Control of GABA Release at Mossy Fiber-CA3 Connections in the Developing Hippocampus

In this review some of the recent work carried out in our laboratory concerning the functional role of GABAergic signalling at immature mossy fibres (MF)-CA3 principal cell synapses has been highlighted. While in adulthood MF, the axons of dentate gyrus granule cells release onto CA3 principal cells and interneurons glutamate, early in postnatal life they release GABA, which exerts into targeted cells a depolarizing and excitatory action. We found that GABAA-mediated postsynaptic currents (MF-GPSCs) exhibited a very low probability of release, were sensitive to L-AP4, a group III metabotropic glutamate receptor agonist, and revealed short-term frequency-dependent facilitation. Moreover, MF-GPSCs were down regulated by presynaptic GABAB and kainate receptors, activated by spillover of GABA from MF terminals and by glutamate present in the extracellular medium, respectively. Activation of these receptors contributed to the low release probability and in some cases to synapses silencing. By pairing calcium transients, associated with network-driven giant depolarizing potentials or GDPs (a hallmark of developmental networks thought to represent a primordial form of synchrony between neurons), generated by the synergistic action of glutamate and GABA with MF activation increased the probability of GABA release and caused the conversion of silent synapses into conductive ones suggesting that GDPs act as coincident detector signals for enhancing synaptic efficacy. Finally, to compare the relative strength of CA3 pyramidal cell output in relation to their MF glutamatergic or GABAergic inputs in adulthood or in postnatal development, respectively, a realistic model was constructed taking into account different biophysical properties of these synapses

Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility

Brugada syndrome (BrS) is a cardiac arrhythmia disorder associated with sudden death in young adults. With the exception of SCN5A, encoding the cardiac sodium channel NaV1.5, susceptibility genes remain largely unknown. Here we performed a genome-wide association meta-analysis comprising 2,820 unrelated cases with BrS and 10,001 controls, and identified 21 association signals at 12 loci (10 new). Single nucleotide polymorphism (SNP)-heritability estimates indicate a strong polygenic influence. Polygenic risk score analyses based on the 21 susceptibility variants demonstrate varying cumulative contribution of common risk alleles among different patient subgroups, as well as genetic associations with cardiac electrical traits and disorders in the general population. The predominance of cardiac transcription factor loci indicates that transcriptional regulation is a key feature of BrS pathogenesis. Furthermore, functional studies conducted on MAPRE2, encoding the microtubule plus-end binding protein EB2, point to microtubule-related trafficking effects on NaV1.5 expression as a new underlying molecular mechanism. Taken together, these findings broaden our understanding of the genetic architecture of BrS and provide new insights into its molecular underpinnings

Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility.

Brugada syndrome (BrS) is a cardiac arrhythmia disorder associated with sudden death in young adults. With the exception of SCN5A, encoding the cardiac sodium channel Na1.5, susceptibility genes remain largely unknown. Here we performed a genome-wide association meta-analysis comprising 2,820 unrelated cases with BrS and 10,001 controls, and identified 21 association signals at 12 loci (10 new). Single nucleotide polymorphism (SNP)-heritability estimates indicate a strong polygenic influence. Polygenic risk score analyses based on the 21 susceptibility variants demonstrate varying cumulative contribution of common risk alleles among different patient subgroups, as well as genetic associations with cardiac electrical traits and disorders in the general population. The predominance of cardiac transcription factor loci indicates that transcriptional regulation is a key feature of BrS pathogenesis. Furthermore, functional studies conducted on MAPRE2, encoding the microtubule plus-end binding protein EB2, point to microtubule-related trafficking effects on Na1.5 expression as a new underlying molecular mechanism. Taken together, these findings broaden our understanding of the genetic architecture of BrS and provide new insights into its molecular underpinnings

Landslide susceptibility mapping by remote sensing and geomorphological data: case studies on the Sorrentina Peninsula (Southern Italy)

