New era of cystic fibrosis: full mutational analysis and personalized therapy

Despite its apparently simple genetics, cystic fibrosis (CF) is a rather complex genetic disease. A lot of variability in the steps of the path from the cystic fibrosis transmembrane conductance regulator (CFTR ) gene to the clinical manifestations originates an uncertain genotype - phenotype relationship. A major determinant of this uncertainty is the incomplete knowledge of the CFTR mutated genotypes, due to the high number of CFTR mutations and to the higher number of their combinations in trans and in cis. Also the very limited knowledge of functional effects of CFTR mutated alleles severely impairs our diagnostic and prognostic ability. The final phenotypic modulation exerted by CFTR modifier genes and interactome further complicates the framework. The next generation sequencing approach is a rapid, lowcost and high-throughput tool that allows a near complete structural characterization of CFTR mutated genotypes, as well as of genotypes of several other genes cooperating to the final CF clinical manifestations. This powerful method perfectly complements the new personalized therapeutic approach for CF. Drugs active on specific CFTR mutational classes are already available for CF patients or are in phase 3 trials. A complete genetic characterization has been becoming crucial for a correct personalized therapy. However, the need of a functional classification of each CFTR mutation potently arises. Future big efforts towards an ever more detailed knowledge of both structural and functional CFTR defects, coupled to parallel personalized therapeutic interventions decisive for CF cure can be foreseen

Environment, epigenetics and neurodegeneration: Focus on nutrition in Alzheimer's disease

Many different environmental factors (nutrients, pollutants, chemicals, physical activity, lifestyle, physical and mental stress) can modulate epigenetic markers in the developing and adult organism. Epigenetics, in turn, can cause and is associated with several neurodegenerative and aging-dependent human diseases. Alzheimer's disease certainly represents one of the most relevant neurodegenerative disorders due to its incidence and its huge socio-economic impact. Therefore, it is easy to understand why recent literature focuses on the epigenetic modifications associated with Alzheimer's disease and other neurodegenerative disorders. One of the most intriguing and, at the same time, worrying evidence is that even "mild" environmental factors (such as behavioral or physical stress) as well as the under-threshold exposure to pollutants and chemicals, can be effective. Finally, even mild nutrients disequilibria can result in long-lasting and functional alterations of many epigenetic markers, although they don't have an immediate acute effect. Therefore, we will probably have to re-define the current risk threshold for many factors, molecules and stresses. Among the many different environmental factors affecting the epigenome, nutrition represents one of the most investigated fields; the reasons are probably that each person interacts with nutrients and that, in turn, nutrients can modulate at molecular level the epigenetic biochemical pathways. The role that nutrition can exert in modulating epigenetic modifications in Alzheimer's disease will be discussed with particular emphasis on the role of B vitamins and DNA methylation

Alcohol addiction: a molecular biology perspective.

Alcohol misuse represents worldwide an important risk factor for death and disability. Excessive alcohol consumption is widely diffused in different ethnicities and alcohol use is part of the lifestyle of both young and old people. The genetic basis of alcohol dependence concerning ethanol metabolism and the pathways of reward circuits are well known. The role of genetic variants in the neurobiology of addiction as well as in response to medication in alcoholism therapy still represents an intriguing argument that needs to be deeply analyzed and explained. The molecular approach to the study of these aspects could be difficult because of the large number of genes and variations involved. Our work is intended to offer an overview of genes and variants involved in alcohol addiction and pharmacogenetics. Our aim is to delineate a molecular approach strategy to look at alcohol dependence from a genetic and applicative point of view. The indications provided in this work should be of help for those who wish to undertake a molecular study of this multifactorial disease

Piaggio Production System: miglioramento e misura delle prestazioni in ottica WCM

Il PPS è un programma di miglioramento continuo dei processi produttivi del Gruppo Piaggio realizzato con interventi sulle dimensioni di estensione e di profondità della cultura aziendale nel Manufacturing basato sul World Class Manufacturing. Per gli stabilimenti italiani il PPS è entrato nel pieno del suo sviluppo durante i sei mesi di attività che ho svolto a partire da gennaio 2012 che si sono concentrati sul monitoraggio e miglioramento continuo delle metodologie WCM. Gli Stabilimenti hanno applicato i concetti di Lean Manufacturing con progetti di miglioramento individuati e fissati nel budget come obiettivi di eliminazione di spreco. Sono stato inserito nello stabilimento due ruote di Pontedera dove ho avuto un ruolo di supporto ai progetti in essere in un ottica di Contiuous Improvement. L’implementazione di un sistema di misura delle performance calibrato sui progetti, è stata la base per lo sviluppo di un cruscotto gestionale mirato alla consuntivazione dei risultati economico/tecnici ed alla spinta verso l’ adozione di una mentalità orientata all’efficienza. I successi economici ottenuti hanno portato a gettare le basi verso il PSS (Piaggio Supplier System), estensione del programma PPS ai Fornitori strategici di Piaggio, che sarà attivato nel 2013, a cui ho dato il mio contribuito nella fase di ideazione e pianificazione

Rethinking Money, Rebuilding Communities: A Multidimensional Analysis of Crypto and Complementary Currencies

In the current scenario of global crisis, our official monetary system's inadequacy to provide solutions to the numerous serious problems affecting our society has become increasingly evident. This has led to the emergence of an astonishing number of projects that aim to rethink money. In order to make sense of these projects, it is necessary to explore the deepest meanings of money, as a multidimensional institution whose concrete nature and functioning are still object of a whole set of unsolved disputes. Under these premises, this article proposes an interdisciplinary reading of crypto and complementary currencies. The goal is twofold: on the one hand, the authors aim to shed light on the conditions which have to be met for the establishment of a sustainable monetary innovation; on the other hand, the article constitutes an attempt to use ongoing experiences as a lens through which to gain new insights into the general phenomenon of money and as a laboratory for exploring the possibility to move towards new socio-economic paradigms

Computational models of melanoma.

