Optimisation of dynamic, hybrid signal function networks

Functional Reactive Programming (FRP) is an approach to reactive programming where systems are structured as networks of functions operating on signals. FRP is based on the synchronous data-flow paradigm and supports both continuous-time and discrete-time signals (hybrid systems). What sets FRP apart from most other languages for similar applications is its support for systems with dynamic structure and for higher-order data-flow constructs. This raises a range of implementation challenges. This paper contributes towards advancing the state of the art of FRP implementation by studying the notion of signal change and change propagation in a setting of hybrid signal function networks with dynamic structure. To sidestep some problems of certain previous FRP implementations that are structured using arrows, we suggest working with a notion of composable, multi-input and multi-output signal functions. A clear conceptual distinction is also made between continuous-time and discrete-time signals. We then show how establishing change-related properties of the signal functions in a network allows such networks to be simplified (static optimisation) and can help reducing the amount of computation needed for executing the networks (dynamic optimisation). Interestingly, distinguishing between continuous-time and discrete-time signals allows us to characterise the change-related properties of signal functions more precisely than what we otherwise would have been able to, which is helpful for optimisation

The Kansas University rewrite engine: a Haskell-embedded strategic programming language with custom closed universes

When writing transformation systems, a significant amount of engineering effort goes into setting up the infrastructure needed to direct individual transformations to specific targets in the data being transformed. Strategic programming languages provide general-purpose infrastructure for this task, which the author of a transformation system can use for any algebraic data structure. The Kansas University Rewrite Engine (KURE) is a typed strategic programming language, implemented as a Haskell-embedded domain-specific language. KURE is designed to support typed transformations over typed data, and the main challenge is how to make such transformations compatible with generic traversal strategies that should operate over any type. Strategic programming in a typed setting has much in common with datatype-generic programming. Compared to other approaches to datatype-generic programming, the distinguishing feature of KURE’s solution is that the user can configure the behaviour of traversals based on the location of each datum in the tree, beyond their behaviour being determined by the type of each datum. This article describes KURE’s approach to assigning types to generic traversals, and the implementation of that approach. We also compare KURE, its design choices, and their consequences, with other approaches to strategic and datatype-generic programming

Executable component-based semantics

The potential benefits of formal semantics are well known. However, a substantial amount of work is required to produce a complete and accurate formal semantics for a major language; and when the language evolves, large-scale revision of the semantics may be needed to reflect the changes. The investment of effort needed to produce an initial definition, and subsequently to revise it, has discouraged language developers from using formal semantics. Consequently, many major programming languages (and most domain-specific languages) do not yet have formal semantic definitions.To improve the practicality of formal semantic definitions, the PLanCompS project has developed a component-based approach. In this approach, the semantics of a language is defined by translating its constructs (compositionally) to combinations of so-called fundamental constructs, or ‘funcons’. Each funcon is defined using a modular variant of Structural Operational Semantics, and forms a language-independent component that can be reused in definitions of different languages. A substantial library of funcons has been developed and tested in several case studies. Crucially, the definition of each funcon is fixed, and does not need changing when new funcons are added to the library.For specifying component-based semantics, we have designed and implemented a meta-language called CBS. It includes specification of abstract syntax, of its translation to funcons, and of the funcons themselves. Development of CBS specifications is supported by an integrated development environment. The accuracy of a language definition can be tested by executing the specified translation on programs written in the defined language, and then executing the resulting funcon terms using an interpreter generated from the CBS definitions of the funcons. This paper gives an introduction to CBS, illustrates its use, and presents the various tools involved in our implementation of CBS

Functional reactive programming, refactored

Functional Reactive Programming (FRP) has come to mean many things. Yet, scratch the surface of the multitude of realisations, and there is great commonality between them. This paper investigates this commonality, turning it into a mathematically coherent and practical FRP realisation that allows us to express the functionality of many existing FRP systems and beyond by providing a minimal FRP core parameterised on a monad. We give proofs for our theoretical claims and we have verified the practical side by benchmarking a set of existing, non-trivial Yampa applications running on top of our new system with very good results

High Intensity Interval Training (HIIT) as a Potential Countermeasure for Phenotypic Characteristics of Sarcopenia: A Scoping Review

