Neural network modelling of the wave-structure interaction processes

This thesis presents a new Artificial Neural Network (ANN) able to predict at once the main parameters representative of the wave-structure interaction processes, i.e. the wave overtopping discharge, the wave transmission coefficient and the wave reflection coefficient. The new ANN has been specifically developed in order to provide managers and scientists with a tool that can be efficiently used for design purposes. The development of this ANN started with the preparation of a new extended and homogeneous database that collects all the available tests reporting at least one of the three parameters, for a total amount of 16’165 data. The variety of structure types and wave attack conditions in the database includes smooth, rock and armour unit slopes, berm breakwaters, vertical walls, low crested structures, oblique wave attacks. Some of the existing ANNs were compared and improved, leading to the selection of a final ANN, whose architecture was optimized through an in-depth sensitivity analysis to the training parameters of the ANN. Each of the selected 15 input parameters represents a physical aspect of the wave-structure interaction process, describing the wave attack (wave steepness and obliquity, breaking and shoaling factors), the structure geometry (submergence, straight or non-straight slope, with or without berm or toe, presence or not of a crown wall), or the structure type (smooth or covered by an armour layer, with permeable or impermeable core). The advanced ANN here proposed provides accurate predictions for all the three parameters, and demonstrates to overcome the limits imposed by the traditional formulae and approach adopted so far by some of the existing ANNs. The possibility to adopt just one model to obtain a handy and accurate evaluation of the overall performance of a coastal or harbor structure represents the most important and exportable result of the work.

Centro-sinistra e autonomia speciale. La DC trentina tra il 1955 e il 1968

La tesi è una ricerca di storia politica che affianca due diverse “storie” di centro-sinistra, quella nazionale e quella che vide protagonista la Democrazia Cristiana del Trentino. Lo studio analizza i fatti attraverso il filtro delle DC come se quello trentino e quello nazionale fossero due partiti, per poi tentare di capire ciò che accadeva alla loro sinistra alla ricerca dei diversi pesi e dei differenti equilibri che al centro e alla periferia si manifestavano nei rapporti con il PSI e con il PCI, e per osservare le reazioni della Chiesa così da valutare se le gerarchie romane e quelle trentine interagirono in modo differente sugli sviluppi delle rispettive esperienze politiche di quegli anni. Il testo è organizzato in quattro capitoli. Il primo e il secondo (speculari e dedicati allo stesso lustro: 1955-1960) rappresentano un confronto tra i differenti iter d’avvicinamento al centro-sinistra che la politica nazionale e quella trentina sperimentarono nella seconda metà degli anni Cinquanta. Nel terzo capitolo (1960-1964) e nel quarto (1964-1968) le vicende nazionali e quelle locali sono invece raccontate in modo intrecciato, ripercorrendo le diverse fasi dell’alleanza tra Democrazia Cristiana e Partito Socialista, e nel contempo dando conto della trasformazione del Trentino da una realtà di tipo agricolo ad una di tipo industriale, del passaggio da una comunità di tipo cattolico tradizionale ad una che si accinge a vivere in un contesto secolarizzato, e da una società che si autopercepisce come periferica ad una che ospita una delle contestazioni studentesche più peculiari, incisive e note d’Italia.

Arte e design in Italia dalla metà degli anni Sessanta alle ultime tendenze

Il lavoro di ricerca è rivolto ad indagare l’emersione di schemi di variazione comuni all’arte e al design, limitatamente al contesto italiano e in un arco di tempo che va dalla metà degli anni Sessanta del secolo scorso a oggi. L’analisi vuole rintracciare, mediante l’applicazione della metodologia fenomenologica, un sentire condiviso tra le due discipline e, nel pieno rispetto dei relativi linguaggi e con nessuna volontà di sudditanza degli uni rispetto agli altri, individuare i rapporti di corrispondenza omologica capaci di mettere in luce lo spirito del tempo che le ha generate. La ricerca si pone l’obiettivo di estendere gli studi sul contemporaneo attraverso un’impostazione che intende applicare gli strumenti metodologici della critica d’arte all’evoluzione stilistica delle tendenze del design italiano. Non si è voluto redigere una “storia” del design italiano ma, considerata anche l’ampiezza dell’argomento, si è necessariamente proceduto a delimitare il territorio di applicazione scegliendo di prendere in considerazione il solo settore del design dell’arredo. Si è dunque optato per una visione globale delle vicende del design del prodotto, tesa ad indagare gli snodi principali, concentrando pertanto l’analisi su alcuni protagonisti della cultura del progetto, ossia su quelle figure risultate dominanti nel proprio tempo perché capaci con il loro lavoro di dare un contribuito determinante alla comprensione delle fasi evolutive del design italiano. Gli strumenti utili a condurre l’analisi provengono principalmente dalla metodologia binaria individuata dallo storico dell’arte Heinrich Wölfflin e dagli studi di Renato Barilli, il cui impianto culturologico ha fornito un indispensabile contributo al processo di sistematizzazione dei meccanismi di variazione interni alle arti; sia quelli di tipo orizzontale, di convergenza reciproca con gli altri saperi, che di tipo verticale, in rapporto cioè con le scoperte scientifiche e tecnologiche della coeva cultura materiale.

