mGlu5 receptor negative allosteric modulation reduces the aberrant cellular reactivity and neurotoxicity of iNPCs-derived human astrocytes differentiated from ALS patients

BACKGROUND. Amyotrophic Lateral Sclerosis (ALS) is a multifactorial and non-cell-autonomous neurodegenerative disease, characterized by brainstem and spinal cord motor neuron (MN) death. The etiopathological mechanisms are numerous and among them, glutamate excitotoxicity plays a major role. The metabotropic glutamate receptor type 5 (mGluR5) fine modulates glutamate neurotransmission other than astrocyte reactivity, and this mechanism can be exploited as potential target to counteract MN loss in ALS. We provided in-vitro and in-vivo evidence showing that genetic ablation or the pharmacological modulation of mGluR5, by the selective negative allosteric modulator CTEP, positively affects the reactive phenotype and neurotoxicity of ALS astrocytes and significantly improved the life span and disease progression in SOD1G93A ALS mice. Here we investigated in-vitro the impact of mGluR5 modulation by CTEP on human i-Astrocytes differentiated from inducible neural progenitor cells (iNPCs) obtained from skin fibroblasts of ALS patients and healthy donors. With this aim, we monitored the cellular phenotype of i-Astrocytes when exposed to 100nM CTEP by exploiting molecular biology and immunohistochemical studies. We monitored the intracellular calcium level by live imaging and fluorometric detection, moreover we quantified the secretion of neurotoxic factors by ELISA assay. The accumulation of reactive oxygen species, as well as oxidative stress markers have been investigated by immunohistochemical and biochemical studies, moreover we measured the activity of antioxidant response enzymes. As an indirect, but very important readout, we finally investigated the neurotoxicity of the astrocyte conditioned medium on human-derived motor neurons differentiated from iPSCs of healthy donors and ALS patients. RESULTS. In-vitro pharmacological modulation with CTEP did not alter the mGluR5 total expression in i-Astrocytes. RT-qPCR analyses, western blot and immunohistochemical experiments showed that 5 days in-vitro exposure to 100nM CTEP reduced the over-expression of astrogliosis (GFAP, S100β, C3) and neuroinflammation (NLRP3) markers (p<0.05; two-way ANOVA) in i-Astrocytes from ALS-patients vs. untreated or control cells. CTEP treatment was also able to restore oxidative stress conditions by promoting Nrf2 nuclear translocation, enhancement of the antioxidant enzymes activity (glutathione reductase, glutathione peroxidase, glucose-6-phosphate dehydrogenase, catalase), and consequent reduction of ROS and direct oxidative stress markers (p<0.001; two-way ANOVA) in ALS i-Astrocytes. Acute CTEP in-vitro treatment significantly reduces the intracellular calcium mobilization upon mGlu5 receptor activation, in ALS and control i-Astrocytes. On the other hand, the reduced astrocyte reactivity by CTEP treatment translates into a beneficial effect towards iPSCs-derived MNs exposed to the conditioned medium collected from i-Astrocytes. CONCLUSIONS. We here show that the in-vitro pharmacological allosteric blockade of the mGluR5 by CTEP positively affects the reactive phenotype of human-derived i-Astrocytes differentiated form from C9orf72 and SOD1A4V ALS patients, mainly by ameliorating the general oxidative stress response and reducing the release of toxic factors. These data extend our previous results in SOD1G93A in-vitro and in-vivo models, thus further encouraging a translational application of mGluR5 modulators in clinical trials

The search for point-like neutrino sources with ANTARES and KM3NeT-ARCA telescopes

The multi-messenger approach has recently paved the way for possible breakthroughs in our comprehension of high energy particle emission in the Universe. Neutrino telescopes are essential for highlighting the hadronic component of these phenomena, in addition to testing possible correlation with known sources of gamma rays. Joint analyses of data from complementary facilities may provide enhanced sensitivity. This contribution explores the sensitivity as a function of the source declination for a combined analysis of data collected by two neutrino telescopes located in the depths of the Mediterranean Sea, ANTARES and KM3NeT/ARCA. A catalogue of approximately one hundred point-like and extended sources is presently investigated for neutrino emissions: the list encompasses bright γ-ray emitters, galactic γ-ray sources, extragalactic sources as radio-loud AGNs and the most significant candidate sources studied by IceCube

Analisi di suscettibilità al dissesto franoso per la sicurezza e la funzionalità di infrastrutture di trasporto di superficie

In caso di eventi franosi che coinvolgono infrastrutture di trasporto di superficie, oltre al danno sugli elementi colpiti direttamente, si verificano impatti negativi derivanti dall’interruzione di servizi fondamentali. D’altra parte, le stesse infrastrutture sono un’importante concausa dello sviluppo di alcuni tipi di frane. In questo contesto la comprensione delle relazioni tra fenomeni di dissesto e infrastrutture di superficie diventa importante per un’efficiente gestione del rischio frana. Nell’ambito del Partenariato Esteso PNRR “RETURN” si sta sperimentando una metodologia statistica per la redazione di mappe di suscettibilità, come strumento per identificare sia le porzioni di territorio maggiormente predisposte al dissesto, sia le caratteristiche più influenti per lo sviluppo di tali fenomeni. Si sta considerando inoltre l’applicazione di tale metodologia, una volta consolidata, anche in ambiti di maggior dettaglio e soggetti a condizioni particolari, tra cui le aree di interazione terreno - struttura dei ponti

