Genetic albation of the c-Cbl ubiquitin ligase domain results in increased energy expenditure and improved insulin action

Casitas b-lineage lymphoma (c-Cbl) is a multiadaptor protein with E3-ubiquitin ligase activity residing within its RING finger domain. We have previously reported that c-Cbl–deficient mice exhibit elevated energy expenditure, reduced adiposity, and improved insulin action. In this study, we examined mice expressing c-Cbl protein with a loss-of-function mutation within the RING finger domain (c-Cbl^A/– mice). Compared with control animals, c-Cbl^A/– mice display a phenotype that includes reduced adiposity, despite greater food intake; reduced circulating insulin, leptin, and triglyceride levels; and improved glucose tolerance. c-Cbl^A/– mice also display elevated oxygen consumption (13%) and are protected against high-fat diet–induced obesity and insulin resistance. Unlike c-Cbl^A/– mice, mice expressing a mutant c-Cbl with the phosphatidylinositol (PI) 3-kinase binding domain ablated (c-Cbl^F/F mice) exhibited an insulin sensitivity, body composition, and energy expenditure similar to that of wild-type animals. These results indicate that c-Cbl ubiquitin ligase activity, but not c-Cbl–dependent activation of PI 3-kinase, plays a key role in the regulation of whole-body energy metabolism.

Aligning system requirements with stakeholder concerns : use of case studies and patterns to capture domain experience

Traditionally system development starts with the specification of system requirements. The focus of such an approach is on the system under construction, which is considered as of primary importance to the development success. The major problem with such an approach, however, is the neglect of concerns held by the various system stakeholders, whose opinions, loyalties and fears may impact considerably the perception and the reception of the implemented system, its functions and its features. Typically, stakeholder concerns are not collected or identified, and are viewed as of little significance in the system development process. In this paper, however, we present the case for recognising the value of stakeholder concerns, and their use in aligning business needs with system requirements. We describe a method of gathering and analysing stakeholder concerns across an application domain, and then packaging the development experience in dealing with these concerns into patterns. Experience patterns can subsequently be used to guide systems analysts in selecting the most appropriate requirements for the target stakeholder community.

Applying domain analysis to the investigation of web-enabled human resource projects

Designing a successful web project requires understanding not only of its owner's business and technological needs, as well as having the substantial management and development experience, but it also depends on a thorough knowledge of the system's application domain and of other existing systems in the domain. In order to gather such domain knowledge, it is necessary to identify the nature of the proposed web services venture with regards to other similar services offered in the domain, the business setting of enterprises that initiate such ventures, the various types of customers involved, and how these factors translate into requirements. In this paper, we present an approach to studying the domain of web-enabled Human Resource and payroll services with the aim of attaining design knowledge that would ensure customer satisfaction and could eventually pave the way to the successful implementation of web-enabled services.

The domain layer for mixed-initiative interaction in generative design

The design space exploration formalism has developed data structures and algorithms of sufficient complexity and scope to support conceptual layout, massing, and enclosure configurations. However, design remains a human enterprise. To support the user in designing with the formalism, we have developed an interaction model that addresses the interleaving of user actions with the formal operations of design space exploration. The central feature of our interaction model is the modeling of control based on mixed-initiative. Initiative is sometimes taken by the designer and sometimes by the formalism in working on a shared design task. The model comprises three layers, domain, task, and dialogue. In this paper we describe the formulation of the domain layer of our mixed-initiative interaction model for design space exploration. We present the view of the domain as understood in the formalism in terms of the three abstract concepts of state, move, and structure. In order to support mixed initiative, it is necessary to develop a shared view of the domain. The domain layer addresses this problem by mapping the designer's view onto the symbol substrate. First, we present the designer's view of the domain in terms of problems, solutions, choices, and history. Second, we show how this view is interleaved with the symbol-substrate through four domain layer constructs, problem state, solution state, choice, and exploration history. The domain layer presents a suitable foundation for integrating the role of the designer with a description formalism. It enables the designer to maintain exploration freedom in terms of formulating and reformulating problems, generating solutions, making choices, and navigating the history of exploration.

Src homology 3-domain growth factor receptor-bound 2-like (endophilin) interacting protein 1, a novel neuronal protein that regulates energy balance

To identify genes involved in the central regulation of energy balance, we compared hypothalamic mRNA from lean and obese Psammomys obesus, a polygenic model of obesity, using differential display PCR. One mRNA transcript was observed to be elevated in obese, and obese diabetic, P. obesus compared with lean animals and was subsequently found to be increased 4-fold in the hypothalamus of lethal yellow agouti (Ay/a) mice, a murine model of obesity and diabetes. Intracerebroventricular infusion of antisense oligonucleotide targeted to this transcript selectively suppressed its hypothalamic mRNA levels and resulted in loss of body weight in both P. obesus and Sprague Dawley rats. Reductions in body weight were mediated by profoundly reduced food intake without a concomitant reduction in metabolic rate. Yeast two-hybrid screening, and confirmation in mammalian cells by bioluminescence resonance energy transfer analysis, demonstrated that the protein it encodes interacts with endophilins, mediators of synaptic vesicle recycling and receptor endocytosis in the brain. We therefore named this transcript Src homology 3-domain growth factor receptor-bound 2-like (endophilin) interacting protein 1 (SGIP1). SGIP1 encodes a large proline-rich protein that is expressed predominantly in the brain and is highly conserved between species. Together these data suggest that SGIP1 is an important and novel member of the group of neuronal molecules required for the regulation of energy homeostasis.

Defining the domain of corporate social responsibility (CSR) in tourism organisations : a preliminary view from stakeholders in Thailand's accommodation sector

This paper aims to define the domain of Corporate Social Responsibility (CSR) for hotel and accommodation organizations in Thailand. It seeks to integrate the diverse components of CSR as defined within the general business/management, tourism and stakeholder literatures. A review of existing literature, codes of practice and standards, identify three broad CSR components – economic issues, social/ethical issues and environmental – although each of the standards varied in terms of the definition and emphasis applied. The components were ‘aggregated’ within each of the broad management and tourism literature, these two sets of groupings were then aggregated into one overarching set of CSR issues. Semi-structured interviews were then undertaken with 38 key informants from hotel and resort businesses in Thailand to identify their views toward the applicability of these over-arching components to hotel and accommodation organisations.

The results of the aggregation of standards suggest that CRS approaches within general business tend to be more socially/ethically orientated whereas within the tourism area approaches tend to be more environmentally orientated. Key respondents’ views were generally consistent with the three broad issues of the integrated CSR domain, although some issues were identified as more salient to hotel and accommodation organisations than others. The paper suggests that there is a need to develop CSR measures and indicators applicable and reflective of the different environmental, legal, cultural and local setting.