Computational Modelling of Cardiac Electrophysiology: from Cell to Bedside

Heart diseases are the leading cause of death worldwide, both for men and women. However, the ionic mechanisms underlying many cardiac arrhythmias and genetic disorders are not completely understood, thus leading to a limited efficacy of the current available therapies and leaving many open questions for cardiac electrophysiologists. On the other hand, experimental data availability is still a great issue in this field: most of the experiments are performed in vitro and/or using animal models (e.g. rabbit, dog and mouse), even when the final aim is to better understand the electrical behaviour of in vivo human heart either in physiological or pathological conditions. Computational modelling constitutes a primary tool in cardiac electrophysiology: in silico simulations, based on the available experimental data, may help to understand the electrical properties of the heart and the ionic mechanisms underlying a specific phenomenon. Once validated, mathematical models can be used for making predictions and testing hypotheses, thus suggesting potential therapeutic targets. This PhD thesis aims to apply computational cardiac modelling of human single cell action potential (AP) to three clinical scenarios, in order to gain new insights into the ionic mechanisms involved in the electrophysiological changes observed in vitro and/or in vivo. The first context is blood electrolyte variations, which may occur in patients due to different pathologies and/or therapies. In particular, we focused on extracellular Ca2+ and its effect on the AP duration (APD). The second context is haemodialysis (HD) therapy: in addition to blood electrolyte variations, patients undergo a lot of other different changes during HD, e.g. heart rate, cell volume, pH, and sympatho-vagal balance. The third context is human hypertrophic cardiomyopathy (HCM), a genetic disorder characterised by an increased arrhythmic risk, and still lacking a specific pharmacological treatment.

Mercato dell'informazione, posizionamento dei media e distorsioni: Un'analisi attraverso l'algoritmo Wordfish

Una stampa libera e plurale è un elemento fondante di ogni sistema democratico ed è fondamentale per la creazione di un’opinione pubblica informata e in grado di esercitare controllo e pressione sulle classi dirigenti. Dal momento della loro creazione i giornali si sono imposti come un’importantissima fonte di informazione per l’opinione pubblica. La seconda metà del Novecento, inoltre, ha conosciuto innovazioni tecnologiche che hanno portato grandi cambiamenti nel ruolo della carta stampata come veicolo di trasmissione delle notizie. Partendo dalla diffusione della televisione fino ad arrivare alla rivoluzione digitale degli anni ’90 e 2000, la velocità di creazione e di trasmissione delle informazioni è aumentata esponenzialmente, i costi di produzione e di acquisizione delle notizie sono crollati e una quantità enorme di dati, che possono fornire moltissime informazioni relative alle idee e ai contenuti proposti dai diversi autori nel corso del tempo, è ora a disposizione di lettori e ricercatori. Tuttavia, anche se grazie alla rivoluzione digitale i costi materiali dei periodici si sono notevolmente ridotti, la produzione di notizie comporta altre spese e pertanto si inserisce in un contesto di mercato, sottoposto alle logiche della domanda e dell'offerta. In questo lavoro verrà analizzato il ruolo della domanda e della non perfetta razionalità dei lettori nel mercato delle notizie, partendo dall’assunto che la differenza di opinioni dei consumatori spinge le testate a regolare l’offerta di contenuti, per venire incontro alla domanda di mercato, per verificare l’applicabilità del modello utilizzato (Mullainhatan e Shleifer, 2005) al contesto italiano. A tale scopo si è analizzato il comportamento di alcuni quotidiani nazionali in occasione di due eventi che hanno profondamente interessato l'opinione pubblica italiana: il fenomeno dei flussi migratori provenienti dalla sponda sud del Mediterraneo nel mese di ottobre 2013 e l'epidemia di influenza H1N1 del 2009.

Predittori precoci di outcome neurologico nei neonati affetti da Encefalopatia Ipossico-Ischemica sottoposti a trattamento ipotermico. Studio combinato Elettroencefalogramma ad integrazione di ampiezza e Spettroscopia nel vicino infrarosso

Background: Brain cooling (BC) represents the elective treatment in asphyxiated newborns. Amplitude Integrated Electroencephalography (aEEG) and Near Infrared Spectroscopy (NIRS) monitoring may help to evaluate changes in cerebral electrical activity and cerebral hemodynamics during hypothermia. Objectives: To evaluate the prognostic value of aEEG time course and NIRS data in asphyxiated cooled infants. Methods: 12 term neonates admitted to our NICU with moderate-severe Hypoxic-Ischemic Encephalopathy (HIE) underwent selective BC. aEEG and NIRS monitoring were started as soon as possible and maintained during the whole hypothermic treatment. Follow-up was scheduled at regular intervals; adverse outcome was defined as death, cerebral palsy (CP) or global quotient < 88.7 at Griffiths’ Scale. Results: 2/12 infants died, 2 developed CP, 1 was normal at 6 months of age and then lost at follow-up and 7 showed a normal outcome at least at 1 year of age. The aEEG background pattern at 24 hours of life was abnormal in 10 newborns; only 4 of them developed an adverse outcome, whereas the 2 infants with a normal aEEG developed normally. In infants with adverse outcome NIRS showed a higher Tissue Oxygenation Index (TOI) than those with normal outcome (80.0±10.5% vs 66.9±7.0%, p=0.057; 79.7±9.4% vs 67.1±7.9%, p=0.034; 80.2±8.8% vs 71.6±5.9%, p=0.069 at 6, 12 and 24 hours of life, respectively). Conclusions: The aEEG background pattern at 24 hours of life loses its positive predictive value after BC implementation; TOI could be useful to predict early on infants that may benefit from other innovative therapies.

