Dementia often has strong negative connotations, partly driven by alarmist media portrayals of the disease, which means that people living with the condition can experience the `double stigma' of ageism and dementia-related discrimination. The stigma attached to dementia can have significant implications for quality of life through, for example, decreased social engagement, reduced self-esteem, increased carer burden and sub-standard healthcare, a situation that is exacerbated by low levels of diagnosis and inadequate training of medical professionals. Despite attempts by governments and not for profit organisations to tackle dementia-related stigma, there remains a strong need to raise awareness of the realities of living with dementia and to reduce the impact of discrimination. This chapter explores the inter-connections and overlaps between ageing and discrimination because someone has dementia. The relationship between dementia and age is discussed, followed by an exploration of the impacts of dementia-related stigma for the individual and society. The chapter continues by analysing the role of the media in fuelling stigma and how having dementia can impact on the receipt of health and social care services. The chapter explores the implications of dementia stigma for social engagement and ends by considering how perceptions of dementia are reflected in research funding

Versterken van veerkracht onder veranderende omstandigheden : operationele veerkracht als organisatievermogen : een introductie

Veerkrachtig vermogen is het vermogen om tijdens de operatie het werk aan te passen aan veranderende omstandigheden door strategieën, middelen en competenties anders te organiseren. In de dagelijkse praktijk verloopt de uitvoering van het werk (de ‘operatie’) niet altijd volgens het boekje. Omstandigheden zorgen soms voor verrassende situaties waar de gewone procedure niet meer bij past. Toch gaat de operatie vaak gewoon door. Veerkrachtig handelen zorgt ervoor dat verrassingen vroeg worden gesignaleerd en dat er vlot op kan worden gereageerd met aanpassingen in de werkwijze. Voor de organisatie i

Fostering resilience through changing realities. Introduction to operational resilience capabilities

The reality of operations does not always follow the book. Operational circumstances may develop into surprising situations that procedures have not accounted for. Still, we make things work. Resilient performance recognizes surprise early and acts upon it through adaptation, which is critical for an organization to succeed. It enables continued safe operations under changing circumstances in everyday or crisis situations by creating innovative ways to deal with progressively changing circumstances. As operational situations become increasingly complex and interconnected, the predictability of disruptions decreases. Consequently, resilience capability becomes more relevant to cope with unexpected situations. Achieving that requires aseamless understanding throughout the organization and the organization’s leadership team about what resilience means. Because of its implicit nature, resilience capability has not yet become part of organizational learning. TORC (Training for Operational Resilience Capabilities) aims to provide a reference guide for operational teams and management to recognize and facilitate resilience as a critical capability and take it out of the shadows of compliance. This booklet introduces the concept of operational resilience and guides you through the training and the TORC game, and it serves as a reference while the organization is maturing these concepts in day-to-day practice

Emergent risks to workplace safety as a result of IT connections of and between work equipment

The ever-greater integration of new technologies in work equipment is regarded by some as the fourth industrial revolution1 and referred to as ‘smart industry’2. Examples that come to mind include automation through the use of embedded software, remotely controlling heavy materials, and the connecting of work equipment to local and public networks such as the internet (for some examples, see the text box on page 6). As well as the opportunities this entails for industry, new threats are also presenting themselves. This includes employees who have to move among robots or autonomous freight vehicles, but also malicious actors who can penetrate computers and computer networks and thereby disrupt processes or bring them to a standstill. The focus in this report lies on the connection between work equipment and cyberspace, including connections to local and public networks such as the internet

Resilient risk management; het creeren van veerkrachtige operationele processen

Paper bij het NVVK Veiligheidscongres (N)iemand verantwoordelijk voor Veiligheid?! 16 en 17 maart 2011 Papendal, Arnhem gepresenteerd