Common Molecular Pathways Mediate Long-Term Potentiation of Synaptic Excitation and Slow Synaptic Inhibition

SummarySynaptic plasticity, the cellular correlate for learning and memory, involves signaling cascades in the dendritic spine. Extensive studies have shown that long-term potentiation (LTP) of the excitatory postsynaptic current (EPSC) through glutamate receptors is induced by activation of N-methyl-D-asparate receptor (NMDA-R)—the coincidence detector—and Ca2+/calmodulin-dependent protein kinase II (CaMKII). Here we report that the same signaling pathway in the postsynaptic CA1 pyramidal neuron also causes LTP of the slow inhibitory postsynaptic current (sIPSC) mediated by metabotropic GABAB receptors (GABAB-Rs) and G protein-activated inwardly rectifying K+ (GIRK) channels, both residing in dendritic spines as well as shafts. Indicative of intriguing differences in the regulatory mechanisms for excitatory and inhibitory synaptic plasticity, LTP of sIPSC but not EPSC was abolished in mice lacking Nova-2, a neuronal-specific RNA binding protein that is an autoimmune target in paraneoplastic opsoclonus myoclonus ataxia (POMA) patients with latent cancer, reduced inhibitory control of movements, and dementia

NOVA2-mediated RNA regulation is required for axonal pathfinding during development.

The neuron specific RNA-binding proteins NOVA1 and NOVA2 are highly homologous alternative splicing regulators. NOVA proteins regulate at least 700 alternative splicing events in vivo, yet relatively little is known about the biologic consequences of NOVA action and in particular about functional differences between NOVA1 and NOVA2. Transcriptome-wide searches for isoform-specific functions, using NOVA1 and NOVA2 specific HITS-CLIP and RNA-seq data from mouse cortex lacking either NOVA isoform, reveals that NOVA2 uniquely regulates alternative splicing events of a series of axon guidance related genes during cortical development. Corresponding axonal pathfinding defects were specific to NOVA2 deficiency: Nova2-/- but not Nova1-/- mice had agenesis of the corpus callosum, and axonal outgrowth defects specific to ventral motoneuron axons and efferent innervation of the cochlea. Thus we have discovered that NOVA2 uniquely regulates alternative splicing of a coordinate set of transcripts encoding key components in cortical, brainstem and spinal axon guidance/outgrowth pathways during neural differentiation, with severe functional consequences in vivo

Splicing Regulation of Pro-Inflammatory Cytokines and Chemokines: At the Interface of the Neuroendocrine and Immune Systems

Alternative splicing plays a key role in posttranscriptional regulation of gene expression, allowing a single gene to encode multiple protein isoforms. As such, alternative splicing amplifies the coding capacity of the genome enormously, generates protein diversity, and alters protein function. More than 90% of human genes undergo alternative splicing, and alternative splicing is especially prevalent in the nervous and immune systems, tissues where cells need to react swiftly and adapt to changes in the environment through carefully regulated mechanisms of cell differentiation, migration, targeting, and activation. Given its prevalence and complexity, this highly regulated mode of gene expression is prone to be affected by disease. In the following review, we look at how alternative splicing of signaling molecules—cytokines and their receptors—changes in different pathological conditions, from chronic inflammation to neurologic disorders, providing means of functional interaction between the immune and neuroendocrine systems. Switches in alternative splicing patterns can be very dynamic and can produce signaling molecules with distinct or antagonistic functions and localization to different subcellular compartments. This newly discovered link expands our understanding of the biology of immune and neuroendocrine cells, and has the potential to open new windows of opportunity for treatment of neurodegenerative disorders

The role of total thyroidectomy for the treatment of Hurthle cell adenomas of the thyroid

Hurthle cell adenomas of the thyroid are rare neoplasms with a controversial biologic behaviour. Some authors believe that are to be considered malignant lesions with a lower progress capacity in comparison with carcinomas, proposing an aggressive surgical approach. Others sustain that they have no malignant potential and prefer lesser resections advocating lower complication rates. The aim of this article is to evaluate the role of total thyroidectomy in the treatment of such neoplasms