A high energy perspective of the co-evolution of black holes and their host galaxies

Thanks to the Chandra and XMM–Newton surveys, the hard X-ray sky is now probed down to a flux limit where the bulk of the X-ray background is almost completely resolved into discrete sources, at least in the 2–8 keV band. Extensive programs of multiwavelength follow-up observations showed that the large majority of hard X–ray selected sources are identified with Active Galactic Nuclei (AGN) spanning a broad range of redshifts, luminosities and optical properties. A sizable fraction of relatively luminous X-ray sources hosting an active, presumably obscured, nucleus would not have been easily recognized as such on the basis of optical observations because characterized by “peculiar” optical properties. In my PhD thesis, I will focus the attention on the nature of two classes of hard X-ray selected “elusive” sources: those characterized by high X-ray-to-optical flux ratios and red optical-to-near-infrared colors, a fraction of which associated with Type 2 quasars, and the X-ray bright optically normal galaxies, also known as XBONGs. In order to characterize the properties of these classes of elusive AGN, the datasets of several deep and large-area surveys have been fully exploited. The first class of “elusive” sources is characterized by X-ray-to-optical flux ratios (X/O) significantly higher than what is generally observed from unobscured quasars and Seyfert galaxies. The properties of well defined samples of high X/O sources detected at bright X–ray fluxes suggest that X/O selection is highly efficient in sampling high–redshift obscured quasars. At the limits of deep Chandra surveys (∼10−16 erg cm−2 s−1), high X/O sources are generally characterized by extremely faint optical magnitudes, hence their spectroscopic identification is hardly feasible even with the largest telescopes. In this framework, a detailed investigation of their X-ray properties may provide useful information on the nature of this important component of the X-ray source population. The X-ray data of the deepest X-ray observations ever performed, the Chandra deep fields, allows us to characterize the average X-ray properties of the high X/O population. The results of spectral analysis clearly indicate that the high X/O sources represent the most obscured component of the X–ray background. Their spectra are harder (G ∼ 1) than any other class of sources in the deep fields and also of the XRB spectrum (G ≈ 1.4). In order to better understand the AGN physics and evolution, a much better knowledge of the redshift, luminosity and spectral energy distributions (SEDs) of elusive AGN is of paramount importance. The recent COSMOS survey provides the necessary multiwavelength database to characterize the SEDs of a statistically robust sample of obscured sources. The combination of high X/O and red-colors offers a powerful tool to select obscured luminous objects at high redshift. A large sample of X-ray emitting extremely red objects (R−K >5) has been collected and their optical-infrared properties have been studied. In particular, using an appropriate SED fitting procedure, the nuclear and the host galaxy components have been deconvolved over a large range of wavelengths and ptical nuclear extinctions, black hole masses and Eddington ratios have been estimated. It is important to remark that the combination of hard X-ray selection and extreme red colors is highly efficient in picking up highly obscured, luminous sources at high redshift. Although the XBONGs do not present a new source population, the interest on the nature of these sources has gained a renewed attention after the discovery of several examples from recent Chandra and XMM–Newton surveys. Even though several possibilities were proposed in recent literature to explain why a relatively luminous (LX = 1042 − 1043erg s−1) hard X-ray source does not leave any significant signature of its presence in terms of optical emission lines, the very nature of XBONGs is still subject of debate. Good-quality photometric near-infrared data (ISAAC/VLT) of 4 low-redshift XBONGs from the HELLAS2XMMsurvey have been used to search for the presence of the putative nucleus, applying the surface-brightness decomposition technique. In two out of the four sources, the presence of a nuclear weak component hosted by a bright galaxy has been revealed. The results indicate that moderate amounts of gas and dust, covering a large solid angle (possibly 4p) at the nuclear source, may explain the lack of optical emission lines. A weak nucleus not able to produce suffcient UV photons may provide an alternative or additional explanation. On the basis of an admittedly small sample, we conclude that XBONGs constitute a mixed bag rather than a new source population. When the presence of a nucleus is revealed, it turns out to be mildly absorbed and hosted by a bright galaxy.

