Ropeway roller batteries dynamics. Modeling, identification, and full-scale validation

A parametric mechanical model based on a Lagrangian formulation is here proposed to predict the dynamic response of roller batteries during the vehicles transit across the so-called compression towers in ropeways transportation systems. The model describes the dynamic interaction between the ropeway substructures starting from the modes and frequencies of the system to the forced dynamic response caused by the vehicles transit. The analytical model is corroborated and validated via an extensive experimental campaign devoted to the dynamic characterization of the roller battery system. The data acquired on site via a custom-design sensor network allowed to identify the frequencies and damping ratios by employing the Frequency Domain Decomposition (FDD) method. The high fidelity modeling and the system identification procedure are discussed

Beyond the Direct Activation of Cannabinoid Receptors: New Strategies to Modulate the Endocannabinoid System in CNS-Related Diseases

Background: Anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) are signalling lipids which belong to the class of endocannabinoids (ECs) and exert their actions by activating cannabinoid receptor type-1 (CB1) and type-2 (CB2). These receptors are involved in many physiological and pathological processes in the central nervous system (CNS) and in peripheral organs. Despite many potent and selective ligands for cannabinoid receptors have been generated over the last two decades, this class of compounds achieved only a very limited therapeutic success, mainly because of the CB1- mediated side effects. Methods: The compounds and results presented in this review article have been gathered from an extensive research in public databases for patents, clinical trials and scientific literature. Reference to patent numbers, clinical trial registry numbers, websites and scientific articles is provided in the text and/or in the reference section. Results: Over the last 10-15 years, many inhibitors for the main EC hydrolytic enzymes fatty acid amide hydrolase (FAAH), monoacylglycerol lipase (MAGL), α,β-hydrolase domain-6 (ABHD6) and -12 (ABHD12) have been synthesized and characterized in vitro and in vivo. Additionally, other targets have been explored for the modulation of the endocannabinoid system (ECS). Among them, several novel inhibitors for COX-2, diacylglycerol lipases and the putative endocannabinoid membrane transporter have been described in the literature. Polypharmacological approaches which combine mild or reversible inhibition of at least two of these targets are also under investigation. Conclusions: The ECS offers several therapeutic opportunities beyond the direct activation of cannabinoid receptors. The modulation of EC levels in vivo represents an interesting therapeutic perspective for several CNS-related diseases. Based on the literature and patent literature this review provides an overview of the different classes of inhibitors for FAAH, MAGL, ABHDs and COX-2 used as tool compounds and for clinical development with a special focus on CNS-related diseases

Payload oscillations control in harbor cranes via semi-active vibration absorbers: modeling, simulations and experimental results

Abstract Semi-active vibration absorbers (SAVAs) are proposed to suppress large amplitude oscillations in container cranes during maneu-vers and wind forcing. The SAVA design and optimization are achieved via suitable nonlinear models, numerical simulations, and laboratory as well as full-scale tests. A comprehensive nonlinear modelling, featuring a full three-dimensional crane model and the adaptive vibration control architecture, is devised. The container is modeled as a rigid body elastically suspended from the trolley traveling along the crane boom. Two identical SAVAs are studied coupling their equations of motion - which include the impact against rubberized end stops - with the container crane dynamics. Suitable parametric analyses are carried out to investigate and optimize the control devices. Full-scale experiments are performed to validate the semi-active control architecture which proves to be a feasible approach

Synthetic cannabinoid receptor agonists and antagonists: implication in CNS disorders

Since the discovery of the cannabinoid receptors, numerous studies associate the endocannabinoid system with several physiological and pathological processes including cancer, appetite, fertility, memory, neuropathic and inflammatory pain, obesity, and neurodegenerative diseases. Over the last two decades, several researches have been dedicated extensively on the cannabinoid receptors ligands since the direct activation of cannabinoid receptors results in several beneficial effects, in the brain and in the periphery

