Approximate Reachability for Dead Code Elimination in Esterel*

Esterel is an imperative synchronous programming language for the design of reactive systems. Esterel* extends Esterel with a non-instantaneous jump instruction (compatible with concurrency, preemption, etc.) so as to enable powerful source-to-source program transformations, amenable to formal verification. In this work, we propose an approximate reachability algorithm for Esterel* and use its output to remove dead code. We prove the correctness of our techniques

TAXYS: a tool for the development and verification of real-time embedded systems

The correct behavior of real-time applications depends not only on the correctness of the results of computations but also on the times at which these results are produced. As a matter of fact, violations of real-time constraints in embedded systems are the most difficult errors to detect, because they are extremely sensitive both to the patterns of external events stimulating the system and to the timing behavior of the system itself. Clearly, the development of realtime systems requires rigorous methods and tools to reduce development costs and "time-to-market" while guaranteeing the quality of the produced code (in particular, respect of the temporal constraints). The above requirements motivated the development of the TAXYS tool, dedicated to the design and validation of real-time telecommunications software. One of the major goal of the TAXYS tool is to produce a formal model that captures the temporal behavior of the whole application which is composed of the embedded computer and its external environment. For this purpose we use the formal model of timed automata. The choice of this model allows the use of results, algorithms and tools available. Here, we use the KRONOS model checker for model analysis. From the source code of the application, an ESTEREL program annotated with temporal constraints, the TAXYS tool produces on one hand a sequential executable code and on the other hand a timed model of the application. This model is again composed with a timed model of the external environment in order to obtain a global model which is statically analyzed to validate timing constraints. This validation should notably shorten design time by limiting tedious test and simulation session

Taxys = Esterel + Kronos: A tool for verifying real-time properties of embedded systems

The goal of TAXYS is to provide a framework for developing real-time embedded code and verifying its correct behavior with respect to quantitative timing requirements. To achieve so, TAXYS connects France Telecom's ESTEREL compiler SAXO-RT with VERIMAG's model-checker KRONOS. TAXYS has been successfully applied on real industrial telecommunication systems, such as a GSM radio link from Alcatel and a phone prototype from France Telecom

A model-based approach for multiple QoS in scheduling: from models to implementation

Meeting multiple Quality of Service (QoS) requirements is an important factor in the success of complex software systems. This paper presents an automated, model-based scheduler synthesis approach for scheduling application software tasks to meet multiple QoS requirements. As a first step, it shows how designers can meet deadlock-freedom and timeliness requirements, in a manner that (i) does not over-provision resources, (ii) does not require architectural changes to the system, and that (iii) leaves enough degrees of freedom to pursue further properties. A major benefit of our synthesis methodology is that it increases traceability, by linking each scheduling constraint with a specific pair of QoS property and underlying platform execution model, so as to facilitate the validation of the scheduling constraints and the understanding of the overall system behaviour, required to meet further QoS properties. The paper shows how the methodology is applied in practice and also presents a prototype implementation infrastructure for executing an application on top of common operating systems, without requiring modifications of the latter

Accelerated apoptotic death and <i>in vivo</i> turnover of erythrocytes in mice lacking functional mitogen- and stress-activated kinase MSK1/2

The mitogen- and stress-activated kinase MSK1/2 plays a decisive role in apoptosis. In analogy to apoptosis of nucleated cells, suicidal erythrocyte death called eryptosis is characterized by cell shrinkage and cell membrane scrambling leading to phosphatidylserine (PS) externalization. Here, we explored whether MSK1/2 participates in the regulation of eryptosis. To this end, erythrocytes were isolated from mice lacking functional MSK1/2 (msk−/−) and corresponding wild-type mice (msk+/+). Blood count, hematocrit, hemoglobin concentration and mean erythrocyte volume were similar in both msk−/− and msk+/+ mice, but reticulocyte count was significantly increased in msk−/− mice. Cell membrane PS exposure was similar in untreated msk−/− and msk+/+ erythrocytes, but was enhanced by pathophysiological cell stressors ex vivo such as hyperosmotic shock or energy depletion to significantly higher levels in msk−/− erythrocytes than in msk+/+ erythrocytes. Cell shrinkage following hyperosmotic shock and energy depletion, as well as hemolysis following decrease of extracellular osmolarity was more pronounced in msk−/− erythrocytes. The in vivo clearance of autologously-infused CFSE-labeled erythrocytes from circulating blood was faster in msk−/− mice. The spleens from msk−/− mice contained a significantly greater number of PS-exposing erythrocytes than spleens from msk+/+ mice. The present observations point to accelerated eryptosis and subsequent clearance of erythrocytes leading to enhanced erythrocyte turnover in MSK1/2-deficient mice

Discovery of a new class of inhibitors for the protein arginine deiminase type 4 (PAD4) by structure-based virtual screening

