ASP-deficient mice (C3 KO) have delayed postprandial TG clearance, are hyperphagic, and display increased energy expenditure. Markers of carbohydrate and fatty acid metabolism in the skeletal muscle ...and heart were examined to evaluate the mechanism. On a high-fat diet, compared with wild-type mice, C3 KO mice have increased energy expenditure, decreased RQ, lower ex vivo glucose oxidation (-39%, P = 0.018), and higher ex vivo fatty acid oxidation (+68%, P = 0.019). They have lower muscle glycogen content (-25%, P < 0.05) and lower activities for the glycolytic enzymes glycogen phosphorylase (-31%, P = 0.005), hexokinase (-43%, P = 0.007), phosphofructokinase (-51%, P < 0.0001), and GAPDH (-15%, P = 0.04). Analysis of mitochondrial enzyme activities revealed that hydroxyacyl-coenzyme A dehydrogenase was higher (+25%, P = 0.004) in C3 KO mice. Furthermore, Western blot analysis of muscle revealed significantly higher fatty acid transporter CD36 (+40%, P = 0.006) and cytochrome c (a marker of mitochondrial content; +69%, P = 0.034) levels in C3 KO mice, whereas the activity of AMP kinase was lower (-48%, P = 0.003). Overall, these results demonstrate a shift in the metabolic potential of skeletal muscle toward increased fatty acid utilization. Whether this is 1) a consequence of decreased adipose tissue storage with repartitioning toward muscle or 2) a direct result of the absence of ASP interaction with the receptor C5L2 in muscle remains to be determined. However, these in vivo data suggest that ASP inhibition could be a potentially viable approach in correcting muscle metabolic dysfunction in obesity.
Neurotrophins are a family of secreted proteins that play an important role in the development, differentiation, and survival of neurons. Studies also suggest that aberrant neurotrophin signaling may ...play a role in processes underlying disease states such as schizophrenia, Alzheimer's disease, and depression. Whereas the development of agents that selectively stimulate neurotrophin signaling has proven to be difficult, compounds have been identified that potentiate neurotrophin 3 (NT-3)-mediated activation of trk A. In the present studies, we extend those initial observations to identify compounds that also potentiate NT-3-mediated activation of trk B. Compound potentiation of NT-3 was observed using several readouts of transfected and endogenous trk receptor activity, including trk receptor phosphorylation, mitogen-activated protein kinase phosphorylation, reporter assay activity (beta-lactamase and luciferase), cell survival and neurite extension assays. Studies using chimeric trk receptors demonstrated that the extracellular domain is essential for compound potentiation and rule out interaction with intracellular signaling molecules as a mechanism of compound activity. Thus, the present studies demonstrate that trk B receptor activity can be potentiated by small-molecule compounds via the extracellular domain of the receptor and provide reagents for further evaluating the role of NT-3-mediated trk A and trk B activity in vivo.
A series of symmetrical E-stilbene prolinamides that originated from the library-synthesized lead 3 was studied with respect to HCV genotype 1a (G-1a) and genotype 1b (G-1b) replicon inhibition and ...selectivity against BVDV and cytotoxicity. SAR emerging from an examination of the prolinamide cap region revealed 11 to be a selective HCV NS5A inhibitor exhibiting submicromolar potency against both G-1a and G-1b replicons. Additional structural refinements resulted in the identification of 30 as a potent, dual G-1a/1b HCV NS5A inhibitor.
A series of fluoroglycosylated fluoroindolocarbazoles was examined with respect to their topoisomerase I activity, cytotoxicity, and selectivity. The lead clinical candidate from this series, ...BMS-250749, displays broad spectrum antitumor activity superior to CPT-11 against some preclinical xenograft models, including curative antitumor activity against Lewis lung carcinoma.
This study aimed to determine the impact of short-term normobaric hypoxia on physiology and performance in highly trained
athletes. Twelve (7 male and 5 female) athletes were randomly assigned into ...two groups and spent 8 h per night for two consecutive
nights a week over 3 weeks under either short-term normobaric hypoxia (simulating 3636 m altitude, inspired O 2 = 13%) or in normobaric normoxia in a single-blind study. Following a 3 week washout period, athletes were then exposed to
the other condition. Athletes were tested for maximal oxygen consumption and time to exhaustion on an electromagnetically
braked cycle ergometer before and after each treatment in addition to being tested for anaerobic performance (Wingate test)
on a modified Monark cycle ergometer. Blood samples were taken throughout the experiment and vastus lateralis muscle biopsies
were taken before and after each treatment. Increases in red blood cell count, haematocrit, haemoglobin, platelet number and
erythropoietin concentration were observed following short-term normobaric hypoxia. Except for a modest decrease in phosphofructokinase
activity following short-term normobaric hypoxia, no changes were observed in muscle enzyme activities, buffer capacity, capillary
density or morphology. No performance measures were changed following short-term normobaric hypoxia or normobaric normoxia.