Crosstalk between oxidative stress and inflammation in Alzheimer-like dementia

Trisomy of Chr 21, commonly known as Down syndrome (DS), is the most prevailing genetic cause of intellectual disability with an incidence of 1:700 births. DS individuals, after the age of 40, develop a type of dementia that closely resembles that of Alzheimer’s disease (AD) with deposition of senile plaques containing Aβ and neurofibrillary tangles (NFTs) composed of hyperphoshorylated tau. Inflammation and oxidative stress (OS) are known to occur in DS and AD brains in response to Aβ plaques and NFTs. Furthermore, several studies demonstrated also the involvement of brain insulin resistance (BIR) in the progression of AD-like pathology. Therefore, we believe that OS, inflammation and BIR could contribute to the severity of AD and DS pathology and act as potential accelerators of AD pathology. Within this scenario, we focused our attention on the dysfunction of molecular pathways that are closely related with increased OS and that might be involved in the development of Alzheimer-like dementia including autophagy (the major cellular pathway responsible for the removal of Aβ and tau aggregates), insulin signaling and inflammation. Recent studies from our laboratory reported, in human DS samples, an early accumulation of protein oxidative damage concomitant with the alteration of mTOR/ autophagy signaling. However, the relationship between OS and mTOR/autophagy signaling is intricate and needs to be clarified (Project 1). Furthermore, increasing evidence supports the involvement of inflammation-related miRNAs in neurodegenerative diseases and because miR146a and miR155 are key regulators of the microglia-mediated inflammatory response we hypothesized that a dysregulation of these miRNAs may occur in DS and AD pathology (Project 2). Finally, BVR-A being a direct target of IR kinase activity and once IR-phosphorylated is able to phosphorylate IRS1 on Ser inhibitory, and because we previously demonstrated that OS induces impairment of BVR-A in human AD brain, we investigate if BVR-A dysregulation could be associated with the onset of BIR in AD (Project 3). Aim of this work In order to clarify the intricate relationship between increased OS and alteration of mTOR/autophagy signaling we analyzed the integrity of the mTOR axis in DS mouse model (Ts65Dn) at different ages and we evaluated the effects of autophagy inhibition (by rapamycin treatment) on protein oxidative damage in SH-SY5Y cell line (Project 1). To elucidate the potential link between deregulation of inflammation-related miRNAs, neurobehavioral deficits and AD pathology; we investigated the expression and cellspecific distribution of both miR146a and miR155 in the developing hippocampus from controls, patients with DS and adults with DS-AD pathology. In addition, we evaluated the levels of these miRNAs, their putative targets as well as the levels of IL-1β in human hippocampus from sporadic AD (sAD) at different stages of the disease and in Ts65Dn mice and in experimental models AD mouse (APP/PS1) (Project 2). To make clear the potential involvement of BVR-A dysregulation in the onset of BIR we analyzed the age dependent changes of (i) BVR-A protein levels and activation, (ii) total OS markers levels (PC, HNE, 3-NT) as well as (iii) IR/IRS1 levels and activation in triple transgenic mouse model of AD (3xTg-AD). Furthermore, ad hoc invitro experiments have been performed to clarify the contribution of oxidative/nitrosative stress on insulin resistance. Finally, because mTOR is able to phosphorylate IRS1 we investigated also if the insulin resistance could be associated with mTOR hyper-activation (Project 3). Results Our results show that: i) defects of mTOR signaling contribute to the buildup of protein oxidative damage which characterizes AD and DS neuropathology; ii) the involvement of both miR146a and miR155 in the hippocampus during brain development and their dysregulation in DS and AD; iii) the OS-induced inactivation of BVR-A promote BIR possibly trhough hyper-activation of mTOR. In conclusion, this study provides the evidence of a central role of mTOR in the neurodegenerative process. Indeed, hyperactivation of mTOR signaling impairs autophagy, insulin signaling and, indirectly, the inflammation-related miRNAs function

Aeroelasticity of suspension bridges using nonlinear aerodynamics and geometrically exact structural models

