A staged screening of registered drugs highlights remyelinating drug candidates for clinical trials

There is no treatment for the myelin loss in multiple sclerosis, ultimately resulting in the axonal degeneration that leads to the progressive phase of the disease. We established a multi-tiered platform for the sequential screening of drugs that could be repurposed as remyelinating agents. We screened a library of 2,000 compounds (mainly Food and Drug Administration (FDA)-approved compounds and natural products) for cellular metabolic activity on mouse oligodendrocyte precursors (OPC), identifying 42 molecules with significant stimulating effects. We then characterized the effects of these compounds on OPC proliferation and differentiation in mouse glial cultures, and on myelination and remyelination in organotypic cultures. Three molecules, edaravone, 5-methyl-7-methoxyisoflavone and lovastatin, gave positive results in all screening tiers. We validated the results by retesting independent stocks of the compounds, analyzing their purity, and performing dose-response curves. To identify the chemical features that may be modified to enhance the compounds' activity, we tested chemical analogs and identified, for edaravone, the functional groups that may be essential for its activity. Among the selected remyelinating candidates, edaravone appears to be of strong interest, also considering that this drug has been approved as a neuroprotective agent for acute ischemic stroke and amyotrophic lateral sclerosis in Japan

The emergence of functional microcircuits in visual cortex.

Sensory processing occurs in neocortical microcircuits in which synaptic connectivity is highly structured and excitatory neurons form subnetworks that process related sensory information. However, the developmental mechanisms underlying the formation of functionally organized connectivity in cortical microcircuits remain unknown. Here we directly relate patterns of excitatory synaptic connectivity to visual response properties of neighbouring layer 2/3 pyramidal neurons in mouse visual cortex at different postnatal ages, using two-photon calcium imaging in vivo and multiple whole-cell recordings in vitro. Although neural responses were already highly selective for visual stimuli at eye opening, neurons responding to similar visual features were not yet preferentially connected, indicating that the emergence of feature selectivity does not depend on the precise arrangement of local synaptic connections. After eye opening, local connectivity reorganized extensively: more connections formed selectively between neurons with similar visual responses and connections were eliminated between visually unresponsive neurons, but the overall connectivity rate did not change. We propose a sequential model of cortical microcircuit development based on activity-dependent mechanisms of plasticity whereby neurons first acquire feature preference by selecting feedforward inputs before the onset of sensory experience--a process that may be facilitated by early electrical coupling between neuronal subsets--and then patterned input drives the formation of functional subnetworks through a redistribution of recurrent synaptic connections

Multilinguisme et variétés linguistiques en Europe à l’aune de l’intelligence artificielle Multilinguismo e variazioni linguistiche in Europa nell’era dell’intelligenza artificiale Multilingualism and Language Varieties in Europe in the Age of Artificial Intelligence

Il presente volume è il frutto di una riflessione interdisciplinare e multilingue maturata attorno a diversi eventi organizzati nell’ambito del panel concernente i diritti e le variazioni linguistiche in Europa nell’era dell’intelligenza artificiale all’interno del progetto Artificial Intelligence for European Integration, promosso dal Centro studi sull’Europa TO-EU dell’Università di Torino e cofinanziato dalla Commissione europea. L’interrogativo iniziale che abbiamo voluto sollevare è se l’IA potesse avere un impatto negativo sulle varietà linguistiche e sul multilinguismo, valore “aggiunto” dell’UE, o se potesse, e in che modo, divenire utile per la promozione di essi. Il volume, interamente inedito, può dirsi tra i primi ad affrontare, almeno in Europa, questo tipo di tematiche.This book is the outcome of an interdisciplinary multilingual reflection carried out on research into linguistic rights, multilingualism and language varieties in Europe in the age of artificial intelligence. It is part of the Artificial Intelligence for European Integration project, promoted by the Centre of European Studies To-EU of the University of Turin and co-financed by the European Commission. Our aim was to investigate more generally the negative and/or positive outcomes of AI on language varieties and multilingualism, the latter a key value for the EU. The result is a volume of original unpublished research being made generally available for the first time, at least in Europe.Ce livre a été élaboré à partir d’une réflexion interdisciplinaire et multilingue qui a été menée dans le cadre d’une recherche sur les droits, le multilinguisme et les variétés linguistiques en Europe à l’aune de l’intelligence artificielle à l’intérieur du projet Artificial Intelligence for European Integration promu par le Centre d’études européennes To-EU de l’Université de Turin et cofinancé par la Commission de l’Union européenne. Notre propos était de réfléchir plus généralement sur les conséquences négatives et/ou positives de l’IA sur les variétés linguistiques et le multilinguisme, ce dernier étant une valeur de l’UE. Ce que nous proposons par ce numéro est un livre inédit qui peut se vanter d’être parmi les premiers à s’occuper de ce type de thématique, du moins en Europe

