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CDKL5 regulates neuronal polarization of hippocampal neurons through interaction with shootin1.
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Mechanisms involved in the adsorption of bioinsecticides and strategies to enhance their passage through the insect midgut.
No full textDuring the past decade a number of products have emerged from the effort to develop alternative biopesticidal technologies. The most recent approach to integrated pest management is based on the detection of new genes encoding for polypeptides with potential insecticidal activity, with a particular attention to biopesticides derived from viruses, microorganisms, fungi, plants and insects. Bacteria and viruses themselves can be used for biological control purpose. In most cases, biopesticides are molecules that have haemocoelic targets and must pass undegraded the gut barrier in order to exert their activity. Therefore for an effective oral delivery of these molecules it will be crucial to develop basic information on the molecular mechanisms mediating the absorption of proteins and peptides by the insect gut and to develop strategies to facilitate their passage through the midgut barrier. These issues have been the subject of my research project during these three years. In particular, I characterized the strategies adopted by Junonia coenia densovirus (JcDNV) to cross the midgut barrier of the lepidopteran pest Spodoptera frugiperda. I also studied a possible mechanism to increase the protein uptake in insect midgut characterizing the mechanisms involved in the internalization of selected Cell Penetrating Peptides (Tat, Penetratin, L-oligoarginine and D-oligoarginine) through the plasma membrane of lepidopteran larveae midgut cells. Even though these two aspects represent the main part of my PhD project, I have also collaborated to the study devoted to the identification of strategies to increase the permeability of the paracellular route
Ruolo dei polimorfismi del CYP450 1A2 negli eventi avversi da clozapina: uno studio osservazionale.
No full textObjectives: The genetically polymorphic enzyme cytochrome P450 (CYP) 1A2
contributes to the biotransformation of the antipsychotic drug clozapine (CLO). Two
polymorphisms are known to affect significantly 1A2 activity: 1A2*1F which increase
metabolism and 1A2*1C which decrease it. These SNPs, located in the promoter region
of the gene, may be responsible of a different CYP1A2 mRNA expression and could
help to explain interindividual differences in enzyme activity. Aim of these research
was to evaluate the impact of these polymorphisms on CLO pharmacokinetics and on
the occurrence of adverse reactions (ADRs).
Methods: All enrolled subjects were patients treated with CLO in our department
during the period 2008-2009. Inclusion criteria for case-group were: diagnosis of
psychotic disorder, normal liver and renal function, absence of concomitant diseases,
occurrence of significant CLO-induced ADRs. Patients who assumed CYP1A2 inducer
or inhibitory drugs, except smoking, were excluded. We considered significant CLOinduced
ADRs all reactions which led to CLO discontinuation or a permanent dose
reduction, and were related to CLO according to the clinical evaluation of the clinicians
confirmed by a “certain” or “probable” result at WHO-Uppsala criteria (WHO Uppsala
Monitoring Centre-UMC: http://www.who-umc.org). In the control-group we enrolled
patients treated for at least 1 year with CLO without showing ADRs, with the same
clinical features, matched for age, sex, CLO doses and smoking habits. Clinical
parameters were correlated with the CYP1A2 genotype and allelic combinations and
with CYP1A2 mRNA expression levels.
Results: The ratings for side effects, like sedation, constipation, scialorrea, were
significantly higher in CYP1A2 poor metabolizers genotypes.
Conclusions: Treatment with clozapine could be dangerous in extremely slow
metabolizers and ineffective in extremely rapid. Although genotyping explained only a
fraction of the adverse events, it could be a good predictor of adverse events
Temporal and spatial dynamics of organic chemicals in the environment with a multimedia fate model.
No full textIn this PhD thesis we have deal with different aspects of treatment and pathogenesis of diabetes mellitus. With regard to type 1 diabetes, we followed three different research lines clarifying aspects not yet well known on different types of patient transplants. Regarding type 2 diabetes, we studied the role of insular amyloid in the development and progression of the disease.
