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Although very high levels of IL 1β are present in the intestines of patients suffering from Inflammatory Bowel Diseases (IBD), little is known about the contribution of IL 1β to intestinal pathology. In the work presented in this thesis, I used several mouse models of chronic intestinal inflammation to address the role of IL 1β in driving innate and adaptive immune pathology in the intestine. My results showed that IL 1β promotes innate immune pathology in Helicobacter hepaticus triggered innate intestinal inflammation, by augmenting the recruitment of granulocytes and the accumulation and activation of a population of IFN γ and IL 17A producing innate lymphoid cells (ILC). To specifically investigate the role of IL 1R signaling on pathogenic T cell responses in the intestine, I used a T cell transfer colitis model. My results demonstrated a key role for IL 1R signals in promoting the accumulation and survival of pathogenic CD4+ T cells in the colon, particularly CD4+ IL 17A+ Th17 cells. Finally, because mutations in the NOD2 gene have been strongly associated with susceptibility to IBD, I investigated the contribution of NOD2 in the H.hepaticusinduced innate immune IBD model. I found that NOD2 expression was significantly increased in the inflamed colon. Furthermore, my preliminary studies suggested that NOD2 played a pro inflammatory role in innate immune colitis, but that NOD2 had little impact on H.hepaticus colonization of the mouse intestine. In summary, my results identify multiple mechanisms through which IL 1β promotes intestinal pathology and suggesting that targeting IL 1β, or innate immune receptors, may represent a useful therapeutic approach in IBD.

A fundamental problem in the field of new technology is how firms develop and sustain disruptive technologies for industrial change. The literature has analyzed several characteristics of disruptive innovations. However, the drivers are hardly known. The study suggests that, in markets with high intensity of rd investments, the emergence of disruptive technologies can be driven by the coevolution of consequential problems and their solutions in rd labs of firms. In general, incumbent and entrant firms have a strong incentive to find innovative solutions to unsolved, consequential and new problems in order to achieve and sustain the prospect of a (temporary) profit monopoly. This study can be useful for bringing a new perspective to explain and generalize one of the sources of disruptive technologies in markets with technological dynamisms that can support industrial and corporate change in a Schumpeterian world of innovation-based competition.

Frame and Carpenter (1979) analysed the pattern of international research collaboration among scientific fields in 1970s. Starting from this pioneering work, this paper investigates international collaborations over 1997-2012 and compares the critical results with earlier studies to detect the evolution of collaboration patterns in different scientific fields. Empirical analysis supports two vital findings, given by: a) a relatively stable structure of international research collaborations over time across different scientific fields; b) a convergent process of collaboration patterns between theoretical and applied research fields. One important deter-minant of the latter result might be due to the increasing interdisciplinary nature of research fields that supports the convergence between basic and applied sciences.

The purpose of this paper is to analyse the spatial dynamics of the pattern of international research collaborations. The formation of new network structures of international research collaborations is driven by the increase of inter-research collaborations of countries across different geographical areas rather than intra-collaborations of countries within the same geographical area. These findings enhance the understanding of the spatial dynamic features in the global research network, which can support fruitful research policies at country level and improve the strategy of collaborative academic research.

To analyze the relationship between pain and presence, site, and type of adhesions in women with endometriosis.This was a multicenter, observational cross-sectional study. Eligible for the study were women with endometriosis and pelvic pain, consecutively observed during the study period at the collaborating centers. A total of 574 women entered the study.Adhesions were observed in 81.9% of cases (470 women). The frequency was lower in women with endometriosis at stage I-II (65%) and higher in women with stage III-IV (88%); this difference was statistically significant (p.01). The frequency of adhesions was lower in women with ovarian endometriosis (74%) and higher in those with ovarian and peritoneal endometriosis (87%) or other sites (96%) (p.01). The presence of adhesions was associated with higher mean visual analog scale (VAS) scores and median multidimensional scale ratings in women with ovarian disease and with stage I-II disease. Women with ovarian adhesions reported higher VAS and multidimensional scale scores (p.05) than women with peritoneal adhesions or adhesions in other sites.The results of this study suggest that there is no overall association between the presence of adhesions and the degree of pain in women with endometriosis. The data suggests that there may be an association between adhesions and pain in women with ovarian and Type I-II endometriosis. However, these associations were no longer significant after correction for multiple comparisons. Further research is indicated to test these associations.

