Multi-scale, whole-system models of liver metabolic adaptation to fat and sugar in non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is a serious public health issue associated with high fat, high sugar diets. However, the molecular mechanisms mediating NAFLD pathogenesis are only partially understood. Here we adopt an iterative multi-scale, systems biology approach coupled to in vitro experimentation to investigate the roles of sugar and fat metabolism in NAFLD pathogenesis. The use of fructose as a sweetening agent is controversial; to explore this, we developed a predictive model of human monosaccharide transport, signalling and metabolism. The resulting quantitative model comprising a kinetic model describing monosaccharide transport and insulin signalling integrated with a hepatocyte-specific genome-scale metabolic network (GSMN). Differential kinetics for the utilisation of glucose and fructose were predicted, but the resultant triacylglycerol production was predicted to be similar for monosaccharides; these predictions were verified by in vitro data. The role of physiological adaptation to lipid overload was explored through the comprehensive reconstruction of the peroxisome proliferator activated receptor alpha (PPARα) regulome integrated with a hepatocyte-specific GSMN. The resulting qualitative model reproduced metabolic responses to increased fatty acid levels and mimicked lipid loading in vitro. The model predicted that activation of PPARα by lipids produces a biphasic response, which initially exacerbates steatosis. Our data support the evidence that it is the quantity of sugar rather than the type that is critical in driving the steatotic response. Furthermore, we predict PPARα-mediated adaptations to hepatic lipid overload, shedding light on potential challenges for the use of PPARα agonists to treat NAFLD

An approach for the interoperation of web-distributed applications with a design model

This paper defines the data and inference requirements for the integration of analysis applications with a product model described by a CAD/CAE application. Application input conditions often require sets of complex data that may be considered views of a product model database. We introduce a method that is compatible with the STEP and PLIB product description standards to define an intermediate model that selects, extracts, and validates views of information from a product model to serve as input for an engineering CAD/CAE application. The intermediate model framework was built and tested in a software prototype, the Internet Broker for Engineering Services (IBES). The first research case for IBES integrates applications that specify certain components, for example pumps and valves, with a CAD/CAE application. This paper therefore explores a sub-set of the general problem of integrating product data semantics between various engineering applications. The IBES integration method provides support for a general set of services that effectively assist interpretation and validate information from a product model for an engineering purpose. Such methods can enable application interoperation for the automation of typical engineering tasks, such as component specification and procurement.

Virtual components consisting of form, function and behavior

Software can produce a product model of a building as a consequence of the designers'actions in drawing and evaluating the design. The actions of the designer include interpreting, predicting and assessing the emerging design and describe the building in terms of forms, functions and behaviours. A software prototype has been implemented that incorporates this understanding of the design process in the field of building design. It employs object-oriented classes to represent forms, functions and behaviours. As a software user draws and interprets the design for multiple evaluation issues, the software creates a unique `virtual component'for each entity. During automated reasoning to evaluate the emerging design, virtual components collect and organize form, function and behaviour instances to describe the parts of the building. In comparison to other product models, our approach, which we refer to as a `Virtual Product Model', better accommodates change, provides increased support for the design process and enriches the product representation by including function and behaviour.

Interdisciplinary Communication Medium For Collaborative Conceptual Building Design

. Collaborative conceptual design involves intensive cross-disciplinary communication of design concepts and decisions. Difficulty in producing and expressing such information leads to extensive delays, miscommunication and confusion, which often have an impact upon the quality of the final design and the time required to achieve design consensus. Computer tools provide little support for the special needs for representation and reasoning posed by crossdisciplinary communication in collaborative conceptual building design. By building upon design theory, literature, and observations of a case study of an actual building design project, we identify and devise computational strategies for addressing these needs. Our objective is to help improve the communication among design team members. Our test case focuses on the communication between architects and structural engineers. We propose a conceptual framework for interdisciplinary communication to support collaborative conceptual design a..