Expression and Role of CD166 in the Chronic Kidney Disease

Background: CD166, an adhesion molecule of the immunoglobulin superfamily, is one of the crucial effectors that traffic lymphocytes into tissues. Till now, the expression and role of CD166 in the chronic kidney disease remains unknown. Objectives: In the present study, we are to examine the expression of CD166 in the chronic kidney disease, and to explore its function with CD4+ T cells. Materials and Methods: CD166 expression was tested by Flow Cytometry (FACS) in the primary macrophages stimulated with LPS. In vivo, the expression of CD166 and CD4 were examined in the kidney tissues of adriamycin-induced nephropathy (AN) mice by immnohistochemistry. Macrophages and lymphocytes were co-cultured, the interaction between CD166 and CD4 was tested by immunofluorescent staining. Furthermore, the effects of CD166 on the activation and proliferation of T cells were explored. Results: In this study, CD166 expression was found to be upregulated on activated macrophages and glomerular endothelia in the adriamycin-induced nephropathy (AN) mice and CD4+ T cells were increased with CD166 expression in the AN mice. The interaction between macrophages and CD4+ T cells indicated that CD166 played a key role in the recruitment of lymphocytes in the chronic kidney disease, and neither proliferation nor activation of T cells was affected by CD166. Conclusions: CD166 expressed on macrophages and endothelia in AN kidney, and the function was related to the recruitment of CD4+ T cells into inflamed kidney, indicating that CD166 may be a potential target for reducing the inflammatory infiltrates in the chronic kidney disease.

AN ASSESSMENT OF FLOW REGIME MAPS AND A NUMERICAL HEAT TRANSFER CORRELATION FOR THE STRATIFIED/ANNULAR REGIME OF SHEAR-DRIVEN INTERNAL CONDENSING FLOWS

Several modern-day cooling applications require the incorporation of mini/micro-channel shear-driven flow condensers. There are several design challenges that need to be overcome in order to meet those requirements. The difficulty in developing effective design tools for shear-driven flow condensers is exacerbated due to the lack of a bridge between the physics-based modelling of condensing flows and the current, popular approach based on semi-empirical heat transfer correlations. One of the primary contributors of this disconnect is a lack of understanding caused by the fact that typical heat transfer correlations eliminate the dependence of the heat transfer coefficient on the method of cooling employed on the condenser surface when it may very well not be the case. This is in direct contrast to direct physics-based modeling approaches where the thermal boundary conditions have a direct and huge impact on the heat transfer coefficient values. Typical heat transfer correlations instead introduce vapor quality as one of the variables on which the value of the heat transfer coefficient depends. This study shows how, under certain conditions, a heat transfer correlation from direct physics-based modeling can be equivalent to typical engineering heat transfer correlations without making the same apriori assumptions. Another huge factor that raises doubts on the validity of the heat-transfer correlations is the opacity associated with the application of flow regime maps for internal condensing flows. It is well known that flow regimes influence heat transfer rates strongly. However, several heat transfer correlations ignore flow regimes entirely and present a single heat transfer correlation for all flow regimes. This is believed to be inaccurate since one would expect significant differences in the heat transfer correlations for different flow regimes. Several other studies present a heat transfer correlation for a particular flow regime - however, they ignore the method by which extents of the flow regime is established. This thesis provides a definitive answer (in the context of stratified/annular flows) to: (i) whether a heat transfer correlation can always be independent of the thermal boundary condition and represented as a function of vapor quality, and (ii) whether a heat transfer correlation can be independently obtained for a flow regime without knowing the flow regime boundary (even if the flow regime boundary is represented through a separate and independent correlation). To obtain the results required to arrive at an answer to these questions, this study uses two numerical simulation tools - the approximate but highly efficient Quasi-1D simulation tool and the exact but more expensive 2D Steady Simulation tool. Using these tools and the approximate values of flow regime transitions, a deeper understanding of the current state of knowledge in flow regime maps and heat transfer correlations in shear-driven internal condensing flows is obtained. The ideas presented here can be extended for other flow regimes of shear-driven flows as well. Analogous correlations can also be obtained for internal condensers in the gravity-driven and mixed-driven configuration.

