Minimally Constrained Stable Switched Systems and Application to Co-simulation

We propose an algorithm to restrict the switching signals of a constrained switched system in order to guarantee its stability, while at the same time attempting to keep the largest possible set of allowed switching signals. Our work is motivated by applications to (co-)simulation, where numerical stability is a hard constraint, but should be attained by restricting as little as possible the allowed behaviours of the simulators. We apply our results to certify the stability of an adaptive co-simulation orchestration algorithm, which selects the optimal switching signal at run-time, as a function of (varying) performance and accuracy requirements.Comment: Technical report complementing the following conference publication: Gomes, Cl\'audio, Beno\^it Legat, Rapha\"el Jungers, and Hans Vangheluwe. "Minimally Constrained Stable Switched Systems and Application to Co-Simulation." In IEEE Conference on Decision and Control. Miami Beach, FL, USA, 201

Theories of gravity with nonminimal matter-curvature coupling and the de Sitter swampland conjectures

We discuss, in the context of alternative theories of gravity with nonminimal coupling between matter and curvature, if inflationary solutions driven by a single scalar field can be reconciled with the swampland conjectures about the emergence of de Sitter solutions in string theory. We find that the slow-roll conditions are incompatible with the swampland conjectures for a fairly generic inflationary solution in such alternative theories of gravity.Comment: 12 page

S100 Proteins in Alzheimer’s Disease

S100 proteins are calcium-binding proteins that regulate several processes associated with Alzheimer’s disease (AD) but whose contribution and direct involvement in disease pathophysiology remains to be fully established. Due to neuroinflammation in AD patients, the levels of several S100 proteins are increased in the brain and some S100s play roles related to the processing of the amyloid precursor protein, regulation of amyloid beta peptide (Aβ) levels and Tau phosphorylation. S100 proteins are found associated with protein inclusions, either within plaques or as isolated S100-positive puncta, which suggests an active role in the formation of amyloid aggregates. Indeed, interactions between S100 proteins and aggregating Aβ indicate regulatory roles over the aggregation process, which may either delay or aggravate aggregation, depending on disease stage and relative S100 and Aβ levels. Additionally, S100s are also known to influence AD-related signaling pathways and levels of other cytokines. Recent evidence also suggests that metal-ligation by S100 proteins influences trace metal homeostasis in the brain, particularly of zinc, which is also a major deregulated process in AD. Altogether, this evidence strongly suggests a role of S100 proteins as key players in several AD-linked physiopathological processes, which we discuss in this review

Natural and amyloid self-assembly of S100 proteins: structural basis of functional diversity

The S100 proteins are 10-12 kDa EF-hand proteins that act as central regulators in a multitude of cellular processes including cell survival, proliferation, differentiation and motility. Consequently, many S100 proteins are implicated and display marked changes in their expression levels in many types of cancer, neurodegenerative disorders, inflammatory and autoimmune diseases. The structure and function of S100 proteins are modulated by metal ions via Ca2+ binding through EF-hand motifs and binding of Zn2+ and Cu2+ at additional sites, usually at the homodimer interfaces. Ca2+ binding modulates S100 conformational opening and thus promotes and affects the interaction with p53, the receptor for advanced glycation endproducts and Toll-like receptor 4, among many others. Structural plasticity also occurs at the quaternary level, where several S100 proteins self-assemble into multiple oligomeric states, many being functionally relevant. Recently, we have found that the S100A8/A9 proteins are involved in amyloidogenic processes in corpora amylacea of prostate cancer patients, and undergo metal-mediated amyloid oligomerization and fibrillation in vitro. Here we review the unique chemical and structural properties of S100 proteins that underlie the conformational changes resulting in their oligomerization upon metal ion binding and ultimately in functional control. The possibility that S100 proteins have intrinsic amyloid-forming capacity is also addressed, as well as the hypothesis that amyloid self-assemblies may, under particular physiological conditions, affect the S100 functions within the cellular milieu

Probing the Kinetic Stabilities of Friedreich’s Ataxia Clinical Variants Using a Solid Phase GroEL Chaperonin Capture Platform

Numerous human diseases are caused by protein folding defects where the protein may become more susceptible to degradation or aggregation. Aberrant protein folding can affect the kinetic stability of the proteins even if these proteins appear to be soluble in vivo. Experimental discrimination between functional properly folded and misfolded nonfunctional conformers is not always straightforward at near physiological conditions. The differences in the kinetic behavior of two initially folded frataxin clinical variants were examined using a high affinity chaperonin kinetic trap approach at 25 °C. The kinetically stable wild type frataxin (FXN) shows no visible partitioning onto the chaperonin. In contrast, the clinical variants FXN-p.Asp122Tyr and FXN-p.Ile154Phe kinetically populate partial folded forms that tightly bind the GroEL chaperonin platform. The initially soluble FXN-p.Ile154Phe variant partitions onto GroEL more rapidly and is more kinetically liable. These differences in kinetic stability were confirmed using differential scanning fluorimetry. The kinetic and aggregation stability differences of these variants may lead to the distinct functional impairments described in Friedreich’s ataxia, the neurodegenerative disease associated to frataxin functional deficiency. This chaperonin platform approach may be useful for identifying small molecule stabilizers since stabilizing ligands to frataxin variants should lead to a concomitant decrease in chaperonin binding