Modeling the cosmological co-evolution of supermassive black holes and galaxies

In this Thesis, we investigate the cosmological co-evolution of supermassive black holes (BHs), Active Galactic Nuclei (AGN) and their hosting dark matter (DM) halos and galaxies, within the standard CDM scenario. We analyze both analytic, semi-analytic and hybrid techniques and use the most recent observational data available to constrain the assumptions underlying our models. First, we focus on very simple analytic models where the assembly of BHs is directly related to the merger history of DM haloes. For this purpose, we implement the two original analytic models of Wyithe & Loeb 2002 and Wyithe & Loeb 2003, compare their predictions to the AGN luminosity function and clustering data, and discuss possible modifications to the models that improve the match to the observation. Then we study more sophisticated semi-analytic models in which however the baryonic physics is neglected as well. Finally we improve the hybrid simulation of De Lucia & Blaizot 2007, adding new semi-analytical prescriptions to describe the BH mass accretion rate during each merger event and its conversion into radiation, and compare the derived BH scaling relations, fundamental plane and mass function, and the AGN luminosity function with observations. All our results support the following scenario: • The cosmological co-evolution of BHs, AGN and galaxies can be well described within the CDM model. • At redshifts z & 1, the evolution history of DM halo fully determines the overall properties of the BH and AGN populations. The AGN emission is triggered mainly by DM halo major mergers and, on average, AGN shine at their Eddington luminosity. • At redshifts z . 1, BH growth decouples from halo growth. Galaxy major mergers cannot constitute the only trigger to accretion episodes in this phase. • When a static hot halo has formed around a galaxy, a fraction of the hot gas continuously accretes onto the central BH, causing a low-energy “radio” activity at the galactic centre, which prevents significant gas cooling and thus limiting the mass of the central galaxies and quenching the star formation at late time. • The cold gas fraction accreted by BHs at high redshifts seems to be larger than at low redshifts.

Impatto di rifaximina sul microbiota intestinale: selezione di bifidobatteri antibiotico resistenti