Geographic Provenancing of Unprocessed Cotton Using Elemental Analysis and Stable Isotope Ratios

Cotton is the most abundant natural fiber in the world. Many countries are involved in the growing, importation, exportation and production of this commodity. Paper documentation claiming geographic origin is the current method employed at U.S. ports for identifying cotton sources and enforcing tariffs. Because customs documentation can be easily falsified, it is necessary to develop a robust method for authenticating or refuting the source of the cotton commodities. This work presents, for the first time, a comprehensive approach to the chemical characterization of unprocessed cotton in order to provide an independent tool to establish geographic origin. Elemental and stable isotope ratio analysis of unprocessed cotton provides a means to increase the ability to distinguish cotton in addition to any physical and morphological examinations that could be, and are currently performed. Elemental analysis has been conducted using LA-ICP-MS, LA-ICP-OES and LIBS in order to offer a direct comparison of the analytical performance of each technique and determine the utility of each technique for this purpose. Multivariate predictive modeling approaches are used to determine the potential of elemental and stable isotopic information to aide in the geographic provenancing of unprocessed cotton of both domestic and foreign origin. These approaches assess the stability of the profiles to temporal and spatial variation to determine the feasibility of this application. This dissertation also evaluates plasma conditions and ablation processes so as to improve the quality of analytical measurements made using atomic emission spectroscopy techniques. These interactions, in LIBS particularly, are assessed to determine any potential simplification of the instrumental design and method development phases. This is accomplished through the analysis of several matrices representing different physical substrates to determine the potential of adopting universal LIBS parameters for 532 nm and 1064 nm LIBS for some important operating parameters. A novel approach to evaluate both ablation processes and plasma conditions using a single measurement was developed and utilized to determine the “useful ablation efficiency” for different materials. The work presented here demonstrates the potential for an a priori prediction of some probable laser parameters important in analytical LIBS measurement.

Sex-Positive Curricula: An Investigation of the Relationship Between Physical Fitness, Self-Concept and Sexual Functioning

Despite the well-recognized benefits of exercise, Americans are gaining weight in astounding proportions and levels of physical activity are on the decline. The purpose of this study was to investigate a relationship between physical fitness, self-concept and sexual health. There is a dearth of knowledge on this relationship specifically in the context of sex-negative curricula, which is the dominate discourse in the United States. One hundred and thirty-three participants between the ages of 18 - 50 volunteered for fitness testing and data collection. Physical fitness was assessed through body fat, resting metabolic rate, cardiovascular endurance, muscular strength, muscular endurance and flexibility. Self-reported exercise was measured using the International Physical Activity Questionnaire. Self-concept was measured by the Six Factor Self-Concept Scale, which presented a total self-concept score and as six individual concepts of self (likability, morality, task accomplishment, giftedness, power and vulnerability). Additionally, sexual function was measured by Derogatis Interview for Sexual Functioning and presented as both an aggregate score and five separate constructs of sexual functioning (fantasy/cognition, arousal, orgasm, behavior/experience, and drive/desire). Questions pertaining to sexual partners, sex education, and demographic information were also included. The results of the General Linear Model indicated significant relationships between physical fitness, self-concept and total sexual functioning. The sexual behavior/experience of men was predicted by body fat percentage and flexibility. In women, behavior/experience was predicted by body fat percentage and arousal was predicted by cardiovascular endurance. Total self-concept was related to muscular endurance. When men were isolated in the analysis, likability was positively related to sexual behavior/experience, and task accomplishment was inversely related to sexual behavior/experience. In women, giftedness was related to cognition/fantasy, arousal, orgasm and total sexual functioning. No relationships were found between physical fitness and the number of sexual partners in men; however, both muscular strength and the power self-concept were significantly related to number of sexual partners in women. As a result of these findings, women may be inclined to exercise to improve arousal and sexual functioning. Furthermore, educators should note the findings of a positive relationship between physical and psychological health and sexual well-being because they provide support for the development and adoption of sex-positive curricula that incorporate potential benefits of sexual activity.