Le vibrazioni indotte dall’azione del vento su ponti sospesi di grandissima luce rappresentano uno dei maggiori problemi per i progettisti di tali opere. Vi `e pertanto la necessit`a di migliorare le attuali tecnologie progettuali, facendo uso delle pi`u avanzate tecniche computazionali, poich`e ci`o `e essenziale per una migliore comprensione della fluido dinamica che governa il problema e che `e la causa dell’accopiamento fluido-strutturale in ponti cos`ı flessibili e dunque delle vibrazioni che ne conseguono. La progettazione di ponti aventi luci significativamente pi`u lunghe di quelle tutt’ora esistenti rappresenta oggi una grande sfida. Per poter effettivamente migliorare gli strumenti computazionali necessari per la progettazione di ponti di grandissima luce, `e proposto un contributo di ricerca multi disciplinare mirato alla modellazione avanzata di ponti sospesi di grande luce. Tali strutture hanno un comportamento aeroelastico alquanto differente da quello dei ponti convenzionali. Nel presente lavoro di ricerca, `e proposto un modello completamente nonlineare di ponte sospeso parametrizzato attraverso una singola coordinata spaziale al fine di descrivere la dinamica tri-dimensionale globale del sistema. Le equazioni del moto non lineari sono ottenute mediante una formulazione Lagrangiana diretta e la cinematica, per l’impalcato e per i cavi di sospensione, `e basata sull’ipotesi di spostamenti finiti e di rotazioni flessionali e torsionali finite delle sezioni trasversali dell’impalcato. Le relazioni di congruenza interna, deformazione-spostamento, dei parametri generalizzati della deformazione - l’elogazione dei cavi, quella dell’impalcato e le tre curvature - conservano le non linearit`a geometriche complete, ovvero nessuno sviluppo in serie `e stato condotto al fine di semplificare le loro espressioni. Le caratteristiche aerodinamiche non lineari della sezione scatolare del Great Belt Bridge in Danimarca sono state investigate mediante l’uso di due metodi di analisi fluidodinamica computazionale tradizionali, il modello di turbolenza k-ϵ, implementato nel codice di calcolo FLUENT-ANSYS, che utilizza le equazioni Reynolds Averaged Navier Stokes (RANS) e il metodo discrete vortex per la soluzione delle equazioni di Navier Stokes (NS), implementato nel codice DVMFLOW-COWI. Tali strumenti di calcolo fluidodinamico sono stati utilizzati per la formulazione di una aerodinamica instazionaria che tenga in conto degli effetti viscosi, come la separazione del filetto fluido e l’accrescimento in spessore dello strato limite, attraverso modelli aerodinamici di ordine ridotto (ROMs). Le rappresentazioni nel dominio delle frequenze delle forzanti aerodinamiche in termini delle derivate aeroelastiche sono state ottenute per determinati valori di angolo d’attacco iniziale del vento. Di conseguenza, funzioni indiciali non lineari sono state derivate per tali angoli e incorporate nei ROMs proposti. Infine, un modello completamente non lineare di accoppiamento fluido strutturale per ponti sospesi `e stato messo a punto per analizzare il comportamento statico e dinamico di tali strutture e mirato allo studio di stabilit`a aeroelastica statica, tipo divergenza torsionale, e di instabilit`a dinamiche, tipo flutter, nonch`e all’analisi della risposta dinamica in regime di post-flutter. La formulazione geometricamente esatta sviluppata in questo lavoro si presta per natura a studi parametrici di sensitivit`a degli stati limite dinamici e statici dei ponti rispetto alle variazioni dei parametri strutturali caratteristici. Ulteriori studi sono stati rivolti all’analisi della risposta dei ponti sotto l’azione di carichi aerodinamici con distribuzioni spaziali e temporali del vento non uniformi, come quelli indotti da raffiche, e alla valutazione degli effetti di distribuzioni spaziali non uniformi del vento sulla condizione critica di flutter. Infine, `e stato studiato il comportamento in post-flutter mediante l’uso di metodi di continuazione con lo scopo di evidenziare gli scenari biforcativi post-critici ed enfatizzare la complessa risposta non lineare di strutture snelle soggette a carichi dinamici autoeccitanti.Wind-induced vibration in super-long-span bridges is a major concern for the designers. There is a need to enhance the structural design technology, through improved computational capabilities, a critical step for a better understanding of fluid-flow physics that induce vibration and fluid-structure dynamics of flexible bridges. The design of bridges with spans significantly longer than those existing today is quite challenging. To refine the computational tools required for such bridges, a multi-disciplinary research effort devoted to the advanced modeling of flexible long-span suspension bridges is proposed. These structures exhibit an aeroelastic behavior quite different from conventional bridges. In the present work, a fully nonlinear model of suspension bridges parameterized by one single space coordinate is proposed to describe the overall three-dimensional motion. The nonlinear equations of motion are obtained via a direct Lagrangian formulation and the kinematics, for the deck-girder and the suspension cables, feature the finite displacements of the associated base lines and the flexural and torsional finite rotations of the deck cross sections. The strain-displacement relationships for the generalized strain parameters - the cable elongations, the deck elongation, and the three curvatures - retain the full geometric nonlinearities. The nonlinear aerodynamic characteristics of the boxed sharp-edge cross section of the Danish Great Belt Bridge are investigated by using two state-of-the-art computational methods, the k-ϵ turbulence model implemented in FLUENT-ANSYS to solve the Reynolds Averaged Navier Stokes (RANS) equations and the Navier Stokes (NS) discrete-vortex method implemented in DVMFLOW-COWI. The computational fluid dynamics tools have been used to develop computationally efficient unsteady aerodynamic models taking into account viscous effects, including flow separation and boundary layer thickening, treated using Reduced-Order Models (ROMs). Frequency-domain representations of the aerodynamic loads in terms of flutter derivatives are obtained for selected values of the wind initial angle of attack. Consequently, nonlinear indicial functions are derived for these angles and incorporated into the proposed ROMs. As a result, a fully nonlinear coupled fluid-structure model for suspension bridges is assembled to study the nonlinear static and dynamic behavior thus addressing problems of static aeroelastic stability, such as torsional divergence, and dynamic aeroelastic instabilities, such as flutter and post-flutter. The geometrically exact formulation developed in this study lends itself naturally to parametric studies about the sensitivity of the static and dynamic limit states of the bridges with respect to variations of the characteristic structural parameters. In addition, the study addresses the dynamic response of the bridges under time- and space-dependent loading conditions due to time- and space-wise distributed gust excitations as well as the study of the effects of spatial nonuniform wind distributions on the critical flutter condition. Finally, the post-flutter behavior is studied by using a continuation method to highlight the post-critical bifurcation scenarios and emphasize the complex nonlinear response of slender self-excited suspended structures