Introduzione: Recentemente la TMS ripetitiva (rTMS) è stata usata per inibire la corteccia motoria sana (M1S) in pazienti con stroke unilaterale, in modo da ridurre transitoriamente l’eccessiva inibizione trascallosale sulla corteccia motoria dell’emisfero leso (M1L) e aumentare conseguentemente l’eccitabilità di M1L. In questo studio indaghiamo l’effetto a lungo termine di un trattamento che combina l’inibizione di M1S e un trattamento riabilitativo (TR) task-oriented in pazienti con esiti di ictus che comportino paresi di entità moderata. Materiali e Metodi: Trenta pazienti a più di sei mesi dallo stroke sono stati arruolati in un trial clinico doppio-cieco randomizzato condotto presso gli Ospedali Riuniti di Ancona. I pazienti ricevevano 10 sessioni giornaliere di rTMS a bassa frequenza (1Hz) su M1S. In gruppi diversi, la stimolazione poteva essere attiva (rTMS-A) o sham (rTMS-S) e poteva essere somministrata immediatamente prima o dopo la seduta di TR condotta con il fisioterapista. Il TR era teso a migliorare la destrezza e la forza della key-grip (presa a chiave). Le misure di outcome includevano la destrezza (Jebsen-Taylor, Box&Block, e Nine hole test), la forza (key-grip), l’inibizione trascallosale e l’eccitabilità delle cortecce motorie ed erano monitorate per tre mesi successivi alla fine del trattamento. Risultati: Dopo rTMS-A si assisteva ad una riduzione di inibizione trascallosale da M1S a M1L e a un aumento di eccitabilità di M1L. Tutti i gruppi presentavano dei miglioramenti nelle abilità esercitate (destrezza e forza manuale). Nei pazienti sottoposti a rTMS-S (linee grigie nel grafico), i miglioramenti erano modesti e transitori. Nei pazienti sottoposti a rTMS-A, i miglioramenti erano significativamente maggiori e perduravano per almeno tre mesi. I pazienti sottoposti a rTMS-A immediatamente prima del TR (linee nere), mostravano miglioramenti robusti e stabili per tutti i follow-up. I pazienti sottoposti a rTMS-A dopo il TR (linee rosse), mostravano un miglioramento tendente al declino negli ultimi follow-up. Conclusioni: I nostri risultati suggeriscono che la rTMS-A prima del TR favorisce la plasticità uso-dipendente e ri-bilancia l’eccitabilità nelle due cortecce motorie. Il trattamento combinato appare un approccio valido e promettente per pazienti con stroke e disturbi motori. Lo studio fornisce evidenza di Classe I che la rTMS prima o dopo il TR migliora misure di destrezza e forza nell’arto malato in pazienti con disturbi motori a più di sei mesi dall’ictus (Avenanti et al., 2012). Bibliografia: Avenanti, Coccia, Ladavas, Provinciali, Ceravolo (2012) Low-frequency rTMS promotes use-dependent motor plasticity in chronic stroke. A randomized trial. Neurology. 2012;78:256-64

Spermine oxidase (SMO) is a FAD-containing enzyme while bovine serum amine-oxidase (BSAO) is a copper amine oxidase and both are able to oxidize polyamines. They play a dominant role in the highly regulated mammalian polyamines catabolism. Spermine oxidase specifically oxidizes spermine (SPM) producing spermidine (SPD), the reactive oxygen species H2O2 and the aldehyde 3-aminopropanal, each with the potential to produce cellular damages and pathologies (1). BSAO deaminates SPM and SPD to H2O2, aldehyde acrolein and ammonia. Since SPM represents a common substrate for SMO and BSAO enzymatic activities, a comparative study was performed on both enzymes in presence of SPM on several tumor cell lines melanoma (M14) and colon adenocarcinoma (LoVo) wild type and their MDR counterparts. SPM is a tetramine that plays mandatory roles in several cell functions, such as DNA synthesis, cellular proliferation, modulation of ion channels function and cellular signaling (1). Our previous studies demonstrated that BSAO and SPM added to human cancer cells induce cytotoxicity and overcome the MDR phenotype (2). We have performed in vitro experiments treating the above human cancer cell lines both phenotype wild type and MDR with SMO in presence of several concentrations of SPM (0-80 μM) for 60 min at 37°C. Cytotoxicity induced by SPM oxidation metabolites, such as H2O2 and the aldehyde 3-aminopropanal, was greater in MDR cells than in the corresponding wild-type ones (WT), maybe due to an increased mitochondrial activity. To get structural information a comparative study was also carried out on both enzymes, by differential Scanning Calorimetry (DSC) (3). The thermal stability of BSAO and SMO is studied by differential scanning calorimetry with a MicroCal MC-2D instrument. Differential scanning calorimetry permits detection of overall changes in protein structure correlated with changes in thermal stability of one or more calorimetric domains. This is particularly important in the case of BSAO and SMO, proteins for which only a little structural information is available. Our previous studies demonstrated that the thermal denaturation profile of the dimeric BSAO is characterized by three distinct endothermic peaks (Tm 58°C, 71.3°C, 77.9°C) (3). The deconvolution of the thermal profile required five two-state transitions, revealed for the dimeric protein a five domain structure, while the monomeric SMO displays one single, endothermic peak (Tm 63°C). The peak may be deconvoluted into two transitions and reveals the presents of two non similar size calorimetric domains: the lowest temperature domain is described by a non two-state transition and the highest temperature domain is described by a two-state transition. The thermal denaturation is irreversible after heating to 100°C. Since the treatments with BSAO/SPM and SMO/SPM increased the amount of reactive oxygen species (ROS) inside the cells, higher in MDR than WT ones, we hypothesize that the enhancement of amine oxidase activity in tissues, undergoing pathological proliferative phenomena, may reasonably be exploited in the treatment of neoplastic diseases, mainly against MDR tumors. References: 1- Cervelli M, Amendola R, Polticelli F, Mariottini P (2012). Spermine oxidase ten years later , AminoAcids 42 :441-450 2-Agostinelli, E., Condello, M., Molinari, A., Tempera, G., Viceconte, N., Arancia, G. (2009) Cytotoxicity of spermine oxidation products to multidrug resistant melanoma M14 ADR2 cells: Sensitization by the MDL 72527 lysosomotropic compound International Journal of Oncology 35: 485-498 3) Giartosio A, Agostinelli E and Mondovì B (1988). Domains in bovine serum amine oxidase. Biochem. Biophys. Res. Comm. 154: 66-72.