Background: Sarcopenia is defined as a progressive and generalized loss of skeletal muscle quantity and function associated predominantly with aging. Physical activity appears the most promising intervention to attenuate sarcopenia, yet physical activity guidelines are rarely met. In recent years high intensity interval training (HIIT) has garnered interested in athletic populations, clinical populations, and general population alike. There is emerging evidence of the efficacy of HIIT in the young old (i.e. seventh decade of life), yet data concerning the oldest old (i.e., ninth decade of life onwards), and those diagnosed with sarcopenic are sparse. Objectives: In this scoping review of the literature, we aggregated information regarding HIIT as a potential intervention to attenuate phenotypic characteristics of sarcopenia. Eligibility Criteria: Original investigations concerning the impact of HIIT on muscle function, muscle quantity or quality, and physical performance in older individuals (mean age ≥60 years of age) were considered. Sources of Evidence: Five electronic databases (Medline, EMBASE, Web of Science, Scopus, and the Cochrane Central Register of Controlled Trials [CENTRAL]) were searched. Methods: A scoping review was conducted using the Arksey and O'Malley methodological framework (2005). Review selection and characterization were performed by two independent reviewers using pretested forms. Results: Authors reviewed 1,063 titles and abstracts for inclusion with 74 selected for full text review. Thirty-two studies were analyzed. Twenty-seven studies had a mean participant age in the 60s, two in the 70s, and three in the 80s. There were 20 studies which examined the effect of HIIT on muscle function, 22 which examined muscle quantity, and 12 which examined physical performance. HIIT was generally effective in Improving muscle function and physical performance compared to non-exercised controls, moderate intensity continuous training, or pre-HIIT (study design-dependent), with more ambiguity concerning muscle quantity. Conclusions: Most studies presented herein utilized outcome measures defined by the European Working Group on Sarcopenia in Older People (EWGSOP). However, there are too few studies investigating any form of HIIT in the oldest old (i.e., ≥80 years of age), or those already sarcopenic. Therefore, more intervention studies are needed in this population

Vitamin C Intravenous Treatment In the Setting of Atrial Fibrillation Ablation: Results From the Randomized, Double-Blinded, Placebo-Controlled CITRIS-AF Pilot Study

BackgroundCatheter ablation is an effective treatment for atrial fibrillation (AF), but high levels of post-procedure inflammation predict adverse clinical events. Ascorbic acid (AA) has shown promise in reducing inflammation but is untested in this population. We sought to test the feasibility, safety, and preliminary effects on inflammatory biomarkers in the CITRIS-AF (Vitamin C Intravenous Treatment In the Setting of Atrial Fibrillation Ablation) pilot study. Methods and ResultsPatients scheduled to undergo AF ablation (N=20) were randomized 1:1 to double-blinded treatment with AA (200 mg/kg divided over 24 hours) or placebo. C-reactive protein and interleukin-6 levels were obtained before the first infusion and repeated at 24 hours and 30 days. Pain levels within 24 hours and early recurrence of AF within 90 days were recorded. Median and interquartile range were aged 63 (56–70) years, 13 (65%) men, and 18 (90%) white. Baseline data were similar between the 2 groups except ejection fraction. Baseline C-reactive protein levels were 2.56 (1.47–5.87) mg/L and similar between groups (P=0.48). Change in C-reactive protein from baseline to 24 hours was +10.79 (+6.56–23.19) mg/L in the placebo group and +3.01 (+0.40–5.43) mg/L in the AA group (P=0.02). Conversely, change in interleukin-6 was numerically higher in the AA group, though not statistically significant (P=0.32). One patient in each arm developed pericarditis; no adverse events related to the infusions were seen. There were no significant differences between aggregated post-procedure pain levels within 24 hours or early recurrence of AF (both P\u3e0.05). ConclusionsHigh-dose AA is safe and well tolerated at the time of AF ablation and may be associated with a blunted rise in C-reactive protein, although consistent findings were not seen in interleukin-6 levels. Further studies are needed to validate these findings and explore the potential benefit in improving clinically relevant outcomes

Worker/wrapper/makes it/faster

Much research in program optimization has focused on formal approaches to correctness: proving that the meaning of programs is preserved by the optimisation. Paradoxically, there has been comparatively little work on formal approaches to efficiency: proving that the performance of optimized programs is actually improved. This paper addresses this problem for a general-purpose optimization technique, the worker/wrapper transformation. In particular, we use the call-by-need variant of improvement theory to establish conditions under which the worker/wrapper transformation is formally guaranteed to preserve or improve the time performance of programs in lazy languages such as Haskell

Impaired hypertrophy in myoblasts is improved with testosterone administration

We investigated the ability of testosterone (T) to restore differentiation in multiple population doubled (PD) murine myoblasts, previously shown to have reduced differentiation in monolayer and bioengineered skeletal muscle cultures vs. their parental controls (CON) (Sharples et al., 2011, 2012 [7] and [26]). Cells were exposed to low serum conditions in the presence or absence of T (100 nM) ± PI3K inhibitor (LY294002) for 72 h and 7 days (early and late muscle differentiation respectively). Morphological analyses were performed to determine myotube number, diameter (μm) and myonuclear accretion as indices of differentiation and myotube hypertrophy. Changes in gene expression for myogenin, mTOR and myostatin were also performed. Myotube diameter in CON and PD cells increased from 17.32 ± 2.56 μm to 21.02 ± 1.89 μm and 14.58 ± 2.66 μm to 18.29 ± 3.08 μm (P ≤ 0.05) respectively after 72 h of T exposure. The increase was comparable in both PD (+25%) and CON cells (+21%) suggesting a similar intrinsic ability to respond to exogenous T administration. T treatment also significantly increased myonuclear accretion (% of myotubes expressing 5+ nuclei) in both cell types after 7 days exposure (P ≤ 0.05). Addition of PI3K inhibitor (LY294002) in the presence of T attenuated these effects in myotube morphology (in both cell types) suggesting a role for the PI3K pathway in T stimulated hypertrophy. Finally, PD myoblasts showed reduced responsiveness to T stimulated mRNA expression of mTOR vs. CON cells and T also reduced myostatin expression in PD myoblasts only. The present study demonstrates testosterone administration improves hypertrophy in myoblasts that basally display impaired differentiation and hypertrophic capacity vs. their parental controls, the action of testosterone in this model was mediated by PI3K/Akt pathway