In Vitro Antioxidant Activity and In Vivo Topical Efficacy of Lipid Nanoparticles Co-Loading Idebenone and Tocopheryl Acetate

Idebenone (IDE) is a strong antioxidant that has been proposed for the treatment of skin disorders, including skin ageing. Unfavorable physico-chemical properties make IDE a poor skin permeant where effectiveness could be improved by its loading into suitable delivery systems such as solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC). In this work, we designed novel IDE-loaded NLC containing tocopheryl acetate (VitE) as a liquid component to obtain a synergic effect between IDE and VitE. The resulting NLC showed small particle sizes (24-42 nm), low polydispersity indices (<0.300), good stability, and were assessed for their in vitro antioxidant activity and in vivo topical effects. IDE-loaded SLN and NLC showed a high antioxidant activity in in vitro assays (DPPH and reducing power method) and provided a similar and significant protection from oxidative stress of fibroblast cells, HS-68, exposed to UV light. After a two-week topical treatment of human volunteers with gels containing IDE-loaded SLN or NLC, a similar increase in skin hydration was observed, while IDE NLC reduced skin pigmentation to a greater extent than IDE SLN. These results suggest that co-loading IDE and VitE into NLC could be a promising strategy to obtain topical formulations with improved photo-protection

Intranasal rapamycin ameliorates Alzheimer-like cognitive decline in a mouse model of Down syndrome