Transplantation is one of the possible therapies for type 1 diabetes and can be performed in patients who no longer respond to insulin therapy in satisfactory manner. For type 1 diabetes treatment there are three possible types of transplantation:
• Pancreas, often associated with kidney transplantation, is the only treatment for type 1 diabetes that can maintain long-term insulin independence and normoglycemia. In type 1 diabetes patients, chronic hyperglycemia leads to both microvascular and macrovascular damages probably due to overproduction of superoxides by the mitochondrial electron transport chain. In patients subjected to pancreas transplantation, it has been noted improvements in the microcirculation and in particular at the level of endothelial cells. In order to identify possible mechanisms by which transplantation improves microcirculation, we analyzed the expression of proteins involved in cellular response to oxidative stress in skin biopsies. According to the results obtained in our studies, some of the identified proteins may be considered as therapeutic targets for a new class of drugs, potentially able to correct cell modifications in cases where normoglycemia cannot be restored.
• Human purified pancreatic islet transplantation. The transplantation of human islets can successfully restore long-term insulin independence and improve glycemic control. However, the number of patients that remain insulin-independent decreases gradually in 2-3 years. Several hypotheses have been formulated in order to explain this negative response. One hypothesis is the “functional exhaustion" of a chronically overstimolated β cells mass. To better understand this possible mechanism, we studied at morphological, immunohistochemical and ultrastructural level the pancreatic islets before and after human islet cells transplantation in athymic nude mice made diabetic.
• Stem cell transplantation. Stem cells seem to be the new frontier for the treatment of type 1 diabetes. Several stem cell types have been identified as potential progenitors of pancreatic β cells and mesenchymal stem cells (MSC) seem to be a possible source of them. In addition, MSCs have immunomodulatory effects as demonstrated in several researches in which these cells have been used to reduce
the burden of a variety of immune-mediated diseases. Since type 1 diabetes is an autoimmune disorder, we explored the possibility to use MSCs transplantation as a therapeutic approach. For this reason, we characterized MSCs obtained from diabetes susceptible (NOD) mice and from diabetes-resistant (BALB/c) mice. After, we injected MSCs into pre-diabetic NOD mice and we evaluated their immunomodulatory effects in vivo.
It has been demonstrated that amyloid deposits are one of the main morphological alteration of the islets of Langerhans in patients affects by long-standing type 2 diabetes. Typically, islet amyloid derives from deposition of amylin which is synthesized and stored in pancreatic β cells together with insulin. Amylin is produced as a pro-peptide and cut by specific proteases. It has been showed in Alzheimer's patients that the protease BACE 1 is involved in amyloid plaques production. In addition, a BACE 1 homologue called BACE 2 has been identified and localised in most adult tissues such as the pancreatic one. However, the role of BACE 2 still remains unclear. By using immunohistochemical, ultrastructural and immunocytochemical techniques, we identified and localised BACE 2 in secretory granules of mice and rats pancreatic β cells. The data collected in our studies could be considered as a starting point for further investigations on human normal and diabetic pancreases. For instance, the correlation between BACE 2 expression and amyloid deposition could help to better understand a possible role of BACE 2 in islet amyloidosis and consequently could improve our understanding of the type 2 diabetes disorder.
However, it is not yet clear if amyloidosis is a primary or secondary event in the pathogenesis of diabetes. In order to better understand this situation, we used the Papio hamadryas (baboon) as an in vivo model. Indeed, baboons spontaneously develop type 2 diabetes associated with obesity as in humans, hypothesizing a similarity in diabetes pathogenesis between the two species. Our results strongly support that the insular amyloidosis associated with β cell apoptosis, α cell proliferation and hypertrophy are determinants of islets dysfunctional remodeling and hyperglycemia in baboons. In addition, our studies allow to hypothise a correlation between severity of amyloidosis, age and fasting plasma glucose levels
La nascita del culto mariano a Bisanzio e l'immagine parentale del potere imperiale.
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The observability of isolated neutron stars and black holes.
