"Of Mice and Measures": A Project to Improve How We Advance Duchenne Muscular Dystrophy Therapies to the Clinic

A new line of dystrophic mdx mice on the DBA/2J (D2) background has emerged as a candidate to study the efficacy of therapeutic approaches for Duchenne muscular dystrophy (DMD). These mice harbor genetic polymorphisms that appear to increase the severity of the dystropathology, with disease modifiers that also occur in DMD patients, making them attractive for efficacy studies and drug development. This workshop aimed at collecting and consolidating available data on the pathological features and the natural history of these new D2/mdx mice, for comparison with classic mdx mice and controls, and to identify gaps in information and their potential value. The overall aim is to establish guidance on how to best use the D2/mdx mouse model in preclinical studies

How to design graphs with low forwarding index and limited number of edges

International audienceThe (edge) forwarding index of a graph is the minimum, over all possible rout-ings of all the demands, of the maximum load of an edge. This metric is of a great interest since it captures the notion of global congestion in a precise way: the lesser the forwarding-index, the lesser the congestion. In this paper, we study the following design question: Given a number e of edges and a number n of vertices, what is the least congested graph that we can construct? and what forwarding-index can we achieve? Our problem has some distant similarities with the well-known (∆, D) problem, and we sometimes build upon results obtained on it. The goal of this paper is to study how to build graphs with low forwarding indices and to understand how the number of edges impacts the forwarding index. We answer here these questions for different families of graphs: general graphs, graphs with bounded degree, sparse graphs with a small number of edges by providing constructions, most of them asymptotically optimal. For instance, we provide an asymptotically optimal construction for (n, n + k) cubic graphs-its forwarding index is ∼ n 2 3k log 2 (k). Our results allow to understand how the forwarding-index drops when edges are added to a graph and also to determine what is the best (i.e least congested) structure with e edges. Doing so, we partially answer the practical problem that initially motivated our work: If an operator wants to power only e links of its network, in order to reduce the energy consumption (or wiring cost) of its networks, what should be those links and what performance can be expected

Disease Rescue and Increased Lifespan in a Model of Cardiomyopathy and Muscular Dystrophy by Combined AAV Treatments

The BIO14.6 hamster is an excellent animal model for inherited cardiomyopathy, because of its lethal and well-documented course, due to a spontaneous deletion of delta-sarcoglycan gene promoter and first exon. The muscle disease is progressive and average lifespan is 11 months, because heart slowly dilates towards heart failure.Based on the ability of adeno-associated viral (AAV) vectors to transduce heart together with skeletal muscle following systemic administration, we delivered human delta-sarcoglycan cDNA into male BIO14.6 hamsters by testing different ages of injection, routes of administration and AAV serotypes. Body-wide restoration of delta-SG expression was associated with functional reconstitution of the sarcoglycan complex and with significant lowering of centralized nuclei and fibrosis in skeletal muscle. Motor ability and cardiac functions were completely rescued. However, BIO14.6 hamsters having less than 70% of fibers recovering sarcoglycan developed cardiomyopathy, even if the total rescued protein was normal. When we used serotype 2/8 in combination with serotype 2/1, lifespan was extended up to 22 months with sustained heart function improvement.Our data support multiple systemic administrations of AAV as a general therapeutic strategy for clinical trials in cardiomyopathies and muscle disorders

From North Africa to Latin America and back: comparative findings and theoretical reflections

Taking the different case studies of the book together, one general observation stands out: Key agents of socioeconomic contention, including movements by organized labor and the unemployed that were important in the run-up to the uprisings and that saw their political opportunities open up in the immediate aftermath of the revolutions, have since been effectively marginalized as political actors. The concluding chapter reflects on the causes of this weakness of socioeconomic contention by identifying comparative insights that emerge from the contributions to this volume and by situating them in the context of broader comparative and theoretical debates on the relationship between social movements and political change. More specifically, the chapter first discusses Egypt’s and Tunisia’s post-revolutionary trajectories from a comparative perspective. Second, it discusses these comparative findings in the light of experiences in Latin America. Third, drawing again on comparative scholarship on Latin America, the chapter offers a theoretical interpretation of some of the main dynamics observed in Egypt and Tunisia based on the notion of a popular-sector incorporation crisis. Fourth and finally, the chapter concludes with general implications and an outlook

Marginal Level Dystrophin Expression Improves Clinical Outcome in a Strain of Dystrophin/Utrophin Double Knockout Mice