Background: Down syndrome (DS) individuals, by the age of 40s, are at increased risk to develop Alzheimer-like dementia, with deposition in brain of senile plaques and neurofibrillary tangles. Our laboratory recently demonstrated the disturbance of PI3K/AKT/mTOR axis in DS brain, prior and after the development of Alzheimer Disease (AD). The aberrant modulation of the mTOR signalling in DS and AD age-related cognitive decline affects crucial neuronal pathways, including insulin signaling and autophagy, involved in pathology onset and progression. Within this context, the therapeutic use of mTOR-inhibitors may prevent/attenuate the neurodegenerative phenomena. By our work we aimed to rescue mTOR signalling in DS mice by a novel rapamycin intranasal administration protocol (InRapa) that maximizes brain delivery and reduce systemic side effects. Methods: Ts65Dn mice were administered with InRapa for 12 weeks, starting at 6 months of age demonstrating, at the end of the treatment by radial arms maze and novel object recognition testing, rescued cognition. Results: The analysis of mTOR signalling, after InRapa, demonstrated in Ts65Dn mice hippocampus the inhibition of mTOR (reduced to physiological levels), which led, through the rescue of autophagy and insulin signalling, to reduced APP levels, APP processing and APP metabolites production, as well as, to reduced tau hyperphosphorylation. In addition, a reduction of oxidative stress markers was also observed. Discussion: These findings demonstrate that chronic InRapa administration is able to exert a neuroprotective effect on Ts65Dn hippocampus by reducing AD pathological hallmarks and by restoring protein homeostasis, thus ultimately resulting in improved cognition. Results are discussed in term of a potential novel targeted therapeutic approach to reduce cognitive decline and AD-like neuropathology in DS individuals

Disturbance of Redox Homeostasis in Down Syndrome: Role of Iron Dysmetabolism

Down syndrome (DS) is the most common genetic form of intellectual disability that leads in the majority of cases to development of early-onset Alzheimer-like dementia (AD). The neuropathology of DS has several common features with AD including alteration of redox homeostasis, mitochondrial deficits, and inflammation among others. Interestingly, some of the genes encoded by chromosome 21 are responsible of increased oxidative stress (OS) conditions that are further exacerbated by decreased antioxidant defense. Previous studies from our groups showed that accumulation of oxidative damage is an early event in DS neurodegeneration and that oxidative modifications of selected proteins affects the integrity of the protein degradative systems, antioxidant response, neuronal integrity and energy metabolism. In particular, the current review elaborates recent findings demonstrating the accumulation of oxidative damage in DS and we focus attention on specific deregulation of iron metabolism, which affects both the central nervous system and the periphery. Iron dysmetabolism is a well-recognized factor that contributes to neurodegeneration; thus we opine that better understanding how and to what extent the concerted loss of iron dyshomestastis and increased OS occur in DS could provide novel insights for the development of therapeutic strategies for the treatment of Alzheimer-like dementia

Disturbance of Redox Homeostasis in Down Syndrome: Role of Iron Dysmetabolism

Down syndrome (DS) is the most common genetic form of intellectual disability that leads in the majority of cases to development of early-onset Alzheimer-like dementia (AD). The neuropathology of DS has several common features with AD including alteration of redox homeostasis, mitochondrial deficits, and inflammation among others. Interestingly, some of the genes encoded by chromosome 21 are responsible of increased oxidative stress (OS) conditions that are further exacerbated by decreased antioxidant defense. Previous studies from our groups showed that accumulation of oxidative damage is an early event in DS neurodegeneration and that oxidative modifications of selected proteins affects the integrity of the protein degradative systems, antioxidant response, neuronal integrity and energy metabolism. In particular, the current review elaborates recent findings demonstrating the accumulation of oxidative damage in DS and we focus attention on specific deregulation of iron metabolism, which affects both the central nervous system and the periphery. Iron dysmetabolism is a well-recognized factor that contributes to neurodegeneration; thus we opine that better understanding how and to what extent the concerted loss of iron dyshomestastis and increased OS occur in DS could provide novel insights for the development of therapeutic strategies for the treatment of Alzheimer-like dementia