No full textThe detection of old neuron stars and black holes in isolation is one of the cornerstones of compact object astrophysics. However, forty years after the first pioneering studies, no succesful candidates have been found to confirm the early predictions, making the search for old isolated compact objects a still open and intriguing subject. The scope of this thesis is thus to investigate the observability of isolated neutron stars and black holes with the final objective of defining new possible strategies for the long sought detection of these elusive objects.
The thesis is organized as follows. In Chapter 1, after a short discussion on the origin of neuron stars and stellar mass black holes in isolation, I summarize the results of past efforts made to constrain their observational properties.
In Chapter 2 I tackle with the dynamics of isolated neutron stars. I describe the set up of a numerical Monte Carlo code, named Population Synthesis of Compact Objects (PSYCO in brief), developed as part of the PhD project. I then present the results of the simulation with particular emphasis for statistical properties of neutron stars in the Galactic disk and in the solar neighbourhood. These first results will be used as base to explore alternative methods to detect old neutron stars and black holes. It should be noted that, following the standard practice, these first results are obtained considering only neutron stars born in the disk of the Milky Way. As it will be shown in Chapter 3, the contribution of neutron stars, and black holes, born in the Galactic bulge cannot be neglected since they could represent the majority of detectable objects.
In Chapter 3 the feasibility of microlensing as a technique to detect isolated neutron stars and black holes is explored, making use of the results illustrated in the previous Chapter. After an overview of results obtained so far by the several surveys, I describe the basic microlensing quantities and expressions. I then describe the models adopted in my work for the distribution of bulge and disk stars, to which the contribution of neutron stars and black oles is then compared to. I compare the optical depth and event rate due to neutron stars and black holes with that of normal stars. Also, I study the distribution of event time scales in both cases.
After the results reported in Chapter 3, in Chapter 4 I present a systematic cross correlation analysis of microlensing events with the catalogues of X-rays sources of the XMM-Newton and Chandra satellites, which appeared recently. I report the results of the cross correlation and the properties of a source resulting from the cross correlation procedure.
Finally, in Chapter 5 I review the results of my PhD project and draw the final conclusion. I also discuss possible future developments
Analisi dei dati di consumo e del flusso informativo dei farmaci rendicontati tramite File F nell’ambito dei rimborsi della spesa farmaceutica: il modello applicato all’Azienda Ospedaliera di Varese.
No full textins ricorda che il dottorato sarebbe in farmacologia e farmacoepidemiologi
Semantics foundations for constructive description logics.
No full textIn this work we present our contributions to the study of semantics foundations for constructive description logics. In particular, we propose a Kripke style semantics for the basic description logic ALC, and we give a sound and complete tableau calculus for this semantics.
Then we exploit an information term semantics for description logics to formalize an action language for ALC. Finally, we define a semantics for ALC which is directly inspired by the Kripke style semantics for intuitionistic modal logics and we give a sound and complete tableau calculus for this semantics
Plant DNA analysis for forensic and environmental purposes.
No full textAmong the disciplines included by forensic science, forensic biology is one of the most applied, particularly for human identity testing.
But other biological evidence can be found at a crime scene, which can possibly be helpful to solve the case and among the possibilities a very frequent one is the presence of plant material. Since the same molecular techniques used for human DNA are suited for plant DNA, they can be used to establish links between the victim, the suspect and the crime scene.
In the last decade a good amount of knowledge about the genetic structure of many plant species has been made available, whose provenance is mainly from population and conservation genetics studies. In fact, the assessment of the amount and distribution of genetic diversity and of the kind of differentiation in a given species are useful tool to understand evolutionary issues and to plan sound conservation strategies.
The aim of this project has been therefore to investigate the limits and potentials of forensic botany, still under-utilized in forensic casework, and investigate the use of the same genetic data for the floristic heritage management. The main species chosen was Turkey Oak (Quercus cerris L.), because of its wide distribution on the Italian territory and its ecological importance. A total of 509 trees from 16 populations have been sampled and genotyped by 8 heterologous microsatellites or SSRs (Single Sequence Repeats).
The amount of variability and genetic differentiation within and among populations was estimated, and the genetically homogenous groups were identified by the Bayesian clustering method. The species appears derived from no more than two homogeneous gene pools of origin and displays low differentiation (FST = 0.057), this indicating that the colonization of the Italian peninsula after the last glaciation is still under way.