Inactivation of all utrophin isoforms in dystrophin-deficient mdx mice results in a strain of utrophin knockout mdx (uko/mdx) mice. Uko/mdx mice display severe clinical symptoms and die prematurely as in Duchenne muscular dystrophy (DMD) patients. Here we tested the hypothesis that marginal level dystrophin expression may improve the clinical outcome of uko/mdx mice. It is well established that mdx3cv (3cv) mice express a near-full length dystrophin protein at ∼5% of the normal level. We crossed utrophin-null mutation to the 3cv background. The resulting uko/3cv mice expressed the same level of dystrophin as 3cv mice but utrophin expression was completely eliminated. Surprisingly, uko/3cv mice showed a much milder phenotype. Compared to uko/mdx mice, uko/3cv mice had significantly higher body weight and stronger specific muscle force. Most importantly, uko/3cv outlived uko/mdx mice by several folds. Our results suggest that a threshold level dystrophin expression may provide vital clinical support in a severely affected DMD mouse model. This finding may hold clinical implications in developing novel DMD therapies

Worsening of Cardiomyopathy Using Deflazacort in an Animal Model Rescued by Gene Therapy

We have previously demonstrated that gene therapy can rescue the phenotype and extend lifespan in the delta-sarcoglycan deficient cardiomyopathic hamster. In patients with similar genetic defects, steroids have been largely used to slow down disease progression. Aim of our study was to evaluate the combined effects of steroid treatment and gene therapy on cardiac function. We injected the human delta-sarcoglycan cDNA by adeno-associated virus (AAV) 2/8 by a single intraperitoneal injection into BIO14.6 Syrian hamsters at ten days of age to rescue the phenotype. We then treated the hamsters with deflazacort. Treatment was administered to half of the hamsters that had received the AAV and the other hamsters without AAV, as well as to normal hamsters. Both horizontal and vertical activities were greatly enhanced by deflazacort in all groups. As in previous experiments, the AAV treatment alone was able to preserve the ejection fraction (70±7% EF). However, the EF value declined (52±14%) with a combination of AAV and deflazacort. This was similar with all the other groups of affected animals. We confirm that gene therapy improves cardiac function in the BIO14.6 hamsters. Our results suggest that deflazacort is ineffective and may also have a negative impact on the cardiomyopathy rescue, possibly by boosting motor activity. This is unexpected and may have significance in terms of the lifestyle recommendations for patients

Genetic Background of Prop1df Mutants Provides Remarkable Protection Against Hypothyroidism-Induced Hearing Impairment

Hypothyroidism is a cause of genetic and environmentally induced deafness. The sensitivity of cochlear development and function to thyroid hormone (TH) mandates understanding TH action in this sensory organ. Prop1df and Pou1f1dw mutant mice carry mutations in different pituitary transcription factors, each resulting in pituitary thyrotropin deficiency. Despite the same lack of detectable serum TH, these mutants have very different hearing abilities: Prop1df mutants are mildly affected, while Pou1f1dw mutants are completely deaf. Genetic studies show that this difference is attributable to the genetic backgrounds. Using embryo transfer, we discovered that factors intrinsic to the fetus are the major contributor to this difference, not maternal effects. We analyzed Prop1df mutants to identify processes in cochlear development that are disrupted in other hypothyroid animal models but protected in Prop1df mutants by the genetic background. The development of outer hair cell (OHC) function is delayed, but Prestin and KCNQ4 immunostaining appear normal in mature Prop1df mutants. The endocochlear potential and KCNJ10 immunostaining in the stria vascularis are indistinguishable from wild type, and no differences in neurofilament or synaptophysin staining are evident in Prop1df mutants. The synaptic vesicle protein otoferlin normally shifts expression from OHC to IHC as temporary afferent fibers beneath the OHC regress postnatally. Prop1df mutants exhibit persistent, abnormal expression of otoferlin in apical OHC, suggesting delayed maturation of synaptic function. Thus, the genetic background of Prop1df mutants is remarkably protective for most functions affected in other hypothyroid mice. The Prop1df mutant is an attractive model for identifying the genes that protect against deafness

Dynamic Assignment and Maintenance of Positional Identity in the Ventral Neural Tube by the Morphogen Sonic Hedgehog

During development of the vertebrate neural tube, cells acquire their positional identity from not only the spatial level of the Sonic Hedgehog signaling gradient, but also the temporal duration

Thermal effects in high density polyethylene and low density polyethylene at high hydrostatic pressures

The temperature changes as a result of rapid hydrostatic pressure applications are reported for high density polyethylene (HDPE) and low density polyethylene (LDPE) in the reference temperature range from 298 to 423 K and in the pressure range from 13.8 to 200 MN m −2 . The adiabatic temperature changes were found to be a function of pressure and temperature. A curve fitting analysis showed that the empirical curve (∂/∂ P ) = ab (Δ P ) b−1 described the experimental thermoelastic coefficients obtained from the experiments. The data were analyzed by determining the predicted thermoelastic coefficients derived from the Thomson equation (∂/∂ P ) θ = α T 0 /ϱ C p . The experimental and predicted Grüneisen parameter γ T were also determined.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44687/1/10853_2005_Article_BF01132919.pd