A methodology for including suspension dynamics in a simple context of rail vehicle simulations

The running behaviour of rail vehicles is highly influenced by suspension components. Dealing with ride comfort, secondary suspensions are adopted to reduce the vibrations transmitted to the carbody. In this context, the dynamics of the suspension elements themselves has to be properly included in multibody system. This paper proposes a strategy for modelling the passive vertical secondary suspension in the frequency domain. To this aim, a mathematical model is defined and its parameters are tuned to be representative of a real system. Then, a sensitivity analysis over the model parameters is proposed to discuss the suspension performances in terms of dynamic stiffness. Finally, a finite element model of the carbody is considered and coupled to the rear and front suspensions. The model is adopted to simulate the vehicle running on a rail track irregularity in the frequency domain, in the 0-30 Hz frequency range

BAG3 induction is required to mitigate proteotoxicity via selective autophagy following inhibition of constitutive protein degradation pathways

Protein quality control systems (PQC), i.e. UPS and aggresome-autophagy pathway, have been suggested to be promising targets in cancer therapy: simultaneous pharmacological inhibition of both pathways have shown increase efficacy in various tumors such as ovarian and colon carcinoma. Here, we investigate the effect of concomitant inhibition of 26S proteasome by FDA approved inhibitor Bortezomib, and HDAC6, as key mediator of the aggresome/autophagy system, by the highly specific inhibitor ST80 in Rhabdomyosarcoma (RMS) cell lines. We demonstrated that simultaneous inhibition of 26S proteasome and selective aggresome/autophagy pathway significantly increases apoptosis in all tested RMS cell lines. Interestingly, we observed that a subpopulation of RMS cells was able to survive the co-treatment and, upon drug removal, to recover similarly to untreated cells. In this study, we identified co-chaperone BAG3 as the key mediator of this recovery: BAG3 is transcriptionally up-regulated specifically in the ST80/Bortezomib surviving cells and mediates clearance of cytotoxic protein aggregates by selective autophagy. Impairment of the autophagic pathway during the recovery phase, both by conditional knock down of ATG7 or by inhibition of lysosomal degradation by BafylomicinA1, triggers accumulation of insoluble protein aggregates, loss of cell recovery and cell death similarly to stable short harpin mRNA BAG3 knock. Our results are the first demonstration that BAG3 mediated selective autophagy is engaged to cope with proteotoxicity induced by simultaneous inhibition of constitutive PQC systems in cancer cell lines during cell recovery. Moreover our data give new insight in regulation of constitutive and on demand PQC mechanisms pointing to BAG3 as a promising target in RMS therapy

Modelling and experimental characterization of secondary suspension elements for rail vehicle ride comfort simulation

Secondary suspensions play an essential role in the dynamic behaviour of rail vehicles. In particular, they are adopted to reduce the vibrations transmitted to the carbody, thus improving ride comfort. In this paper, an experimental characterization of the viscous damper and coil spring elements composing a vertical secondary suspension is presented. The elements are separately tested with the aim of analysing their dynamic behaviour. Then, modified prototypes are manufactured to reduce the transmitted force. The results of the experimental campaign are later adopted to tune the parameters of the mathematical model of the whole secondary suspension, including the dynamics of both the coil spring and the damper elements. This model allows discussing the effectiveness of the proposed modifications, proving the design of both the components to be fundamental for the improvement of ride comfort

An in plane flexible ring model for the analysis of the free and forced response of a rolling tyre

The increased demand for vibroacoustic comfort as well as regulations on noise and vibration levels made the NVH performances of a vehicle one of the fundamental design criteria. Therefore, predictive models for the analysis of noise and vibration transmission mechanisms represent interesting tools to support the R&D department of the automotive companies. Focusing the attention on passenger’s comfort, the vibrations induced by the tyre/road interaction propagate from the contact area to the hub and finally inside the cockpit through structure-borne transmission paths. This can be regarded as one of the major contributors to car cabin interior noise at low frequencies (20-500 Hz). Simplified models able to interpret the waves propagating inside the tyre structure and influenced by the angular speed may support the studies in this research field. To this end, an analytical model based on the theory of the flexible ring on elastic foundation was developed. It allows analysing the tyre dynamics in both static and rotating conditions. Model parameters were calibrated based on an Experimental Modal Analysis of the static tyre. The free response of the tyre shows the bifurcation effect at different rotating speeds, while a cleat test simulation allows investigating the forced response of the tyre

The (endo)cannabinoid signaling in female reproduction: What are the latest advances?