Analysis of molecular variance (AMOVA), performed to partition the total genetic variation among the regions indicated by the Bayesian analysis revealed a significant amount of variability between the populations derived from the two putative gene pools.
The low differentiation observed between the Turkey oak populations unfortunately prevents this species from being a good candidate to be used as forensic tool. However, a population assignment test indicated that some welldifferentiated populations can be easily recognized by a multilocus genotyping.
Finally, after necessary authorization, we applied the knowledge acquired till now to a murder casework analyzing, by means of 4 SSRs, leaves of Hophornbeam tree (Ostrya carpinifolia Scop.), found near the corpse of a young woman. In this second case, albeit the area under study was small and the genetic information non-existent in this species, we were able to pinpoint the provenance of the leaves to a specific tree present on the crime scene
Pharmacological properties of the phytocannabinoids Δ9-tetrahydrocannabivarin and cannabidiol.
No full textCannabis and its derivatives have been used for medicinal purpose for thousand of years. More recently, the main cannabis constituents, cannabinoids, have been found to act and target at cannabinoid as well as other receptors. This brought particular interest around the pharmacology of phytocannabinoids and their possible clinical applications. The research object of this study focused on two phytocannabinoids, Δ9-tetrahydrocannabivarin (Δ9-THCV) and cannabidiol (CBD), and it has been divided in three individual investigations:
In the first study, we investigated the pharmacology of Δ9-THCV at cannabinoid type 1 (CB1) and type 2 (CB2) receptors. We found and confirmed that Δ9-THCV acts as antagonist at CB1 receptors in experiments of [35S]GTPγS binding assay on human CB1-CHO (Chinese hamster ovary) cell membranes. Also, in the same set of experiments, Δ9-THCV displayed a slight inverse agonism at CB1 receptors, which was confirmed in experiments of cyclic AMP assay in hCB1-CHO cells. At CB2 receptors, we found that Δ9-THCV can behave as a partial agonist when the measured response is inhibition of forskolin-induced stimulation of cyclic AMP production in hCB2-CHO cells or stimulation of [35S]GTPγS binding to membranes obtained either from hCB2-CHO cells or from mouse spleen membranes. No such effect was displayed by Δ9-THCV in untransfected CHO cells, pertussis toxin (PTX)-treated hCB2-CHO cells or CB2 -/- mouse spleen membranes.
In collaboration with Dr. Barbara Costa and Dr. Dino Maione, we also showed that Δ9-THCV shares the ability of established selective CB2 receptor agonist to reduce signs of inflammation and inflammatory pain (Guindon, Hohmann 2008). These experiments were performed on in vivo models of λ-carrageenan-induced oedema and thermal hyperalgesia, and formalin-induced nociception.
In the second investigation we brought further evidences that Δ9-THCV is a partial agonist at CB2 receptors. In detail, we applied a protocol to hCB2-CHO cells in order to convert the selective CB2 receptor antagonist/inverse agonist, AM630, into an apparent neutral antagonist. In these experimental conditions, we found that Δ9-THCV still behaves as a CB2 receptor agonist and is antagonized by AM630 in experiments of cyclic AMP assay. Additional tests were also conducted to better understand the pharmacology of the ligand, AM630, at CB2 receptors.
In the third study, we investigated the effect of CBD at serotonin type 1A (5-HT1A) autoreceptors. This research was based on previous in vivo findings showing that CBD-induced anti-emetic and anti-nausea effects were mediated by somatodendritic 5-HT1A autoreceptors located in the raphe nuclei (Rock et al. 2009, Parker et al. 2010). Experiments of [35S]GTPγS binding conducted in rat brainstem membranes revealed that CBD, in a bell-shaped manner, is able to enhance the dose-response curve of the selective 5-HT1A receptor agonist, DPAT. In addition, our results suggest that CBD does not interact directly with 5-HT1A receptors, and that CBD-mediated DPAT dose-response curve enhancement might implicate the involvement of an other receptor