Design of Fault-Tolerant Control for Trajectory Tracking

International audienceThe paper proposes a fault-tolerant integrated control system with the brake and the steering for developing a driver assistance system. The purpose is to design a fault-tolerant control which is able to guarantee the trajectory tracking and lateral stability of the vehicle against actuator fault scenarios. Since both actuators affect the lateral dynamics of the vehicle, in the control design a balance and priority between them must be achieved. The method is extended with a fault-tolerant feature based on a robust LPV method, into which the detected fault information are incorporated. The control design is performed by using the Matlab/Simulink software and the verification of the designed controller is performed by using the CarSim software

Neutrophil cell surface receptors and their intracellular signal transduction pathways

AbstractNeutrophils play a critical role in the host defense against bacterial and fungal infections, but their inappropriate activation also contributes to tissue damage during autoimmune and inflammatory diseases. Neutrophils express a large number of cell surface receptors for the recognition of pathogen invasion and the inflammatory environment. Those include G-protein-coupled chemokine and chemoattractant receptors, Fc-receptors, adhesion receptors such as selectins/selectin ligands and integrins, various cytokine receptors, as well as innate immune receptors such as Toll-like receptors and C-type lectins. The various cell surface receptors trigger very diverse signal transduction pathways including activation of heterotrimeric and monomeric G-proteins, receptor-induced and store-operated Ca2+ signals, protein and lipid kinases, adapter proteins and cytoskeletal rearrangement. Here we provide an overview of the receptors involved in neutrophil activation and the intracellular signal transduction processes they trigger. This knowledge is crucial for understanding how neutrophils participate in antimicrobial host defense and inflammatory tissue damage and may also point to possible future targets of the pharmacological therapy of neutrophil-mediated autoimmune or inflammatory diseases

Gastric mucosal protection and central nervous system.

Several human and experimental data suggest the particular importance of gastric protective processes in maintaining mucosal integrity. Both peripheral and central mechanisms are involved in this process. In the periphery, pre-epithelial mucus-bicarbonate layer, mucus, phospholipids, trefoil peptides, prostaglandins, heat shock proteins, sensory neuropeptides, nitric oxide, and hydrogen sulfide may mediate mucosal protection. In the central nervous system hypothalamus and dorsal vagal complex (DVC) have particular important role in the regulation of centrally-induced gastroprotection. Stimulation of paraventricular nuclei either aggravates or inhibits the mucosal injury depending on the ulcer model. Vagal nerve also has a dual role, its activation can induce mucosal injury (by high dose of thyrotropin- releasing hormone (TRH), electrical stimulation), however, integrity of vagal nerve is necessary for gastroprotection induced either peripherally (by PGE2, prostacyclin, adaptive cytoprotection), or centrally (e.g. by neuropeptides). The centrally induced gastroprotection is likely to be vagal dependent, though vagal independent pathways have also been shown. Endomorphin-1 and endomorphin-2, selective μ-opioid receptor ligands, proved to be highly potent and effective gastroprotective agents in ethanol ulcer model (0.03-3 pmol intracerebroventricularly). Inhibition of the degradation of endomorphins by diprotin A resulted in gastroprotective effect, indicating the potential role of these endogenous opioids in the regulation of gastric mucosal integrity. Endomorphin-2 injected intracerebroventricularly restored the reduced levels of CGRP and somatostatin in gastric mucosa induced by ethanol. In conclusion, neuropeptides expressed in dorsal vagal complex and hypothalamus may have a regulatory role in maintaining gastric mucosal integrity by stimulating the formation of mucosal protective compounds