The Sorrentina Peninsula is a densely populatedarea with high touristic impact. It is located in a morphologically complex zone of Southern Italy frequently affected by dangerous and calamitous landslides. This work contributes tothe prevention of such natural disasters by applying a GIS-based interdisciplinary approach aimed to map the areas more potentially prone to trigger slope instability phenomena. We have developed the Landslide Susceptibility Index (LSI) combining five weighted and ranked susceptibility parameters on a GIS platform. These parameters are recognized in the literature as the main predisposing factors for triggering landslides. This work combines analyses conducted on Remote Sensing, Geo-Lithology and Morphometry data and it is organized in the following logical steps: i) Multi-temporal InSAR technique was applied to Envisat-ASAR (2003–2010) and COSMO-SkyMed (2013–2015) datasets to obtain the ground displacement time series and the relative mean ground velocity maps. InSAR allowed the detection of the areas that are subjected to ground deformation and the main affected municipalities;ii) Such deformation areas were investigated through airborne photointerpretation to identify the presence of geomorphological peculiarities connected to potential slope instability. Subsequently, some of these peculiarities were checked on the field; iii) In these deformation areas the susceptibility parameters were mapped in the entire territory of Amalfi and Conca dei Marini and then investigated with a multivariate analysisto derive the classes and the respective weights used in the LSI calculation. The resultingLSI map classifies the two municipalities with high spatial resolution (2m) according to five classes of instability. The map highlights that the high/very high susceptibility zones cover6% of the investigated territory and correspond to potential landslide source areas characterized by 25°-70° slope angles. A spatial analysis between the map of the historical landslides and the areas classifiedaccording to susceptibility allowed testing of the reliability of the LSI Index, resulting in 85% prediction accuracy.Published940-9657SR AMBIENTE – Servizi e ricerca per la societàJCR Journa

Évaluation des effets sur le neurodéveloppement de l’exposition prénatale et postnatale aux produits phytopharmaceutiques. Présentation du projet NEUROPHYTO

International audiencePrenatal and neonatal periods are windows of vulnerability to environmental chemical contaminants. A growing number of epidemiological and toxicological studies suggest that exposure to pesticides during these periods may impact the health of children at birth as well as their development, with potential delayed adverse effects.The NEUROPHYTO project is a new research project that aims to evaluate the exposure to pesticides of French children from prenatal period to early childhood and to study the possible effects of these exposures on their motor and neuropsychological development. New exposure data will be generated: levels of 140 pesticides and metabolites will be measured in biological samples (urine and hair) of 200 children from the national cohort Elfe (French longitudinal study of children). The levels of active substance(s) in the brain will be estimated using a mathematical model and then related to early neurodevelopmental effects. Two approaches will be used to better identify and characterize these links. The first strategy will rely on epidemiological methods and the second will be based on the understanding of the neurotoxicity mechanisms of the substances. Finally, a child-specific risk analysis will provide support to public policies by targeted evidence during pre- and post-natal windows of vulnerability.Les périodes prénatale et néonatale constituent des fenêtres de sensibilité vis-à-vis des contaminants chimiques de l’environnement. Un nombre croissant d’études épidémiologiques et toxicologiques suggère que l’exposition aux pesticides pendant ces périodes pourrait impacter la santé des enfants à la naissance ainsi que leur développement, avec des retentissements possibles tout au long de la vie.Le projet NEUROPHYTO est un nouveau projet de recherche qui vise à évaluer les expositions aux produits phytosanitaires d’enfants français lors de la période prénatale à la petite enfance et à étudier les effets possibles de ces expositions sur leur développement moteur et neuropsychologique. De nouvelles données d’exposition seront produites : les concentrations de 140 pesticides et métabolites seront mesurés dans les échantillons biologiques (urine et cheveux) de 200 enfants de la cohorte nationale Elfe (Etude longitudinale française depuis l’enfance). Les concentrations de substance(s) active(s) dans le cerveau seront estimées par modélisation puis mis en relation avec des effets neurodéveloppementaux précoces. Deux approches seront mises en œuvre afin de mieux identifier et caractériser ces liens : l’une épidémiologique et l’autre basée sur la compréhension des mécanismes de neurotoxicité des substances. Enfin, une analyse spécifique des risques pour les enfants permettra d’appuyer les politiques publiques en apportant des éléments ciblés sur les fenêtres de sensibilité pré et postnatales

