Age-associated Collagen Crosslinking and its Role in Skeletal Muscle Regeneration

Advanced glycation end-products (AGEs) non-enzymatically accumulate on skeletal muscle collagen in old age via the Maillard reaction, causing an increase in intramuscular collagen and a stiffening of the muscle’s microenvironment. AGEs abrogate muscle regeneration through stiffening the muscle stem cell (MuSC) microenvironment and by binding to the receptor for advanced glycation end products (RAGE). Stiffer substrates promote MuSC proliferation at the expense of differentiation, and soluble AGEs are known to abrogate myogenic differentiation. Previously our group has demonstrated that decellularized muscle matrix (DMM), a type of extracellular matrix (ECM) scaffold extracted from skeletal muscle, encourages regeneration in a challenging rat volumetric muscle loss (VML) injury. Clinically, most human tissue for organ transplantation is sourced from older donors. My dissertation addresses whether old age is an important factor for DMM, and if this concern is AGE dependent. We isolated DMM from an aged murine model, and proved that AGE cross-links are present and that they are associated with increased stiffness. Further, we demonstrate that AGE-cross-linked collagen is stiffer, and disrupts myoblasts’ proliferation and differentiation in a RAGE-dependent manner. Curiously, AGE cross-links reduced RAGE in myoblasts, and RAGE inhibition shut down late myogenesis. Impressively, when myoblasts were challenged with the RAGE agonist S100b, myofiber formation was restored. We next proved that RAGE is significantly regulated in VML injuries, and we could regulate this with adipose-derived stromal cell delivery. Interestingly, AGEs were reduced in VML injuries, most likely due to an increase in new collagen deposition. Finally, we proved that an AGE-laden DMM disrupts muscle regeneration in a VML model and promotes inflammation while downregulating ECM synthesis. This was associated with upregulations in the AGE receptors RAGE and Galectin-3. Altogether, this dissertation provides strong evidence that age matters in the clinical translation of DMM, and AGEs are a prime target for rejuvenation therapies in skeletal muscle aging. Also, future study is warranted into the role that S100b can play in countering the AGE-RAGE axis in old age

THE IMPACT OF INFORMATION TECHNOLOGY ON ORGANIZATIONAL FLEXIBILITY

This paper argues that information technology can have a significant impact on organizational flexibility. Information technology (IT) contributes to flexibility by 1) changing the nature of organization boundaries and the time at which work takes place and 2) altering the nature and pace of work. IT also has important second and third order impacts on organizations and industries. The paper presents examples to illustrate the impact of information technology on two industries and three companies. The paper concludes that management should consider the use of information technology to increase flexibility and should predict the higher order impact of their actions on the organization and their industry.Information Systems Working Papers Serie

THE IMPACT OF INFORMATION TECHNOLOGY ON ORGANIZATIONAL FLEXIBILITY

This paper argues that information technology can have a significant impact on organizational flexibility. Information technology (IT) contributes to flexibility by 1) changing the nature of organization boundaries and the time at which work takes place and 2) altering the nature and pace of work. IT also has important second and third order impacts on organizations and industries. The paper presents examples to illustrate the impact of information technology on two industries and three companies. The paper concludes that management should consider the use of information technology to increase flexibility and should predict the higher order impact of their actions on the organization and their industry.Information Systems Working Papers Serie

The Impact of Office Automation on the Organization: Some Implications for Research and Practice

Computer technology has recently been applied to the automation of office tasks and procedures. Much of the technology is aimed not at improving the efficiency of current office procedures, but at altering the nature of office work altogether. The development of automated office systems raises a number of issues for the organization. How will this technology be received by organization members? How will it affect the definition of traditional office work? What will be its impact on individuals, work groups, and the structure of the organization? This paper presents a descriptive model and propositions concerning the potential impacts of office automation on the organization and it stresses the need, when implementing automated office systems, to take a broad perspective of their potential positive and negative effects on the organization. The need for further research examining the potential effects of office automation is emphasized.Information Systems Working Papers Serie

