Muscle-Specific Loss of \u3cem\u3eBmal1\u3c/em\u3e Leads to Disrupted Tissue Glucose Metabolism and Systemic Glucose Homeostasis

Background: Diabetes is the seventh leading cause of death in the USA, and disruption of circadian rhythms is gaining recognition as a contributing factor to disease prevalence. This disease is characterized by hyperglycemia and glucose intolerance and symptoms caused by failure to produce and/or respond to insulin. The skeletal muscle is a key insulin-sensitive metabolic tissue, taking up ~80 % of postprandial glucose. To address the role of the skeletal muscle molecular clock to insulin sensitivity and glucose tolerance, we generated an inducible skeletal muscle-specific Bmal1 −/− mouse (iMSBmal1 −/−). Results: Progressive changes in body composition (decreases in percent fat) were seen in the iMSBmal1 −/− mice from 3 to 12 weeks post-treatment as well as glucose intolerance and non-fasting hyperglycemia. Ex vivo analysis of glucose uptake revealed that the extensor digitorum longus (EDL) muscles did not respond to either insulin or 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) stimulation. RT-PCR and Western blot analyses demonstrated a significant decrease in mRNA expression and protein content of the muscle glucose transporter (Glut4). We also found that both mRNA expression and activity of two key rate-limiting enzymes of glycolysis, hexokinase 2 (Hk2) and phosphofructokinase 1 (Pfk1), were significantly reduced in the iMSBmal1 −/− muscle. Lastly, results from metabolomics analyses provided evidence of decreased glycolytic flux and uncovered decreases in some tricarboxylic acid (TCA) intermediates with increases in amino acid levels in the iMSBmal1 −/− muscle. These findings suggest that the muscle is relying predominantly on fat as a fuel with increased protein breakdown to support the TCA cycle. Conclusions: These data support a fundamental role for Bmal1, the endogenous circadian clock, in glucose metabolism in the skeletal muscle. Our findings have implicated altered molecular clock dictating significant changes in altered substrate metabolism in the absence of feeding or activity changes. The changes in body composition in our model also highlight the important role that changes in skeletal muscle carbohydrate, and fat metabolism can play in systemic metabolism

Temperature as a Circadian Marker in Older Human Subjects: Relationship to Metabolic Syndrome and Diabetes

Background: Circadian rhythms are characterized by approximate 24-hour oscillations in physiological and behavioral processes. Disruptions in these endogenous rhythms, most commonly associated with shift work and/or lifestyle, are recognized to be detrimental to health. Several studies have demonstrated a high correlation between disrupted circadian rhythms and metabolic disease. The aim of this study was to determine which metabolic parameters correlate with physiological measures of circadian temperature amplitude (TempAmp) and stability (TempStab). Methods: Wrist skin temperature was measured in 34 subjects (ages 50 to 70, including lean, obese, and diabetic subjects) every 10 minutes for 7 consecutive days. Anthropometric measures and fasting blood draws were conducted to obtain data on metabolic parameters: body mass index, hemoglobin A1C, triglycerides, cholesterol, high-density lipoprotein, and low-density lipoprotein. A history of hypertension and current blood pressure was noted. Results: Analysis of the data indicated a substantial reduction in TempAmp and TempStab in subjects with metabolic syndrome (three or more risk factors). To determine the impact of individual interdependent metabolic factors on temperature rhythms, stepwise multilinear regression analysis was conducted using metabolic syndrome measurements. Interestingly, only triglyceride level was consistently correlated by the analysis. Triglyceride level was shown to contribute to 33% of the variability in TempAmp and 23% of the variability in TempStab. Conclusion: Our results demonstrate that elevated triglycerides are associated with diminished TempAmp and TempStab in human subjects, and triglycerides may serve as a primary metabolic predictor of circadian parameters

