Exercise associated factors affecting cardiovascular health and function: from myocyte signaling to genetic variations

The exact mechanisms of the exercise induced adaptations is not lucid, but recent studies have delineated two means of signaling by which the adaptations occur (1) substrate availability signaling (metabolic stress) (2) hormone-receptor signaling. We have decided to specifically investigate two metabolic signaling enzymes [AMP-activated kinase (AMPK) and Sirtuin 1(SIRT1)] and two hormones [Adiponectin and Adrenergic stimulation].Tis based on four papers with the following conclusions: (1)Increase in SIRT1 activity and expression in H9c2 cells treated with phenylephrine is an adaptive response to the hypertrophic stress, mediated by AMPK. (2)The lack of optimal nutritional conditions (energetic substrates) due to a prolonged activation of AMPK can contrast the establishment of hypertrophy, possibly also by means of the negative modulation of ODC activity. (3) Our findings offer a possibile hypothesis as to the fact the the G allele on site 45 could lead to the increasd risk of Type II diabetes through a decrease in lean body mass. (4) Our results suggest that there is an ADIPOQ gene effect in relation to bone parameters. Statistical analysis show that the presence of the T allele in position 45 favors an increase in lumbar spine bone mineral content (BMC) when compared to subjects with a G allele substitution, which can be do the the increase in lean body mass in this genotype group.

Sea Level Variations from Decades to Millennia: A few Case Studies

The main goals of this Ph.D. study are to investigate the regional and global geophysical components related to present polar ice melting and to provide independent cross validation checks of GIA models using both geophysical data detected by satellite mission, and geological observations from far field sites, in order to determine a lower and upper bound of uncertainty of GIA effect. The subject of this Thesis is the sea level change from decades to millennia scale. Within ice2sea collaboration, we developed a Fortran numerical code to analyze the local short-term sea level change and vertical deformation resulting from the loss of ice mass. This method is used to investigate polar regions: Greenland and Antarctica. We have used mass balance based on ICESat data for Greenland ice sheet and a plausible mass balance for Antarctic ice sheet. We have determined the regional and global fingerprint of sea level variations, vertical deformations of the solid surface of the Earth and variations of shape of the geoid for each ice source mentioned above. The coastal areas are affected by the long wavelength component of GIA process. Hence understanding the response of the Earth to loading is crucial in various contexts. Based on the hypothesis that Earth mantle materials obey to a linear rheology, and that the physical parameters of this rheology can be only characterized by their depth dependence, we investigate the Glacial Isostatic Effect upon the far field sites of Mediterranean area using an improved SELEN program. We presented new and revised observations for archaeological fish tanks located along the Tyrrhenian and Adriatic coast of Italy and new RSL for the SE Tunisia. Spatial and temporal variations of the Holocene sea levels studied in central Italy and Tunisia, provided important constraints on the melting history of the major ice sheets.

Studies on the dual in Mycenaean, in the Homeric poetry and in the Attic Theatre of the 5th century — morphological, dialectal and stylistical variations

The present dissertation focuses on the dual number in Ancient Greek in a diachronical lapse stretching from the Mycenaean age to the Attic Drama and Comedy of the 5th century BC. In the first chapter morphological issues are addressed, chiefly in a comparative perspective. The Indo European evidence on the dual is hence gathered in order to sketch patterns of grammaticalisation and paradigmatisation of specific grams, growing increasingly functional within the Greek domain. In the second chapter syntactical problems are tackled. After a survey of scholarly literature on the Greek dual, we engage in a functional and typological approach, in order to disentangle some biased assessments on the dual, namely its alleged lack of regularity and intermittent agreement. Some recent frameworks in General Linguistics provide useful grounds for casting new light on the subject. Internal Reconstruction, for instance, supports the facultativity of the dual in each and every stage of its development; Typology and the Animacy Hierarcy add precious cross linguistical insight on the behaviour of the dual toward agreement. Glaring differences also arise as to the adoption — or avoidance — of the dual by different authors. Idiolectal varieties prove in fact conditioned by stylistical and register necessity. By means of a comparison among Epics, Tragedy and Comedy it is possible to enhance differences in the evaluation of the dual, which led sometimes to forms of ‘censure’ — thus triggering the onset of competing strategies to express duality. The last two chapters delve into the tantalising variety of the Homeric evidence, first of all in an account of the notorious issue of the Embassy of Iliad IX, and last in a commentary of all significant Homeric duals — mostly represented by archaisms, formulae, and ad hoc coinages.

A SMO inhibitor drug reduces the progenitor cell's maintenance in the Drosophila hematopoietic organ: a novel model to study Chronic Myelogenous Leukemia relapse