The Impact of Office Automation on the Organization: Some Implications for Research and Practice

Computer technology has recently been applied to the automation of office tasks and procedures. Much of the technology is aimed not at improving the efficiency of current office procedures, but at altering the nature of office work altogether. The development of automated office systems raises a number of issues for the organization. How will this technology be received by organization members? How will it affect the definition of traditional office work? What will be its impact on individuals, work groups, and the structure of the organization? This paper presents a descriptive model and propositions concerning the potential impacts of office automation on the organization and it stresses the need, when implementing automated office systems, to take a broad perspective of their potential positive and negative effects on the organization. The need for further research examining the potential effects of office automation is emphasized.Information Systems Working Papers Serie

Developments in overlapping Schwarz preconditioning of high-order nodal discontinuous Galerkin discretizations

A preconditioned two-level overlapping Schwarz method for solving unstructured nodal discontinuous Galerkin discretizations of the indefinite Helmholtz problem is studied. We employ triangles in two dimensions and in a local discontinuous Galerkin (LDG) variational setting. We highlight the necessary components of the algorithm needed to achieve efficient results in the context of high-order elements and indefinite algebraic systems. More specifically, we demonstrate the importance of not only coarse-grid solution sweeps, but also for increased overlap in the subdomain solves as the order of the elements increases. In this paper, we detail the discretization strategy and offer an effective approach to solving the resulting system of equations, with numerical evidence in support

Developing a Model of Aged Decellularized Muscle Matrix with Advanced Glycation Cross-linking

Volumetric muscle loss (VML) has been found to overwhelm muscle regeneration, resulting in loss of long-term muscle functionality. Decellularized muscle matrices (DMMs) provide an effective environment for muscle regeneration; however, the age of their source has not been adequately explored for clinical translation. Advanced glycation end-products (AGEs) are chemical cross-links that contribute to the aging process by accumulating on collagen fibers, resulting in a stiffening of the collagenous matrix and an increase in inflammation via the receptor for advanced glycation end-products (RAGE). In previous experiments, we found increased levels of AGE-specific cross-links within DMMs in old mice compared to young as proven by ALT-711 treatment. In this study, we developed a model of aged rat DMMs using AGE cross-links and hypothesized that our AGE-DMM model will contain a higher number of collagen cross-links compared to the control. This AGE-DMM model aims to elucidate the effect of AGEs on muscle regeneration when used in vitro or implanted in a volumetric muscle loss model.https://scholarscompass.vcu.edu/uresposters/1424/thumbnail.jp

A MULTIDISCIPLINARY APPROACH TO INFORMATION SYSTEMS RESEARCH

Information Systems Working Papers Serie

Description of Hymenolepis microstoma (Nottingham strain): a classical tapeworm model for research in the genomic era

<p>Abstract</p> <p>Background</p> <p><it>Hymenolepis microstoma </it>(Dujardin, 1845) Blanchard, 1891, the mouse bile duct tapeworm, is a rodent/beetle-hosted laboratory model that has been used in research and teaching since its domestication in the 1950s. Recent characterization of its genome has prompted us to describe the specific strain that underpins these data, anchoring its identity and bringing the 150+ year-old original description up-to-date.</p> <p>Results</p> <p>Morphometric and ultrastructural analyses were carried out on laboratory-reared specimens of the 'Nottingham' strain of <it>Hymenolepis microstoma </it>used for genome characterization. A contemporary description of the species is provided including detailed illustration of adult anatomy and elucidation of its taxonomy and the history of the specific laboratory isolate.</p> <p>Conclusions</p> <p>Our work acts to anchor the specific strain from which the <it>H. microstoma </it>genome has been characterized and provides an anatomical reference for researchers needing to employ a model tapeworm system that enables easy access to all stages of the life cycle. We review its classification, life history and development, and briefly discuss the genome and other model systems being employed at the beginning of a genomic era in cestodology.</p