VIP, PACAP-38, BDNF and ADNP in NMDA-induced excitotoxicity in the rat retina

Purpose: To evaluate the effect of intravitreal injection of N-methyl-D-aspartate(NMDA) on brain-derived neurotrophic factor (BDNF), pituitary adenylatecyclase-activating peptide-38 (PACAP-38), vasoactive intestinal peptide (VIP) andthe VIP-associated glial protein activity-dependent neuroprotective protein(ADNP) in the rat retina. These elements have well-documented neuroprotectiveproperties and may thus be integrated in endogenous neuroprotective mechanismsin the retina which break down in NMDA excitotoxicity.Methods: A volume of 2 ll of 100 nmol NMDA was intravitreally injected intoone eye of rats, the untreated eye served as a control. Time-dependent effects ofNMDA on VIP, PACAP-38 and BDNF were detected by radioimmunoassay andELISA, and the effect on the expression of VIP, PACAP-38 and ADNP was evaluatedby quantitative RT-PCR 20 days after NMDA injection. Topical flunarizineserved to find out whether the effect of NMDA is counteracted.Results: Compared to PACAP-38, VIP levels significantly decreased on days 1, 7,14, 28 and 56 after NMDA injection indicating that VIPergic cells are more vulnerablethan PACAP-38-expressing cells. The expression of VIP and ADNP but not ofPACAP-38 was found to be reduced, and application of topical flunarizine counteractedthe decrease of VIP. BDNF levels significantly increased after days 1 and 3.Conclusion: The early upregulation of BDNF seems to act neuroprotectively andleads to a delay of ganglion cell loss. Although there is no direct evidence, thedecrease of VIP and ADNP ? the consequence of the presence of NMDA receptorson these peptide-expressing cells ? might contribute to the breakdown ofendogenous neuroprotective mechanisms given that the decrease of the VIP-relatedADNP runs in parallel with the decrease of VIP. Activating and maintaining thesemechanisms must be the primary aim in the therapy of diseases with retinal neuronaldegeneratio

Hepatic insulin sensitizing substance: a novel ‘sensocrine' mechanism to increase insulin sensitivity in anaesthetized rats

1. We recently described the sensory nitrergic nature of the hepatic insulin sensitizing substance (HISS) mechanism linked to postprandial activation of anterior hepatic plexus fibres in rabbits. This study is designed to assess the involvement of the sensory pathways in this mechanism. 2. Selective sensory denervation of the anterior hepatic plexus (AHP) was achieved by a 3-day perineurial treatment with 2% capsaicin solution in Wistar rats (230–250 g). After 1 week, hyperinsulinaemic (100 μU kg(−1)) euglycaemic (5.5 mmol kg(−1)) glucose clamp studies were performed to estimate insulin sensitivity. 3. The rats with regional AHP sensory denervation exhibited a significantly decreased insulin sensitivity, that is, 9.1±1.0 mg kg(−1) min(−1) glucose reinstalled euglycaemia vs 13.3±1.9 mg kg(−1) min(−1) glucose (P<0.01) in control rats. 4. Acute partial hepatic denervation by AHP cut was without effect on insulin sensitivity, whereas chronic hepatic denervation induced insulin resistance was similar to that achieved by regional AHP capsaicin treatment. 5. Intraportal administration of L-NAME (10 mg kg(−1)) decreased, whereas capsaicin (0.3 mg kg(−1) min(−1)) increased insulin sensitivity. Neither atropine (1 mg kg(−1)) nor acetylcholine (1–10 μg mg min(−1)) produced any significant effect. In animals with preceding regional capsaicin desensitization, none of the pharmacological manoeuvres modified the resulting insulin-resistant state. 6. Cysteamine (200 mg kg(−1) s.c.) is known to cause functional somatostatin depletion-induced insulin resistance similar to that produced by either chronic partial hepatic denervation or perineurial AHP capsaicin desensitization. Intraportal capsaicin (0.3 mg kg(−1) min(−1)) was unable to modify insulin resistance achieved by cysteamine. 7. We conclude that capsaicin-sensitive sensory fibres play a crucial role in neurogenic insulin sensitization known as the HISS mechanism without involvement of anatomical reflex-mediated circuits. The results also suggest that HISS is identical to somatostatin of AHP sensory neural origin

