The Experts below are selected from a list of 28230 Experts worldwide ranked by ideXlab platform
Robin J M Franklin - One of the best experts on this subject based on the ideXlab platform.
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the translational biology of remyelination past present and future
Glia, 2014Co-Authors: Robin J M Franklin, Vittorio GalloAbstract:Amongst neurological diseases, multiple sclerosis (MS) presents an attractive target for Regenerative medicine. This is because the primary pathology, the loss of myelin-forming oligodendrocytes, can be followed by a spontaneous and efficient Regenerative Process called remyelination. While cell transplantation approaches have been explored as a means of replacing lost oligodendrocytes, more recently therapeutic approaches that target the endogenous Regenerative Process have been favored. This is in large part due to our increasing understanding of (1) the cell types within the adult brain that are able to generate new oligodendrocytes, (2) the mechanisms and pathways by which this achieved, and (3) an emerging awareness of the reasons why remyelination efficiency eventually fails. Here we review some of these advances and also highlight areas where questions remain to be answered in both the biology and translational potential of this important Regenerative Process.
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rejuvenation of regeneration in the aging central nervous system
Cell Stem Cell, 2012Co-Authors: Julia M Ruckh, Jingwei Zhao, Jennifer L Shadrach, Peter Van Wijngaarden, Amy J Wagers, Robin J M FranklinAbstract:Summary Remyelination is a Regenerative Process in the central nervous system (CNS) that produces new myelin sheaths from adult stem cells. The decline in remyelination that occurs with advancing age poses a significant barrier to therapy in the CNS, particularly for long-term demyelinating diseases such as multiple sclerosis (MS). Here we show that remyelination of experimentally induced demyelination is enhanced in old mice exposed to a youthful systemic milieu through heterochronic parabiosis. Restored remyelination in old animals involves recruitment to the repairing lesions of blood-derived monocytes from the young parabiotic partner, and preventing this recruitment partially inhibits rejuvenation of remyelination. These data suggest that enhanced remyelinating activity requires both youthful monocytes and other factors, and that remyelination-enhancing therapies targeting endogenous cells can be effective throughout life.
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myelin regeneration a recapitulation of development
Annual Review of Neuroscience, 2011Co-Authors: Stephen P J Fancy, Robin J M Franklin, Jonah R Chan, Sergio E Baranzini, David H RowitchAbstract:The developmental Process of myelination and the adult Regenerative Process of remyelination share the common objective of investing nerve axons with myelin sheaths. A central question in myelin biology is the extent to which the mechanisms of these two Processes are conserved, a concept encapsulated in the recapitulation hypothesis of remyelination. This question also has relevance for translating myelin biology into a better understanding of and eventual treatments for human myelin disorders. Here we review the current evidence for the recapitulation hypothesis and discuss recent findings in the development and regeneration of myelin in the context of human neurological disease.
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overcoming remyelination failure in multiple sclerosis and other myelin disorders
Experimental Neurology, 2010Co-Authors: Stephen P J Fancy, Mark R N Kotter, Emily P Harrington, Jeffrey K Huang, Chao Zhao, David H Rowitch, Robin J M FranklinAbstract:Protecting axons from degeneration represents a major unmet need in the treatment of myelin disorders and especially the currently untreatable secondary progressive stages of multiple sclerosis (MS). Several lines of evidence indicate that ensuring myelin sheaths are restored to demyelinated axons, the Regenerative Process of remyelination, represents one of the most effective means of achieving axonal protection. Remyelination can occur as a highly effective spontaneous Regenerative Process following demyelination. However, for reasons that have not been fully understood, this Process is often incomplete or fails in MS. Recognizing the reasons for remyelination failure and hence identifying therapeutic targets will depend on detailed histopathological studies of myelin disorders and a detailed understanding of the molecular mechanisms regulating remyelination. Pathology studies have revealed that chronically demyelinated lesions in MS often fail to repair because of a failure of differentiation of the precursor cell responsible for remyelination rather than a failure of their recruitment. In this article we review three mechanisms by which differentiation of precursor cells into remyelinating oligodendrocytes are regulated-the Notch pathway, the Wnt pathway and the pathways activated by inhibitor of differentiation in myelin debris-and indicate how these might be pharmacologically targeted to overcome remyelination failure.