Cannabis extracts like marijuana have the highest consumption rate worldwide. Yet, their societal acceptance as recreational and therapeutic drugs could represent a serious hazard to female human reproduction, because cannabis ingredients [termed (phyto)cannabinoids] can perturb an endogenous system of lipid signals known as endocannabinoids. Accumulated evidence on animal models and humans has demonstrated a crucial role of these endogenous signals on different aspects of female reproduction, where they act through an ensamble of proteins that synthesize, transport, degrade and traffic them. Several reports have recently evidenced the potential role of endocannabinoids as biomarkers of female infertility for disease treatment and prevention, as well as their possible epigenetic effects on pregnancy. The purpose of this review is to provide an update of data collected in the last decade on the effects of cannabinoids and endocannabinoids on female reproductive events, from development and maturation of follicles and oocytes, to fertilization, oviductal transport, implantation and labor. In this context, a particular attention has ben devoted to the ovary and the production of fertilizable oocytes, because recent studies have addressed this hot topic with conflicting results among species

pPKCα mediated-HIF-1α activation related to the morphological modifications occurring in neonatal myocardial tissue in response to severe and mild hyperoxia

In premature babies birth an high oxygen level exposure can occur and newborn hyperoxia exposure can be associated with free radical oxygen release with impairment of myocardial function, while in adult animal models short exposure to hyperoxia seems to protect heart against ischemic injury. Thus, the mechanisms and consequences which take place after hyperoxia exposure are different and related to animals age. The aim of our work has been to analyze the role played by HIF-1α in the occurrence of the morphological modifications upon hyperoxia exposure in neonatal rat heart. Hyperoxia exposure induces connective compartment increase which seems to allow enhanced blood vessels growth. An increased hypoxia inducible factor-1α (HIF-1α) translocation and vascular endothelial growth factor (VEGF) expression has been found upon 95% oxygen exposure to induce morphological modifications. Upstream pPKC-α expression increase in newborn rats exposed to 95% oxygen can suggest PKC involvement in HIF-1α activation. Since nitric oxide synthase (NOS) are involved in heart vascular regulation, endothelial NOS (e-NOS) and inducible NOS (i-NOS) expression has been investigated: a lower eNOS and an higher iNOS expression has been found in newborn rats exposed to 95% oxygen related to the evidence that hyperoxia provokes a systemic vasoconstriction and to the iNOS pro-apoptotic action, respectively. The occurrence of apoptotic events, evaluated by TUNEL and Bax expression analyses, seems more evident in sample exposed to severe hyperoxia. All in all such results suggest that in newborn rats hyperoxia can trigger oxygen free radical mediated membrane injury through a pPKCα mediated HIF-1α signalling system, even though specificity of such response could be obtained by in vivo administration to the rats of specific inhibitors of PKCα. This intracellular signalling can switch molecular events leading to blood vessels development in parallel to pro-apoptotic events due to an immature anti-oxidant defensive system in newborn rat hearts

p53 and telomerase control rat myocardial tissue response to hypoxia and ageing

Cellular senescence implies loss of proliferative and tissue regenerative capability. Also hypoxia, producing Reactive Oxygen Species (ROS), can damage cellular components through the oxidation of DNA, proteins and lipids, thus influencing the shortening of telomeres

Nano-Electrochemical Characterization of a 3D Bioprinted Cervical Tumor Model

Current cancer research is limited by the availability of reliable in vivo and in vitro models that are able to reproduce the fundamental hallmarks of cancer. Animal experimentation is of paramount importance in the progress of research, but it is becoming more evident that it has several limitations due to the numerous differences between animal tissues and real, in vivo human tissues. 3D bioprinting techniques have become an attractive tool for many basic and applied research fields. Concerning cancer, this technology has enabled the development of three-dimensional in vitro tumor models that recreate the characteristics of real tissues and look extremely promising for studying cancer cell biology. As 3D bioprinting is a relatively recently developed technique, there is still a lack of characterization of the chemical cellular microenvironment of 3D bioprinted constructs. In this work, we fabricated a cervical tumor model obtained by 3D bioprinting of HeLa cells in an alginate-based matrix. Characterization of the spheroid population obtained as a function of culturing time was performed by phase-contrast and confocal fluorescence microscopies. Scanning electrochemical microscopy and platinum nanoelectrodes were employed to characterize oxygen concentrations - a fundamental characteristic of the cellular microenvironment - with a high spatial resolution within the 3D bioprinted cervical tumor model; we also demonstrated that the diffusion of a molecular model of drugs in the 3D bioprinted construct, in which the spheroids were embedded, could be measured quantitatively over time using scanning electrochemical microscop

Measurement and Processing of Road Irregularity for Surface Generation and Tyre Dynamics Simulation in NVH Context

Nowadays, finite element tyre models are often used to perform vehicle NVH (noise, vibration, harshness) simulations. To account for the specific operating conditions, a road surface must be properly included in the model. This paper deals with a methodology to experimentally evaluate and process road irregularity measurements, so as to generate a road surface input. These surfaces are used to simulate the tyre/road interaction at the footprint, which is modelled as a contact surface in finite element tyre models. For this reason, a linear profile of the road surface is not suitable for these simulations and the whole surface must be considered. Starting from the measurements taken through a test equipment specifically designed to carry laser sensors and scan road profiles, the Power Spectral Density (PSD) of a specific track is estimated and then interpolated considering piecewise functions. Finally, a model to generate a road surface starting from the measured PSD is developed, discussed and validated