Hydrogen sorption properties of the composed system calcium hydride – magnesium boride

The hydrogen sorption properties of the calcium hydride – magnesium boride system as evaluated by manometric and calorimetric analyses are discussed

Ball-milling and AlB2 addition effects on the hydrogen sorption properties of the CaH2+MgB2 system

Among the borohydrides proposed for solid state hydrogen storage, Ca(BH4)2 is particularly interesting because of its favourable thermodynamics and relatively cheap price. Composite systems, where other species are present in addition to the borohydride, show some advantages in hydrogen sorption properties with respect to the borohydrides alone, despite a reduction of the theoretical storage capacity. We have investigated the milling time influence on the sorption properties of the CaH2 + MgB2 system from which Ca(BH4)2 and MgH2 can be synthesized by hydrogen absorption process. Manometric and calorimetric measurements showed better kinetics for long time milled samples. We found that the total substitution of MgB2 with aluminum boride in the starting material can improve the sorption properties significantly, while the co-existence of both magnesium and aluminum borides in the starting mixture did not cause any improvement. Rietveld refinements of the X-ray powder diffraction spectra were used to confirm the hypothesized reactions

Self-balancing robot

Ideja je bila izraditi samobalansirajući robot koji će preko Atmega32 mikrokontrolera komunicirati sa MPU6050 žiroskopom i akcelerometrom čije se vrijednosti šalju na PD regulator čiji se odziv šalje na aktuatore. Cilj zadatka je konstruirati robota i napisati čitav programski kod u C programskom jeziku. Potrebno je ostvariti komunikaciju sa MPU6050 te filtrirati dobivene signale komplementarnim filtrom. Zatim, realizirati PD regulator te podesiti parametre kako bi se dobilo željeno dinamičko vladanje. Za aktuatore je potrebno izraditi štampanu pločicu sa L293D čipom i napisati programski kod za kontrolu. Robot uspješno vrši balansiranje prema zamišljenom planu.The idea was to build self-balancing robot which will communicate to MPU6050 gyroscope and accelerometer with Atmega32 microcontroller which values are then sent to PD controller whose output is sent to actuators. Main goal is to construct the robot and to write program code in C programming language. It is necessary to communicate with MPU6050 and filter the values with complementary filter. Furthermore it is needed to design PD controller and adjust the parametars to get desired dynamic behavior. Printed circuit board with L293D chips was needed for the actuators and to write a programing code forcontrol of the motors. Every goal that was defined in the beginning wasachieved and we have a stable and functional self-balancing robot

Open issues in the therapeutic management of unresectable stage III NSCLC in the immunotherapy era

Treatment of stage III non-small cell lung cancer (NSCLC) has traditionally been controversial and challenging: multidisciplinary approach is mandatory and defining resectability is a critical issue; furthermore, patients are often frail due to age or comorbidities. After PACIFIC trial publication, a new therapeutic path has been defined for patients with unresectable NSCLC, with a prominent prognostic advantage. A trimodality treatment, with chemo-radiotherapy followed by maintenance durvalumab is now the standard of care, recommended by international guidelines. However, despite an impressive activity, the use of consolidative immunotherapy after concurrent chemoradiotherapy is highly debated in some clinically-relevant situations, including patients harboring EGFR mutations, older and/or frail patients not suitable for combined treatment, PD-L1 tumor expression. Here we report an expert virtual Italian meeting summary, where six medical oncologists and six radiation oncologists discussed all these aspects trying to underline the critical aspects and to find the possible clinical solutions