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why does remyelination fail in multiple sclerosis
Nature Reviews Neuroscience, 2002Co-Authors: Robin J M FranklinAbstract:Multiple sclerosis is a common cause of neurological disability in young adults. The disease is complex — its aetiology is multifactorial and largely unknown; its pathology is heterogeneous; and, clinically, it is difficult to diagnose, manage and treat. However, perhaps its most frustrating aspect is the inadequacy of the healing response of remyelination. This Regenerative Process generally occurs with great efficiency in experimental models, and sometimes proceeds to completion in multiple sclerosis. But as the disease progresses, the numbers of lesions in which demyelination persists increases, significantly contributing to clinical deterioration. Understanding why remyelination fails is crucial for devising effective methods by which to enhance it.
Kishor S. Trivedi - One of the best experts on this subject based on the ideXlab platform.
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Performability Modeling for RAID Storage Systems by Markov Regenerative Process
IEEE Transactions on Dependable and Secure Computing, 2018Co-Authors: Fumio Machida, Ruofan Xia, Kishor S. TrivediAbstract:This paper presents a performability model for RAID storage systems using Markov Regenerative Process to compare different RAID architectures. While homogeneous Markov models are extensively used for reliability analysis of RAID storage systems, the memory-less property of the sojourn time assumed in such models is not satisfied in reality, especially in disk rebuild Process whose progress is not interrupted even at an event of another disk failure. In this paper, we use Markov Regenerative Process which allows us to model the generally distributed rebuild times providing a needed extension of the traditional Markov models. The Markov Regenerative Process is then used to assess the performability of the storage system by assigning reward rates to each state based on the real storage benchmark results. Our numerical study characterizes the performability advantage of RAID6 architecture over RAID10 architecture in terms of sequential read access. Our findings include that the effect of exponential assumption for the rebuild times has practically negligible effect when we focus on data availability. However, the effect this approximation on performability prediction may not be negligible especially when the performance level drastically changes in degraded states. Our MRGP model provides more accurate prediction of performability in such cases.
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optimization of two granularity software rejuvenation policy based on the markov Regenerative Process
IEEE Transactions on Reliability, 2016Co-Authors: Gaorong Ning, Rivalino Matias, Javier Alonso, Jing Zhao, Kishor S. TrivediAbstract:Software rejuvenation is a proactive software control technique that is used to improve a computing system performance when it suffers from software aging. In this paper, a two-granularity inspection-based software rejuvenation policy, which works as a closed-loop control technique, is proposed. This policy mitigates the negative impact of two-level software aging. The two levels considered are the user-level applications and the operating system. A Markov Regenerative Process model is constructed based on the system condition. We obtain the degradation rate of the application software and operating system from fault injection experiments. The diagnostic accuracy of the adopted monitor and analysis system, which is applied to inspect the application software and operating system, is considered as we provide the optimal rejuvenation strategies. Finally, the availability and the overall loss probability with their corresponding optimal inspection time intervals are obtained numerically based on the parameter values estimated from the experiments. Experimental results show that two-granularity software rejuvenation is much more effective than traditional single-level software rejuvenation. In our experi-mental study, when two-granularity software rejuvenation is used, the unavailability and the overall loss probability of the system were reduced by 17.9% and 2.65%, respectively, in comparison with the single-level rejuvenation.
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markov dependability models of complex systems analysis techniques
1996Co-Authors: Jogesh K Muppala, Manish Malhotra, Kishor S. TrivediAbstract:Continuous time Markov chains are commonly used for modelling large systems, in order to study their performance and dependability. In this paper, we review solution techniques for Markov and Markov reward models. Several methods are presented for the transient analysis of Markov models, ranging from fully-symbolic to fully-numeric. The Markov reward model is explored further, and methods for computing various reward based measures are discussed including the expected values of rewards and the distributions of accumulated rewards. We also briefly discuss the different types of dependencies that arise in dependability modelling of systems, and show how Markov models can handle some of these dependencies. Finally, we briefly review the Markov Regenerative Process, which relaxes some of the constraints imposed by the Markov Process.