The chronic myeloid leukemia complexity and the difficulties of disease eradication have recently led to the development of drugs which, together with the inhibitors of TK, could eliminate leukemia stem cells preventing the occurrence of relapses in patients undergoing transplantation. The Hedgehog (Hh) signaling pathway positively regulates the self-renewal and the maintenance of leukemic stem cells and not, and this function is evolutionarily conserved. Using Drosophila as a model, we studied the efficacy of the SMO inhibitor drug that inhibit the human protein Smoothened (SMO). SMO is a crucial component in the signal transduction of Hh and its blockade in mammals leads to a reduction in the disease induction. Here we show that administration of the SMO inhibitor to animals has a specific effect directed against the Drosophila ortholog protein, causing loss of quiescence and hematopoietic precursors mobilization. The SMO inhibitor induces in L3 larvae the appearance of melanotic nodules generated as response by Drosophila immune system to the increase of its hemocytes. The same phenotype is induced even by the dsRNA:SMO specific expression in hematopoietic precursors of the lymph gland. The drug action is also confirmed at cellular level. The study of molecular markers has allowed us to demonstrate that SMO inhibitor leads to a reduction of the quiescent precursors and to an increase of the differentiated cells. Moreover administering the inhibitor to heterozygous for a null allele of Smo, we observe a significant increase in the phenotype penetrance compared to administration to wild type animals. This helps to confirm the specific effect of the drug itself. These data taken together indicate that the study of inhibitors of Smo in Drosophila can represent a useful way to dissect their action mechanism at the molecular-genetic level in order to collect information applicable to the studies of the disease in humans.

Diversity of the proximal femur in humans: morphological variations of the head-neck junction

The proximal femur is a high-diversity region of the human skeleton, especially at the anterior junction between head and neck, where various bony morphologies have been recognized since mid nineteenth century. Classical literature on this topic is chaotic and contradictory, making almost impossible the comparison of data from different researches. Starting from an extensive bibliographic review, the first standardized method to score these traits has been created. This method allows representing both the anatomical diversity of the region already described in literature and a part of variability not considered before, giving few and univocal definitions and allowing to collect comparable data. The method has been applied to three identified and five archaeological European skeletal collections, with the aim of investigating the distribution of these features by sex, age and side, in different places and time periods. It has also been applied to 3D digital reconstructions of femurs from CT scan files of coxo-femoral joints from fresh cadavers. In addition to the osseous traits described in the standardized method, the presence and frequency of some features known as herniation pits have been scored both on bones and on CT scans. The various osseous traits of the proximal femur are present at similar frequencies in skeletal samples from different countries and different historical periods, even if with clear local differentiation. Some of the features examined show significant trends related to their distribution by gender and age. Some hypotheses are proposed about the etiology of these morphologies and their possible implication with the acquisition of bipedalism in Humans. It is therefore highlighted the possible relation of some of these traits with the development of disorders of the hip joint. Moreover, it is not recommended the use of any of these features as a specific activity-related marker.

In vitro characterisation and expansion of human regulatory T cells for their in vivo application in the induction of tolerance in haematopoietic stem cell and solid organ transplantation

Solid organ transplantation (SOT) is considered the treatment of choice for many end-stage organ diseases. Thus far, short term results are excellent, with patient survival rates greater than 90% one year post-surgery, but there are several problems with the long term acceptance and use of immunosuppressive drugs. Hematopoietic Stem Cells Transplantation (HSCT) concerns the infusion of haematopoietic stem cells to re-establish acquired and congenital disorders of the hematopoietic system. The main side effect is the Graft versus Host Disease (GvHD) where donor T cells can cause pathology involving the damage of host tissues. Patients undergoing acute or chronic GvHD receive immunosuppressive regimen that is responsible for several side effects. The use of immunosuppressive drugs in the setting of SOT and GvHD has markedly reduced the incidence of acute rejection and the tissue damage in GvHD however, the numerous adverse side effects observed boost the development of alternative strategies to improve the long-term outcome. To this effect, the use of CD4+CD25+FOXP3+ regulatory T cells (Treg) as a cellular therapy is an attractive approach for autoimmunity disease, GvHD and limiting immune responses to allograft after transplantation. Treg have a pivotal role in maintaining peripheral immunological tolerance, by preventing autoimmunity and chronic inflammation. Results of my thesis provide the characterization and cell processing of Tregs from healthy controls and patients in waiting list for liver transplantation, followed by the development of an efficient expansion-protocol and the investigation of the impact of the main immunosuppressive drugs on viability, proliferative capacity and function of expanded cells after expansion. The conclusion is that ex vivo expansion is necessary to infuse a high Treg dose and although many other factors in vivo can contribute to the success of Treg therapy, the infusion of Tregs during the administration of the highest dose of immunosuppressants should be carefully considered.

Global and regional sea level variations in the recent past and future: insight from observations and modeling

This work is focused on the analysis of sea–level change (last century), based mainly on instrumental observations. During this period, individual components of sea–level change are investigated, both at global and regional scales. Some of the geophysical processes responsible for current sea-level change such as glacial isostatic adjustments and current melting terrestrial ice sources, have been modeled and compared with observations. A new value of global mean sea level change based of tide gauges observations has been independently assessed in 1.5 mm/year, using corrections for glacial isostatic adjustment obtained with different models as a criterion for the tide gauge selection. The long wavelength spatial variability of the main components of sea–level change has been investigated by means of traditional and new spectral methods. Complex non–linear trends and abrupt sea–level variations shown by tide gauges records have been addressed applying different approaches to regional case studies. The Ensemble Empirical Mode Decomposition technique has been used to analyse tide gauges records from the Adriatic Sea to ascertain the existence of cyclic sea-level variations. An Early Warning approach have been adopted to detect tipping points in sea–level records of North East Pacific and their relationship with oceanic modes. Global sea–level projections to year 2100 have been obtained by a semi-empirical approach based on the artificial neural network method. In addition, a model-based approach has been applied to the case of the Mediterranean Sea, obtaining sea-level projection to year 2050.