The ideal approach for the long term treatment of intestinal disorders, such as inflammatory bowel disease (IBD), is represented by a safe and well tolerated therapy able to reduce mucosal inflammation and maintain homeostasis of the intestinal microbiota. A combined therapy with antimicrobial agents, to reduce antigenic load, and immunomodulators, to ameliorate the dysregulated responses, followed by probiotic supplementation has been proposed. Because of the complementary mechanisms of action of antibiotics and probiotics, a combined therapeutic approach would give advantages in terms of enlargement of the antimicrobial spectrum, due to the barrier effect of probiotic bacteria, and limitation of some side effects of traditional chemiotherapy (i.e. indiscriminate decrease of aggressive and protective intestinal bacteria, altered absorption of nutrient elements, allergic and inflammatory reactions). Rifaximin (4-deoxy-4’-methylpyrido[1’,2’-1,2]imidazo[5,4-c]rifamycin SV) is a product of synthesis experiments designed to modify the parent compound, rifamycin, in order to achieve low gastrointestinal absorption while retaining good antibacterial activity. Both experimental and clinical pharmacology clearly show that this compound is a non systemic antibiotic with a broad spectrum of antibacterial action, covering Gram-positive and Gram-negative organisms, both aerobes and anaerobes. Being virtually non absorbed, its bioavailability within the gastrointestinal tract is rather high with intraluminal and faecal drug concentrations that largely exceed the MIC values observed in vitro against a wide range of pathogenic microorganisms. The gastrointestinal tract represents therefore the primary therapeutic target and gastrointestinal infections the main indication. The little value of rifaximin outside the enteric area minimizes both antimicrobial resistance and systemic adverse events. Fermented dairy products enriched with probiotic bacteria have developed into one of the most successful categories of functional foods. Probiotics are defined as “live microorganisms which, when administered in adequate amounts, confer a health benefit on the host” (FAO/WHO, 2002), and mainly include Lactobacillus and Bifidobacterium species. Probiotic bacteria exert a direct effect on the intestinal microbiota of the host and contribute to organoleptic, rheological and nutritional properties of food. Administration of pharmaceutical probiotic formula has been associated with therapeutic effects in treatment of diarrhoea, constipation, flatulence, enteropathogens colonization, gastroenteritis, hypercholesterolemia, IBD, such as ulcerative colitis (UC), Crohn’s disease, pouchitis and irritable bowel syndrome. Prerequisites for probiotics are to be effective and safe. The characteristics of an effective probiotic for gastrointestinal tract disorders are tolerance to upper gastrointestinal environment (resistance to digestion by enteric or pancreatic enzymes, gastric acid and bile), adhesion on intestinal surface to lengthen the retention time, ability to prevent the adherence, establishment and/or replication of pathogens, production of antimicrobial substances, degradation of toxic catabolites by bacterial detoxifying enzymatic activities, and modulation of the host immune responses. This study was carried out using a validated three-stage fermentative continuous system and it is aimed to investigate the effect of rifaximin on the colonic microbial flora of a healthy individual, in terms of bacterial composition and production of fermentative metabolic end products. Moreover, this is the first study that investigates in vitro the impact of the simultaneous administration of the antibiotic rifaximin and the probiotic B. lactis BI07 on the intestinal microbiota. Bacterial groups of interest were evaluated using culture-based methods and molecular culture-independent techniques (FISH, PCR-DGGE). Metabolic outputs in terms of SCFA profiles were determined by HPLC analysis. Collected data demonstrated that rifaximin as well as antibiotic and probiotic treatment did not change drastically the intestinal microflora, whereas bacteria belonging to Bifidobacterium and Lactobacillus significantly increase over the course of the treatment, suggesting a spontaneous upsurge of rifaximin resistance. These results are in agreement with a previous study, in which it has been demonstrated that rifaximin administration in patients with UC, affects the host with minor variations of the intestinal microflora, and that the microbiota is restored over a wash-out period. In particular, several Bifidobacterium rifaximin resistant mutants could be isolated during the antibiotic treatment, but they disappeared after the antibiotic suspension. Furthermore, bacteria belonging to Atopobium spp. and E. rectale/Clostridium cluster XIVa increased significantly after rifaximin and probiotic treatment. Atopobium genus and E. rectale/Clostridium cluster XIVa are saccharolytic, butyrate-producing bacteria, and for these characteristics they are widely considered health-promoting microorganisms. The absence of major variations in the intestinal microflora of a healthy individual and the significant increase in probiotic and health-promoting bacteria concentrations support the rationale of the administration of rifaximin as efficacious and non-dysbiosis promoting therapy and suggest the efficacy of an antibiotic/probiotic combined treatment in several gut pathologies, such as IBD. To assess the use of an antibiotic/probiotic combination for clinical management of intestinal disorders, genetic, proteomic and physiologic approaches were employed to elucidate molecular mechanisms determining rifaximin resistance in Bifidobacterium, and the expected interactions occurring in the gut between these bacteria and the drug. The ability of an antimicrobial agent to select resistance is a relevant factor that affects its usefulness and may diminish its useful life. Rifaximin resistance phenotype was easily acquired by all bifidobacteria analyzed [type strains of the most representative intestinal bifidobacterial species (B. infantis, B. breve, B. longum, B. adolescentis and B. bifidum) and three bifidobacteria included in a pharmaceutical probiotic preparation (B. lactis BI07, B. breve BBSF and B. longum BL04)] and persisted for more than 400 bacterial generations in the absence of selective pressure. Exclusion of any reversion phenomenon suggested two hypotheses: (i) stable and immobile genetic elements encode resistance; (ii) the drug moiety does not act as an inducer of the resistance phenotype, but enables selection of resistant mutants. Since point mutations in rpoB have been indicated as representing the principal factor determining rifampicin resistance in E. coli and M. tuberculosis, whether a similar mechanism also occurs in Bifidobacterium was verified. The analysis of a 129 bp rpoB core region of several wild-type and resistant bifidobacteria revealed five different types of miss-sense mutations in codons 513, 516, 522 and 529. Position 529 was a novel mutation site, not previously described, and position 522 appeared interesting for both the double point substitutions and the heterogeneous profile of nucleotide changes. The sequence heterogeneity of codon 522 in Bifidobacterium leads to hypothesize an indirect role of its encoded amino acid in the binding with the rifaximin moiety. These results demonstrated the chromosomal nature of rifaximin resistance in Bifidobacterium, minimizing risk factors for horizontal transmission of resistance elements between intestinal microbial species. Further proteomic and physiologic investigations were carried out using B. lactis BI07, component of a pharmaceutical probiotic preparation, as a model strain. The choice of this strain was determined based on the following elements: (i) B. lactis BI07 is able to survive and persist in the gut; (ii) a proteomic overview of this strain has been recently reported. The involvement of metabolic changes associated with rifaximin resistance was investigated by proteomic analysis performed with two-dimensional electrophoresis and mass spectrometry. Comparative proteomic mapping of BI07-wt and BI07-res revealed that most differences in protein expression patterns were genetically encoded rather than induced by antibiotic exposure. In particular, rifaximin resistance phenotype was characterized by increased expression levels of stress proteins. Overexpression of stress proteins was expected, as they represent a common non specific response by bacteria when stimulated by different shock conditions, including exposure to toxic agents like heavy metals, oxidants, acids, bile salts and antibiotics. Also, positive transcription regulators were found to be overexpressed in BI07-res, suggesting that bacteria could activate compensatory mechanisms to assist the transcription process in the presence of RNA polymerase inhibitors. Other differences in expression profiles were related to proteins involved in central metabolism; these modifications suggest metabolic disadvantages of resistant mutants in comparison with sensitive bifidobacteria in the gut environment, without selective pressure, explaining their disappearance from faeces of patients with UC after interruption of antibiotic treatment. The differences observed between BI07-wt e BI07-res proteomic patterns, as well as the high frequency of silent mutations reported for resistant mutants of Bifidobacterium could be the consequences of an increased mutation rate, mechanism which may lead to persistence of resistant bacteria in the population. However, the in vivo disappearance of resistant mutants in absence of selective pressure, allows excluding the upsurge of compensatory mutations without loss of resistance. Furthermore, the proteomic characterization of the resistant phenotype suggests that rifaximin resistance is associated with a reduced bacterial fitness in B. lactis BI07-res, supporting the hypothesis of a biological cost of antibiotic resistance in Bifidobacterium. The hypothesis of rifaximin inactivation by bacterial enzymatic activities was verified by using liquid chromatography coupled with tandem mass spectrometry. Neither chemical modifications nor degradation derivatives of the rifaximin moiety were detected. The exclusion of a biodegradation pattern for the drug was further supported by the quantitative recovery in BI07-res culture fractions of the total rifaximin amount (100 μg/ml) added to the culture medium. To confirm the main role of the mutation on the β chain of RNA polymerase in rifaximin resistance acquisition, transcription activity of crude enzymatic extracts of BI07-res cells was evaluated. Although the inhibition effects of rifaximin on in vitro transcription were definitely higher for BI07-wt than for BI07-res, a partial resistance of the mutated RNA polymerase at rifaximin concentrations > 10 μg/ml was supposed, on the basis of the calculated differences in inhibition percentages between BI07-wt and BI07-res. By considering the resistance of entire BI07-res cells to rifaximin concentrations > 100 μg/ml, supplementary resistance mechanisms may take place in vivo. A barrier for the rifaximin uptake in BI07-res cells was suggested in this study, on the basis of the major portion of the antibiotic found to be bound to the cellular pellet respect to the portion recovered in the cellular lysate. Related to this finding, a resistance mechanism involving changes of membrane permeability was supposed. A previous study supports this hypothesis, demonstrating the involvement of surface properties and permeability in natural resistance to rifampicin in mycobacteria, isolated from cases of human infection, which possessed a rifampicin-susceptible RNA polymerase. To understand the mechanism of membrane barrier, variations in percentage of saturated and unsaturated FAs and their methylation products in BI07-wt and BI07-res membranes were investigated. While saturated FAs confer rigidity to membrane and resistance to stress agents, such as antibiotics, a high level of lipid unsaturation is associated with high fluidity and susceptibility to stresses. Thus, the higher percentage of saturated FAs during the stationary phase of BI07-res could represent a defence mechanism of mutant cells to prevent the antibiotic uptake. Furthermore, the increase of CFAs such as dihydrosterculic acid during the stationary phase of BI07-res suggests that this CFA could be more suitable than its isomer lactobacillic acid to interact with and prevent the penetration of exogenous molecules including rifaximin. Finally, the impact of rifaximin on immune regulatory functions of the gut was evaluated. It has been suggested a potential anti-inflammatory effect of rifaximin, with reduced secretion of IFN-γ in a rodent model of colitis. Analogously, it has been reported a significant decrease in IL-8, MCP-1, MCP-3 e IL-10 levels in patients affected by pouchitis, treated with a combined therapy of rifaximin and ciprofloxacin. Since rifaximin enables in vivo and in vitro selection of Bifidobacterium resistant mutants with high frequency, the immunomodulation activities of rifaximin associated with a B. lactis resistant mutant were also taken into account. Data obtained from PBMC stimulation experiments suggest the following conclusions: (i) rifaximin does not exert any effect on production of IL-1β, IL-6 and IL-10, whereas it weakly stimulates production of TNF-α; (ii) B. lactis appears as a good inducer of IL-1β, IL-6 and TNF-α; (iii) combination of BI07-res and rifaximin exhibits a lower stimulation effect than BI07-res alone, especially for IL-6. These results confirm the potential anti-inflammatory effect of rifaximin, and are in agreement with several studies that report a transient pro-inflammatory response associated with probiotic administration. The understanding of the molecular factors determining rifaximin resistance in the genus Bifidobacterium assumes an applicative significance at pharmaceutical and medical level, as it represents the scientific basis to justify the simultaneous use of the antibiotic rifaximin and probiotic bifidobacteria in the clinical treatment of intestinal disorders.

