Approximated stability analysis of bi-modal hybrid co-simulation scenarios

This is an accepted manuscript of an article published by Springer in: Cerone A., Roveri M. (eds) Software Engineering and Formal Methods. SEFM 2017. Lecture Notes in Computer Science, vol 10729, available online at: https://doi.org/10.1007/978-3-319-74781-1_24 The accepted version of the publication may differ from the final published version. For information on re-use, please refer to the publisher’s terms and conditions.Co-simulation is a technique to orchestrate multiple simulators in order to approximate the behavior of a coupled system as a whole. Simulators execute in a lockstep fashion, each exchanging inputs and output data points with the other simulators at pre-accorded times. In the context of systems with a physical and a cyber part, the communication frequency with which the simulators of each part communicate can have a negative impact in the accuracy of the global simulation results. In fact, the computed behavior can be qualitatively different, compared to the actual behavior of the original system, laying waste to potentially many hours of computation. It is therefore important to develop methods that answer whether a given communication frequency guarantees trustworthy co-simulation results. In this paper, we take a small step in that direction. We develop a technique to approximate the lowest frequency for which a particular set of simulation tools can exchange values in a co-simulation and obtain results that can be trusted.Published versio

Stability-indicating HPLC-DAD/UV-ESI/MS impurity profiling of the anti-malarial drug lumefantrine

<p>Abstract</p> <p>Background</p> <p>Lumefantrine (benflumetol) is a fluorene derivative belonging to the aryl amino alcohol class of anti-malarial drugs and is commercially available in fixed combination products with β-artemether. Impurity characterization of such drugs, which are widely consumed in tropical countries for malaria control programmes, is of paramount importance. However, until now, no exhaustive impurity profile of lumefantrine has been established, encompassing process-related and degradation impurities in active pharmaceutical ingredients (APIs) and finished pharmaceutical products (FPPs).</p> <p>Methods</p> <p>Using HPLC-DAD/UV-ESI/ion trap/MS, a comprehensive impurity profile was established based upon analysis of market samples as well as stress, accelerated and long-term stability results. <it>In-silico </it>toxicological predictions for these lumefantrine related impurities were made using Toxtree^®and Derek^®.</p> <p>Results</p> <p>Several new impurities are identified, of which the desbenzylketo derivative (DBK) is proposed as a new specified degradant. DBK and the remaining unspecified lumefantrine related impurities are predicted, using Toxtree^®and Derek^®, to have a toxicity risk comparable to the toxicity risk of the API lumefantrine itself.</p> <p>Conclusions</p> <p>From unstressed, stressed and accelerated stability samples of lumefantrine API and FPPs, nine compounds were detected and characterized to be lumefantrine related impurities. One new lumefantrine related compound, DBK, was identified and characterized as a specified degradation impurity of lumefantrine in real market samples (FPPs). The <it>in-silico </it>toxicological investigation (Toxtree^®and Derek^®) indicated overall a toxicity risk for lumefantrine related impurities comparable to that of the API lumefantrine itself.</p

Skeletal muscle overexpression of sAnk1.5 in transgenic mice does not predispose to type 2 diabetes

Genome-wide association studies (GWAS) and cis-expression quantitative trait locus (cis-eQTL) analyses indicated an association of the rs508419 single nucleotide polymorphism (SNP) with type 2 diabetes (T2D). rs508419 is localized in the muscle-specific internal promoter (P2) of the ANK1 gene, which drives the expression of the sAnk1.5 isoform. Functional studies showed that the rs508419 C/C variant results in increased transcriptional activity of the P2 promoter, leading to higher levels of sAnk1.5 mRNA and protein in skeletal muscle biopsies of individuals carrying the C/C genotype. To investigate whether sAnk1.5 overexpression in skeletal muscle might predispose to T2D development, we generated transgenic mice (TgsAnk1.5/+) in which the sAnk1.5 coding sequence was selectively overexpressed in skeletal muscle tissue. TgsAnk1.5/+ mice expressed up to 50% as much sAnk1.5 protein as wild-type (WT) muscles, mirroring the difference reported between individuals with the C/C or T/T genotype at rs508419. However, fasting glucose levels, glucose tolerance, insulin levels and insulin response in TgsAnk1.5/+ mice did not differ from those of age-matched WT mice monitored over a 12-month period. Even when fed a high-fat diet, TgsAnk1.5/+ mice only presented increased caloric intake, but glucose disposal, insulin tolerance and weight gain were comparable to those of WT mice fed a similar diet. Altogether, these data indicate that sAnk1.5 overexpression in skeletal muscle does not predispose mice to T2D susceptibility

Synaptotagmin 5 regulates Ca2+-dependent Weibel-Palade body exocytosis in human endothelial cells.