A Multi-Criteria GIS-Based Route Selection Tool for Hazardous Material Transport: Consideration of Environmental Consequence, Traffic Congestions and Costs

Hazardous materials are substances that, if not regulated, can pose a threat to human populations and their environmental health, safety or property when transported in commerce. About 1.5 million tons of hazardous material shipments are transported by truck in the US annually, with a steady increase of approximately 5% per year. The objective of this study was to develop a routing tool for hazardous material transport in order to facilitate reduced environmental impacts and less transportation difficulties, yet would also find paths that were still compelling for the shipping carriers as a matter of trucking cost. The study started with identification of inhalation hazard impact zones and explosion protective areas around the location of hypothetical hazardous material releases, considering different parameters (i.e., chemicals characteristics, release quantities, atmospheric condition, etc.). Results showed that depending on the quantity of release, chemical, and atmospheric stability (a function of wind speed, meteorology, sky cover, time and location of accidents, etc.) the consequence of these incidents can differ. The study was extended by selection of other evaluation criteria for further investigation because health risk as an evaluation criterion would not be the only concern in selection of routes. Transportation difficulties (i.e., road blockage and congestion) were incorporated as important factor due to their indirect impact/cost on the users of transportation networks. Trucking costs were also considered as one of the primary criteria in selection of hazardous material paths; otherwise the suggested routes would have not been convincing for the shipping companies. The last but not least criterion was proximity of public places to the routes. The approach evolved from a simple framework to a complicated and efficient GIS-based tool able to investigate transportation networks of any given study area, and capable of generating best routing options for cargos. The suggested tool uses a multi-criteria-decision-making method, which considers the priorities of the decision makers in choosing the cargo routes. Comparison of the routing options based on each criterion and also the overall suitableness of the path in regards to all the criteria (using a multi-criteria-decision-making method) showed that using similar tools as the one proposed by this study can provide decision makers insights in the area of hazardous material transport. This tool shows the probable consequences of considering each path in a very easily understandable way; in the formats of maps and tables, which makes the tradeoffs of costs and risks considerably simpler, as in some cases slightly compromising on trucking cost may drastically decrease the probable health risk and/or traffic difficulties. This will not only be rewarding to the community by making cities safer places to live, but also can be beneficial to shipping companies by allowing them to advertise as environmental friendly conveyors.

Sex-biased differences in the effects of host individual, host population and environmental traits driving tick parasitism in red deer

The interactions between host individual, host population, and environmental factors modulate parasite abundance in a given host population. Since adult exophilic ticks are highly aggregated in red deer (Cervus elaphus) and this ungulate exhibits significant sexual size dimorphism, life history traits and segregation, we hypothesized that tick parasitism on males and hinds would be differentially influenced by each of these factors. To test the hypothesis, ticks from 306 red deer-182 males and 124 females-were collected during 7 years in a red deer population in south-central Spain. By using generalized linear models, with a negative binomial error distribution and a logarithmic link function, we modeled tick abundance on deer with 20 potential predictors. Three models were developed: one for red deer males, another for hinds, and one combining data for males and females and including "sex" as factor. Our rationale was that if tick burdens on males and hinds relate to the explanatory factors in a differential way, it is not possible to precisely and accurately predict the tick burden on one sex using the model fitted on the other sex, or with the model that combines data from both sexes. Our results showed that deer males were the primary target for ticks, the weight of each factor differed between sexes, and each sex specific model was not able to accurately predict burdens on the animals of the other sex. That is, results support for sex-biased differences. The higher weight of host individual and population factors in the model for males show that intrinsic deer factors more strongly explain tick burden than environmental host-seeking tick abundance. In contrast, environmental variables predominated in the models explaining tick burdens in hinds.