Fine-Scale Genetic Structure Arises during Range Expansion of an Invasive Gecko

Processes of range expansion are increasingly important in light of current concerns about invasive species and range shifts due to climate change. Theoretical studies suggest that genetic structuring may occur during range expansion. Ephemeral genetic structure can have important evolutionary implications, such as propagating genetic changes along the wave front of expansion, yet few studies have shown evidence of such structure. We tested the hypothesis that genetic structure arises during range expansion in Hemidactylus mabouia, a nocturnal African gecko recently introduced to Florida, USA. Twelve highly variable microsatellite loci were used to screen 418 individuals collected from 43 locations from four sampling sites across Florida, representing a gradient from earlier (∼1990s) to very recent colonization. We found earlier colonized locations had little detectable genetic structure and higher allelic richness than more recently colonized locations. Genetic structuring was pronounced among locations at spatial scales of tens to hundreds of meters near the leading edge of range expansion. Despite the rapid pace of range expansion in this introduced gecko, dispersal is limited among many suitable habitat patches. Fine-scale genetic structure is likely the result of founder effects during colonization of suitable habitat patches. It may be obscured over time and by scale-dependent modes of dispersal. Further studies are needed to determine if such genetic structure affects adaptation and trait evolution in range expansions and range shifts

Implementation of Component Based Design: a Pedagogical and Actual Case Study

This paper explores pedagogical and practical ramifications of implementing the component-based design paradigm through the actual construction process of a simple wood frame house for Habitat for Humanity. The house was digitally-modeled as part of an elective construction class, then physically constructed by students and faculty of the College of DAAP at the University of Cincinnati as part of a community service exercise. The digital model and a detailed database of individual components were mined in order to explore and exploit the complete and accurate electronic modelling of building, prior to actual construction

Component-Based, Three-Dimensional "Working Drawings"

It is now possible to communicate technical information about a building utilizing accurate threedimensional computer modelling of component assemblies of an entire building for the production of an alternative set of “working drawings.” Most assembly illustrations and final appearance can be presented as output from the computer model. The use of these three-dimensional images in the practice of architecture may improve communication between the members of the building design team and, therefore, may improve the overall design integration of the various systems in a building.  Additionally, this type of component model construction for the production of technical drawings offers a unique bridge over the gap between the practice of architecture and the teaching of architecture. Rather than teaching students how to “do working drawings,” something all practitioners wish the academic institutions did, students would develop the ability to design, integrate, and construct complex three-dimensional assemblies and present them in a variety of ways using the standard sections, layers, view, etc. inherent in any reasonable threedimensional computer based modelling system

Component-Based Spatial Reasoning

The design process and ordering of individual components through which architecture is realized relies on the use of abstract “modelsi to represent a proposed design. The emergence and use of these abstract “models” for building representation has a long history and tradition in the field of architecture. Models have been made and continue to be made for the patron, occasionally the public, and as a guide for the builders. Models have also been described as a means to reflect on the design and to allow the design to be in dialogue with the creator.  The term “modeli in the above paragraph has been used in various ways and in this context is defined as any representation through which design intent is expressed. This includes accurate/ rational or abstract drawings (2- dimensional and 3-dimensional), physical models (realistic and abstract) and computer models (solid, void and virtual reality). The various models that fall within the categories above have been derived from the need to “view” the proposed design in various ways in order to support intuitive reasoning about the proposal and for evaluation purposes. For example, a 2-dimensional drawing of a floor plan is well suited to support reasoning about spatial relationships and circulation patterns while scaled 3-dimensional models facilitate reasoning about overall form, volume, light, massing etc. However, the common denominator of all architectural design projects (if the intent is to construct them in actual scale, physical form) are the discrete building elements from which the design will be constructed. It is proposed that a single computational model representing individual components supports all of the above “models” and facilitates “viewing” the design according to the frame of reference of the viewer.  Furthermore, it is the position of the authors that all reasoning stems from this rudimentary level of modelling individual components.  The concept of component representation has been derived from the fact that a “real” building (made from individual components such as nuts, bolts and bar joists) can be “viewed” differently according to the frame of reference of the viewer. Each individual has the ability to infer and abstract from the assemblies of components a variety of different “models” ranging from a visceral, experiential understanding to a very technical, physical understanding. The component concept has already proven to be a valuable tool for reasoning about assemblies, interferences between components, tracing of load path and numerous other component related applications. In order to validate the component-based modelling concept this effort will focus on the development of spatial understanding from the component-based model. The discussions will, therefore, center about the representation of individual components and the development of spatial models and spatial reasoning from the component model. In order to frame the argument that spatial modelling and reasoning can be derived from the component representation, a review of the component-based modelling concept will precede the discussions of spatial issues