Membrane protein insertion is an essential cellular process. The broad biophysical and topological range of membrane proteins necessitates multiple insertion pathways, which remain incompletely defined. Here, we have discovered a new membrane protein insertion pathway, identified the class of substrates it handles, explained why other known pathways do not work for these substrates and reconstituted the pathway using purified components

Formal verification techniques for model transformations: A tridimensional classification

In Model Driven Engineering (Mde), models are first-class citizens, and model transformation is Mde's "heart and soul". Since model transformations are executed for a family of (conforming) models, their validity becomes a crucial issue. This paper proposes to explore the question of the formal verification of model transformation properties through a tridimensional approach: the transformation involved, the properties of interest addressed, and the formal verification techniques used to establish the properties. This work is intended for a double audience. For newcomers, it provides a tutorial introduction to the field of formal verification of model transformations. For readers more familiar with formal methods and model transformations, it proposes a literature review (although not systematic) of the contributions of the field. Overall, this work allows to better understand the evolution, trends and current practice in the domain of model transformation verification. This work opens an interesting research line for building an engineering of model transformation verification guided by the notion of model transformation intent

ATP13A3 is a major component of the enigmatic mammalian polyamine transport system

Polyamines, such as putrescine, spermidine, and spermine, are physiologically important polycations, but the transporters responsible for their uptake in mammalian cells remain poorly characterized. Here, we reveal a new component of the mammalian polyamine transport system using CHO-MG cells, a widely used model to study alternative polyamine uptake routes and characterize polyamine transport inhibitors for therapy. CHO-MG cells present polyamine uptake deficiency and resistance to a toxic polyamine biosynthesis inhibitor methylglyoxal bis-(guanylhydrazone) (MGBG), but the molecular defects responsible for these cellular characteristics remain unknown. By genome sequencing of CHO-MG cells, we identified mutations in an unexplored gene, ATP13A3, and found disturbed mRNA and protein expression. ATP13A3 encodes for an orphan P5B-ATPase (ATP13A3), a P-type transport ATPase that represents a candidate polyamine transporter. Interestingly, ATP13A3 complemented the putrescine transport deficiency and MGBG resistance of CHO-MG cells, whereas its knockdown in WT cells induced a CHO-MG phenotype demonstrated as a decrease in putrescine uptake and MGBG sensitivity. Taken together, our findings identify ATP13A3, which has been previously genetically linked with pulmonary arterial hypertension, as a major component of the mammalian polyamine transport system that confers sensitivity to MGBG

Pycnogenol® and Ginkgo biloba extract: effect on peroxynitrite-oxidized sarcoplasmic reticulum Ca2+-ATPase

The effect of two natural standardized plant extracts, Pycnogenol® and EGb 761, on sarcoplasmic reticulum Ca2+-ATPase (SERCA) activity and posttranslational modifications induced by peroxynitrite was investigated to assess their possible protective role. EGb 761 was found to have a protective effect on SERCA activity in the concentration range of 5–40 µg/ml. On the other hand, Pycnogenol® caused a decrease of SERCA activity at concentrations of 25 µg/ml. EGb 761 did not prevent protein carbonyl formation upon oxidation with peroxynitrite. On the contrary, Pycnogenol® at the concentrations of 5 and 10 µg/ml significantly decreased the level of protein carbonyls by 44% and 54%, respectively. Neither Pycnogenol® nor EGb 761 exerted a protective effect against thiol group oxidation.The plant extracts studied modulated peroxynitrite-injured SERCA activity by different ways and failed to correlate with posttranslational modifications. Their effect seems to be associated with their ability to change SERCA conformation rather than by their antioxidant capacity