La flotta spagnola del Mediterraneo nel secolo XVI: politica, amministrazione e strategia

Dalla fine del XV secolo la conduzione di un conflitto bellico richiese un crescente sforzo finanziario da parte dei governi. Fu il mutamento delle strutture militari a dare l'impulso al progressivo incremento della spesa bellica: aumentarono il numero delle imbarcazioni nelle operazioni navali ed anche il numero di effettivi nelle armate data la necessità di schierare grandi nuclei di fanteria. Si diffusero le armi da fuoco mentre le innovazioni delle fortificazioni furono tali da richiedere grandi investimenti di denaro per il loro mantenimento anche in tempo di pace. Affrontare uno studio sulle innovazioni nel campo militare fra tardo medioevo e prima età moderna permette di esaminare un gran numero di problemi, tanto militari quanto istituzionali. Questa tesi infatti tenterà di analizzare la questione della reciproca relazione tra stato e guerra sotto diversi punti di vista

The ‘magic tail’ of G protein-coupled receptors: an anchorage for functional protein networks

AbstractAll cell types express a great variety of G protein-coupled receptors (GPCRs) that are coupled to only a limited set of G proteins. This disposition favors cross-talk between transduction pathways. However, GPCRs are organized into functional units. They promote specificity and thus avoid unsuitable cross-talk. New methodologies (mostly yeast two-hybrid screens and proteomics) have been used to discover more than 50 GPCR-associated proteins that are involved in building these units. In addition, these protein networks participate in the trafficking, targeting, signaling, fine-tuning and allosteric regulation of GPCRs. To date, proteins that interact with the GPCR C-terminus are the most abundant and are the focus of this review

Homer1a-Dependent Crosstalk Between NMDA and Metabotropic Glutamate Receptors in Mouse Neurons

A large number of evidences suggest that group-I metabotropic glutamate receptors (mGluR1a, 1b, 1c, 5a, 5b) can modulate NMDA receptor activity. Interestingly, a physical link exists between these receptors through a Homer-Shank multi-protein scaffold that can be disrupted by the immediate early gene, Homer1a. Whether such a versatile link supports functional crosstalk between the receptors is unknown.Here we used biochemical, electrophysiological and molecular biological approaches in cultured mouse cerebellar neurons to investigate this issue. We found that Homer1a or dominant negative Shank3 mutants that disrupt the physical link between the receptors allow inhibition of NMDA current by group-I mGluR agonist. This effect is antagonized by pertussis toxin, but not thapsigargin, suggesting the involvement of a G protein, but not intracellular calcium stores. Also, this effect is voltage-sensitive, being present at negative, but not positive membrane potentials. In the presence of DHPG, an apparent NMDA "tail current" was evoked by large pulse depolarization, only in neurons transfected with Homer1a. Co-immunoprecipitation experiments showed interaction between G-protein betagamma subunits and NMDA receptor in the presence of Homer1a and group-I mGluR agonist.Altogether these results suggest a direct inhibition of NMDA receptor-channel by Gbetagamma subunits, following disruption of the Homer-Shank3 complex by the immediate early gene Homer1a. This study provides a new molecular mechanism by which group-I mGluRs could dynamically regulate NMDA receptor function

CrisMap: A Big Data Crisis Mapping System Based on Damage Detection and Geoparsing

Natural disasters, as well as human-made disasters, can have a deep impact on wide geographic areas, and emergency responders can benefit from the early estimation of emergency consequences. This work presents CrisMap, a Big Data crisis mapping system capable of quickly collecting and analyzing social media data. CrisMap extracts potential crisis- related actionable information from tweets by adopting a classification technique based on word embeddings and by exploiting a combination of readily-available semantic annotators to geoparse tweets. The enriched tweets are then visualized in customizable, Web-based dashboards, also leveraging ad-hoc quantitative visualizations like choropleth maps. The maps produced by our system help to estimate the impact of the emergency in its early phases, to identify areas that have been severely struck, and to acquire a greater situational awareness. We extensively benchmark the performance of our system on two Italian natural disasters by validating our maps against authoritative data. Finally, we perform a qualitative case-study on a recent devastating earthquake occurred in Central Italy