Technological change is a vital human activity that interacts with geographic factors and environment. The purpose of the study here is to analyse the relationship between geo-climate zones of the globe and technological outputs in order to detect favourable areas that spur higher technological change and, as a consequence, human development. The main finding is that innovative outputs are higher in geographical areas with a temperate climate latitudes. In fact, warm temperate climates are favourable environments for human societies that, by a long-run process of adaptation and learning, create platforms of institutions and communications systems, infrastructures, legal systems, economic governance and socio-economic networks that support inventions and diffusion of innovations. The linkages between observed facts show the vital geo-climate sources of fruitful patterns of the technological innovation and economic growth.

An interesting problem is the analysis of effects of the predominant impact of technological change on the health of societies. This study considers technological change as the human activity that generates a huge impact on societies and causes environmental disorders affecting the health of population. In particular, technical innovations support the industrialisation and human development, which by a social change based on population growth, mass production and consumption, and resources depletion, engenders pollution and several environmental carcinogens. This study shows that a main effect of the critical impact of technological change on societies is the high cancer incidence of population living in industrialised areas of opulent and advanced countries. Vital empirical evidence and linkages between observed facts endeavour to explain the major relationships concerning the interactions among technology, ecosystems and the health of societies.

An interesting problem in the economics of innovation and strategic management of labs is to explain the drivers of breakthroughs and paradigm shifts in science. This study confronts the issue by analysing a main case study the technological determinant of the discovery of quasi-periodic materials that has generated a scientific paradigm shift in crystallography. Unlike user-friendly radical innovations, the study here detects some specific radical innovations, defined lab-oriented and adopted by high-skilled users i.e. researchers such as Transmission Electron Microscopy, which tend to support breakthroughs and scientific discoveries. This finding is the foundation for a framework, which endeavours to pinpoint the main characteristics and properties of these strategic lab-oriented radical innovations, which in turn spur scientific advances. Technological analysis of this study explains the critical role of specific technologies supporting knowledge creation and scientific discoveries to understand vital drivers of scientific fields and fruitful linkages that run from technological to scientific progress.

The fundamental problem in the field of the economics of innovation is which economic subjects are the sources of radical innovations and high technological performances. The study here confronts this problem by developing a theoretical framework underpinned in the concept of purposeful system having a purpose of global leadership, which endeavours to analyse the sources of General-Purpose Technologies GPTs in a Schumpeterian world of innovation-based competition. Through an inductive study based on some societies that in the history have generated technological and economic change Roman and Britain Empire, and current USA, the analysis shows vital characteristics that can be the sources of changes in the techno-economic paradigm. In particular, purposeful country-systems with high economic military potential, supported by a strategy of high RD expenditures, and the objective of global leadership, winning international conflicts against other great powers a very strong competition for the hegemony, tend to generate several inventions and radical innovations that are spread, in the long run, across wide geo-economic areas. It seems that the initial sources of GPTs e.g. aqueduct, steam engine, jet aircraft, computer, etc. are, de facto, associated with the global posture of great powers to achieve/sustain global leadership in intensive effective and/or potential international competitions, rather than warfare per se. This study refers to this nexus as leadership-driven innovation. International conflict is the context that spurs the GPTs, which are driven by global leadership of critical societies, whereas initial military RD, demand and procurement are important mechanisms underlying the process that induces emerging path-breaking technologies. The vital linkages between observed facts can support a general socio-economic framework of the sources of path-breaking innovations based on a leadership of main economic subjects that support innovative activity mainly in communications and energy systems parallel to transportation technology and the evolution and development of human societies.

The purpose of this article is to analyze the organizational behavior of public research organizations based on their human resources development and management. The study here focuses on the largest Italian public research body. The pyramid of R&D people shows the irregular spatial structure of the research personnel per macro regions and the index of seniority indicates older research personnel in the North and Central Part of Italy than in the South Italy. The analysis of human resources displays organizational weaknesses and threats for public research labs generated by research policy based on shrinking public research lab budgets and downsizing of research personnel. Some critical human resource management implications are discussed in order to improve the strategic change and research performances of public research institutions in turbulent and fast-changing markets.