Studio e validazione di una nuova metodica per la valutazione dello stato di forma

We observed 82 healthy subjects, from both sexes, aged between 19 and 77 years. All subjects performed two different tests: for being scientifically acknowledged, the first one was used as a reference and it was a stress test (CPX). During the entire test, heart rate and gas exchange were recorded continuously; the second, the actual object of this study, was a submaximal test (TOP). Only heart rate was recorded continuously. The main purpose was to determinate an index of physical fitness as result of TOP. CPX test allowed us to individuate anaerobic threshold. We used an incremental protocol of 10/20 Watt/min, different by age. For our TOP test we used an RHC400 UPRIGHT BIKE, by Air Machine. Each subject was monitored for heart frequency. After 2 minutes of resting period there was a first step: 3 minutes of pedalling at a constant rate of 60 RPM, (40 watts for elder subjects and 60 watts for the younger ones). Then, the subject was allowed to rest for a recovery phase of 5 minutes. Third and last step consisted of 3 minutes of pedalling again at 60 RPM but now set to 60 watts for elder subjects and 80 watts for the young subjects. Finally another five minutes of recovery. A good correlation was found between TOP and CPX results especially between punctua l heart rate reserve (HRR’) and anaerobic threshold parameters such as Watt, VO2, VCO2 . HRR’ was obtained by subtracting maximal heart rate during TOP from maximal theoretic heart rate (206,9-(0,67*age)). Data were analyzed through cluster analysis in order to obtain 3 homogeneous groups. The first group contains the least fit subjects (inactive, women, elderly). The other groups contain the “average fit” and the fittest subjects (active, men, younger). Concordance between test resulted in 83,23%. Afterwards, a linear combinations of the most relevant variables gave us a formula to classify people in the correct group. The most relevant result is that this submaximal test is able to discriminate subjects with different physical condition and to provide information (index) about physical fitness through HRR’. Compared to a traditional incremental stress test, the very low load of TOP, short duration and extended resting period, make this new method suitable to very different people. To better define the TOP index, it is necessary to enlarge our subject sample especially by diversifying the age range.

