A New Elimination Rule for the Calculus of Inductive Constructions

Published in the post-proceedings of TYPES but actually not presented orally to the conferenceInternational audienceIn Type Theory, definition by dependently-typed case analysis can be expressed by means of a set of equations — the semantic approach — or by an explicit pattern-matching construction — the syntactic approach. We aim at putting together the best of both approaches by extending the pattern-matching construction found in the Coq proof assistant in order to obtain the expressivity and flexibility of equation-based case analysis while remaining in a syntax-based setting, thus making dependently-typed programming more tractable in the Coq system. We provide a new rule that permits the omission of impossible cases, handles the propagation of inversion constraints, and allows to derive Streicher's K axiom. We show that subject reduction holds, and sketch a proof of relative consistency

Optimizing a Certified Proof Checker for a Large-Scale Computer-Generated Proof

In recent work, we formalized the theory of optimal-size sorting networks with the goal of extracting a verified checker for the large-scale computer-generated proof that 25 comparisons are optimal when sorting 9 inputs, which required more than a decade of CPU time and produced 27 GB of proof witnesses. The checker uses an untrusted oracle based on these witnesses and is able to verify the smaller case of 8 inputs within a couple of days, but it did not scale to the full proof for 9 inputs. In this paper, we describe several non-trivial optimizations of the algorithm in the checker, obtained by appropriately changing the formalization and capitalizing on the symbiosis with an adequate implementation of the oracle. We provide experimental evidence of orders of magnitude improvements to both runtime and memory footprint for 8 inputs, and actually manage to check the full proof for 9 inputs.Comment: IMADA-preprint-c

Primary and secondary agonists can use P2X1 receptors as a major pathway to increase intracellular Ca2+ in the human platelet

See also Nurden AT. Does ATP act through P2X1 receptors to regulate platelet activation and thrombus formation? This issue, pp 907–9

AMP-activated protein kinase controls liposaccharide-induced hyperpermeability

Organ dysfunction determines the severity of sepsis and is correlated to mortality. Endothelial increased permeability contributes to the development of organ failure. AMP-activated protein kinase (AMPK) has been shown to modulate cytoskeleton and could mediate endothelial permeability. Our hypothesis is that AMPK controls sepsis-induced hyperpermeability in the heart and is involved in septic cardiomyopathy. Sepsis was induced by intraperitoneal injection of liposaccharide, 10 mg/kg (LPS). Alpha-1 AMPK knockout mice (α1KO) were compared with wild-type. Vascular permeability was characterized by Evans blue extravasation. Inflammatory cytokine mRNA expression was determined by qPCR analysis. Left ventricular mass was assessed by echocardiography. In addition, to emphasize the beneficial role of AMPK on heart vascular permeability, AMPK activator (acadesine) was administered to C57Bl6 mice before LPS injection. The ANOVA test with Bonferroni's post hoc test and the log-rank test were used. P < 0.05 was considered as significant. Increased cardiac vascular permeability was observed in the LPS group in comparison to untreated animals (2.5% vs. 16%; P < 0.05). The α1KO mice exhibited an increase vascular permeability after LPS injection in comparison to wild-type mice (41.5% vs. 16%; P < 0.05). α1KO animals had a significant mortality increase after LPS injection (70% vs. 10%; P < 0.05). LPS markedly induced the production of proinflammatory cytokines (TNFα, IL-1β, IL-6) that were significantly higher in the α1KO animals. More importantly, LPS treatment leads to an increased left ventricular mass in the α1KO mice within 24 hours, suggesting the onset of edema. Finally LPS-induced vascular hyperpermeability was greatly reduced after AMPK activation by acadesine (13.2% vs. 40%; P < 0.05). AMPK importantly regulates cardiac vascular permeability and could control the sepsis-induced cardiomyopathy. AMPK could represent a new pharmacological target of sepsis

Belgian clinical guidance on anticoagulation management in hospitalised and ambulatory patients with COVID-19

Objectives COVID-19 predisposes patients to thrombotic disease. The aim of this guidance document is to provide Belgian health-care workers with recommendations on anticoagulation management in COVID-19 positive patients. Methods These recommendations were based on current knowledge and a limited level of evidence. Results We formulated recommendations for the prophylaxis and treatment of COVID-related venous thromboembolism in ambulatory and hospitalised patients, as well as recommendations for the use of antithrombotic drugs in patients with prior indication for anticoagulation who develop COVID-19. Conclusions These recommendations represent an easy-to-use practical guidance that can be implemented in every Belgian hospital and be used by primary care physicians and gynaecologists. Of note, they are likely to evolve with increased knowledge of the disease and availability of data from ongoing clinical trials