Studies on the redox centers of the terminal oxidase from Desulfovibrio gigas and evidence for its interaction with rubredoxin

Abstract: Rubredoxin-oxygen oxidoreductase (ROO) is the final component of a soluble electron transfer chain that couples NADH oxidation to oxygen consumption in the anaerobic sulfate reducer Desulfovibrio gigas. It is an 86-kDa homodimeric flavohemeprotein containing two FAD molecules, one mesoheme IX, and one Fe-uroporphyrin I per monomer, capable of fully reducing oxygen to water. EPR studies on the native enzyme reveal two components with g values at similar to 2.46, 2.29, and 1.89, which are assigned to low spin hemes and are similar to the EPR features of P-450 hemes, suggesting that ROO hemes have a cysteinyl axial ligation. At pH 7.6, the flavin redox transitions occur at 0 +/- 15 mV for the quinone/semiquinone couple and at -130 +/- 15 mV for the semiquinone/hydroquinone couple; the hemes reduction potential is -350 +/- 15 mV. Spectroscopic studies provided unequivocal evidence that the flavins are the electron acceptor centers from rubredoxin, and that their reduction proceed through an anionic semiquinone radical. The reaction with oxygen occurs in the flavin moiety. These data are strongly corroborated by the finding that rubredoxin and ROO are located in the same polycistronic unit of D. gigas genome. For the first time, a clear role for a rubredoxin in a sulfate-reducing bacterium is presented

Optimal cruciform specimen design using the direct multi-search method and design variable influence study

Nowadays the development of new testing machines and the optimization of new specimen geometries are two very demanding activities. In order to study complex material stress and strain distributions, as in-plane biaxial loading, one must develop new technical solutions. A new type of testing machine has been developed by the present authors, for the fatigue testing of cruciform specimens, but the low capacity of the testing machine requires the optimization of the specimen in order to achieve higher but uniform stress and strain distributions on the specimen center. In this paper, the authors describe the procedure to optimize one possible geometry for cruciform specimens, able to determine the fatigue initiation life of material subjected to out of phase in-plane biaxial fatigue loadings. The high number of design variables were optimized using the direct multi-search method, considering two objective functions, the stress level on the specimen center and the uniformity of the strain distribution on a 1.0 mm radius of the specimen center. Several Pareto Fronts were obtained for different material thickness, considering the commercially available sheet metal thickness. With the optimal solution, the influence of every design variable was studied in order to provide others with a powerful tool that allows selecting the optimal geometry for the desired application. The results are presented in the form of design equations considering that the main design variable, the material thickness, was chosen from a Renard series of preferred numbers. The end user is then able to configure the optimal specimen for the required fatigue test.info:eu-repo/semantics/publishedVersio

A Novel Type of Nitric-oxide Reductase ESCHERICHIA COLI FLAVORUBREDOXIN

Escherichia coli flavorubredoxin is a member of the family of the A-type flavoproteins, which are built by two core domains: a metallo-β-lactamase-like domain, at the N-terminal region, harboring a non-heme di-iron site, and a flavodoxin-like domain, containing one FMN moiety. The enzyme fromE. coli has an extra module at the C terminus, containing a rubredoxin-like center. The A-type flavoproteins are widespread among strict and facultative anaerobes, as deduced from the analysis of the complete prokaryotic genomes. In this report we showed that the recombinant enzyme purified from E. coli has nitric-oxide reductase activity with a turnover number of ∼15 mol of NO·mol enzyme−1·s−1, which was well within the range of those determined for the canonical hemeb3 -FeB containing nitric-oxide reductases (e.g. ∼10–50 mol NO·mol enzyme−1·s−1 for the Paracoccus denitrificans NOR). Furthermore, it was shown that the activity was due to the A-type flavoprotein core, as the rubredoxin domain alone exhibited no activity. Thus, a novel family of prokaryotic NO reductases, with a non-heme di-iron site as the catalytic center, was established

The ‘strict’ anaerobe Desulfovibrio gigas contains a membrane-bound oxygen-reducing respiratory chain

AbstractSulfate-reducing bacteria are considered as strict anaerobic microorganisms, in spite of the fact that some strains have been shown to tolerate the transient presence of dioxygen. This report shows that membranes from Desulfovibrio gigas grown in fumarate/sulfate contain a respiratory chain fully competent to reduce dioxygen to water. In particular, a membrane-bound terminal oxygen reductase, of the cytochrome bd family, was isolated, characterized, and shown to completely reduce oxygen to water. This oxidase has two subunits with apparent molecular masses of 40 and 29 kDa. Using NADH or succinate as electron donors, the oxygen respiratory rates of D. gigas membranes are comparable to those of aerobic organisms (3.2 and 29 nmol O2 min−1 mg protein−1, respectively). This ‘strict anaerobic’ bacterium contains all the necessary enzymatic complexes to live aerobically, showing that the relationships between oxygen and anaerobes are much more complex than originally thought