Genes, proteins, or cells influence each other and consequently create patterns, which can be increasingly better observed by experimental biology and medicine. Thereby, descriptive methods of statistics and bioinformatics sharpen and structure our perception. However, additionally considering the interconnectivity between biological elements promises a deeper and more coherent understanding of melanoma. For instance, integrative network-based tools and well-grounded inductive in silico research reveal disease mechanisms, stratify patients, and support treatment individualization. This review gives an overview of different modeling techniques beyond statistics, shows how different strategies align with the respective medical biology, and identifies possible areas of new computational melanoma research

Hematopoietic Stem Cell Transplantation in Thalassemia and Sickle Cell Disease. Unicenter Experience in a Multi-Ethnic Population.

Hematopoietic stem cell transplantation (HSCT) still remains the only definitive cure currently available for patients with thalassemia and sickle cell anemia. Results of transplant in thalassemia and in sickle cell anemia have steadily improved over the last two decades due to improvements in preventive strategies, and effective control of transplant-related complications. From 2004 through 2009, 145 consecutive patients with thalassemia and sickle cell anemia, ethnically heterogeneous from Mediterranean and Middle East countries, were given HSCT in the International Center for Transplantation in Thalassemia and Sickle Cella Anemia in Rome. This experience is characterized by two peculiarities: patients were ethnically very heterogeneous and the vast majority of these patients were not regularly transfesed/chelated and therefore were highly sensitized due to RBC transfusions without leukodepletion filters. Consequently, they could have a high risk of graft rejection as a result of sensitization to HLA antigens. The Rome experience of SCT in patients with thalassemia and sickle cell anemia confirmed the results obtained in Pesaro, and most importantly showed the reproducibility of these results in other centers

Involvement of sperm acetylated histones and the nuclear isoform of Glutathione peroxidase 4 in fertilization

We previously demonstrated that the nuclear form of Glutathione peroxidase 4 (nGPx4) has a peculiar distribution in sperm head, being localized to nuclear matrix and acrosome and that sperm lacking nGPx4 are more prone to decondensation in vitro. In this study we have hypothesized that sperm retained acetylated histones and nGPx4 are implicated in paternal chromatin decondensation and male pronucleus formation at fertilization. Indeed, significant higher amounts of acetylated histone H4 and acetylated histone H3 were observed by both immunofluorescence and western blotting in nGPx4-KO sperm vs WT ones. In vitro fertilization of zona pellucida- deprived oocytes by WT sperm in the presence of trichostatin (TSA) also demonstrated that paternal histone acetylation was inversely related to the timing of sperm nucleus decondensation at fertilization. In contrast, TSA had no effect on nGPx4-KO sperm, indicating they had a maximal level of histone acetylation. Moreover the paternally imprinted gene Igf2/H19 was hypomethylated in KO sperm compared to WT ones. The lack of nGPx4 negatively affected male fertility, causing a marked decrease in total pups and pregnancies with delivery, a significant reduction in pronuclei (PN) embryos in in vitro fertilization assays and an approximately 2 h delay in egg fertilization in vivo. Because the zona pellucida binding and fusion to oolemma of nGPx4-KO and WT sperm were similar, the subfertility of nGPx4 sperm reflected a decreased sperm progression through egg cumulus/zona pellucida, pinpointing a defective acrosome in line with acrosomal nGPx4 localization. We conclude that paternal acetylated histones and acrosomal nGPx4 are directly involved in fertilization

Chapter Introduzione. Umberto Gori e le Relazioni Internazionali in Italia

Umberto Gori has held the first chair of International Relations in Italy and has been the first scholar to address a series of central topics in the analysis of foreign policy and international politics. Those who browse, even if only rapidly, his rich bibliography cannot but be struck by the great variety of the topics examined: from the first works of a predominantly legal nature, we move on to studies centered on methodological and epistemological issues, relations between states, analysis of foreign policy in general and Italian foreign policy in particular, Peace Research, strategic affairs, intelligence, and finally the impact of the information and digital revolution on international politics and contemporary strategy. What holds together so many different issues is, firstly, a constant attention to methodology and, secondly, a clear preference for a predominantly operational approach, in the belief that knowledge must always be functional to decision and action. These basic attitudes are reflected not only in his strongly characterized research agenda, but also in the twofold nature of his teaching commitment: on the one hand, Gori taught outside the university classrooms, at military and governmental institutions, for decades; on the other hand, he introduced issues traditionally reserved to diplomacy and security institutions into the Italian academic context. Such a propensity to build bridges between different worlds - academic, military, technological, diplomatic, financial - and a research vocation that has never failed make Umberto Gori a figure indissolubly linked to the birth and development of International Relations in Italy