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Diet, genetic and epigenetic signatures in women of childbearing age from a Mediterranean population: perspectives for public health
No full textThe aim of the study was to determine the association between Mediterranean diet (MD), folate intake and global DNA methylation in women of childbearing age.
A total of 177 women were enrolled in a cross-sectional study. Folate intake and MD were assessed by a validated food frequency questionnaire. LINE-1 methylation level in leukocytes was measured by pyrosequencing.
Women reported poor adherence to MD (mean value 4.1) and high prevalence of folate deficiency (83.1%). Mean level of LINE-1 methylation was 65.3%. A strong association between folate deficiency and global hypomethylation, was found: women with folate deficiency had a 4 fold increased risk to be hypometylated compared with women with no folate deficiency (OR = 4; 95% CI: 1.3 11.8). In multivariate analysis, the association decreased with a borderline confidence interval (p=0.053, OR = 3; 95% CI: 1 3.3).
Poor adherence to MD was not directly associated with global methylation level, however, women whose consumption of fruit was below the median (201 gr/day) had a 2.8 fold increased risk to be hypometylated in comparison with those women whose consumption was above the median value (OR = 2.8; 95% CI: 1.3 5.8; p=0.019). In multivariate logistic regression analysis, results, adjusted for age, nutritional status, smoking habits and dietary caloric intake, showed a significant relationship between low fruits intake and low methylation level (p = 0.006; OR = 3.8; 95% CI: 1.5 9.7).
The inverse association between high consumption of fruit, which represents a mainsource of folate, and DNA hypomethylation, suggests that dietary pattern characterized by a high intake of fruits and, in a broader view, great adherence to MD may protect against DNA hypomethylation
Implications of dopamine D3 receptor for glaucoma: in-silico and in-vivo studies
No full textGlaucoma is a progressive optic neuropathy and it is considered by the World Health Organization to be the cause of 12% of visual impairment and 2% of blindness. Glaucoma is characterized by alterations of optic disc and visual field. High intraocular pressure (IOP) is the main risk factor of glaucoma. IOP reduction represents the first step in the management of glaucoma which is eventually followed by laser surgery of the trabecular meshwork (TM) and glaucoma-filtering surgery.
Currently, there are five main classes of approved ocular hypotensive drugs: beta-blockers, carbonic anhydrase inhibitors, prostaglandin analogs, sympathomimetics and miotics. However, there is still the need to have more potent medications available for this disease.
In the panorama of pharmacological targets for regulation of IOP, there are some interesting G protein coupled receptors (GPCRs) such as dopaminergic receptors. The work of the present thesis has been focused on GPCRs and in particular on dopamine D3 receptor as pharmacological target for ocular hypotensive drugs. Cabergoline, bromocriptine, cianergoline and legotrile, classical D2 receptor agonists, have been shown to decrease intraocular pressure. D3 receptor belongs to the D2 class of dopaminergic receptors, along with D2 and D4 receptor. It shares high sequence homology and identity with D2 receptor and several efforts have been carried out in order to design selective ligands for either D3 or D2 subtype. Drug design and discovery, based on structure based approach, need the knowledge of the tertiary structure of the target protein. In 2010 the x-ray structure of human D3 receptor (mutated hD3-lysozime chimera) was solved, then this structure was used to carry out the homology modeling of wild-type (wt) hD3 and hD2L receptors. The homology models of these receptors were not able to discriminate selective ligands by a molecular docking study, thus these structures have been subjected to optimization by means of molecular dynamics in a water-membrane environment. After optimization the structures differentiated in the binding pockets and have been validated, strengthen the validity and reliability of the in silico approach. A similar computational approach was carried out in order to study the structure differences between the D3 receptors and 5HT1A, 5HT2A-C receptors, known to be involved in regulation of intraocular pressure.