<p>Abstract</p> <p>Background</p> <p>Rheumatoid arthritis (RA) is an autoimmune disease with unknown etiology. Anticitrullinated protein autoantibody has been documented as a highly specific autoantibody associated with RA. Protein arginine deiminase type 4 (PAD4) is the enzyme responsible for catalyzing the conversion of peptidylarginine into peptidylcitrulline. PAD4 is a new therapeutic target for RA treatment. In order to search for inhibitors of PAD4, structure-based virtual screening was performed using LIDAEUS (Ligand discovery at Edinburgh university). Potential inhibitors were screened experimentally by inhibition assays.</p> <p>Results</p> <p>Twenty two of the top-ranked water-soluble compounds were selected for inhibitory screening against PAD4. Three compounds showed significant inhibition of PAD4 and their IC₅₀values were investigated. The structures of the three compounds show no resemblance with previously discovered PAD4 inhibitors, nor with existing drugs for RA treatment.</p> <p>Conclusion</p> <p>Three compounds were discovered as potential inhibitors of PAD4 by virtual screening. The compounds are commercially available and can be used as scaffolds to design more potent inhibitors against PAD4.</p

Advances in the treatment of prolactinomas

Prolactinomas account for approximately 40% of all pituitary adenomas and are an important cause of hypogonadism and infertility. The ultimate goal of therapy for prolactinomas is restoration or achievement of eugonadism through the normalization of hyperprolactinemia and control of tumor mass. Medical therapy with dopamine agonists is highly effective in the majority of cases and represents the mainstay of therapy. Recent data indicating successful withdrawal of these agents in a subset of patients challenge the previously held concept that medical therapy is a lifelong requirement. Complicated situations, such as those encountered in resistance to dopamine agonists, pregnancy, and giant or malignant prolactinomas, may require multimodal therapy involving surgery, radiotherapy, or both. Progress in elucidating the mechanisms underlying the pathogenesis of prolactinomas may enable future development of novel molecular therapies for treatment-resistant cases. This review provides a critical analysis of the efficacy and safety of the various modes of therapy available for the treatment of patients with prolactinomas with an emphasis on challenging situations, a discussion of the data regarding withdrawal of medical therapy, and a foreshadowing of novel approaches to therapy that may become available in the future

A short history of the 5-HT2C receptor: from the choroid plexus to depression, obesity and addiction treatment

This paper is a personal account on the discovery and characterization of the 5-HT2C receptor (first known as the 5- HT1C receptor) over 30 years ago and how it translated into a number of unsuspected features for a G protein-coupled receptor (GPCR) and a diversity of clinical applications. The 5-HT2C receptor is one of the most intriguing members of the GPCR superfamily. Initially referred to as 5-HT1CR, the 5-HT2CR was discovered while studying the pharmacological features and the distribution of [3H]mesulergine-labelled sites, primarily in the brain using radioligand binding and slice autoradiography. Mesulergine (SDZ CU-085), was, at the time, best defined as a ligand with serotonergic and dopaminergic properties. Autoradiographic studies showed remarkably strong [3H]mesulergine-labelling to the rat choroid plexus. [3H]mesulergine-labelled sites had pharmacological properties different from, at the time, known or purported 5-HT receptors. In spite of similarities with 5-HT2 binding, the new binding site was called 5-HT1C because of its very high affinity for 5-HT itself. Within the following 10 years, the 5-HT1CR (later named 5- HT2C) was extensively characterised pharmacologically, anatomically and functionally: it was one of the first 5-HT receptors to be sequenced and cloned. The 5-HT2CR is a GPCR, with a very complex gene structure. It constitutes a rarity in theGPCR family: many 5-HT2CR variants exist, especially in humans, due to RNA editing, in addition to a few 5-HT2CR splice variants. Intense research led to therapeutically active 5-HT2C receptor ligands, both antagonists (or inverse agonists) and agonists: keeping in mind that a number of antidepressants and antipsychotics are 5- HT2CR antagonists/inverse agonists. Agomelatine, a 5-HT2CR antagonist is registered for the treatment of major depression. The agonist Lorcaserin is registered for the treatment of aspects of obesity and has further potential in addiction, especially nicotine/ smoking. There is good evidence that the 5-HT2CR is involved in spinal cord injury-induced spasms of the lower limbs, which can be treated with 5-HT2CR antagonists/inverse agonists such as cyproheptadine or SB206553. The 5-HT2CR may play a role in schizophrenia and epilepsy. Vabicaserin, a 5-HT2CR agonist has been in development for the treatment of schizophrenia and obesity, but was stopped. As is common, there is potential for further indications for 5-HT2CR ligands, as suggested by a number of preclinical and/or genome-wide association studies (GWAS) on depression, suicide, sexual dysfunction, addictions and obesity. The 5-HT2CR is clearly affected by a number of established antidepressants/antipsychotics and may be one of the culprits in antipsychotic-induced weight gain