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

CHCHD2 harboring Parkinson's disease-linked T61I mutation precipitates inside mitochondria and induces precipitation of wild-type CHCHD2

The T61I mutation in CHCHD2, a protein residing in the mitochondrial intermembrane space, causes an autosomal dominant form of Parkinson’s disease (PD), but the underlying pathogenic mechanisms are not well understood. Here, we compared the subcellular localization and solubility of wild-type and T61I mutant CHCHD2 in human cells. We found that mitochondrial targeting of both wild-type and T61I CHCHD2 depended on the four cysteine residues in the C-terminal coiled-coil-helix-coiled-coil-helix (CHCH) domain but not on the N-terminal predicted mitochondrial targeting sequence. The T61I mutation did not interfere with mitochondrial targeting of the mutant protein, but induced its precipitation in the IMS. Moreover, T61I CHCHD2 induced increased mitochondrial production of reactive oxygen species (ROS) and apoptosis, which was prevented by treatment with anti-oxidants. Retention of T61I CHCHD2 in the cytosol through mutation of the cysteine residues in the CHCH domain prevented its precipitation as well as its apoptosis-inducing effect. Importantly, T61I CHCHD2 potently impaired the solubility of wild-type CHCHD2. In conclusion, our data show that the T61I mutation renders mutant CHCHD2 insoluble inside mitochondria, suggesting loss of function of the mutant protein. In addition, T61I CHCHD2 exerts a dominant-negative effect on the solubility of wild-type CHCHD2, explaining the dominant inheritance of this form of PD

Cellular function and pathological role of ATP13A2 and related P-type transport ATPases in Parkinson's disease and other neurological disorders

Mutations in ATP13A2 lead to Kufor-Rakeb syndrome, a parkinsonism with dementia. ATP13A2 belongs to the P-type transport ATPases, a large family of primary active transporters that exert vital cellular functions. However, the cellular function and transported substrate of ATP13A2 remain unknown. To discuss the role of ATP13A2 in neurodegeneration, we first provide a short description of the architecture and transport mechanism of P-type transport ATPases. Then, we briefly highlight key P-type ATPases involved in neuronal disorders such as the copper transporters ATP7A (Menkes disease), ATP7B (Wilson disease), the Na+/K+-ATPases ATP1A2 (familial hemiplegic migraine) and ATP1A3 (rapid-onset dystonia parkinsonism). Finally, we review the recent literature of ATP13A2 and discuss ATP13A2’s putative cellular function in the light of what is known concerning the functions of other, better-studied P-type ATPases. We critically review the available data concerning the role of ATP13A2 in heavy metal transport and propose a possible alternative hypothesis that ATP13A2 might be a flippase. As a flippase, ATP13A2 may transport an organic molecule, such as a lipid or a peptide, from one membrane leaflet to the other. A flippase might control local lipid dynamics during vesicle formation and membrane fusion events

DIMAS Development of an integrated database for the management of accidental spills. Part 2. Global change, ecosystems and biodiversity - SPSDII: final report

DIMAS is a 2-year project executed by three Belgian partners (EURAS, VLIZ and Ghent University) and funded by the SPSD II research program of the Belgian Science Policy (BELSPO). Several shipping accidents in Belgian territorial waters, made the various government agencies involved aware of the need to develop tools to assess the risks and impact on marine resources in the case of an accidental release of hazardous substances. DIMAS aims at the protection of the North Sea and Western Scheldt in case of accidental spills from ships. In the present project, a relational database is developed, providing reliable, easy to interpret and up-to-date information on marine specific issues. The database contains the latest information on effects (acute and chronic), absorption, distribution, bioaccumulation/biomagnification, GESAMP hazard profiles and physico-chemical properties for a selection of priority substances and is publicly available (www.vliz.be/projects/dimas). The selection of the substances is based on criteria such as occurrence on priority lists, volumes transported over sea, frequency of involvement in accidental spills and frequency of transports over sea. The first beneficiaries of this database are the people directly involved in the first phase of a containment plan for an accidental spill. The final indirect beneficiaries are the general public (scientists, journalists, general public, etc.) who will be better informed about the potential impact to man and the environment