The role of D3 receptor activation by cabergoline in lowering IOP was confirmed in C57BL/6J wt and D3-/- mice, using a pharmacological approach along with D3 gene deletion. Cabergoline was not effective in ocular hypertensive D3-/- mice, whereas exerted a greater and longer hypotensive effect in ocular hypertensive wt mice, in comparison to normotensive animals. The in silico approach, validated for D3 and D2L receptors, has been used to model and optimize the structures of 5HT1A, 5HT2A-B-C receptors which are other putative ocular targets of cabergoline. In silico results showed that cabergoline binds in a similar way into pockets of D3 and 5HT2A-C and it has higher affinity for D3 receptor in comparison to serotonergic receptors, according to experimental affinity data. Moreover docking revealed that binding of cabergoline into D3 and 5HT1A receptors is associated with a better desolvation energy in comparison to 5HT2A C binding.
The structure-based computational approach hereby adopted was able to build, refine, and validate structure models of homologous dopaminergic and serotonergic receptors that may be of interest for structure-based drug discovery of ligands, with dopaminergic selectivity or with multi-pharmacological profile, potentially useful to treat optic neuropathies such as glaucoma.
Finally, the present work represents an excellent example of successful integration of two different approaches to biomedical research, in silico and in vivo, which are not in contrast but complementary
Analysis of the involvement of exosomal miRNAs and proteins in the response of CRC cells to Cetuximab
No full textIt has been demonstrated that intercellular communication via cell- released vesicles is very important both for normal and tumor cells, and specifically to determine tumor development and progression as well as invasion and angiogenesis. Cell communication could involve the exosomes, small vescicles of endocytic origin, which are released from different kinds of donor cells; they can transfer molecular signals as proteins and RNAs through the extracellular environment to specific recipient cells in a autocrine, paracrine or endocrine way. Exosomes can strongly influence the recipient cells phenotype by transferring oncogenes that could influence the response of cells to drugs or immune reactions. Recently, it has been demonstrated the presence of miRNAs inside the exosomes and their potential involvement in cancer development. Considering the important role of miRNAs in colorectal cancer, one of the most diffused and studied tumor, it was considered interesting to investigate the role of exosomal miRNAs and associated proteins in the response of CRC cells to Cetuximab (an anti-EGFR therapeutic antibody). The EGFR signaling pathway is very importantly in relationship both to CRC and miRNA biogenesis and expression, and recently also to the exosomal communication system. Therefore, one of the major aims of this thesis was to analyze the possible involvement of exosomes in the response to Cetuximab of two CRC cell lines (wild-type KRAS Caco-2 cells and KRAS mutated HCT-116 cells) through the transfer of specific miRNAs and proteins to recipient cells. To carry out this analysis, we performed cellular and exosomal miRNA profiling after Cetuximab treatment, for 745 miRNAs by using Real-Time PCR. The results of the analysis showed that exosomal miRNA profiles globally reflect those of whole cells at steady-state, but there exists an important quantitative asymmetrical distribution. After Cetuximab treatment, Caco-2 sensitive cells showed several exosomal differentially expressed (DE) miRNAs in comparison to HCT-116 cells. Many DE miRNAs are involved in cancer and immunity. These data could be explained by considering that the EGFR pathway can regulate miRNA biogenesis via the MAPK/ERK cascade. Exosomal proteins analysis was performed for 741 cancer-related proteins through a specific antibody microarrays platform. Also the profile of exosomal proteins from Caco-2 cells showed important alterations after Cetuximab treatment. Globally, several DE miRNAs and proteins from Caco-2 exosomes were related to cancer, stimulation of immunity and inflammation. Interestingly, exosomes transfection experiments between Caco-2 and HCT-116 cell lines (performed to investigate their effect on cell viability) showed that the transfection of steady state Caco-2 exosomes in the HCT-116 cell line determined a decrease of cell viability of recipient cells, while Cetuximab-treated Caco-2 cells exosomes, transfected in HCT-116 cells, increased their viability. These data could be explained considering that exosomes from Cetuximab-treated cells are enriched in oncogenic- and immune stimulation-related miRNAs. Finally, DE proteins were searched to find potential RNA-binding proteins. Globally, the results of this thesis could be useful to: (1) verify the existence of horizontal transfer of genetic informations in eukaryotes; (2) search for potential miRNAs and proteins biomarkers of Cetuximab response in CRC in vivo. Eventually, it will be interesting to perform the characterization of exosomal miRNAs and proteins expression profiles of plasma from CRC patients after Cetuximab treatment. Moreover, the characterization of the asymmetrical distribution of miRNAs between cells and exosomes could be important to further investigate the potential and specific mechanism of miRNA sorting within exosomes
"Dalla violenza endofamiliare allo stalking"
No full textScopo di questa ricerca è una descrizione di alcune dinamiche che si riscontrano all interno delle famiglie che presentano delle problematiche di violenza domestica e di stalking, inteso non come un fenomeno isolato e determinato ma come un punto lungo un continuum preceduto da vessazioni e violenze di varie forme. Gli studi di cui la letteratura ci porta a conoscenza di stampo psicologico e criminologico si sono incentrati, perlopiù, sull individuazione di un certo profilo del reo, su dipendenze patologiche e su analisi circa la complementarità dei profili personologici dei membri della coppia patogena, che appaiono avere un significato rilevante sull andamento della spirale di violenza.
