Formal Methods for Systems Engineering Behavior Models

International audienceSafety analysis in Systems Engineering (SE) processes, as usually implemented, rarely relies on formal methods such as model checking since such techniques, however powerful and mature, are deemed too complex for efficient use. This paper thus aims at improving the verification practice in SE design: considering the widely-used model of EFFBDs (Enhanced Function Flow Block Diagrams), it formally establishes its syntax and behavioral semantics. It also proposes a structural translation of EFFBDs to transition time Petri nets (TPNs); this translation is then proved to preserve the behavioral semantics (i.e. timed bisimilarity). After proving results on the boundedness of the resulting TPNs, it was possible to extend a number of fundamental properties (such as the decidability of liveness, state-access, etc.) from bounded TPNs to so-called \emph{bounded EFFBDs}. Finally, these results led to implement and integrate an operational formal verification tool within a development platform, used in systems design for defense applications, where the underlying complexity is totally concealed from the end-us

How is climate information being factored into long-term decision-making in Africa?

Looking at the barriers to, and opportunities for, the uptake of longterm climate information in Africa. An output from a project funded by the UK Department for International Development (DFID) and the Natural Environment Research Council (NERC) for the benefi t of developing countries and the advance of scientific research

Differential effects of RYGB surgery and best medical treatment for obesity-diabetes on intestinal and islet adaptations in obese-diabetic ZDSD rats

Modification of gut-islet secretions after Roux-En-Y gastric bypass (RYBG) surgery contributes to its metabolic and anti-diabetic benefits. However, there is limited knowledge on tissue-specific hormone distribution post-RYGB surgery and how this compares with best medical treatment (BMT). In the present study, pancreatic and ileal tissues were excised from male Zucker-Diabetic Sprague Dawley (ZDSD) rats 8-weeks after RYGB, BMT (daily oral dosing with metformin 300mg/kg, fenofibrate 100mg/kg, ramipril 1mg/kg, rosuvastatin 10mg/kg and subcutaneous liraglutide 0.2mg/kg) or sham operation (laparotomy). Insulin, glucagon, somatostatin, PYY, GLP-1 and GIP expression patterns were assessed using immunocytochemistry and analyzed using ImageJ. After RYGB and BMT, body weight and plasma glucose were decreased. Intestinal morphometry was unaltered by RYGB, but crypt depth was decreased by BMT. Intestinal PYY cells were increased by both interventions. GLP-1- and GIP-cell counts were unchanged by RYGB but BMT increased ileal GLP-1-cells and decreased those expressing GIP. The intestinal contents of PYY and GLP-1 were significantly enhanced by RYGB, whereas BMT decreased ileal GLP-1. No changes of islet and beta-cell area or proliferation were observed, but the extent of beta-cell apoptosis and islet integrity calculated using circularity index were improved by both treatments. Significantly decreased islet alpha-cell areas were observed in both groups, while beta- and PYY-cell areas were unchanged. RYGB also induced a decrease in islet delta-cell area. PYY and GLP-1 colocalization with glucagon in islets was significantly decreased in both groups, while co-staining of PYY with glucagon was decreased and that with somatostatin increased. These data characterize significant cellular islet and intestinal adaptations following RYGB and BMT associated with amelioration of obesity-diabetes in ZDSD rats. The differential responses observed and particularly those within islets, may provide important clues to the unique ability of RYGB to cause diabetes remission

A nonlinear mixed-effects approach for the mechanistic interpretation of time-series transcriptomics data

Mechanistic models are essential to unravel the molecular mechanisms driving cellular responses. However, the integration of high-throughput data with mechanistic knowledge is limited by the availability of scalable computational approaches able to disentangle biological and technical sources of variation. Results: We present an approach based on nonlinear mixed-effects modelling for the parameter estimation of large-scale mechanistic models from time-series transcriptomics data. It allows to factor out technical variability, to compensate for the limited number of conditions and time points by a population approach, and it incorporates mechanistic details to gain insight on the molecular causes of biological variability. We applied our approach for the biological interpretation of microarray and RNA-Seq gene expression profiles, with different levels of technical noise, but it is generalisable to numerous types of data. When integrated in a model describing the degradation kinetics of all cellular mRNAs, the data allowed to identify the targets of post-transcriptional regulatory mechanisms. Our approach paves the way for the interpretation of high-throughput biological data with more comprehensive mechanistic models. Availability: The Monolix script for estimation and output files are freely available at https://gitlab.inria. fr/tetienne/eccb_script, together with the microarray data. The RNA-Seq dataset is being prepared for publication (Roux et al., in preparation) and will be made available on demand upon acceptance of the article

Drug development in oncology assisted by noninvasive optical imaging.