Climate Change Adaptation Case Study: Benefit-Cost Analysis of Coastal Flooding Hazard Mitigation

The damage Hurricane Sandy caused had far-reaching repercussions up and down the East Coast of the United States. Vast coastal flooding accompanied the storm, inundating homes, businesses, and utility and emergency facilities. Since the storm, projects to mitigate similar future floods have been scrutinized. Such projects not only need to keep out floodwaters but also be designed to withstand the effect that climate change might have on rising sea levels and increased flood risk. In this study, we develop an economic model to assess the costs and benefits of a berm (sea wall) to mitigate the effects of flooding from a large storm. We account for the lifecycle costs of the project, which include those for the upfront construction of the berm, ongoing maintenance, land acquisition, and wetland and recreation zone construction. Benefits of the project include avoided fatalities, avoided residential and commercial damages, avoided utility and municipal damages, recreational and health benefits, avoided debris removal expenses, and avoided loss of function of key transportation and commercial infrastructure located in the area. Our estimate of the beneficial effects of the berm includes ecosystem services from wetlands and health benefits to the surrounding community from a park and nature system constructed along the berm. To account for the effects of climate change and verify that the project will maintain its effectiveness over the long term, we allow the risk of flooding to increase over time. Over our 50-year time horizon, we double the risk of 100- and 500-year flood events to account for the effects of sea level rise on coastal flooding. Based on the economic analysis, the project is highly cost beneficial over its 50-year timeframe. This analysis demonstrates that climate change adaptation investments can be cost beneficial even though they mitigate the impacts of low-probability, high-consequence events.

Evaluation of tumor recurrences after radical prostatectomy using 18F-Choline PET/CT and 3T multiparametric MRI without endorectal coil: a single center experience

The aim os this study is to evaluate and compare the utility of 18F-fluorocholine (18F-CH) PET/CT versus 3-Tesla multiparametric MRI (mpMRI) without endorectal coil to detect tumor recurrences in patients with biochemical relapse following radical prostatectomy (RP). Secondarily, to identify possible prognostic variables associated with mpMRI and 18F-CH PET/CT findings. Retrospective study of 38 patients who developed biochemical recurrence after RP between the years 2011 and 2015 at our institution. PET/CT and mpMRI were both performed within 30 days of each other in all patients. The PET/CT was reviewed by a nuclear medicine specialist while the mpMRI was assessed by a radiologist, both of whom were blinded to outcomes. The median prostate-specific antigen (PSA) value pre-MRI/PET-CT was 0.9 ng/mL (interquartile range 0.4–2.2 ng/mL). There were no differences in the detection rate between 18F-CH PET/CT and mpMRI for local recurrence (LR), lymph node recurrence (LNR) and bone metastases (BM). Separately, mpMRI and 18F-CH PET/CT were positive for recurrence in 55.2% and 52.6% of cases, respectively, and in 65.7% of cases when findings from both modalities were considered together. The detection of LR was better with combined mpMRI and choline PET/CT versus choline PET/CT alone (34.2% vs 18.4%, p = 0.04). Salvage treatment was modified in 22 patients (57.8%) based on the imaging findings. PSA values on the day of biochemical failure were significantly associated with mpMRI positivity (adjusted odds ratio (OR): 30.9; 95% confidence interval (CI): 1.5–635.8). Gleason score > 7 was significantly associated with PET/CT positivity (OR: 13.9; 95% CI: 1.5–125.6). A significant association was found between PSA doubling time (PSADT) (OR: 1.3; 95% CI: 1.0–1.7), T stage (OR: 21.1; 95% CI: 1.6–272.1), and LR. Multiparametric MRI and 18F-CH PET/CT yield similar detection rates for LR, LNR and pelvic BM. The combination of both imaging techniques provides a better LR detection versus choline PET/CT alone. The initially planned salvage treatment was modified in 57.8% of patients due to imaging findings. In addition to PSA values, Gleason score, T stage, and PSADT may provide valuable data to identify those patients that are most likely to benefit from undergoing both imaging procedures.

MEF2C: expression, regulation and interaction with target genes in health and diseases

Tese de doutoramento, Ciências Biomédicas, Departamento de Ciências Biomédicas e Medicina, Universidade do Algarve, 2015

Lymphotoxin-beta receptor and RANK signaling in TEL-JAK2-induced T-cell leukemia

Tese de doutoramento, Ciências Biomédicas, Departamento de Ciências Biomédicas e Medicina, Universidade do Algarve, 2015

Herbivores strongly influence algal recruitment in both coral- and algal-dominated coral reef habitats