Soprattutto, essi si sono soffermati sulla presenza degli script che si identificano all interno di queste famiglie e come questi si ricolleghino alla formazione dei legami di attaccamento che si creano tra i membri della famiglia stessa. I risultati più significativi emersi da tali analisi indicano che esiste una correlazione tra tipo di legame stabilito dai soggetti con i genitori, tipologia di famiglia di provenienza e la condizione attuale.
Nello specifico, essi concludono che stile di attaccamento e tipologia familiare sono determinanti nella spiegazione dell aggressività all interno della famiglia.
In questi studi emerge una complementarità del tipo di seguito riportato:
lo stile di attaccamento della vittima è di tipo insicuro-evitante. Detto attaccamento è tipico della famiglia disimpegnata-rigida e si accoppierebbe, in maniera complementare, allo stile insicuro-ambivalente dell aggressore, proveniente quest ultimo da una tipologia familiare invischiata-caotica .
Gli studi sulla formazione della coppia basati sulla teoria dell attaccamento confermano che gli accoppiamenti avvengono tra sicuri e tra insicuri: i sicuri tenderebbero, dunque, ad avere compagni altrettanto sicuri, cosi come gli insicuri evitanti si accoppierebbero con gli insicuri ambivalenti, salvo poi concludere, nonostante le correlazioni esplicitate, che lo stile di attaccamento può variare nel corso della vita e che tutti gli accoppiamenti sono possibili.
La nostra ricerca, alla luce di analisi secondarie delle storie delle vittime di violenza intrafamiliare unitamente ai fatti riportati dalla cronaca, ha mostrato qualche perplessità circa la necessaria complementarità degli stili di attaccamento tra vittima e reo e circa la correlazione tra il loro attaccamento e la tipologia familiare percepita, ritenendo dubbia l inferenza all universo di riferimento, dal momento che la stessa teoria riserva margini di mutamento che rendono problematica, a nostro avviso, ogni tipo di classificazione.
