Maximal Sharing in the Lambda Calculus with letrec

Increasing sharing in programs is desirable to compactify the code, and to avoid duplication of reduction work at run-time, thereby speeding up execution. We show how a maximal degree of sharing can be obtained for programs expressed as terms in the lambda calculus with letrec. We introduce a notion of `maximal compactness' for lambda-letrec-terms among all terms with the same infinite unfolding. Instead of defined purely syntactically, this notion is based on a graph semantics. lambda-letrec-terms are interpreted as first-order term graphs so that unfolding equivalence between terms is preserved and reflected through bisimilarity of the term graph interpretations. Compactness of the term graphs can then be compared via functional bisimulation. We describe practical and efficient methods for the following two problems: transforming a lambda-letrec-term into a maximally compact form; and deciding whether two lambda-letrec-terms are unfolding-equivalent. The transformation of a lambda-letrec-term $L$ into maximally compact form $L_0$ proceeds in three steps: (i) translate L into its term graph $G = [[ L ]]$; (ii) compute the maximally shared form of $G$ as its bisimulation collapse $G_0$; (iii) read back a lambda-letrec-term $L_0$ from the term graph $G_0$ with the property $[[ L_0 ]] = G_0$. This guarantees that $L_0$ and $L$ have the same unfolding, and that $L_0$ exhibits maximal sharing. The procedure for deciding whether two given lambda-letrec-terms $L_1$ and $L_2$ are unfolding-equivalent computes their term graph interpretations $[[ L_1 ]]$ and $[[ L_2 ]]$, and checks whether these term graphs are bisimilar. For illustration, we also provide a readily usable implementation.Comment: 18 pages, plus 19 pages appendi

Slit1 and Slit2 Cooperate to Prevent Premature Midline Crossing of Retinal Axons in the Mouse Visual System

AbstractDuring development, retinal ganglion cell (RGC) axons either cross or avoid the midline at the optic chiasm. In Drosophila, the Slit protein regulates midline axon crossing through repulsion. To determine the role of Slit proteins in RGC axon guidance, we disrupted Slit1 and Slit2, two of three known mouse Slit genes. Mice defective in either gene alone exhibited few RGC axon guidance defects, but in double mutant mice a large additional chiasm developed anterior to the true chiasm, many retinal axons projected into the contralateral optic nerve, and some extended ectopically—dorsal and lateral to the chiasm. Our results indicate that Slit proteins repel retinal axons in vivo and cooperate to establish a corridor through which the axons are channeled, thereby helping define the site in the ventral diencephalon where the optic chiasm forms

Rewriting Systems for Reachability in Vector Addition Systems with Pairs

15 pagesInternational audienceWe adapt hypergraph rewriting system to a generalization of Vector Addition Systems with States (VASS) that we call vector addition systems with pairs (VASP). We give rewriting systems and strategies, that allow us to obtain reachability equivalence results between some classes of VASP and VASS. Reachability for the later is well known be equivalent to reachability in Petri nets. VASP generalize also Branching Extension of VASS (BVASS) for which it is unknown if they are more expressive than VASS. We consider here a more restricted notion of reachability for VASP than that for BVASS. However the reachability decision problem corresponding is already equivalent to decidability of the provability in Multiplicative and Exponential Linear Logic (MELL), a question left open for more than 20 years

Proteomic Analysis of Aortae from Human Lipoprotein(a) Transgenic Mice Shows an Early Metabolic Response Independent of Atherosclerosis

Background: Elevated low density lipoprotein (LDL) and lipoprotein(a) are independent risk factors for the development of atherosclerosis. Using a proteomic approach we aimed to determine early changes in arterial protein expression in transgenic mice containing both human LDL and lipoprotein(a) in circulation. Methods and Results: Plasma lipid analyses showed the lipoprotein(a) transgenic mice had significantly higher lipid levels than wildtype, including a much increased LDL and high density lipoprotein (HDL) cholesterol. Analysis of aortae from lipoprotein(a) mice showed lipoprotein(a) accumulation but no lipid accumulation or foam cells, leaving the arteries essentially atherosclerosis free. Using two-dimensional gel electrophoresis and mass spectrometry, we identified 34 arterial proteins with significantly altered abundance (P,0.05) in lipoprotein(a) transgenic mice compared to wildtype including 17 that showed a $2 fold difference. Some proteins of interest showed a similarly altered abundance at the transcript level. These changes collectively indicated an initial metabolic response that included a down regulation in energy, redox and lipid metabolism proteins and changes in structural proteins at a stage when atherosclerosis had not yet developed. Conclusions: Our study shows that human LDL and lipoprotein(a) promote changes in the expression of a unique set o

