Mechanisms of synaptic depression triggered by metabotropic glutamate receptors

Abstract.: Glutamate, by activation of metabotropic receptors (mGluRs), can lead to a reduction of synaptic efficacy at many synapses. These forms of synaptic plasticity are referred to as long-term depression (mGluR-LTD). We will distinguish between mGluR-LTD induced by pre- or postsynaptic receptors and mGluR-LTD induced by the locus of the expression mechanism of the synaptic depression. We will also review recent evidence that mGluR-mediated responses themselves are subject to depression, which may constitute a form of metaplasticit

Il gioco della logica tra uso del linguaggio e costruzione della scienza.

E tanto più intendo tanto più ignoro, motto di Tommaso Campanella, può servire a spiegare, bene, le virgolette messe attorno alla parola: gioco, ed il suo carattere, ambiguo e contraddittorio, essendo tutto ciò vero tanto nello uso del linguaggio, quanto nella costruzione della scienza. Quanto segue si dipana in alcuni meandri della filosofia analitica, a partire dal positivismo logico, dove molto forte è l’accanirsi contro la metafisica. A riguardo, avendo presente l’uso rinnovato del termine, fatto da giovani filosofi contemporanei, corre il dovere di precisare la sua validità, se significa andare oltre le cose fisiche, con le assunzioni necessarie per pensare e fare scienza. Al contrario, validissimo è il rigetto della metafisica, quando questa voglia dire, come nella tradizione della storia del pensiero, rifarsi a principi primi indiscutibili ed assoluti. Rudolf Carnap e Karl Raimund Popper sono i maggiori esponenti delle scuole filosofiche, prese in esame. La trattazione collega linguaggio e costruzione della scienza, perché una concezione moderna descrive la scienza come un linguaggio, capace di leggere la realtà fisica, dove la complessità della analisi cresce al crescere della complessità della modellazione adottata. Infatti oltre a muoversi liberamente nello spazio, parametrizzato con righe, colonne e pile, è spesso necessario muoversi congiuntamente nel tempo e/o nel cosiddetto spazio delle scale, entrambi parametrizzati con pioli e montanti, a seconda che si permanga ad un dato livello, oppure si passi da un livello ad un altro. Da altra parte, un esempio musicale dà il segno della complessità: le cinque note pentatoniche (la si do re mi fa sol) permettono 720 permutazioni, mentre le dodici note (mettendo insieme i tasti bianchi e neri del pianoforte) permettono 479.001.600 permutazioni e, anche limitandosi alle ventiquattro scale armoniche, maggiori e minori (sulle sette note del clavicembalo ben temperato), il numero di permutazioni è 120.960. In questo contesto, il superamento della empiria fa passare dalla capacità di verificazione alla sola possibilità di falsificazione, dove è possibile dire quello che è errato, ma non è possibile certificare quello che è esatto. Infatti la verità è sempre provvisoria e precaria, valida fino ad una possibile smentita, più o meno prossima, e le costruzioni tecniche, sociali, economiche e politiche sono, sempre e solo, governate dal dubbio ed altrettanto precarie e provvisorie. Infine con un salto notevole di contenuto, ma affatto estraneo alla vita ed alle concezioni dei pensatori (qui già citati e/o citati nel seguito), è davvero difficile, soprattutto in questi tempi così tanto travagliati, separare il parlare alto di ricerca scientifica e tecnologica, nonché di storia della scienza e della tecnica, e di epistemologia, dai casi della vita quotidiana, vari e diversi. Di fronte a tutti questi è davvero difficile scegliere la strada migliore, in ogni caso, ben sapendo come occorra, sempre ed ovunque, il coraggio e lo impegno e talvolta anche la ribellione

Probing beta decay matrix elements through heavy ion charge exchange reactions

To access information on neutrinoless double beta decay (0νββ) nuclear matrix elements, it has been proposed by the NUMEN collaboration to exploit the analogies between double beta decay processes and double charge exchange (DCE) nuclear reactions, looking in particular at the conditions where the corresponding cross section can be factorized into nuclear reaction and nuclear structure terms. DCE reactions can be treated as a convolution of two correlated or uncorrelated single charge exchange (SCE) processes, resembling 0νββ and 2νββ, respectively. Thus it is important to model first SCE processes, to get a deeper insight into the possibility to factorize the corresponding cross section, so one can gain a better understanding of DCE cross section factorization. In this contribution, DCE reactions are discussed in terms of the convolution of two uncorrelated SCE processes, which should allow one to extract information on 2νββ nuclear matrix elements. These theoretical investigations are performed in close synergy with the experimental activity running at INFN-LNS within the NUMEN project

SHANK3 controls maturation of social reward circuits in the VTA.