Paradoxical roles of antioxidant enzymes:Basic mechanisms and health implications

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are generated from aerobic metabolism, as a result of accidental electron leakage as well as regulated enzymatic processes. Because ROS/RNS can induce oxidative injury and act in redox signaling, enzymes metabolizing them will inherently promote either health or disease, depending on the physiological context. It is thus misleading to consider conventionally called antioxidant enzymes to be largely, if not exclusively, health protective. Because such a notion is nonetheless common, we herein attempt to rationalize why this simplistic view should be avoided. First we give an updated summary of physiological phenotypes triggered in mouse models of overexpression or knockout of major antioxidant enzymes. Subsequently, we focus on a series of striking cases that demonstrate “paradoxical” outcomes, i.e., increased fitness upon deletion of antioxidant enzymes or disease triggered by their overexpression. We elaborate mechanisms by which these phenotypes are mediated via chemical, biological, and metabolic interactions of the antioxidant enzymes with their substrates, downstream events, and cellular context. Furthermore, we propose that novel treatments of antioxidant enzyme-related human diseases may be enabled by deliberate targeting of dual roles of the pertaining enzymes. We also discuss the potential of “antioxidant” nutrients and phytochemicals, via regulating the expression or function of antioxidant enzymes, in preventing, treating, or aggravating chronic diseases. We conclude that “paradoxical” roles of antioxidant enzymes in physiology, health, and disease derive from sophisticated molecular mechanisms of redox biology and metabolic homeostasis. Simply viewing antioxidant enzymes as always being beneficial is not only conceptually misleading but also clinically hazardous if such notions underpin medical treatment protocols based on modulation of redox pathways

A pivotal role for starch in the reconfiguration of 14C-partitioning and allocation in Arabidopsis thaliana under short-term abiotic stress.

Plant carbon status is optimized for normal growth but is affected by abiotic stress. Here, we used 14C-labeling to provide the first holistic picture of carbon use changes during short-term osmotic, salinity, and cold stress in Arabidopsis thaliana. This could inform on the early mechanisms plants use to survive adverse environment, which is important for efficient agricultural production. We found that carbon allocation from source to sinks, and partitioning into major metabolite pools in the source leaf, sink leaves and roots showed both conserved and divergent responses to the stresses examined. Carbohydrates changed under all abiotic stresses applied; plants re-partitioned 14C to maintain sugar levels under stress, primarily by reducing 14C into the storage compounds in the source leaf, and decreasing 14C into the pools used for growth processes in the roots. Salinity and cold increased 14C-flux into protein, but as the stress progressed, protein degradation increased to produce amino acids, presumably for osmoprotection. Our work also emphasized that stress regulated the carbon channeled into starch, and its metabolic turnover. These stress-induced changes in starch metabolism and sugar export in the source were partly accompanied by transcriptional alteration in the T6P/SnRK1 regulatory pathway that are normally activated by carbon starvation

Regular dietary intake of palmitate causes vascular and valvular calcification in a rabbit model

Aims: Palmitic acid (PA) and oleic acid (OA) are two main dietary fatty acids. Dietary intake of PA has been associated with cardiovascular disease risk, and the effect of OA remains uncertain. Our study aimed to assess the effect of a short-term intake of lard, as source of PA and OA, on aorta and aortic valve.Methods and Results: Rabbits were fed with two lard-enriched diets, containing either elevated levels of PA or of both PA and OA as compared to chow diet. After 16 weeks of each diet, calcification was observed in the aortic intima and in the aortic valve. The extent of calcification did not differ between the two diets. In contrast, rabbits fed chow diet did not develop any calcification. In blood, PA enrichment resulted in decreased lymphocyte and monocyte counts and increased levels of hemoglobin and haematocrit. Levels of the calcification inhibitor fetuin-A were also diminished, whereas creatinine levels were raised. Of note, none of the diets changed cholesterol levels in LDL or HDL. Comprehensive quantitative lipidomics analysis identified diet-related changes in plasma lipids. Dietary PA enrichment led to a drop of polyunsaturated fatty acids (PUFA), in particular of linoleic acid in cholesteryl esters, triglycerides and diacylglycerols (DAG). Ratios of PA to 18-carbon PUFA in DAG were positively correlated with the extent of aortic valve calcification, and inversely with monocyte counts. PA content in blood correlated with aorta calcification.Conclusions: Regular dietary PA intake induces vascular and valvular calcification independently of traditional risk factors. Our findings raise awareness about PA-rich food consumption and its potential deleterious effect on cardiovascular health.Proteomic