Index ordering by query-independent measures

Conventional approaches to information retrieval search through all applicable entries in an inverted file for a particular collection in order to find those documents with the highest scores. For particularly large collections this may be extremely time consuming. A solution to this problem is to only search a limited amount of the collection at query-time, in order to speed up the retrieval process. In doing this we can also limit the loss in retrieval efficacy (in terms of accuracy of results). The way we achieve this is to firstly identify the most “important” documents within the collection, and sort documents within inverted file lists in order of this “importance”. In this way we limit the amount of information to be searched at query time by eliminating documents of lesser importance, which not only makes the search more efficient, but also limits loss in retrieval accuracy. Our experiments, carried out on the TREC Terabyte collection, report significant savings, in terms of number of postings examined, without significant loss of effectiveness when based on several measures of importance used in isolation, and in combination. Our results point to several ways in which the computation cost of searching large collections of documents can be significantly reduced

Understanding the role of adenosine A2AR heteroreceptor complexes in neurodegeneration and neuroinflammation

Adenosine is a nucleoside mainly formed by degradation of ATP, located intracellularly or extracellularly, and acts as a neuromodulator. It operates as a volume transmission signal through diffusion and flow in the extracellular space to modulate the activity of both glial cells and neurons. The effects of adenosine are mediated via four adenosine receptor subtypes: A1R, A2AR, A2BR, A3R. The A2AR has a wide-spread distribution but it is especially enriched in the ventral and dorsal striatum where it is mainly located in the striato-pallidal GABA neurons at a synaptic and extrasynaptic location. A number of A2AR heteroreceptor complexes exist in the striatum. The existence of A2AR-D2R heteroreceptor complexes with antagonistic A2AR-D2R interactions in the striato-pallidal GABA neurons is well-known with A2AR activation inhibiting Gi/o mediated signaling of D2Rs. A2AR-mGluR5 heteroreceptor complexes were also found in with synergistic receptor-receptor interactions enhancing the inhibition of the D2R protomer signaling. They are located mainly in extrasynaptic regions of the striato-pallidal GABA neurons. Results recently demonstrated the existence of brain A2AR-A2BR heteroreceptor complexes, in which A2BR protomer constitutively inhibited the function of the A2AR protomer. These adenosine A2AR heteroreceptor complexes may modulate alpha-synuclein aggregation and toxicity through postulated bidirectional direct interactions leading to marked increases in A2AR signaling both in nerve cells and microglia. It is of high interest that formation of A2AR-A2ABR heteroreceptor complexes provides a brake on A2AR recognition and signaling opening up a novel strategy for treatment of A2AR mediated neurodegeneration. KEYWORDS: G protein-coupled receptor; Parkinson's diseases; adenosine A2A receptor; adenosine receptor; heteroreceptor complexes; neurodegeneration; neuroinflammation; oligomerizatio

SHANK3 mutations identified in autism lead to modification of dendritic spine morphology via an actin-dependent mechanism

Genetic mutations of SHANK3 have been reported in patients with intellectual disability, autism spectrum disorder (ASD) and schizophrenia. At the synapse, Shank3/ProSAP2 is a scaffolding protein that connects glutamate receptors to the actin cytoskeleton via a chain of intermediary elements. Although genetic studies have repeatedly confirmed the association of SHANK3 mutations with susceptibility to psychiatric disorders, very little is known about the neuronal consequences of these mutations. Here, we report the functional effects of two de novo mutations (STOP and Q321R) and two inherited variations (R12C and R300C) identified in patients with ASD. We show that Shank3 is located at the tip of actin filaments and enhances its polymerization. Shank3 also participates in growth cone motility in developing neurons. The truncating mutation (STOP) strongly affects the development and morphology of dendritic spines, reduces synaptic transmission in mature neurons and also inhibits the effect of Shank3 on growth cone motility. The de novo mutation in the ankyrin domain (Q321R) modifies the roles of Shank3 in spine induction and morphology, and actin accumulation in spines and affects growth cone motility. Finally, the two inherited mutations (R12C and R300C) have intermediate effects on spine density and synaptic transmission. Therefore, although inherited by healthy parents, the functional effects of these mutations strongly suggest that they could represent risk factors for ASD. Altogether, these data provide new insights into the synaptic alterations caused by SHANK3 mutations in humans and provide a robust cellular readout for the development of knowledge-based therapies