Preliminary evaluation of central nervous system activity of (E)-N-2-methyl-3-phenylprop-2-enyl ((E)-N- α-methylcinnamyl) derivatives of selected aminoalkanols

A series of (E)-α-methylcinnamyl derivatives of selected aminoalkanols was synthetized and evaluated for activity in central nervous system. All compounds were tested as anticonvulsants and one additionally in antidepressant- and anxiolytic-like assays. The compounds possessed pharmacophoric elements regarded as beneficial for anticonvulsant activity: hydrophobic unit and two hydrogen bonds donor/acceptor features. The compounds were verified in mice after intraperitoneal (i.p.) administration in maximal electroshock (MES) and subcutaneous pentetrazole (scPTZ) induced seizures as well as neurotoxicity assessments. Eight of the tested substances showed protection in MES test at the dose of 100 mg/kg. The derivative of 2 aminopropan-1-ol was also tested in 6-Hz test in mice i.p. and showed anticonvulsant activity but at the same time the neurotoxicity was noted. The derivative of 2-amino-1-phenylethanol which possessed additional hydrophobic unit in aminoalkanol moiety was tested in other in vivo assays to evaluate antidepressant- and anxiolytic-like activity. The compound proved beneficial properties especially as anxiolytic agent remaining active in four-plate test in mice at the dose of 2.5 mg/kg (i.p.). In vitro biotransformation studies of 2-amino-1-phenylethanol derivative carried out in mouse liver microsomal assay indicated two main metabolites as a result of aliphatic and aromatic hydroxylation or aliphatic carbonylation. To identify possible mechanism of action, we evaluated serotonin receptors (5-HT1A, 5-HT6 and 5-HT7) binding affinities of the compounds but none of them proved to bind to any of tested receptors

Mitogen-activated protein kinase phosphatase-2 deletion modifies ventral tegmental area function and connectivity and alters reward processing

Mitogen-activated protein kinases (MAPKs) regulate normal brain functioning, and their dysfunction is implicated in a number of brain disorders. Thus, there is great interest in understanding the signalling systems that control MAPK functioning. One family of proteins that contribute to this process, the mitogen-activated protein kinase phosphatases (MKPs), directly inactivate MAPKs through dephosphorylation. Recent studies have identified novel functions of MKPs in foetal development, the immune system, cancer and synaptic plasticity and memory. In the present study, we performed an unbiased investigation using MKP-2-/- mice to assess whether MKP-2 plays a global role in modulating brain function. Local cerebral glucose utilization is significantly increased in the ventral tegmental area (VTA) of MKP-2-/- mice, with connectivity analysis revealing alterations in VTA functional connectivity, including a significant reduction in connectivity to the nucleus accumbens and hippocampus. In addition, spontaneous excitatory postsynaptic current frequency, but not amplitude, onto putative dopamine neurons in the VTA is increased in MKP-2-/- mice, which indicates that increased excitatory drive may account for the increased VTA glucose utilization. Consistent with modified VTA function and connectivity, in behavioural tests MKP-2-/- mice exhibited increased sucrose preference and impaired amphetamine-induced hyperlocomotion. Overall, these data reveal that MKP-2 plays a role in modulating VTA function and that its dysfunction may contribute to brain disorders in which altered reward processing is present

Functional Characterization of a Newly Identified Group B Streptococcus Pullulanase Eliciting Antibodies Able to Prevent Alpha-Glucans Degradation

Streptococcal pullulanases have been recently proposed as key components of the metabolic machinery involved in bacterial adaptation to host niches. By sequence analysis of the Group B Streptococcus (GBS) genome we found a novel putative surface exposed protein with pullulanase activity. We named such a protein SAP. The sap gene is highly conserved among GBS strains and homologous genes, such as PulA and SpuA, have been described in other pathogenic streptococci. The SAP protein contains two N-terminal carbohydrate-binding motifs, followed by a catalytic domain and a C-terminal LPXTG cell wall-anchoring domain. In vitro analysis revealed that the recombinant form of SAP is able to degrade α-glucan polysaccharides, such as pullulan, glycogen and starch. Moreover, NMR analysis showed that SAP acts as a type I pullulanase. Studies performed on whole bacteria indicated that the presence of α-glucan polysaccharides in culture medium up-regulated the expression of SAP on bacterial surface as confirmed by FACS analysis and confocal imaging. Deletion of the sap gene resulted in a reduced capacity of bacteria to grow in medium containing pullulan or glycogen, but not glucose or maltose, confirming the pivotal role of SAP in GBS metabolism of α-glucans. As reported for other streptococcal pullulanases, we found specific anti-SAP antibodies in human sera from healthy volunteers. Investigation of the functional role of anti-SAP antibodies revealed that incubation of GBS in the presence of sera from animals immunized with SAP reduced the capacity of the bacterium to degrade pullulan. Of interest, anti-SAP sera, although to a lower extent, also inhibited Group A Streptococcus pullulanase activity. These data open new perspectives on the possibility to use SAP as a potential vaccine component inducing functional cross-reacting antibodies interfering with streptococcal infections

On the Experimental Analysis of Integral Sliding Modes for Yaw Rate and Sideslip Control of an Electric Vehicle with Multiple Motors