George K Michalopoulos - One of the best experts on this subject based on the ideXlab platform.
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advances in liver regeneration
Expert Review of Gastroenterology & Hepatology, 2014Co-Authors: George K MichalopoulosAbstract:Liver regeneration after partial hepatectomy is the only example of a Regenerative Process in mammals in which the organ/body weight ratio returns to 100% of the original when the Process is complete. The adjustment of liver weight to the needs of the body suggests a complicated set of control points, a ‘hepatostat’. There has been much progress in elucidation of mechanisms involved in initiation of liver regeneration. More recent studies have focused on termination pathways, because these may be the underlying controls of the hepatostat and their elimination may be relevant to hepatic neoplasia. When the standard Regenerative Process is thwarted due to failure of either hepatocytes or biliary epithelial cells to proliferate, each of the two epithelial compartments can function as a source of facultative stem cells for the other.
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signals and cells involved in regulating liver regeneration
Cells, 2012Co-Authors: Liangi Kang, Wendy M Mars, George K MichalopoulosAbstract:Liver regeneration is a complex phenomenon aimed at maintaining a constant liver mass in the event of injury resulting in loss of hepatic parenchyma. Partial hepatectomy is followed by a series of events involving multiple signaling pathways controlled by mitogenic growth factors (HGF, EGF) and their receptors (MET and EGFR). In addition multiple cytokines and other signaling molecules contribute to the orchestration of a signal which drives hepatocytes into DNA synthesis. The other cell types of the liver receive and transmit to hepatocytes complex signals so that, in the end of the Regenerative Process, complete hepatic tissue is assembled and regeneration is terminated at the proper time and at the right liver size. If hepatocytes fail to participate in this Process, the biliary compartment is mobilized to generate populations of progenitor cells which transdifferentiate into hepatocytes and restore liver size.
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liver regeneration after partial hepatectomy critical analysis of mechanistic dilemmas
American Journal of Pathology, 2010Co-Authors: George K MichalopoulosAbstract:Liver regeneration after partial hepatectomy is one of the most studied models of cell, organ, and tissue regeneration. The complexity of the signaling pathways initiating and terminating this Process have provided paradigms for Regenerative medicine. Many aspects of the signaling mechanisms involved in hepatic regeneration are under active investigation. The purpose of this review is to focus on the areas still not well understood. The review also aims to provide insights into the ways by which current concepts of liver regeneration can provide understanding regarding malfunction of the Regenerative Process in liver diseases, such as acute liver failure.
David J. Mooney - One of the best experts on this subject based on the ideXlab platform.
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boon and bane of inflammation in bone tissue regeneration and its link with angiogenesis
Tissue Engineering Part B-reviews, 2015Co-Authors: Katharina Schmidtbleek, David J. Mooney, Brian Kwee, Georg N. DudaAbstract:Delayed healing or nonhealing of bone is an important clinical concern. Although bone, one of the two tissues with scar-free healing capacity, heals in most cases, healing is delayed in more than 10% of clinical cases. Treatment of such delayed healing condition is often painful, risky, time consuming, and expensive. Tissue healing is a multistage Regenerative Process involving complex and well-orchestrated steps, which are initiated in response to injury. At best, these steps lead to scar-free tissue formation. At the onset of healing, during the inflammatory phase, stationary and attracted macrophages and other immune cells at the fracture site release cytokines in response to injury. This initial reaction to injury is followed by the recruitment, proliferation, and differentiation of mesenchymal stromal cells, synthesis of extracellular matrix proteins, angiogenesis, and finally tissue remodeling. Failure to heal is often associated with poor revascularization. Since blood vessels mediate the transport...
