The melanocortin receptors and their accessory proteins.

The five melanocortin receptors (MCRs) named MC1R-MC5R have diverse physiological roles encompassing pigmentation, steroidogenesis, energy homeostasis and feeding behavior as well as exocrine function. Since their identification almost 20 years ago much has been learnt about these receptors. As well as interacting with their endogenous ligands the melanocortin peptides, there is now a growing list of important peptides that can modulate the way these receptors signal, acting as agonists, antagonists, and inverse agonists. The discovery of melanocortin 2 receptor accessory proteins as a novel accessory factor to the MCRs provides further insight into the regulation of these important G protein-coupled receptor

Localisation of the melanocortin-2-receptor and its accessory proteins in the developing and adult adrenal gland

The melanocortin-2-receptor (MC2R)/MC2R accessory protein (MRAP) complex is critical to the production of glucocorticoids from the adrenal cortex. Inactivating mutations in either MC2R or MRAP result in the clinical condition familial glucocorticoid deficiency. The localisation of MC2R together with MRAP within the adrenal gland has not previously been reported. Furthermore, MRAP2, a paralogue of MRAP, has been shown in vitro to have a similar function to MRAP, facilitating MC2R trafficking and responsiveness to ACTH. Despite similar MC2R accessory functions, in vivo, patients with inactivating mutations of MRAP fail to be rescued by a functioning MRAP2 gene, suggesting differences in adrenal expression, localisation and/or function between the two MRAPs. In this study on the rat adrenal gland, we demonstrate that while MRAP and MC2R are highly expressed in the zona fasciculata, MRAP2 is expressed throughout the adrenal cortex in low quantities. In the developing adrenal gland, both MRAP and MRAP2 are equally well expressed. The MC2R/MRAP2 complex requires much higher concentrations of ACTH to activate compared with the MC2R/MRAP complex. Interestingly, expression of MC2R and MRAP in the undifferentiated zone would support the notion that ACTH may play an important role in adrenal cell differentiation and maintenance.</jats:p

DeepFactors: Real-time probabilistic dense monocular SLAM

The ability to estimate rich geometry and camera motion from monocular imagery is fundamental to future interactive robotics and augmented reality applications. Different approaches have been proposed that vary in scene geometry representation (sparse landmarks, dense maps), the consistency metric used for optimising the multi-view problem, and the use of learned priors. We present a SLAM system that unifies these methods in a probabilistic framework while still maintaining real-time performance. This is achieved through the use of a learned compact depth map representation and reformulating three different types of errors: photometric, reprojection and geometric, which we make use of within standard factor graph software. We evaluate our system on trajectory estimation and depth reconstruction on real-world sequences and present various examples of estimated dense geometry

An overview of a mobile focus group method for investigating space and place

This case study outlines the development and implementation of a mobile-focus group technique. Ostensibly, this is a blending of various aspects of conventional focus group and mobile interview methods. The case study was developed as one of a suite of methods used to evaluate a series of national-level interventions to promote the active inclusion and participation of young people in the quasi-formal development, and day-to-day activities in, a variety of deprived, predominantly urban, neighbourhoods in the UK. The method involved a group of young people leading researchers (and evaluators) on a guided tour of their neighbourhood. From the outset, the aim is to place participants in charge of where to go, and where not to go, and what to reveal and (perhaps) what to keep hidden. So, the young people adopt the role of local tour guides or experts, ‘showing’ their neighbourhood to an ‘interested stranger’. The case study outlines the rationale for developing the approach, presents a step-by-step account of how the approach was deployed, and details of practical considerations and challenges researchers may face when using the approach. The case study concludes by considering how the mobile and interactional dimensions of the method might recreate authentic ways in which local places are produced and experienced

Share capitalism and worker wellbeing

We show that worker wellbeing is determined not only by the amount of compensation workers receive but also by how compensation is determined. While previous theoretical and empirical work has often been preoccupied with individual performance-related pay, we find that the receipt of a range of group-performance schemes (profit shares, group bonuses and share ownership) is associated with higher job satisfaction. This holds conditional on wage levels, so that pay methods are associated with greater job satisfaction in addition to that coming from higher wages. We use a variety of methods to control for unobserved individual and job-specific characteristics. We suggest that half of the share-capitalism effect is accounted for by employees reciprocating for the “gift”; we also show that share capitalism helps dampen the negative wellbeing effects of what we typically think of as “bad” aspects of job quality

Severe loss-of-function mutations in the adrenocorticotropin receptor (ACTHR, MC2R) can be found in patients diagnosed with salt-losing adrenal hypoplasia