Haploinsufficiency of SHANK3, encoding the synapse scaffolding protein SHANK3, leads to a highly penetrant form of autism spectrum disorder. How SHANK3 insufficiency affects specific neural circuits and how this is related to specific symptoms remains elusive. Here we used shRNA to model Shank3 insufficiency in the ventral tegmental area of mice. We identified dopamine (DA) and GABA cell-type-specific changes in excitatory synapse transmission that converge to reduce DA neuron activity and generate behavioral deficits, including impaired social preference. Administration of a positive allosteric modulator of the type 1 metabotropic glutamate receptors mGluR1 during the first postnatal week restored DA neuron excitatory synapse transmission and partially rescued the social preference defects, while optogenetic DA neuron stimulation was sufficient to enhance social preference. Collectively, these data reveal the contribution of impaired ventral tegmental area function to social behaviors and identify mGluR1 modulation during postnatal development as a potential treatment strategy

Clustering and Alignment of Polymorphic Sequences for HLA-DRB1 Genotyping

Located on Chromosome 6p21, classical human leukocyte antigen genes are highly polymorphic. HLA alleles associate with a variety of phenotypes, such as narcolepsy, autoimmunity, as well as immunologic response to infectious disease. Moreover, high resolution genotyping of these loci is critical to achieving long-term survival of allogeneic transplants. Development of methods to obtain high resolution analysis of HLA genotypes will lead to improved understanding of how select alleles contribute to human health and disease risk. Genomic DNAs were obtained from a cohort of n = 383 subjects recruited as part of an Ulcerative Colitis study and analyzed for HLA-DRB1. HLA genotypes were determined using sequence specific oligonucleotide probes and by next-generation sequencing using the Roche/454 GSFLX instrument. The Clustering and Alignment of Polymorphic Sequences (CAPSeq) software application was developed to analyze next-generation sequencing data. The application generates HLA sequence specific 6-digit genotype information from next-generation sequencing data using MUMmer to align sequences and the R package diffusionMap to classify sequences into their respective allelic groups. The incorporation of Bootstrap Aggregating, Bagging to aid in sorting of sequences into allele classes resulted in improved genotyping accuracy. Using Bagging iterations equal to 60, the genotyping results obtained using CAPSeq when compared with sequence specific oligonucleotide probe characterized 4-digit genotypes exhibited high rates of concordance, matching at 759 out of 766 (99.1%) alleles. © 2013 Ringquist et al

Amino Acid Position 11 of HLA-DRβ1 is a Major Determinant of Chromosome 6p Association with Ulcerative Colitis

The major histocompatibility complex (MHC) on chromosome 6p is an established risk locus for ulcerative colitis (UC) and Crohn’s disease (CD). We aimed to better define MHC association signals in UC and CD by combining data from dense single nucleotide polymorphism (SNP) genotyping and from imputation of classical HLA types, their constituent SNPs and corresponding amino acids in 562 UC, 611 CD, and 1,428 control subjects. Univariate and multivariate association analyses were performed, controlling for ancestry. In univariate analyses, absence of the rs9269955 C allele was strongly associated with risk for UC (P = 2.67×$10^{-13}$). rs9269955 is a SNP in the codon for amino acid position 11 of HLA-DRβ1, located in the P6 pocket of the HLA-DR antigen binding cleft. This amino acid position was also the most significantly UC-associated amino acid in omnibus tests (P = 2.68×$10^{-13}$). Multivariate modeling identified rs9269955-C and 13 other variants in best predicting UC versus control status. In contrast, there was only suggestive association evidence between the MHC and CD. Taken together, these data demonstrate that variation at HLA-DRβ1, amino acid 11 in the P6 pocket of the HLA-DR complex antigen binding cleft is a major determinant of chromosome 6p association with ulcerative colitis

Exports and Productivity: Comparable Evidence for 14 Countries

We use comparable micro level panel data for 14 countries and a set of identically specified empirical models to investigate the relationship between exports and productivity. Our overall results are in line with the big picture that is by now familiar from the literature: Exporters are more productive than non-exporters when observed and unobserved heterogeneity are controlled for, and these exporter productivity premia tend to increase with the share of exports in total sales; there is strong evidence in favour of self-selection of more productive firms into export markets, but nearly no evidence in favour of the learning-by-exporting hypothesis. We document that the exporter premia differ considerably across countries in identically specified empirical models. In a meta-analysis of our results we find that countries that are more open and have more effective government report higher productivity premia. However, the level of development per se does not appear to be an explanation for the observed cross-country differences.exports; productivity; micro data; international comparison

MCMC implementation for Bayesian hidden semi-Markov models with illustrative applications

Copyright © Springer 2013. The final publication is available at Springer via http://dx.doi.org/10.1007/s11222-013-9399-zHidden Markov models (HMMs) are flexible, well established models useful in a diverse range of applications. However, one potential limitation of such models lies in their inability to explicitly structure the holding times of each hidden state. Hidden semi-Markov models (HSMMs) are more useful in the latter respect as they incorporate additional temporal structure by explicit modelling of the holding times. However, HSMMs have generally received less attention in the literature, mainly due to their intensive computational requirements. Here a Bayesian implementation of HSMMs is presented. Recursive algorithms are proposed in conjunction with Metropolis-Hastings in such a way as to avoid sampling from the distribution of the hidden state sequence in the MCMC sampler. This provides a computationally tractable estimation framework for HSMMs avoiding the limitations associated with the conventional EM algorithm regarding model flexibility. Performance of the proposed implementation is demonstrated through simulation experiments as well as an illustrative application relating to recurrent failures in a network of underground water pipes where random effects are also included into the HSMM to allow for pipe heterogeneity