Atto di disposizione, expressio causae e dichiarazione di scienza

A far data dalla pubblicazione di un importante ed illustre contributo scientifico (GIORGIANNI, voce Causa (dir. priv.), in Enc. dir., VI, Milano, 1960), e dalla proposta, in esso contenuta, di restituire spazio a fattispecie attributive di diritti giustificate, sotto il profilo causale, dal solo riferimento espresso al rapporto fondamentale che ne costituisca fondamento (le c.d. ), un serrato dibattito ha visto contrapporsi nel tempo fautori di soluzioni possibiliste e sostenitori di una più uniforme descrizione del sistema della circolazione dei diritti e dei rimedi connessi alla mancanza di causa negli atti di disposizione, per quanto avulsi dal contratto cui essi intendano dare compiuta attuazione. La ricerca ha cercato di dimostrare, attraverso una compiuta analisi di ciò che la formula expressio causae davvero significhi, come la presenza o assenza di questa non sia in grado di giustificare un effetto tanto pregnante come la sottrazione della vicenda traslativa alle conseguenze derivanti dalla mancanza di causa, per tale intendendosi il rapporto fondamentale che ne costituisce l’antecedente logico. Allo scrivente è parso che il vero nodo teorico da sciogliere non sia costituito dal concetto di causa che questi Autori assumono a fondamento, quanto piuttosto da una impropria valutazione dell’expressio causae. Tale valutazione conduce ad attribuire al momento ricognitivo, di cui l’enunciazione della causa consiste, una valenza sostanzialmente astratta che non si rinviene nemmeno nelle più estreme ricostruzioni delle fattispecie contemplate all’art. 1988 c.c. e che, in materia di accertamento negoziale, è senza eccezioni rifiutata. Ciò che sembra decisivo, infatti, è che la natura dell'expressio causae, in primo luogo ricognitiva del rapporto cui si dà esecuzione, ben lungi dal rappresentare elemento sufficiente per una autonoma considerazione della causa dell'atto (sussistente) e della causa dell'attribuzione (la cui conservazione è decisa dalle sorti del Rechtsgrund), non pare idonea a suffragare – seppur in via provvisoria, ma con una divergente considerazione dell’avente causa rispetto ai terzi ulteriori acquirenti – una soluzione compiutamente esaustiva del problema della giustificazione dell'effetto, rimandando a modelli – quello della dichiarazione di scienza, innanzitutto – rispetto ai quali una astrazione più che processuale sembra del tutto preclusa, anche per considerazioni storiche che si è cercato di descrivere. Del resto, l’analisi delle ipotesi in cui la ricognizione di un rapporto fondamentale, o la promessa di quanto già dovuto in forza di un rapporto fondamentale (art. 1988 c.c.) mostra come, indipendentemente dalla soluzione che si ritenga pertinente circa la natura di tali figure (meramente dichiarativa del vincolo o addirittura costitutiva), un effetto di astrazione materiale, per quanto relativa, è da escludersi. Trasposta nell’ambito delle prestazioni isolate, questa consapevolezza significa impossibilità di rendere invece materialmente astratta l’attribuzione (efficace immediatamente, e solo soggetta ad essere da un atto di segno contrario dall’avente causa al dante causa, oggetto di una pretesa giudiziale personale). La dichiarazione del rapporto fondamentale, che è intimamente connessa ed insopprimibile in ogni fenomeno di imputazione soggettiva (si deve infatti enunciare ciò cui si dà esecuzione), appare sicuramente sussumibile nello schema della dichiarazione di scienza, nell’effetto in senso lato ricognitivo. Ritenere che essa possa di fatto rendere irrilevante, ai fini della conservazione dell’efficacia della prestazione isolata cui si collega, la reale situazione del rapporto fondamentale (in ipotesi mai esistito, o successivamente venuto meno) significa introdurre surrettiziamente una ipotesi di riconoscimento costitutivo e astratto. Ma tale ultima soluzione non può trovare spazio in alcuna delle opzioni interpretative proposte in materia di riconoscimento e, nemmeno, in quella più estrema che ravvisa nel riconoscimento del debito titolato una forma di accertamento unilaterale. In conclusione, la dottrina delle prestazioni isolate nel fare dell’expressio causae l’elemento capace di decidere in via definitiva del verificarsi dell’effetto traslativo – effetto che va, giova ripeterlo, solo rimosso con un atto uguale e contrario assolutamente diverso da quanto nel nostro sistema appare essere, oggi, la ripetizione di indebito – determina una supervalutazione del momento ricognitivo, insito in ogni fenomeno di imputazione/esecuzione. Detto esito costituisce non tanto la recezione del Trennungsprinzip vigente in Germania, ammissibile nella misura in cui si reputi dispositiva la norma di cui all’art. 1376 c.c., quanto piuttosto la silenziosa riproposizione del modello della Schuldanerkenntnis (§781 B.G.B.), la cui totale estraneità rispetto alla tradizione giuridica delle codificazioni franco-italiane (Code civil, c.c. del 1865, c.c. del 1942) si crede di avere sufficientemente dimostrato.

