The receptor for advanced glycation end products (RAGE) contributes to the progression of emphysema in mice

Several recent clinical studies have implied a role for the receptor for advanced glycation end products (RAGE) and its variants in chronic obstructive pulmonary disease (COPD). In this study we have defined a role for RAGE in the pathogenesis of emphysema in mice. RAGE deficient mice (RAGE-/-) exposed to chronic cigarette smoke were significantly protected from smoke induced emphysema as determined by airspace enlargement and had no significant reduction in lung tissue elastance when compared to their air exposed controls contrary to their wild type littermates. The progression of emphysema has been largely attributed to an increased inflammatory cell-mediated elastolysis. Acute cigarette smoke exposure in RAGE-/- mice revealed an impaired early recruitment of neutrophils, approximately a 6-fold decrease compared to wild type mice. Hence, impaired neutrophil recruitment with continued cigarette smoke exposure reduces elastolysis and consequent emphysema

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

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

Differential effects of Parkinson\u27s disease and dopamine replacement on memory encoding and retrieval.

Increasingly memory deficits are recognized in Parkinson\u27s disease (PD). In PD, the dopamine-producing cells of the substantia nigra (SN) are significantly degenerated whereas those in the ventral tegmental area (VTA) are relatively spared. Dopamine-replacement medication improves cognitive processes that implicate the SN-innervated dorsal striatum but is thought to impair those that depend upon the VTA-supplied ventral striatum, limbic and prefrontal cortices. Our aim was to examine memory encoding and retrieval in PD and how they are affected by dopamine replacement. Twenty-nine PD patients performed the Rey Auditory Verbal Learning Test (RAVLT) and a non-verbal analogue, the Aggie Figures Learning Test (AFLT), both on and off dopaminergic medications. Twenty-seven, age-matched controls also performed these memory tests twice and their data were analyzed to correspond to the ON-OFF order of the PD patients to whom they were matched. We contrasted measures that emphasized with those that accentuated retrieval and investigated the effect of PD and dopamine-replacement on these processes separately. For PD patients relative to controls, encoding performance was normal in the off state and was impaired on dopaminergic medication. Retrieval was impaired off medication and improved by dopamine repletion. This pattern of findings suggests that VTA-innervated brain regions such as ventral striatum, limbic and prefrontal cortices are implicated in encoding, whereas the SN-supplied dorsal striatum mediates retrieval. Understanding this pattern of spared functions and deficits in PD, and the effect of dopamine replacement on these distinct memory processes, should prompt closer scrutiny of patients\u27 cognitive complaints to inform titration of dopamine replacement dosages along with motor symptoms

The effect of dopamine therapy on ventral and dorsal striatum-mediated cognition in Parkinson\u27s disease: support from functional MRI.

The central aim of our study was to elucidate functions mediated by the ventral and dorsal striatum, respectively, to better understand the cognitive effects of dopamine replacement in Parkinson\u27s disease. We proposed that the ventral striatum underlies general learning of stimulus associations, whereas the dorsal striatum promotes integration of various influences on selecting. In Parkinson\u27s disease, dopamine depletion is substantially less notable in the ventral relative to the dorsal striatum, and therefore greater improvements are expected for dorsal striatum-mediated functions with dopamine replacement. Using a simple selection task, we found that dopamine replacement impaired encoding and facilitation of consistent stimulus-stimulus relations across trials. This finding was in line with our contention that ventral striatum mediates learning stimulus associations, even when explicit feedback or reward is not provided. In contrast, dopamine replacement enhanced interference related to assimilating conflicting influences on selection across trials, consistent with our hypothesis that the dorsal striatum supports deciding in ambiguous contexts. We further confirmed these separable roles for the ventral and dorsal striatum in our selection task with healthy young volunteers using functional magnetic resonance imaging. In summary, we present a within-subject, double dissociation of the effects of dopamine replacement in patients with Parkinson\u27s disease for ventral striatum-mediated facilitation and dorsal striatum-mediated interference, confirmed in a separate functional magnetic resonance imaging experiment. Defining the distinct functions of the ventral and dorsal striatum will have direct clinical implications. Titration of therapy in Parkinson\u27s disease is generally geared towards optimizing dorsal striatum-mediated motor symptoms, possibly at the expense of ventral striatum operations, a consequence that is only beginning to be recognized. Enhanced awareness of these different processes will translate into medication strategies that take into account those symptoms that dopamine replacement might hinder, as well as improve. Here, we show impairments in learning new stimulus associations compared with improvements in integrating varied influences related to selection. Ultimately, this knowledge will lead clinicians to survey a broader range of symptoms in determining optimal therapy based on individual patient priorities

Development of a murine infection model with Leishmania killicki, responsible for cutaneous Leishmaniosis in Algeria : application in pharmacology

In Algeria, Leishmania infantum, Leishmania major, and Leishmania killicki (Leishmania tropica) are responsible for cutaneous leishmaniosis. We established a murine model of L. killicki infection to investigate its infective capacity, some immunophysiopathological aspects, and its suitability for pharmacological purposes. Following the injection of L. major or L. killicki metacyclic promastigotes in the ear dermis of BALB/c mice, the course of infection was followed. The infection with L. killicki caused slower lesion formation than with L. major. The presence of L. killicki or L. major DNA and parasites was detected in the ear dermis and in lymph nodes, spleen, and liver. Lesions induced by L. killicki were nonulcerative in their aspect, whereas those caused by L. major were highly ulcerative and necrotic, which matches well with the lesion phenotype reported in humans for L. killicki and L. major, respectively. The treatment of L. killicki lesions by injection of Glucantime (R) significantly reduced the lesion thickness and parasite burden. Ear dermal injection of BALB/c mice constitutes a model to study lesions physiopathology caused by L. killicki and presents interest for in vivo screening of new compounds against this pathogen, emerging in Algeria

Examining dorsal striatum in cognitive effort using Parkinson\u27s disease and fMRI.

OBJECTIVE: Understanding cognition mediated by the striatum can clarify cognitive deficits in Parkinson\u27s disease (PD). Previously, we claimed that dorsal striatum (DS) mediates cognitive flexibility. To refute the possibility that variation in cognitive effort confounded our observations, we reexamined our data to dissociate cognitive flexibility from effort. PD provides a model for exploring DS-mediated functions. In PD, dopamine-producing cells supplying DS are significantly degenerated. DS-mediated functions are impaired off and improved on dopamine replacement medication. Functional magnetic resonance imaging (fMRI) can confirm striatum-mediated functions. METHODS: Twenty-two PD patients, off-on dopaminergic medication, and 22 healthy age-matched controls performed a number selection task. Numerical distance between number pairs varied systematically. Selecting between two numbers that are closer versus distant in magnitude is more effortful: the symbolic distance effect. However, selecting between closer versus distant number pairs is equivalent in the need to alter attention or response strategies (i.e., cognitive flexibility). In Experiment 2, 28 healthy participants performed the same task with simultaneous measurement of brain activity with fMRI. RESULTS: The symbolic distance effect was equivalent for PD versus control participants and across medication sessions. Furthermore, symbolic distance did not correlate with DS activation using fMRI. In this dataset, we showed previously that integrating conflicting influences on decision making is (1) impaired in PD and improved by dopaminergic therapy and (2) associated with preferential DS activation using fMRI. INTERPRETATION: These findings support the notion that DS mediates cognitive flexibility specifically, not merely cognitive effort, accounting for some cognitive deficits in PD and informing treatment

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

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