Elderly specific DRT in Italy and Japan: the factors influencing the DRT usage in Genoa and Toyoake City

The ageing of the world's population is a growing phenomenon. Numerous studies have shown that mobility is a key factor for active and healthy ageing. In this context, demand-responsive transport (DRT) plays a key role, as it offers better accessibility and inclusiveness to the over-65s compared to traditional public transport, which is often under-used by the elderly. The aim of this article is to compare two DRT services for older people operating in distinct geographical and cultural contexts , such as Genoa (Italy) and Toyoake City (Japan). Two questionnaires were administered to the users in order to identify the factors influencing the increase in DRT usage. It is then possible to suggest to decision makers what improvements should be made to increase DRT in both areas. The results show that availability of DRT and accessibility to DRT stops are key factors in both contexts

Towards Intuitive Interaction: Cognitive Architecture for Artificial Personality, Emotional Intelligence, and Cognitive Capabilities.

Robotic personality shows significant potential in enhancing Human-Robot Interaction. However, shortcomings at both theoretical and implementation levels lead to stereotypical and fragmented models of artificial personality. To overcome these limitations, this study aims to further validate the Conscientiousness, Extroversion, and Agreeableness (CEA) taxonomy for synthetic personalities based on the corresponding three traits of the Big Five model. In the proposed implementation, the robotic personality, directly inspired by human psychology, not only influences how actions are executed but also impacts the robot’s inner hedonic drives and, consequently, the action selection process. Our objective is to introduce a task- and platform-independent framework that drives agent behavior through the interplay between personality dynamics, emotional responses to others, memory encoding, anticipation of future actions, and associated hedonic experiences. To validate the effectiveness of the framework in generating perceivable personality traits and emotionally and cognitively intelligent behaviors, and to explore the impact of embodiment on social interaction, a dual experiment was conducted. This experiment involved participants engaging in dyadic conversations with either a digital human or a robot

La terra lacerata in noi.

Con lo strumentario dell'antropologia e dell'etnopsichiatria, una discussione degli effetti intimi, emotivi e psichici, della strutturazione geopolitica del mondo, con il suo correlato di violenza storica coloniale e capitalista

Tecnologie e valutazione all’università. Prospettive e pratiche di Faculty Development

In un contesto storico in cui l’università è chiamata a ripensare profondamente le proprie pratiche didattiche e valutative, il Faculty Development si afferma come leva strategica per sostenere l’innovazione e la qualità dell’insegnamento, supportando la trasformazione del docente quale professionista con un ruolo sempre più complesso e centrale nell’istruzione superiore. Per accompagnare consapevolmente l’evoluzione del contesto accademico e della figura del docente universitario, il volume esplora in profondità come sostenere l’acquisizione di competenze valutative digitali attraverso percorsi formativi flessibili, mirati e basati sull’evidenza. Partendo da una panoramica legata al tema del Faculty Development e alle competenze caratterizzanti il profilo contemporaneo del docente universitario, la ricerca indaga lo stato dell’arte delle pratiche di Technology-Enhanced Assessment (TEA) in relazione agli esistenti modelli di Faculty Development, evidenziandone la scarsa diffusione, i vincoli istituzionali e i bisogni formativi dei docenti. Sulla base di tre studi principali, culmina nella progettazione e sperimentazione di un MOOC pensato per accompagnare i docenti nello sviluppo di specifiche competenze valutative digitali e nell’adozione consapevole della tecnologia nella didattica e nei processi di valutazione. Al cuore del lavoro si colloca il modello IMPRESS, quale strumento per supportare l’implementazione di programmi di Faculty Development per l’innovazione dei processi valutativi potenziati dalla tecnologia, il quale ha rappresentato l’esito di un articolato percorso di ricerca che combina analisi teorica, indagine empirica e sperimentazione sul campo. Oltre alla presentazione del modello, il volume include una serie di casi di studio basati su una sperimentazione condotta con docenti universitari che hanno scelto di mettersi in gioco, ripensando le proprie pratiche didattiche e valutative, con il supporto di un instructional designer, alla luce degli approcci di Technology-Enhanced Assessment. Il testo si rivolge a docenti universitari, formatori, instructional designer, responsabili della qualità della didattica e policy maker interessati a promuovere un cambiamento autentico nell’istruzione superiore. Grazie a una solida cornice teorica, a una prospettiva internazionale e a numerosi esempi operativi, il volume offre strumenti, modelli e spunti concreti ed originali per progettare e attuare percorsi di Faculty Development efficaci e sostenibili. Un contributo scientifico e pratico, che guarda al futuro della formazione universitaria partendo dal cuore della professionalità docente: la valutazione come motore di apprendimento, potenziata dalle tecnologie e guidata da una visione pedagogica consapevole

On the Lie derivative of an affine connection and its geometrical meaning

In this paper, we present geometrical interpretations of the Lie derivative and the Lie-invariance for an affine connection, based on two geometrical constructions: the former is given on the tangent bundle and relies on the notion of linear Ehresmann connection; the latter is developed on the frame bundle and is based on the more common notion of principal connection