Coral reefs can exist as coral- and macroalgae-dominated habitats often separated by only a few hundred metres. While herbivorous fish are known to depress the abundance of algae and help maintain the function of coral-dominated habitats, less is known about their influence in algae-dominated habitats. Here, we quantified herbivorous fish and benthic algal communities over a 6 mo period in coral-dominated (back-reef) and algal-dominated (lagoon) habitats in a relatively undisturbed fringing coral reef (Ningaloo, Western Australia). Simulta - neously, we tested the effects of herbivorous fish on algal recruitment in both habitats using recruitment tiles and fish exclusion cages. The composition of established algal communities differed consistently between habitats, with the back-reef hosting a more diverse community than the Sargassum-dominated lagoon. However, total algal biomass and cover only differed between habitats in autumn, coinciding with maximum Sargassum biomass. The back-reef hosted high coral cover and a diverse herbivorous fish community, with herbivore biomass an order of magnitude greater than the lagoon. Despite these differences in herbivore composition, exclusion of large herbivores had a similar positive effect to foliose macroalgae recruitment on experimental tiles in both back-reef and lagoon habitats. Additionally, territorial damselfish found in the backreef increased turf algae cover and decreased crustose coralline algae cover on recruitment tiles. Collectively, our results show that disparate herbivorous fish communities in coral- and algaedominated habitats are similarly able to limit the recruitment of foliose macroalgae, but suggest that when herbivorous fish biomass and diversity are relatively low, macroalgal communities are able to escape herbivore control through increased growth.

Investigating Angiotensin II in cardiac remodelling and the counter-regulatory actions of Angiotensin-(1-9)