Objective: Familial glucocorticoid deficiency type I (FGD1) is a rare form of primary adrenal insufficiency resulting from recessive mutations in the ACTH receptor (MC2R, MC2R). Individuals with this condition typically present in infancy or childhood with signs and symptoms of cortisol insufficiency, but disturbances in the renin-angiotensin system, aldosterone synthesis or sodium homeostasis are not a well-documented association of FGD1. As ACTH stimulation has been shown to stimulate aldosterone release in normal controls, and other causes of hyponatraemia can occur in children with cortisol deficiency, we investigated whether MC2R changes might be identified in children with primary adrenal failure who were being treated for mineralocorticoid insufficiency. Design: Mutational analysis of MC2R by direct sequencing. Patients: Children (n = 22) who had been diagnosed with salt-losing forms of adrenal hypoplasia (19 isolated cases, 3 familial), and who were negative for mutations in DAX1 (NR0B1) and SF1 (NR5A1). Results: MC2R mutations were found in three individuals or kindred (I: homozygous S74I; II: novel compound heterozygous R146H/560delT; III: novel homozygous 579-581delTGT). These changes represent severely disruptive loss-of-function mutations in this G-protein coupled receptor, including the first reported homozygous frameshift mutation. The apparent disturbances in sodium homeostasis were mild, manifest at times of stress (e.g. infection, salt-restriction, heat), and likely resolved with time. Conclusions: MC2R mutations should be considered in children who have primary adrenal failure with apparent mild disturbances in renin-sodium homeostasis. These children may have been misdiagnosed as having salt-losing adrenal hypoplasia. Making this diagnosis has important implications for treatment, counselling and long-term prognosi

Measuring Coverage of Prolog Programs Using Mutation Testing

Testing is an important aspect in professional software development, both to avoid and identify bugs as well as to increase maintainability. However, increasing the number of tests beyond a reasonable amount hinders development progress. To decide on the completeness of a test suite, many approaches to assert test coverage have been suggested. Yet, frameworks for logic programs remain scarce. In this paper, we introduce a framework for Prolog programs measuring test coverage using mutations. We elaborate the main ideas of mutation testing and transfer them to logic programs. To do so, we discuss the usefulness of different mutations in the context of Prolog and empirically evaluate them in a new mutation testing framework on different examples.Comment: 16 pages, Accepted for presentation in WFLP 201

‘Our voice started off as a whisper and now it is a great big roar’ : The Salford Dementia Associate Panel as a model of involvement in research activities

This paper presents the work of the ‘Salford Dementia Associate Panel’, based at the Salford Institute for Dementia, Salford University (UK). We discuss the roles of the Dementia Associates, in particular around the areas of engagement and research. The panel is made up of people living with dementia, and current and former care partners. It highlights the development of this group over a four-year period and demonstrates over time how the role of a Dementia Associate member has evolved. The panel is involved in research, education and public engagement activities conducted by staff and students within the Institute. The motivations for becoming involved are clearly articulated and demonstrate how the personal backgrounds of individuals have driven the collective involvement and desire to bring about change. The benefits and challenges associated with working as part of a panel are discussed. We conclude by bringing together our experiences as a set of suggestions for others who may wish to create a similar forum to promote the involvement of people living with dementia and former and current care partners

Sea-level constraints on the amplitude and source distribution of Meltwater Pulse 1A.

During the last deglaciation, sea levels rose as ice sheets retreated. This climate transition was punctuated by periods of more intense melting; the largest and most rapid of these—Meltwater Pulse 1A—occurred about 14,500 years ago, with rates of sea-level rise reaching approximately 4 m per century1, 2, 3. Such rates of rise suggest ice-sheet instability, but the meltwater sources are poorly constrained, thus limiting our understanding of the causes and impacts of the event4, 5, 6, 7. In particular, geophysical modelling studies constrained by tropical sea-level records1, 8, 9 suggest an Antarctic contribution of more than seven metres, whereas most reconstructions10 from Antarctica indicate no substantial change in ice-sheet volume around the time of Meltwater Pulse 1A. Here we use a glacial isostatic adjustment model to reinterpret tropical sea-level reconstructions from Barbados2, the Sunda Shelf3 and Tahiti1. According to our results, global mean sea-level rise during Meltwater Pulse 1A was between 8.6 and 14.6 m (95% probability). As for the melt partitioning, we find an allowable contribution from Antarctica of either 4.1 to 10.0 m or 0 to 6.9 m (95% probability), using two recent estimates11, 12 of the contribution from the North American ice sheets. We conclude that with current geologic constraints, the method applied here is unable to support or refute the possibility of a significant Antarctic contribution to Meltwater Pulse 1A