International audienceEarly and accurate detection of tumors, like the development of targeted treatments, is a major field of research in oncology. The generation of specific vectors, capable of transporting a drug or a contrast agent to the primary tumor site as well as to the remote (micro-) metastasis would be an asset for early diagnosis and cancer therapy. Our goal was to develop new treatments based on the use of tumor-targeted delivery of large biomolecules (DNA, siRNA, peptides, or nanoparticles), able to induce apoptosis while dodging the specific mechanisms developed by tumor cells to resist this programmed cell death. Nonetheless, the insufficient effectiveness of the vectorization systems is still a crucial issue. In this context, we generated new targeting vectors for drug and biomolecules delivery and developed several optical imaging systems for the follow-up and evaluation of these vectorization systems in live mice. Based on our recent work, we present a brief overview of how noninvasive optical imaging in small animals can accelerate the development of targeted therapeutics in oncology

Rirha : chronique des fouilles, années 2018-2019

International audienc

Addiction

The primary aim of this study was to evaluate the impact of drug consumption rooms (DCRs) in France on injection equipment-sharing, while the secondary aims focused upon their impact on access to hepatitis C virus (HCV) testing and opioid agonist treatment (OAT). The COhort to identify Structural and INdividual factors associated with drug USe (COSINUS cohort) was a 12-month longitudinal study of 665 people who inject drugs (PWID), conducted in Bordeaux, Marseille, Paris and Strasbourg. We used data from face-to-face interviews at enrolment and at 6-month and 12-month visits. The participants were recruited in harm reduction programmes in Bordeaux and Marseille and in DCRs in Strasbourg and Paris. Participants were aged more than 18 years, French-speaking and had injected substances the month before enrolment. We measured the impact of DCR exposure on injection equipment sharing, HCV testing and the use of medications for opioid use disorder, after adjustment for significant correlates. We used a two-step Heckman mixed-effects probit model, which allowed us to take into account the correlation of repeated measures and to control for potential bias due to non-randomization between the two groups (DCR-exposed versus DCR-unexposed participants). The difference of declared injection equipment sharing between PWID exposed to DCRs versus non-exposed was 10% (1% for those exposed versus 11% for those non-exposed, marginal effect = -0.10; 95% confidence interval = -0.18, -0.03); there was no impact of DCRs on HCV testing and OAT. In the French context, drug consumption rooms appear to have a positive impact on at-risk practices for infectious diseases such as human immunodeficiency virus (HIV) and hepatitis C virus

Increased peptide YY blood concentrations, not decreased acyl-ghrelin, are associated with reduced hunger and food intake in healthy older women: Preliminary evidence.

With ageing there is frequently a loss of appetite, termed anorexia of ageing, which can result in under-nutrition. We do not know how appetite control alters with ageing. The objective of this study was to investigate whether differences in the release of, and response to, gastrointestinal appetite hormones is altered in young compared to old healthy volunteers. We hypothesised that an increase in PYY and GLP-1 or a decrease ghrelin may result in a decreased appetite. A comparative experimental design, using a cross-sectional sample of ages from a healthy population, matched for sex and BMI was used. The study compared total ghrelin, acyl-ghrelin, PYY, GLP-1 and subjective appetite responses to ingestion of a standardised 2781kj (660 kcal) test meal. 31 female volunteers aged between 21 and 92yrs took part. Multiple linear regression showed that both age and sex had an independent effect on energy intake. Subjective appetite scores showed that hunger, pleasantness to eat, and prospective food intake were significantly lower in the older age groups. PYY incremental area under the curve (IAUC) was greater in the oldest old compared to younger ages (f(3,27) = 2.9, p = 0.05. No differences in GLP-1, ghrelin or acyl-ghrelin were observed in the older compared to younger age groups. Our data suggest that there may be increases in postprandial PYY(3-36) levels in female octogenarians, potentially resulting in reduced appetite. There does not appear to be any change in ghrelin or acyl-ghrelin concentrations with ageing

Improvement in Peripheral Glucose Uptake After Gastric Bypass Surgery Is Observed Only After Substantial Weight Loss Has Occurred and Correlates with the Magnitude of Weight Lost

# 2009 The Author(s). This article is published with open access at Springerlink.com Introduction Altered gut and pancreatic hormone secretion may bolster resolution of insulin resistance after Roux-en-Y gastric bypass (RYGB), but the independent effects of weight loss and hormonal secretion on peripheral glucose disposal are unknown. Methods Two groups of nondiabetic morbidly obese patients were studied: RYGB followed by standardized caloric restriction (RYGB, n=12) or caloric restriction alone (diet, n=10). Metabolic evaluations (euglycemic–hyperinsulinemic clamp, meal tolerance test) were done at baseline and 14 days (both groups) and 6 months after RYGB