An Integrative Approach to Computer-Aided Design Education in Architecture

With the advent of CAD, schools of architecture are now obliged to prepare their graduates for using the emerging new design tools and methods in architectural practices of the future. In addition to this educational obligation, schools of architecture (possibly in partnership with practicing firms) are also the most appropriate agents for pursuing research in CAD that will lead to the development of better CAD software for use by the profession as a whole. To meet these two rather different obligations, two kinds of CAD education curricula are required: one which prepares tool- users, and another that prepares tool-builders. The first educates students about the use of CAD tools for the design of buildings, whereas the second educates them about the design of CAD tools themselves. The School of Architecture and Planning in SUNY at Buffalo has recognized these two obligations, and in Fall 1982 began to meet them by planning and implementing an integrated CAD environment. This environment now consists of 3 components: a tool-building sequence of courses, an advanced research program, and a general tool-users architectural curriculum. Students in the tool-building course sequence learn the principles of CAD and may, upon graduation, become researchers and the managers of CAD systems in practicing offices. While in school they form a pool of research assistants who may be employed in the research component of the CAD environment, thereby facilitating the design and development of advanced CAD tools. The research component, through its various projects, develops and provides state of the art tools to be used by practitioners as well as by students in the school, in such courses as architectural studio, environmental controls, performance programming, and basic design courses. Students in these courses who use the tools developed by the research group constitute the tool-users component of the CAD environment. While they are being educated in the methods they will be using throughout their professional careers, they also act as a'real-world'laboratory for testing the software and thereby provide feedback to the research component. The School of Architecture and Planning in SUNY at Buffalo has been the first school to incorporate such a comprehensive CAD environment in its curriculum, thereby successfully fulfilling its obligation to train students in the innovative methods of design that will be used in architectural practices of the future, and at the same time making a significant contribution to the profession of architecture as a whole. This paper describes the methodology and illustrates the history of the CAD environment's implementation in the Schoo

Component Based Computer Aided Learning for Students of Architecture and Civil Engineering

The paper describes the methodology and the current efforts to develop an interdisciplinary computer aided learning system for architects and civil engineers. The system being developed incorporates a component oriented relational database with an existing interactive 3-dimensional modelling system developed in the School of Architecture and Planning at SUNY Buffalo. The software will be used in existing courses in architecture and civil engineering as a teaching aid to help students understand the complex 3-dimensional interrelationships of structural components. Initial implementation has focused on the modelling of the components and assemblies for a lowrise steel frame structure. Current implementation efforts are focusing on the capability to view connections in various ways including the ability to “explode” a connection to better understand the sequence of construction and load paths. Appropriate codes, limit states of failure and specific data will be linked to each specific component in an expert system shell so that the system can offer feedback about a student generated connection and perhaps offer other possible connections a library of standard connections. Future expansion of the system will include adding other “systems” of a building, such as mechanical, electrical, plumbing, enclosure etc., to help students visualize the integration of the various parts

Component-Based Design: a Summary and Scheme for Implementation

This paper summarizes the major advantages ofcomponent-based design as a paradigm for handling alldesign and construction information about a buildingat every stage of design. The paper reviews some ofthe current issues that plague the building design andconstruction industry. The component-based paradigmis reviewed as a model that reunites the fragmentedbuilding industry and as a solution for dealing withvast amounts of information that accretes during thedesign-construction process. Based on interviews witharchitects, engineers, contractors and fabricators aswell as on-site documentation of construction wefeature the design and construction of the main stairin the Rosenthal Center for Contemporary Artdesigned by Zaha Hadid as a specific case study toillustrate the viability of component-based design andto highlight the obstacles challenging itsimplementation

Design and Representation: ACADIA ‘97 Conference Proceedings

The organizers for ACADIA'97 called for papers that would address the nature of representation and its relationship to a design and the resulting architectural artifact and the role of representation in design process