Asymmetric interlimb transfer of concurrent adaptation to opposing dynamic forces

Interlimb transfer of a novel dynamic force has been well documented. It has also been shown that unimanual adaptation to opposing novel environments is possible if they are associated with different workspaces. The main aim of this study was to test if adaptation to opposing velocity dependent viscous forces with one arm could improve the initial performance of the other arm. The study also examined whether this interlimb transfer occurred across an extrinsic, spatial, coordinative system or an intrinsic, joint based, coordinative system. Subjects initially adapted to opposing viscous forces separated by target location. Our measure of performance was the correlation between the speed profiles of each movement within a force condition and an ‘average’ trajectory within null force conditions. Adaptation to the opposing forces was seen during initial acquisition with a significantly improved coefficient in epoch eight compared to epoch one. We then tested interlimb transfer from the dominant to non-dominant arm (D → ND) and vice-versa (ND → D) across either an extrinsic or intrinsic coordinative system. Interlimb transfer was only seen from the dominant to the non-dominant limb across an intrinsic coordinative system. These results support previous studies involving adaptation to a single dynamic force but also indicate that interlimb transfer of multiple opposing states is possible. This suggests that the information available at the level of representation allowing interlimb transfer can be more intricate than a general movement goal or a single perceived directional error

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

The endoplasmic reticulum Ca2+-ATPase SERCA2b is upregulated in activated microglia and its inhibition causes opposite effects on migration and phagocytosis

This is the peer reviewed version of the following article: Morales-Ropero JM, Arroyo-Urea S, Neubrand VE, Martín-Oliva D, Marín-Teva JL, Cuadros MA, Vangheluwe P, Navascués J, Mata AM, Sepúlveda MR. The endoplasmic reticulum Ca2+ -ATPase SERCA2b is upregulated in activated microglia and its inhibition causes opposite effects on migration and phagocytosis. Glia. 2021 Apr;69(4):842-857, which has been published in final form at https://onlinelibrary.wiley.com/doi/10.1002/glia.23931. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wiley or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Wiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages thereof by third parties from platforms, services and websites other than Wiley Online Library must be prohibited.The accepted version is under embargo until April 2022.Activation of microglia is an early immune response to damage in the brain. Although a key role for Ca2+ as trigger of microglial activation has been considered, little is known about the molecular scenario for regulating Ca2+ homeostasis in these cells. Taking into account the importance of the endoplasmic reticulum as a cellular Ca2+ store, the sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA2b) is an interesting target to modulate intracellular Ca2+ dynamics. We found upregulation of SERCA2b in activated microglia of human brain with Alzheimer´s disease and we further studied the participation of SERCA2b in microglial functions by using the BV2 murine microglial cell line and primary microglia isolated from mouse brain. To trigger microglia activation, we used the bacterial lipopolysaccharide (LPS), which is known to induce an increase of cytosolic Ca2+. Our results showed an upregulated expression of SERCA2b in LPS-induced activated microglia likely associated to an attempt to restore the increased cytosolic Ca2+ concentration. We analyzed SERCA2b contribution in microglial migration by using the specific SERCA inhibitor thapsigargin in scratch assays. Microglial migration was strongly stimulated with thapsigargin, even more than with LPS-induction, but delayed in time. However, phagocytic capacity of microglia was blocked in the presence of the SERCA inhibitor, indicating the importance of a tight control of cytosolic Ca2+ in these processes. All together, these results provide for the first time compelling evidence for SERCA2b as a major player regulating microglial functions, affecting migration and phagocytosis in an opposite manner.Grant mP_BS_35-2014 from CEI BioTic GranadaPP2016-PJI05 from University of GranadaA1-CTS-324-UGR18 from FEDER-Junta de Andalucía, SpainPP2016-PIP08 from University of GranadaBFU2017-85723-P from Spanish Ministry of Economy and Competitiveness co-financed with FEDERG044212N from Flanders Research Foundatio