Clinical protein science in translational medicine targeting malignant melanoma

Melanoma of the skin is the sixth most common type of cancer in Europe and accounts for 3.4% of all diagnosed cancers. More alarming is the degree of recurrence that occurs with approximately 20% of patients lethally relapsing following treatment. Malignant melanoma is a highly aggressive skin cancer and metastases rapidly extend to the regional lymph nodes (stage 3) and to distal organs (stage 4). Targeted oncotherapy is one of the standard treatment for progressive stage 4 melanoma, and BRAF inhibitors (e.g. vemurafenib, dabrafenib) combined with MEK inhibitor (e.g. trametinib) can effectively counter BRAFV600E-mutated melanomas. Compared to conventional chemotherapy, targeted BRAFV600E inhibition achieves a significantly higher response rate. After a period of cancer control, however, most responsive patients develop resistance to the therapy and lethal progression. The many underlying factors potentially causing resistance to BRAF inhibitors have been extensively studied. Nevertheless, the remaining unsolved clinical questions necessitate alternative research approaches to address the molecular mechanisms underlying metastatic and treatment-resistant melanoma. In broader terms, proteomics can address clinical questions far beyond the reach of genomics, by measuring, i.e. the relative abundance of protein products, post-translational modifications (PTMs), protein localisation, turnover, protein interactions and protein function. More specifically, proteomic analysis of body fluids and tissues in a given medical and clinical setting can aid in the identification of cancer biomarkers and novel therapeutic targets. Achieving this goal requires the development of a robust and reproducible clinical proteomic platform that encompasses automated biobanking of patient samples, tissue sectioning and histological examination, efficient protein extraction, enzymatic digestion, mass spectrometry–based quantitative protein analysis by label-free or labelling technologies and/or enrichment of peptides with specific PTMs. By combining data from, e.g. phosphoproteomics and acetylomics, the protein expression profiles of different melanoma stages can provide a solid framework for understanding the biology and progression of the disease. When complemented by proteogenomics, customised protein sequence databases generated from patient-specific genomic and transcriptomic data aid in interpreting clinical proteomic biomarker data to provide a deeper and more comprehensive molecular characterisation of cellular functions underlying disease progression. In parallel to a streamlined, patient-centric, clinical proteomic pipeline, mass spectrometry–based imaging can aid in interrogating the spatial distribution of drugs and drug metabolites within tissues at single-cell resolution. These developments are an important advancement in studying drug action and efficacy in vivo and will aid in the development of more effective and safer strategies for the treatment of melanoma. A collaborative effort of gargantuan proportions between academia and healthcare professionals has led to the initiation, establishment and development of a cutting-edge cancer research centre with a specialisation in melanoma and lung cancer. The primary research focus of the European Cancer Moonshot Lund Center is to understand the impact that drugs have on cancer at an individualised and personalised level. Simultaneously, the centre increases awareness of the relentless battle against cancer and attracts global interest in the exceptional research performed at the centre

Reprint of Neutrophil cell surface receptors and their intracellular signal transduction pathways

Neutrophils play a critical role in the host defense against bacterial and fungal infections, but their inappropriate activation also contributes to tissue damage during autoimmune and inflammatory diseases. Neutrophils express a large number of cell surface receptors for the recognition of pathogen invasion and the inflammatory environment. Those include G-protein-coupled chemokine and chemoattractant receptors, Fc-receptors, adhesion receptors such as selectins/selectin ligands and integrins, various cytokine receptors, as well as innate immune receptors such as Toll-like receptors and C-type lectins. The various cell surface receptors trigger very diverse signal transduction pathways including activation of heterotrimeric and monomeric G-proteins, receptor-induced and store-operated Ca2 + signals, protein and lipid kinases, adapter proteins and cytoskeletal rearrangement. Here we provide an overview of the receptors involved in neutrophil activation and the intracellular signal transduction processes they trigger. This knowledge is crucial for understanding how neutrophils participate in antimicrobial host defense and inflammatory tissue damage and may also point to possible future targets of the pharmacological therapy of neutrophil-mediated autoimmune or inflammatory diseases. © 2013 The Authors