27 research outputs found
Energy Games with Resource-Bounded Environments
An energy game is played between two players, modeling a resource-bounded system and its environment. The players take turns moving a token along a finite graph. Each edge of the graph is labeled by an integer, describing an update to the energy level of the system that occurs whenever the edge is traversed. The system wins the game if it never runs out of energy. Different applications have led to extensions of the above basic setting. For example, addressing a combination of the energy requirement with behavioral specifications, researchers have studied richer winning conditions, and addressing systems with several bounded resources, researchers have studied games with multi-dimensional energy updates. All extensions, however, assume that the environment has no bounded resources.
We introduce and study both-bounded energy games (BBEGs), in which both the system and the environment have multi-dimensional energy bounds. In BBEGs, each edge in the game graph is labeled by two integer vectors, describing updates to the multi-dimensional energy levels of the system and the environment. A system wins a BBEG if it never runs out of energy or if its environment runs out of energy. We show that BBEGs are determined, and that the problem of determining the winner in a given BBEG is decidable iff both the system and the environment have energy vectors of dimension 1. We also study how restrictions on the memory of the system and/or the environment as well as upper bounds on their energy levels influence the winner and the complexity of the problem
Halofuginone and muscular dystrophy
Muscular dystrophies (MDs) include
different inherited diseases that all result in progressive
muscle degeneration, impaired locomotion and often
premature death. The major focus of MD research has
been on alleviating the primary genetic deficit - using
gene therapy and myoblast-transfer approaches to
promote expression of the deficient or mutated genes in
the muscle fibers. Although promising, these approaches
have not yet entered into clinical practice and
unfortunately for MD patients, there is currently no cure.
Thus, the development of complementary and supportive
therapies that slow disease progression and improve
patients' quality of life is critically important. The main
features of MDs are sarcolemmal instability and
increased myofiber vulnerability to mechanical stress,
resulting in myofiber degeneration. Fibrosis, with
progressive replacement of muscle tissue, is a prominent
feature in some MDs, preventing complete regeneration
and hampering muscle functions. TGFß is the leading
candidate for activating fibroblasts and eliciting
overproduction of extracellular matrix (ECM) proteins.
Halofuginone, an inhibitor of Smad3 phosphorylation
downstream of TGFß signaling, inhibits the activation of
fibroblasts and their ability to synthesize ECM,
regardless of their origin or location. In animal models
of MDs with prominent muscle fibrosis, halofuginone
treatment has resulted in both prevention of collagen
production in young animals and resolution of
established fibrosis in older ones: the reduction in
muscle collagen content was associated with improved
muscle histopathology and major improvements in
muscle function. Recently, these halofuginonedependent
improvements were also observed in MD
with minor fibrosis involvement, probably due to a
direct effect of halofuginone on muscle cells, resulting in
myotube fusion that is dependent on Akt and MAPK pathway activation. In summary, halofuginone improves
muscle histopathology and muscle functions in various
MDs, via inhibition of muscle fibrosis on the one hand,
and increased myotube fusion on the other
Low-energy laser irradiation enhances de novo protein synthesis via its effects on translation-regulatory proteins in skeletal muscle myoblasts
AbstractLow-energy laser irradiation (LELI) drives quiescent skeletal muscle satellite cells into the cell cycle and enhances their proliferation, thereby promoting skeletal muscle regeneration. Ongoing protein synthesis is a prerequisite for these processes. Here, we studied the signaling pathways involved in the LELI regulation of protein synthesis. High levels of labeled [35S]methionine incorporation were detected in LELI cells as early as 20 min after irradiation, suggesting translation of pre-existing mRNAs. Induced levels of protein synthesis were detected up until 8 h after LELI implying a role for LELI in de novo protein synthesis. Elevated levels of cyclin D1, associated with augmented phosphorylation of the eukaryotic initiation factor 4E (eIF4E) and its inhibitory binding protein PHAS-I, suggested the involvement of LELI in the initiation steps of protein translation. In the presence of the MEK inhibitor, PD98059, eIF4E phosphorylation was abolished and levels of cyclin D1 were dramatically reduced. The LELI-induced PHAS-I phosphorylation was abolished after preincubation with the PI3K inhibitor, Wortmannin. Concomitantly, LELI enhanced Akt phosphorylation, which was attenuated in the presence of Wortmannin. Taken together, these results suggest that LELI induces protein translation via the PI3K/Akt and Ras/Raf/ERK pathways
In ovo exposure to monochromatic green light promotes skeletal muscle cell proliferation and affects myofiber growth in posthatch chicks
Thermal manipulations in late-term chick embryos have immediate and longer term effects on myoblast proliferation and skeletal muscle hypertrophy
We investigated the cellular and molecular bases for the promotion of muscle development and growth by temperature manipulations (TMs) during late-term chick embryogenesis. We show that incubation at 39.5°C (increase of 1.7°C from normal conditions) from embryonic days 16 to 18 (E16 to E18) for 3 or 6 h daily increased diameter of myofibers as of day 13 of age and enhanced absolute muscle growth relative to controls, until day 35 of age. TMs had immediate (E17) and later (up to 2 wk posthatch) effects in elevating muscle cell proliferation relative to controls. This was indicated by higher DNA incorporation of thymidine and a higher number of cells expressing PCNA in intact muscle, accompanied by higher Pax7 levels, all reflecting a higher number of myogenic cells, and suggesting that the increased hypertrophy can be attributed to a higher reservoir of myogenic progeny cells produced in response to the TM. IGF-I levels were higher in the TM groups than in controls, implying a mechanism by which heat manipulations in chicks affect muscle development, with locally secreted IGF-I playing a major role. Whereas hypertrophy was similar in both TM groups, cell proliferation and Pax7 levels were more robust in the 6-h muscle, mainly posthatch, suggesting a differential effect of various TM periods on cell reservoir vs. hypertrophy and a high sensitivity of myoblasts to relatively small changes in heat duration with respect to these processes, which is manifested in the short and long term