Utility of the hypertriglyceridemic waist phenotype in the cardiometabolic risk assessment of youth stratified by body mass index

Background: It is unclear whether the Hypertriglyceridemic Waist Phenotype can be used to identify those at most risk of cardiometabolic disorders. Objectives: The utility of the Hypertriglyceridemic Waist Phenotype (HTWP) as a useful predictor of cardiometabolic risk in youth stratified by body mass index (BMI) was assessed. Methods: Three hundred and eighty seven children (12-17.5 years) were used within this cross-sectional study. Participants were classified as normal weight or overweight/obese according to the IOTF criteria. The HTWP phenotype was defined as having a waist circumference ≥ 90th percentile for age and gender with concomitant triglyceride concentrations ≥ 1.24 mmol/L. Cardiometabolic risk profiles were compared using MANCOVA. Results: Normal weight participants with the HTWP had significantly higher levels of C-reactive protein 2.6 ± 0.4 vs. 1.6 ± 0.3 mg/L (P < 0.05) and cardiometabolic risk scores (1.3 ± 0.3 vs. -0.7 ± 0.2 and 2.1 ± 0.4 vs. -0.5 ± 0.2; both P < 0.05) compared to those of a normal weight without the HTWP. Overweight/obese participants with the HTWP had significantly higher C-reactive protein levels (3.5 ± 0.6 vs. 2.6 ± 0.5; P < 0.05) as well as both cardiometabolic risk scores (1.6 ± 0.6 vs. 0.9 ± 0.2 and 2.2 ± 0.6 vs. 0.8 ± 0.2; both P < 0.001) when compared to overweight/obese participants without the HTWP. Conclusions: The HTWP may serve as a simple and clinically useful approach to identify youth at increased cardiometabolic risk

Testosterone enables growth and hypertrophy in fusion impaired myoblasts that display myotube atrophy: deciphering the role of androgen and IGF-I receptors

We have previously highlighted the ability of testosterone to improve differentiation and myotube hypertrophy in fusion impaired myoblasts that display reduced myotube hypertrophy at 72hrs (after transfer to low serum media) via multiple population doublings (PD) vs. their parental controls (CON); an observation which is abrogated via PI3K/Akt inhibition (Deane et al. 2013). However, whether the most predominant molecular mechanism responsible for T induced hypertrophy occurs directly via androgen receptor or indirectly via IGF-IR/PI3K/Akt pathway is currently debated. PD and CON C2C12 muscle cells were exposed to low serum conditions in the presence or absence of T (100 nM) ± inhibitors of AR (flutamide/F, 40 μm) and IGF-IR (Picropodophyllin/PPP, 150 nM) for 72 hrs and 7 days (early/late muscle differentiation respectively). T increased AR and Akt abundance, myogenin expression, and myotube hypertrophy, but not ERK1/2 activity in both CON and PD cell types. Akt activity was not increased significantly in either cell type with T. Testosterone was unable to promote early differentiation in the presence of IGF-IR inhibitor (PPP) yet still able to promote appropriate later increases in myotube hypertrophy and AR abundance despite IGF-IR inhibition. The addition of the AR inhibitor powerfully attenuated all T induced increases in differentiation and myotube hypertrophy with corresponding reductions in AR abundance, phosphorylated Akt, ERK1/2 and gene expression of IGF-I, myoD and myogenin with increases in myostatin mRNA both cell types. Interestingly, despite basally reduced differentiation and myotube hypertrophy, PD cells showed larger increased in AR abundance vs. CON cells, a response abrogated in the presence of AR but not IGF-IR inhibitors. Furthermore, T induced increases in Akt abundance were sustained despite the presence of IGF-IR inhibition in PD cells only. However, flutamide alone reduced IGF-IR mRNA in both cell types across time points, with an observed reduction in activity of ERK and Akt, perhaps suggesting that IGF-IR was transcriptionally regulated by AR. However, where testosterone increased AR protein content there was no increases observed in IGF-IR gene expression. Overall, this suggested that sufficient AR was important to enable normal gene expression of IGF-IR and downstream signalling, yet elevated levels of AR due to testosterone had no further effect on IGF-IR, despite testosterone increasing Akt abundance in the presence of IGF-IR inhibitor. In conclusion, testosterones ability to improve differentiation and myotube hypertrophy occurred predominately via increases in AR and Akt abundance in both CON and PD cells, with fusion impaired cells (PD) showing an increased responsiveness to T induced AR levels. Finally, T induced increases in myotube hypertrophy (but not early differentiation) occurred independently of upstream IGF-IR input, however it appears that normal AR function in basal conditions is required for adequate IGF-IR gene expression and downstream Akt abundance