With the advent of electric vehicles with multiple motors, the steady-state and transient cornering responses can be designed and implemented through the continuous torque control of the individual wheels, i.e., torque-vectoring or direct yaw moment control. The literature includes several papers on sliding mode control theory for torque-vectoring, but the experimental investigation is so far limited. More importantly, to the knowledge of the authors, the experimental comparison of direct yaw moment control based on sliding modes and typical controllers used for stability control in production vehicles is missing. This paper aims to reduce this gap by presenting and analyzing an integral sliding mode controller for concurrent yaw rate and sideslip control. A new driving mode, the Enhanced Sport mode, is proposed, inducing sustained high values of sideslip angle, which can be limited to a specified threshold. The system is experimentally assessed on a four-wheel-drive electric vehicle. The performance of the integral sliding mode controller is compared with that of a linear quadratic regulator during step steer tests. The results show that the integral sliding mode controller significantly enhances the tracking performance and yaw damping compared to the more conventional linear quadratic regulator based on an augmented singletrack vehicle model formulation. © 2018, The Korean Society of Automotive Engineers and Springer-Verlag GmbH Germany, part of Springer Natur

Protease-activated receptor 2 activation induces behavioural changes associated with depression-like behaviour through microglial-independent modulation of inflammatory cytokines

Rationale: Major depressive disorder (MDD) is a leading cause of disability worldwide but currently prescribed treatments do not adequately ameliorate the disorder in a significant portion of patients. Hence, a better appreciation of its aetiology may lead to the development of novel therapies. Objectives: In the present study, we have built on our previous findings indicating a role for protease-activated receptor-2 (PAR2) in sickness behaviour to determine whether the PAR2 activator, AC264613, induces behavioural changes similar to those observed in depression-like behaviour. Methods: AC264613-induced behavioural changes were examined using the open field test (OFT), sucrose preference test (SPT), elevated plus maze (EPM), and novel object recognition test (NOR). Whole-cell patch clamping was used to investigate the effects of PAR2 activation in the lateral habenula with peripheral and central cytokine levels determined using ELISA and quantitative PCR. Results: Using a blood–brain barrier (BBB) permeable PAR2 activator, we reveal that AC-264613 (AC) injection leads to reduced locomotor activity and sucrose preference in mice but is without effect in anxiety and memory-related tasks. In addition, we show that AC injection leads to elevated blood sera IL-6 levels and altered cytokine mRNA expression within the brain. However, neither microglia nor peripheral lymphocytes are the source of these altered cytokine profiles. Conclusions: These data reveal that PAR2 activation results in behavioural changes often associated with depression-like behaviour and an inflammatory profile that resembles that seen in patients with MDD and therefore PAR2 may be a target for novel antidepressant therapies

A new method for testing and evaluating grassy airfields and its effects upon flying safety

The paper contains a review of methods and technologies developed during a research project entitled “Methods of testing and evaluation of grassy airfields”, conducted at the Lublin University of Technology between 2011 and 2014. Based on the terramechanical studies of wheel-soil interactions, the authors have developed a method for the determination of wheel-grass friction and rolling resistance coefficients, which are of critical importance for the ground performance of an airplane. Moreover, a mobile application has been created for use by pilots, controllers or airfield administration crew. The application connects online with a weather service to gather atmospheric data as inputs for a mathematical model that produces a real-time cone index (CI) value for a given airfield. The paper also discusses the applicability of the method within the air transportation system, as well as possible effects of the described technology upon the safety of flight operations on grassy airfields

Some methodological aspects of stress measurements in granular materials

Pomiary naporu w ośrodkach rozdrobionych znajdują praktyczne zastosowanie w badaniach mechaniki gleb, gruntów, ziaren oraz materiałów sypkich. Specyfika tego rodzaju materiałów wymaga stosowania nietypowych metod pomiarowych. w referacie przedstawiono syntezę prowadzonych od lat wspólnych badań, w razmach których opracowano własne metody badawcza: przetworniki naporu, metody ich kalibracji, procedury pomiarowe. Przedstawiono opisy tych metod. Zamieszczono również przykładowe wyniki, uzyskane w ramach realizacji licznych projektów badawczych.Measurements of stresses in granular materials are of practical importance in soil. grains and powders mechanics. Those materials require special measuring methods and sensors. The paper presents a synthesis of author`s research on this field. Measuring methods, transducers, their calibration and procedures are presented and described in the work. Sample results obtained in numerous research projects

Badanie stabilności ruchu samochodu na podłożach odkształcalnych

The paper includes results form a research of ride stability of a SUV (Sport Utility Vehicle), driven over deformable surfaces. An analytical method, in which stability of a mathematical model of vehicle's lateral dynamics is tested. The mathematical model has been reconstructed by means of a system identification method. We have used steering wheel angle as an input signal and lateral acceleration, side slip angle and yaw velocity as output signals to create the model. The data required to perform system identification have been gathered in a full size experiment, with the use of an instrumented vehicle. Final results in a form of poles and zeros diagrams have been included in the paper together with a discussion.W artykule zawarto wyniki badań stabilności ruchu samochodu osobowo-terenowego na podłożu odkształcalnym. Zastosowano analityczną metodę badania stabilności, w której badana jest stabilność matematycznego modelu danego obiektu. W rozpatrywanym przypadku, model matematyczny odtworzono na podstawie analizy sygnałów wejściowych (kąt obrotu kierownicy) oraz wyjściowych (przyspieszenie boczne i kąt bocznego znoszenia środka ciężkości, prędkość kątowa odchylania od kierunku ruchu, moment na kole kierownicy), z zastosowaniem metody identyfikacji systemów