Cardiovascular diseases (CVDs) including, hypertension, coronary heart disease and heart failure are the leading cause of death worldwide. Hypertension, a chronic increase in blood pressure above 140/90 mmHg, is the single main contributor to deaths due to heart disease and stroke. In the heart, hypertension results in adaptive cardiac remodelling, including LV hypertrophy to normalize wall stress and maintain cardiac contractile function. However, chronic increases in BP results in the development of hypertensive heart disease (HHD). HHD describes the maladaptive changes during cardiac remodelling which result in reduced systolic and diastolic function and eventually heart failure. This includes ventricular dilation due to eccentric hypertrophy, cardiac fibrosis which stiffens the ventricular wall and microvascular rarefaction resulting in a decrease in coronary blood flow albeit an increase in energy demand. Chronic activation of the renin-angiotensin-system (RAS) with its effector peptide angiotensin (Ang)II plays a key role in the development of hypertension and the maladaptive changes in HHD. Ang II acts via the angiotensin type 1 receptor (AT1R) to mediate most of its pathological actions during HHD, including stimulation of cardiomyocyte hypertrophy, activation of cardiac fibroblasts and increased collagen deposition. The counter-regulatory axis of the RAS which is centred on the ACE2/Ang-(1-7)/Mas axis has been demonstrated to counteract the pathological actions of Ang II in the heart and vasculature. Ang-(1-7) via the Mas receptor prevents Ang II-induced cardiac hypertrophy and fibrosis and improves cardiac contractile function in animal models of HHD. In contrast, less is known about Ang-(1-9) although evidence has demonstrated that Ang-(1-9) also antagonises Ang II and is anti-hypertrophic and anti-fibrotic in animal models of acute cardiac remodelling. However, so far it is not well documented whether Ang-(1-9) can reverse established cardiac dysfunction and remodelling and whether it is beneficial when administered chronically. Therefore, the main aim of this thesis was to assess the effects of chronic Ang-(1-9) administration on cardiac structure and function in a model of Ang II-induced cardiac remodelling. Furthermore, this thesis aimed to investigate novel pathways contributing to the pathological remodelling in response to Ang II. First, a mouse model of chronic Ang II infusion was established and characterised by comparing the structural and functional effects of the infusion of a low and high dose of Ang II after 6 weeks. Echocardiographic measurements demonstrated that low dose Ang II infusion resulted in a gradual decline in cardiac function while a high dose of Ang II induced acute cardiac contractile dysfunction. Both doses equally induced the development of cardiac hypertrophy and cardiac fibrosis characterised by an increase in the deposition of collagen I and collagen III. Moreover, increases in gene expression of fibrotic and hypertrophic markers could be detected following high dose Ang II infusion over 6 weeks. Following this characterisation, the high dose infusion model was used to assess the effects of Ang-(1-9) on cardiac structural and functional remodelling in established disease. Initially, it was evaluated whether Ang-(1-9) can reverse Ang II-induced cardiac disease by administering Ang-(1-9) for 2-4 weeks following an initial 2 week infusion of a high dose of Ang II to induce cardiac contractile dysfunction. The infusion of Ang-(1-9) for 2 weeks was associated with a significant improvement of LV fractional shortening compared to Ang II infusion. However, after 4 weeks fractional shortening declined to Ang II levels. Despite the transient improvement in cardiac contractile function, Ang-(1-9) did not modulate blood pressure, LV hypertrophy or cardiac fibrosis. To further investigate the direct cardiac effects of Ang-(1-9), cardiac contractile performance in response to Ang-(1-9) was evaluated in the isolated Langendorff-perfused rat heart. Perfusion of Ang-(1-9) in the paced and spontaneously beating rat heart mediated a positive inotropic effect characterised by an increase in LV developed pressure, cardiac contractility and relaxation. This was in contrast to Ang II and Ang-(1-7). Furthermore, the positive inotropic effect to Ang-(1-9) was blocked by the AT1R antagonist losartan and the protein kinase A inhibitor H89. Next, endothelial-to-mesenchymal transition (EndMT) as a novel pathway that may contribute to Ang II-induced cardiac remodelling was assessed in Ang II-infused mice in vivo and in human coronary artery endothelial cells (HCAEC) in vitro. Infusion of Ang II to mice for 2-6 weeks resulted in a significant decrease in myocardial capillary density and this was associated with the occurrence of dual labelling of endothelial cells for endothelial and mesenchymal markers. In vitro stimulation of HCAEC with TGFβ and Ang II revealed that Ang II exacerbated TGF-induced gene expression of mesenchymal markers. This was not correlated with any changes in SMAD2 or ERK1/2 phosphorylation with co-stimulation of TGFβ and Ang II. However, superoxide production was significantly increased in HCAEC stimulated with Ang II but not TGFβ. Finally, the role of Ang II in microvesicle (MV)-mediated cardiomyocyte hypertrophy was investigated. MVs purified from neonatal rat cardiac fibroblasts were found to contain detectable Ang II and this was increased by stimulation of fibroblasts with Ang II. Treatment of cardiomyocytes with MVs derived from Ang II-stimulated fibroblasts induced cardiomyocyte hypertrophy which could be blocked by the AT1R antagonist losartan and an inhibitor of MV synthesis and release brefeldin A. Furthermore, Ang II was found to be present in MVs isolated from serum and plasma of Ang II-infused mice and SHRSP and WKY rats. Overall, the findings of this thesis demonstrate for the first time that the actions of Ang-(1-9) in cardiac pathology are dependent on its time of administration and that Ang-(1-9) can reverse Ang II-induced cardiac contractile dysfunction by acting as a positive inotrope. Furthermore, this thesis demonstrates evidence for an involvement of EndMT and MV signalling as novel pathways contributing to Ang II-induced cardiac fibrosis and hypertrophy, respectively. These findings provide incentive to further investigate the therapeutic potential of Ang-(1-9) in the treatment of cardiac contractile dysfunction in heart disease, establish the importance of novel pathways in Ang II-mediated cardiac remodelling and evaluate the significance of the presence of Ang II in plasma-derived MVs.

The Determinants of Individual Performance: Empirical Essays on the Importance of Soft Skills and Monetary Incentives