X-Ray studies of the physics of matter around super-massive black-holes in nearby Seyfert galaxies

Seyfert galaxies are the closest active galactic nuclei. As such, we can use them to test the physical properties of the entire class of objects. To investigate their general properties, I took advantage of different methods of data analysis. In particular I used three different samples of objects, that, despite frequent overlaps, have been chosen to best tackle different topics: the heterogeneous BeppoS AX sample was thought to be optimized to test the average hard X-ray (E above 10 keV) properties of nearby Seyfert galaxies; the X-CfA was thought the be optimized to compare the properties of low-luminosity sources to the ones of higher luminosity and, thus, it was also used to test the emission mechanism models; finally, the XMM–Newton sample was extracted from the X-CfA sample so as to ensure a truly unbiased and well defined sample of objects to define the average properties of Seyfert galaxies. Taking advantage of the broad-band coverage of the BeppoS AX MECS and PDS instruments (between ~2-100 keV), I infer the average X-ray spectral propertiesof nearby Seyfert galaxies and in particular the photon index (~1.8), the high-energy cut-off (~290 keV), and the relative amount of cold reflection (~1.0). Moreover the unified scheme for active galactic nuclei was positively tested. The distribution of isotropic indicators used here (photon index, relative amount of reflection, high-energy cut-off and narrow FeK energy centroid) are similar in type I and type II objects while the absorbing column and the iron line equivalent width significantly differ between the two classes of sources with type II objects displaying larger absorbing columns. Taking advantage of the XMM–Newton and X–CfA samples I also deduced from measurements that 30 to 50% of type II Seyfert galaxies are Compton thick. Confirming previous results, the narrow FeK line is consistent, in Seyfert 2 galaxies, with being produced in the same matter responsible for the observed obscuration. These results support the basic picture of the unified model. Moreover, the presence of a X-ray Baldwin effect in type I sources has been measured using for the first time the 20-100 keV luminosity (EW proportional to L(20-100)^(−0.22±0.05)). This finding suggests that the torus covering factor may be a function of source luminosity, thereby suggesting a refinement of the baseline version of the unifed model itself. Using the BeppoSAX sample, it has been also recorded a possible correlation between the photon index and the amount of cold reflection in both type I and II sources. At a first glance this confirms the thermal Comptonization as the most likely origin of the high energy emission for the active galactic nuclei. This relation, in fact, naturally emerges supposing that the accretion disk penetrates, depending to the accretion rate, the central corona at different depths (Merloni et al. 2006): the higher accreting systems hosting disks down to the last stable orbit while the lower accreting systems hosting truncated disks. On the contrary, the study of the well defined X–C f A sample of Seyfert galaxies has proved that the intrinsic X-ray luminosity of nearby Seyfert galaxies can span values between 10^(38−43) erg s^−1, i.e. covering a huge range of accretion rates. The less efficient systems have been supposed to host ADAF systems without accretion disk. However, the study of the X–CfA sample has also proved the existence of correlations between optical emission lines and X-ray luminosity in the entire range of L_(X) covered by the sample. These relations are similar to the ones obtained if high-L objects are considered. Thus the emission mechanism must be similar in luminous and weak systems. A possible scenario to reconcile these somehow opposite indications is assuming that the ADAF and the two phase mechanism co-exist with different relative importance moving from low-to-high accretion systems (as suggested by the Gamma vs. R relation). The present data require that no abrupt transition between the two regimes is present. As mentioned above, the possible presence of an accretion disk has been tested using samples of nearby Seyfert galaxies. Here, to deeply investigate the flow patterns close to super-massive black-holes, three case study objects for which enough counts statistics is available have been analysed using deep X-ray observations taken with XMM–Newton. The obtained results have shown that the accretion flow can significantly differ between the objects when it is analyzed with the appropriate detail. For instance the accretion disk is well established down to the last stable orbit in a Kerr system for IRAS 13197-1627 where strong light bending effect have been measured. The accretion disk seems to be formed spiraling in the inner ~10-30 gravitational radii in NGC 3783 where time dependent and recursive modulation have been measured both in the continuum emission and in the broad emission line component. Finally, the accretion disk seems to be only weakly detectable in rk 509, with its weak broad emission line component. Finally, blueshifted resonant absorption lines have been detected in all three objects. This seems to demonstrate that, around super-massive black-holes, there is matter which is not confined in the accretion disk and moves along the line of sight with velocities as large as v~0.01-0.4c (whre c is the speed of light). Wether this matter forms winds or blobs is still matter of debate together with the assessment of the real statistical significance of the measured absorption lines. Nonetheless, if confirmed, these phenomena are of outstanding interest because they offer new potential probes for the dynamics of the innermost regions of accretion flows, to tackle the formation of ejecta/jets and to place constraints on the rate of kinetic energy injected by AGNs into the ISM and IGM. Future high energy missions (such as the planned Simbol-X and IXO) will likely allow an exciting step forward in our understanding of the flow dynamics around black holes and the formation of the highest velocity outflows.