Although short-term normobaric hypoxia exposure increased levels of a number of haematological parameters, this was not associated
with improved aerobic or anaerobic performance in highly trained athletes.
During the last 10 years, many organizations have invested resources and energy in order to be rated at the highest level as possible according to some maturity models for software development. Since ...measures play an important role in these models, it is essential that CASE tools offer facilities to automatically measure the sizes of various documents produced using them. This paper introduces a tool, called μcROSE, that automatically measures the functional software size, as defined by the COSMIC-FFP method, for
Rational Rose RealTime models. μ
cROSE streamlines the measurement process, ensuring repeatability and consistency in measurement while reducing measurement cost. It is the first tool to address automatic measurement of COSMIC-FFP and it can be integrated into the
Rational Rose RealTime toolset.
A series of fluoroindolocarbazoles were studied with respect to their topoisomerase I activity, cytotoxicity, selectivity, and in vivo antitumor activity. Emerging from this series was BMS-251873, a ...potential clinical candidate possessing a robust pharmacological profile including curative antitumor activity against prostate carcinoma.
Describes a synthesis method that automatically derives controllers for timed discrete-event systems with nonterminating behavior modeled by timed transition graphs and specifications of control ...requirements expressed by metric temporal logic (MTL) formulas. Synthesis is performed by using: 1) a forward-chaining search that evaluates the satisfiability of MTL formulas over sequences of states generated by occurrences of actions and 2) a control-directed backtracking technique that takes into consideration the controllability of actions. This method has several interesting features. First, the issues of controllability, safety, liveness, and real time are integrated in a single framework. Second, the synthesis process does not require explicit storage of an entire transition structure over which formulas are checked and can be stopped at any moment, giving an approximate but useful result. Third, search and control mechanisms allow circumvention of the state explosion problem.
The relative contribution of anthropometric and skeletal muscle characteristics to cardiorespiratory fitness was studied in sedentary men. Cardiorespiratory fitness (maximal oxygen consumption) was ...assessed using an incremental bicycle ergometer protocol in 37 men aged 34-53 years. Vastus lateralis muscle biopsy samples were used to assess fiber type composition (I, IIA, IIX) and areas, capillary density, and activities of glycolytic and oxidative energy metabolic pathway enzymes. Correlations (all p < 0.05) were observed between maximal oxygen consumption (L·min
-1
) and body mass (r = 0.53), body mass index (r = 0.39), waist circumference (r = 0.34), fat free mass (FFM;; r = 0.68), fat mass (r = 0.33), the enzyme activity of cytochrome c oxidase (COX;; r = 0.39), muscle type IIA (r = 0.40) and IIX (r = 0.50) fiber area, and the number of capillaries per type IIA (r = 0.39) and IIX (r = 0.37) fiber. When adjusted for FFM in partial correlations, all correlations were lost, with the exception of COX (r = 0.48). Stepwise multiple regression revealed that maximal oxygen consumption was independently predicted by FFM, COX activity, mean capillary number per fiber, waist circumference, and, to a lesser extent, muscle capillary supply. In the absence of regular physical activity, cardiorespiratory fitness is strongly predicted by the potential for aerobic metabolism of skeletal muscle and negatively correlated with abdominal fat deposition.
A traditional approach for planning is to evaluate goal statements over state trajectories modeling predicted behaviors of an agent. This paper describes a powerful extension of this approach for ...handling complex goals for reactive agents. We describe goals by using a modal temporal logic that can express quite complex time, safety, and liveness constraints. Our method is based on an incremental planner algorithm that generates a reactive plan by computing a sequence of partially satisfactory reactive plans converging to a completely satisfactory one. Partial satisfaction means that an agent controlled by the plan accomplishes its goal only for some environment events. Complete satisfaction means that the agent accomplishes its goal whatever environment events occur during the execution of the plan. As such, our planner can be stopped at any time to yield a useful plan. An implemented prototype is used to evaluate our planner on empirical problems.
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