Il disegno come ricerca. Strumenti grafici e modelli rappresentativi per il progetto

Il volume è concepito come un taccuino di viaggio alla scoperta del significato del ruolo delle diverse forme della rappresentazione nel progetto, e nasce da uno sforzo dei docenti dei Laboratori del Disegno per riordinare e rendere più efficace la didattica della rappresentazione nei corsi di Design degli Interni. Esso restituisce un impegno comune di sperimentazione, confronto e aggiornamento a partire dalle basi concettuali del disegno per avventurarsi nelle potenzialità offerte dagli strumenti digitali, senza perdere il contatto con le sue radici culturali. Questa disciplina è propedeutica al saper fare come al sapere, perchè costituisce il fondamento sul quale si è costruita la cultura del progetto. Le molteplici forme di rappresentazione oltre il disegno tecnico offrono un contributo essenziale alla crescita del progettista, come metodo privilegiato di indagine e di ricerca all’interno del progetto stesso. La rappresentazione digitale ha rinnovato il disegno e quindi il progetto, che però sta riscoprendo la dignità e il fascino del segno manuale che, come afferma Vasari, è un riflesso immediato della mente. Rinnovare la didattica della rappresentazione significa ripensare il disegno come espressione di un ragionamento cognitivo prima che progettuale, per mettere in relazione gli strumenti che ne rafforzano le potenzialità di ricerca. Nel progetto contemporaneo la rappresentazione analogica e quella digitale si instegrano senza contrapporsi e per questo occorre rivedere i modi della didattica, che è condizionata da una compressione forzata dei tempi. Il ruolo conoscitivo del disegno si esprime nel rilievo. In virtù dell’elevata specializzazione professionale che ha raggiunto grazie alla precisione offerta dagli strumenti di misura digitali, nell’architettura esso si è configurato come disciplina autonoma, e la didattica tende ad abbandonare le componenti che sono preliminari al progetto, qualitative prima che quantitative. La dimensione cognitiva del rilievo offre un contributo teorico e pratico importante anche alla formazione del progettista di interni, ma ocorre ripensarne i contenuti applicativi in funzione di quello che può servire nella pratica professionale specifica. L’esperienza insegna che le arti manuali si imparano con la pratica costante; l’esercizio del disegno è il primo spunto di un viaggio con un gruppo di studenti del primo anno, invitati a riflettere sul diverso spirito che anima lo spazio dell’abitare, quello urbano in particolare attraverso il ricorso ad uno strumento antico, ma in continua evoluzione. Il viaggio di studio reintroduce all’interno dei laboratori un momento importante di verifica e di addestramento alla ricerca autonoma che trovava spazio nei seminari a tema, con l’immersione totale in un contesto diverso che rinnova una tradizione secolare. L’esperienza concreta di un viaggio alla scoperta della realtà americana offre l’opportunità di verificare l’attualità delle immagini statiche e bidimensionali del disegno e la resa grafica di tecniche essenziali, ma è anche un pretesto per riflettere sulle differenze tra la città amenricana e quella europea, e capire meglio gli spazi nei quali si esercita, prima del progetto, il nostro abitare quoitidiano. Il tema della continuità, che è proprio dello spazio urbano ed è una delle caratteristiche forti degli interni dell’architettura nordamericana emerge nei grandi interventi urbanistici, che assumono l’immagine di luoghi multiformi ma ricononscibili nella connotazione fisica del progetto. La scommessa è quella di verificare come la concezione urbana condiziona il progetto per imparare a controllarne gli effetti