This dissertation consists of three papers. The first paper "Managing the Workload: an Experiment on Individual Decision Making and Performance" experimentally investigates how decision-making in workload management affects individual performance. I designed a laboratory experiment in order to exogenously manipulate the schedule of work faced by each subject and to identify its impact on final performance. Through the mouse click-tracking technique, I also collected interesting behavioral measures on organizational skills. I found that a non-negligible share of individuals performs better under externally imposed schedules than in the unconstrained case. However, such constraints are detrimental for those good in self-organizing. The second chapter, "On the allocation of effort with multiple tasks and piecewise monotonic hazard function", tests the optimality of a scheduling model, proposed in a different literature, for the decisional problem faced in the experiment. Under specific assumptions, I find that such model identifies what would be the optimal scheduling of the tasks in the Admission Test. The third paper "The Effects of Scholarships and Tuition Fees Discounts on Students' Performances: Which Monetary Incentives work Better?" explores how different levels of monetary incentives affect the achievement of students in tertiary education. I used a Regression Discontinuity Design to exploit the assignment of different monetary incentives, to study the effects of such liquidity provision on performance outcomes, ceteris paribus. The results show that a monetary increase in the scholarships generates no effect on performance since the achievements of the recipients are all centered near the requirements for non-returning the benefit. Secondly, students, who are actually paying some share of the total cost of college attendance, surprisingly, perform better than those whose cost is completely subsidized. A lower benefit, relatively to a higher aid, it motivates students to finish early and not to suffer the extra cost of a delayed graduation.

Modeling Alzheimer disease with iPSCs and mouse model for the identification of risk factors, new targets, and potential therapeutical strategies

Alzheimer's disease (AD) is the most common neurodegenerative disease in elderly. Donepezil is the first-line drug used for AD. In section one, the experimental activity was oriented to evaluate and characterize molecular and cellular mechanisms that contribute to neurodegeneration induced by the Aβ1-42 oligomers (Aβ1-42O) and potential neuroprotective effects of the hybrids feruloyl-donepezil compound called PQM130. The effects of PQM130 were compared to donepezil in a murine AD model, obtained by intracerebroventricular (i.c.v.) injection of Aβ1-42O. The intraperitoneal administration of PQM130 (0.5-1 mg/kg) after i.c.v. Aβ1-42O injection improved learning and memory, protecting mice against spatial cognition decline. Moreover, it reduced oxidative stress, neuroinflammation and neuronal apoptosis, induced cell survival and protein synthesis in mice hippocampus. PQM130 modulated different pathways than donepezil, and it is more effective in counteracting Aβ1-42O damage. The section two of the experimental activity was focused on studying a loss of function variants of ABCA7. GWA studies identified mutations in the ABCA7 gene as a risk factor for AD. The mechanism through which ABCA7 contributes to AD is not clear. ABCA7 regulates lipid metabolism and critically controls phagocytic function. To investigate ABCA7 functions, CRISPR/Cas9 technology was used to engineer human iPSCs and to carry the genetic variant Y622*, which results in a premature stop codon, causing ABCA7 loss-of-function. From iPSCs, astrocytes were generated. This study revealed the effects of ABCA7 loss in astrocytes. ABCA7 Y622* mutation induced dysfunctional endocytic trafficking, impairing Aβ clearance, lipid dysregulation and cell homeostasis disruption, alterations that could contribute to AD. Though further studies are needed to confirm the PQM130 neuroprotective role and ABCA7 function in AD, the provided results showed a better understanding of AD pathophysiology, a new therapeutic approach to treat AD, and illustrated an innovative methodology for studying the disease.

Numerical modelling of hydrodinamics and morphodynamics for the Friuli Venezia Giulia coast

Integrated Coastal Zone Management (ICZM) should be considered as one of the main components to be able to implement sustainable development. Friuli Venezia Giulia region with its 93 km of coastline is committed to investing its resources in projects aimed at studying the evolution of the coast. In this report, reference will be made to the area in front of the municipality of Grado, where the Banco della Mula di Muggia is located. Starting from previous studies and surveys, morphology of the coastal stretch between the municipality of Grado and the mouth of the Isonzo river will be reproduced through numerical modeling tools, to simulate its hydrodynamic behavior on an annual basis and also as a function of significant events such as storms, calm events or floods of the Isonzo river. The software employed will be the MIKE by DHI with in particular the implementation of "Littoral Drift" and "MIKE 21/3" Coupled models. The first to calculate net and gross longshore transport on an annual basis along a transverse profile, the latter is a modelling system for coastal application that will be used for the analysis of significant events effects. Although not primary focus of this work, there will be included an initial review of finger bars. These particular sand formations are present at the south-western border of the Banco della Mula di Muggia and may have an impact on it. This work could form the starting point of future investigations to build on the findings of this report.