Labelled Graph Rewriting Meets Social Networks

International audienceThe intense development of computing techniques and the increasing volumes of produced data raise many modelling and analysis challenges. There is a need to represent and analyse information that is: complex –due to the presence of massive and highly heterogeneous data–, dynamic –due to interactions, time, external and internal evolutions–, connected and distributed in networks. We argue in this work that relevant concepts to address these challenges are provided by three ingredients: labelled graphs to represent networks of data or objects; rewrite rules to deal with concurrent local transformations; strategies to express control versus autonomy and to focus on points of interests. To illustrate the use of these concepts, we choose to focus our interest on social networks analysis, and more precisely in this paper on random network generation. Labelled graph strategic rewriting provides a formalism in which different models can be generated and compared. Conversely, the study of social networks, with their size and complexity, stimulates the search for structure and efficiency in graph rewriting. It also motivated the design of new or more general kinds of graphs, rules and strategies (for instance, to define positions in graphs), which are illustrated here. This opens the way to further theoretical and practical questions for the rewriting community

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD

Distinct Characteristics of Circulating Vascular Endothelial Growth Factor-A and C Levels in Human Subjects

The mechanisms that lead from obesity to atherosclerotic disease are not fully understood. Obesity involves angiogenesis in which vascular endothelial growth factor-A (VEGF-A) plays a key role. On the other hand, vascular endothelial growth factor-C (VEGF-C) plays a pivotal role in lymphangiogenesis. Circulating levels of VEGF-A and VEGF-C are elevated in sera from obese subjects. However, relationships of VEGF-C with atherosclerotic risk factors and atherosclerosis are unknown. We determined circulating levels of VEGF-A and VEGF-C in 423 consecutive subjects not receiving any drugs at the Health Evaluation Center. After adjusting for age and gender, VEGF-A levels were significantly and more strongly correlated with the body mass index (BMI) and waist circumference than VEGF-C. Conversely, VEGF-C levels were significantly and more closely correlated with metabolic (e.g., fasting plasma glucose, hemoglobin A1c, immunoreactive insulin, and the homeostasis model assessment of insulin resistance) and lipid parameters (e.g., triglycerides, total cholesterol (TC), low-density-lipoprotein cholesterol (LDL-C), and non-high-density-lipoprotein cholesterol (non-HDL-C)) than VEGF-A. Stepwise regression analyses revealed that independent determinants of VEGF-A were the BMI and age, whereas strong independent determinants of VEGF-C were age, triglycerides, and non-HDL-C. In apolipoprotein E-deficient mice fed a high-fat-diet (HFD) or normal chow (NC) for 16 weeks, levels of VEGF-A were not significantly different between the two groups. However, levels of VEGF-C were significantly higher in HFD mice with advanced atherosclerosis and marked hypercholesterolemia than NC mice. Furthermore, immunohistochemistry revealed that the expression of VEGF-C in atheromatous plaque of the aortic sinus was significantly intensified by feeding HFD compared to NC, while that of VEGF-A was not. In conclusion, these findings demonstrate that VEGF-C, rather than VEGF-A, is closely related to dyslipidemia and atherosclerosis

LDL Receptor Knock-Out Mice Are a Physiological Model Particularly Vulnerable to Study the Onset of Inflammation in Non-Alcoholic Fatty Liver Disease

Non-alcoholic steatohepatitis (NASH) involves steatosis combined with inflammation, which can progress into fibrosis and cirrhosis. Exploring the molecular mechanisms of NASH is highly dependent on the availability of animal models. Currently, the most commonly used animal models for NASH imitate particularly late stages of human disease. Thus, there is a need for an animal model that can be used for investigating the factors that potentiate the inflammatory response within NASH. We have previously shown that 7-day high-fat-high-cholesterol (HFC) feeding induces steatosis and inflammation in both APOE2ki and Ldlr(-/-) mice. However, it is not known whether the early inflammatory response observed in these mice will sustain over time and lead to liver damage. We hypothesized that the inflammatory response in both models is sufficient to induce liver damage over time.APOE2ki and Ldlr(-/-) mice were fed a chow or HFC diet for 3 months. C57Bl6/J mice were used as control.Surprisingly, hepatic inflammation was abolished in APOE2ki mice, while it was sustained in Ldlr(-/-) mice. In addition, increased apoptosis and hepatic fibrosis was only demonstrated in Ldlr(-/-) mice. Finally, bone-marrow-derived-macrophages of Ldlr(-/-) mice showed an increased inflammatory response after oxidized LDL (oxLDL) loading compared to APOE2ki mice.Ldlr(-/-) mice, but not APOE2ki mice, developed sustained hepatic inflammation and liver damage upon long term HFC feeding due to increased sensitivity for oxLDL uptake. Therefore, the Ldlr(-/-) mice are a promising physiological model particularly vulnerable for investigating the onset of hepatic inflammation in non-alcoholic steatohepatitis