Gastric cancer in north Sardinia, Italy: an epidemiological report

Aims:The aim of this study was to describe the epidemiological characteristics and trends of gastric cancer in north Sardinia, Italy, in the period 1992-2010. Materials and methods. Data were obtained from the cancer registry of the province of Sassari, which makes part of a wider registry web coordinated by the Italian Association for Tumor Registries. Results. The overall number of gastric cancer cases registered was 1227. The male-to-female ratio was 1.7:1 and the mean age 69 years for males and 71 years for females. The standardized incidence rates were 15.6/100,000 and 7.3/100,000 and the standardized mortality rates 11.7/100,000 and 5.8/100,000 for males and females respectively. Conclusions. Low and stable trends in incidence and mortality of gastric cancer in both sexes were evidenced in North Sardinia, in the period under investigation. Nevertheless, the relative survival at 5 years from diagnosis was relatively low. This suggests that there must be an enhancement of surveillance policies, and that the diagnosis and treatment methods adopted in the area must improve.</br

Dis-eguaglianza e mercato

Il rapporto tra diseguaglianza e mercato pu\uf2 essere affrontato da molteplici punti di vista. Sul piano economico, coinvolge alcune tra le pi\uf9 controverse problematiche relative al conflitto tra efficienza ed equit\ue0 nell\u2019ambito dell\u2019economia di mercato: problematiche che, paradossalmente, hanno finito per assumere toni sempre pi\uf9 polemici con il progressivo arricchirsi delle societ\ue0. Sul piano politico, comprende l\u2019ampio ventaglio delle azioni pubbliche volte a ridurre le diseguaglianze sociali prodotte dalle dinamiche di mercato: azioni che sono il frutto di scelte del legislatore e delle amministrazioni circa i tempi e i modi dell\u2019intervento pubblico nell\u2019economia (a monte, all\u2019interno o a valle del mercato; in forma di regolazione, gestione o perequazione). Sul piano giuridico, riguarda tutto l\u2019insieme delle norme e delle istituzioni che in un determinato ordinamento disciplinano il funzionamento del mercato, cercando di contemperare adeguatamente libert\ue0 individuale ed equit\ue0 sociale. La prospettiva adottata in questa sede \ue8 quella del diritto costituzionale. Dopo avere sinteticamente ricostruito il modello economico delineato dalla Costituzione italiana, nei suoi presupposti teorici e nei suoi sviluppi dottrinali e giurisprudenziali, si cerca di comprendere se esso sia stato effettivamente attuato o sia stato in tutto o in parte disatteso. Partendo dai fondamenti del pensiero economico e di quello politico per arrivare alle loro applicazioni pratiche, si valuta quindi la compatibilit\ue0 con il sistema costituzionale \u2013 e, segnatamente, con il principio di eguaglianza formale e sostanziale di cui all\u2019art. 3 Cost. \u2013 dell\u2019odierno \uabcapitalismo di mercato\ubb

SLC25A10 biallelic mutations in intractable epileptic encephalopathy with complex I deficiency

Mitochondrial diseases are a plethora of inherited neuromuscular disorders sharing defects in mitochondrial respiration, but largely different from one another for genetic basis and pathogenic mechanism. Whole exome sequencing was performed in a familiar trio (trio-WES) with a child affected by severe epileptic encephalopathy associated to respiratory complex I deficiency and mitochondrial DNA depletion in skeletal muscle. By trio-WES we identified biallelic mutations in SLC25A10, a nuclear gene encoding a member of the mitochondrial carrier family. Genetic and functional analyses conducted on patient fibroblasts showed that SLC25A10 mutations are associated to reduction in RNA quantity and aberrant RNA splicing, and to absence of SLC25A10 protein and its transporting function. The yeast SLC25A10 ortholog knockout strain showed defects in mitochondrial respiration and mitochondrial DNA content, similarly to what observed in the patient skeletal muscle, and growth susceptibility to oxidative stress. Albeit patient fibroblasts were depleted in the main antioxidant molecules NADPH and glutathione, transport assays demonstrated that SLC25A10 is unable to transport glutathione. Here we report the first recessive mutations of SLC25A10 associated to an inherited severe mitochondrial neurodegenerative disorder. We propose that SLC25A10 loss-of-function causes pathological disarrangements in respiratory-demanding conditions and oxidative stress vulnerability