L indagine empirica condotta ha tentato di testare le classificazioni fornite dai succitati studi, giungendo ad allontanarsene per pervenire all emersione di una realtà trasversale declinata in termini prevalentemente culturali
Role of Acetyl-L-Carnitine in Hepatic Encephalopathy
No full textHepatic encephalopathy is a common complication of hepatic cirrhosis. The clinical diagnosis is based on two concurrent types of symptoms: impaired mental status and impaired neuromotor function. Impaired mental status is characterized by deterioration in mental status with psychomotor dysfunction, impaired memory, and increased reaction time, sensory abnormalities, poor concentration, disorientation and coma. Impaired neuromotor function include hyperreflexia, rigidity, myoclonus and asterixis. The pathogenesis of hepatic encephalopathy has not been clearly defined. The general consensus is that elevated levels of ammonia and an inflammatory response work in synergy to cause astrocyte to swell and fluid to accumulate in the brain which is thought to explain the symptoms of hepatic encephalopathy. Acetyl-L-carnitine, the short-chain ester of carnitine is endogenously produced within mitochondria and peroxisomes and is involved in the transport of acetyl-moieties across the membranes of these organelles. Acetyl-L-carnitine administration has shown the recovery of neuropsychological activities related to attention/concentration, visual scanning and tracking, psychomotor speed and mental flexibility, language short-term memory, attention, and computing ability. In fact, Acetyl-L-carnitine induces ureagenesis leading to decreased blood and brain ammonia levels. Acetyl-L-carnitine treatment decreases the severity of mental and physical fatigue, depression cognitive impairment and improves health-related quality of life. The aim of this review was to provide an explanation on the possible toxic effects of ammonia in HE and evaluate the potential clinical benefits of ALC
Sviluppo di algoritmi di ricostruzione utilizzabili da telescopi per neutrini e risultati ottenuti con il rivelatore KM3NeT
No full textNeutrino-astronomy is one of the most interesting frontiers of the astro-particle physics.
Neutrino telescopes detect neutrinos indirectly through charged leptons produced in weak charged current interaction. In transparent media, tracks of relativistic particles can be reconstructed detecting light produced via Cherenkov effect, with 3D arrays of optical sensors.
At present the most sensitive neutrino telescope in the world is the IceCube detector at the South Pole, that recently has reported evidence of a flux of cosmic high energy neutrinos exceeding the expected flux of atmospheric neutrinos by a statistically significant factor, de facto opening a new era of neutrino astronomy.
KM3NeT will be the next-generation cubic kilometers scale neutrino telescope to be installed in the depths of the Mediterranean Sea. With several cubic kilometers of sea water instrumented with thousand of optical sensors, KM3NeT will be the most sensitive high energy neutrino telescope, with a sensitivity exceeding that of IceCube by a substantial factor.
The construction of KM3NeT is based on a novel type of optical sensor, the Digital Optical Module, realised by arranging many small photomultipliers inside a pressure resistant glass sphere. This concept allows better performances with respect to the standard single large-area photomultiplier used in Antares and IceCube, since photon counting and directionality are possible due to photocatode segmentation.
The aim of this work was to develop a new muon track reconstruction procedure appropriate for such a detector and evaluate the performances of the telescope through a complete Monte-Carlo simulation.
Using this algorithm, the detector sensitivity (flux that can be excluded at 90% CL) and discovery potential (flux that can be detected at 5 sigma or 3 sigma above the background noise) for two galactic sources that appear to be the best candidates neutrino sources, the Supernova Remnants RXJ1713.7-3946 and Pulsar Wind Nebula Vela X, have been evaluated. The observation time required for the discovery of these sources at 5 sigma is about 5 year (2 years at 3 sigma) for the RXJ1713.7-3946 and about 3 years (1 year at 3sigma) for the Vela X. This analysis leads to the conclusion that at least the more intense galactic sources are at reach for KM3NeT.
Recently it has been also proposed to exploit underwater Cherenkov neutrino telescopes to investigate the neutrino mass hierarchy by studying atmospheric neutrino oscillations at low energies (about 10 GeV). To perform such studies an as much as possible accurate determination of the neutrino energy and of the zenith angle are crucial. This requires a much denser array of photosensors with adequate containment conditions. First simulations show that with an effective volume of 3 Mton and an observation time of 5 years a significance of 3 sigma (5 sigma) can be achieved if the energy resolution is 25% (10%), assuming only contained events and a perfect knowledge of the muon zenith angle.
To approach these assumptions an ad hoc reconstruction algorithm has been developed and is presented in this thesis. This algorithm allows to identify with an error of a few meters the interaction vertex that is used for the containment conditions. The error on the reconstructed zenith angle is less than 1 degree above about 8 GeV. The muon energy is reconstructed through the muon track length allowing to achieve a neutrino energy resolution of about 35% at 10 GeV. Further improvements are expected by including also the reconstruction of the hadronic shower, which will require a dedicated algorithm that has not yet been developed. The contamination due to electron and tau neutrino still needs to be considered
Knowledge bases and stochastic algorithms for mining biological data: applications on A-to-I RNA editing and RNAi
No full textUntil the second half of twenty century, the connection between Biology and
Computer Science was not so strict and the data were usually collected on
perishable materials such as paper and then stored up in filing cabinets.