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the role of multifunctional delivery scaffold in the ability of cultured myoblasts to promote muscle regeneration
Biomaterials, 2011Co-Authors: Cristina Borselli, Christine A. Cezar, Herman H. Vandenburgh, Dmitry Shvartsman, David J. MooneyAbstract:Many cell types of therapeutic interest, including myoblasts, exhibit reduced engraftment if cultured prior to transplantation. This study investigated whether polymeric scaffolds that direct cultured myoblasts to migrate outwards and repopulate the host damaged tissue, in concert with release of angiogenic factors designed to enhance revascularizaton of the regenerating tissue, would enhance the efficacy of this cell therapy and lead to functional muscle regeneration. This was investigated in the context of a severe injury to skeletal muscle tissue involving both myotoxin-mediated direct damage and induction of regional ischemia. Local and sustained release of VEGF and IGF-1 from macroporous scaffolds used to transplant and disperse cultured myogenic cells significantly enhanced their engraftment, limited fibrosis, and accelerated the Regenerative Process. This resulted in increased muscle mass and, improved contractile function. These results demonstrate the importance of finely controlling the microenvironment of transplanted cells in the treatment of severe muscle damage.
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Functional muscle regeneration with combined delivery of angiogenesis and myogenesis factors
Proceedings of the National Academy of Sciences of the United States of America, 2009Co-Authors: Cristina Borselli, Christine A. Cezar, Herman H. Vandenburgh, Hannah Storrie, Frank Benesch-lee, Dmitry Shvartsman, Jeff W. Lichtman, David J. MooneyAbstract:Regenerative efforts typically focus on the delivery of single factors, but it is likely that multiple factors regulating distinct aspects of the Regenerative Process (e.g., vascularization and stem cell activation) can be used in parallel to affect regeneration of functional tissues. This possibility was addressed in the context of ischemic muscle injury, which typically leads to necrosis and loss of tissue and function. The role of sustained delivery, via injectable gel, of a combination of VEGF to promote angiogenesis and insulin-like growth factor-1 (IGF1) to directly promote muscle regeneration and the return of muscle function in ischemic rodent hindlimbs was investigated. Sustained VEGF delivery alone led to neoangiogenesis in ischemic limbs, with complete return of tissue perfusion to normal levels by 3 weeks, as well as protection from hypoxia and tissue necrosis, leading to an improvement in muscle contractility. Sustained IGF1 delivery alone was found to enhance muscle fiber regeneration and protected cells from apoptosis. However, the combined delivery of VEGF and IGF1 led to parallel angiogenesis, reinnervation, and myogenesis; as satellite cell activation and proliferation was stimulated, cells were protected from apoptosis, the inflammatory response was muted, and highly functional muscle tissue was formed. In contrast, bolus delivery of factors did not have any benefit in terms of neoangiogenesis and perfusion and had minimal effect on muscle regeneration. These results support the utility of simultaneously targeting distinct aspects of the Regenerative Process.
Alexandre B M Da Silveira - One of the best experts on this subject based on the ideXlab platform.
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Regenerative Process evaluation of neuronal subclasses in chagasic patients with megacolon
Human Immunology, 2013Co-Authors: Milena Dionizio Moreira, Axel Brehmer, Enio Chaves De Oliveira, Salustiano Gabriel Neto, Alejandro O Luquetti, Lilian Lacerda Bueno, Ricardo Toshio Fujiwara, Michelle A R Freitas, Alexandre B M Da SilveiraAbstract:Chagas' disease is one of the most serious parasitic diseases of Latin America, with a social and economic impact far outweighing the combined effects of other parasitic diseases such as malaria, leishmaniasis and schistosomiasis. In the chronic phase of this disease, the destruction of enteric nervous system (ENS) components leads to megacolon development. Previous data presented that the regeneration tax in the ENS neurons is augmented in chagasic patients. Although, there are several neuronal types with different functions in the intestine a detailed study about the regeneration of every neuronal type was never performed before. Therefore, the aim of this study was to evaluate the regeneration tax of every neuronal cell type in the ENS from chagasic patients with megacolon and non-infected individuals. A neuronal regeneration marker (GAP-43) was used in combination with a pan-neuronal marker (Peripherin) and several neuropeptides markers (cChat, Substance P, NPY, VIP and NOS), and it was considered as positive just with the combination of these markers. Our results demonstrated that the regeneration levels of cChat, Substance P, and NPY were similar in chagasic patients and non-infected individuals. However, levels of VIP and NOS neuropeptides were increased in chagasic patients when compared with non-infected individuals. We believe that the augment in the regeneration occur due to an increased destruction of selective neuronal types. These results corroborates with previous studies that pointed out to selective destruction of VIP and NOS neurons in chagasic patients.