This situation changed thanks to the Bioinformatics, a relatively novel
field that aims to deal with biological problems by making use of computational
approaches. This interdisciplinary science has two particular fields of
action: on the one hand, the construction of biological databases in order to
store in a rational way the huge amount of data, and, on the other hand, the
development and application of algorithms also approximate for extracting
predicting patterns from such kind of data.
This thesis will present novel results on both of the above aspects. It
will introduce three new database called miRandola, miReditar and VIRGO,
respectively. All of them have been developed as open sources and equipped
with user-friendly web interfaces.
Then, some results concerning the application of stochastic approaches on
microRNA targeting and RNA A-to-I interference will be introduced
A stochastic approach to safety management of roadway segment
No full textThe targets of the thesis are road safety analysis based on crash event and road features for the benefit cost analysis where a treatment has to be applied.
There is a growing attention to road safety in Europe. New regulations applied on TERN network push Agencies to introduce new methodological approaches to Road Safety, monitoring the treatment and controlling the level of safety on the managed road network.
The regression to the mean effect as well as the functional relationship between crashes and exposure factors don t allow a reliable estimation of the effect of a treatment. Have a high reliability in the estimation of the effects of a countermeasures should be one of the most important issue in a Benefit-Cost analysis. The traditional techniques don t take into account the possible site to site variability of a treatment applying a deterministic approach to the problem. The present research work seek to address this issue introducing in the Benefit-Cost analysis a variability accounted by the cross site variance of the investigated treatment. The comparison between the stochastic and the determinist approach shown a general overestimation of the benefit of the latter. To do this two different methodologies were introduced either for existing infrastructure or for new infrastructure. For the latter a further variability for the predicted crashes was introduced in the computation of the possible benefit and loss. Furthermore a Montecarlo simulation was performed to consider the combination of two different Crash Modification Factor in the benefit-cost analysis
Uwb-based real-time location system performances for cow identification and localisation and cow's location data analysis and management in free-stall barns
No full textThe main objective of this study was to evaluate the localisation and identification performances of a Real-Time Location System (RTLS) based on
Ultra Wide Band (UWB) technology within a free-stall barn which represents
a particularly harsh environment for the functioning of this kind of
system. Each dairy cow was equipped with an active tag applied to one ear.
A video-recording system was installed in the barn to perform the assessment
of the RTLS. Top-view camera images of the area of the barn under study
were rectified and synchronised with the RTLS. Each position of the cow
computed by the RTLS was validated by performing cow visual recognition
on the camera images.
To perform this validation a software specifically designed for the purpose
was utilized. It is a quick, accurate, automatic and interactive tool which
includes selection and control tabs for data management, visualization and
labelling of the images with the aim of the computation of the tag true
positions.
Localisation and identification performances of the RTLS were assessed
by applying an outlier data cleaning technique to tag localisation errors and
using precision and sensitivity indices. Trade-off between these performances
was found through the computation of three performance metrics.
The results showed that, in the environmental conditions of the barn, the
RTLS produced errors which were comparable to the errors declared by the
RTLS producer for the fixed reference tag whereas localisation errors related
to the tags in movement were higher and, in detail, a mean error of 0.56 m
and an error at the 90th percentile of 1.03 m were obtained.
Outlier data cleaning produced significant improvements of the results by
reducing the average localisation error of about 0.046 m for the cows tags and
made data distribution more homogeneous. Trade-off of RTLS performances
yielded an average localisation error equal to about 0.52 m with a position
accuracy of 98% for cows tag and an error of about 0.11 m with a nearly
100% accuracy for the reference tag.
RTLS performances in the considered environment proved to be generally
not dependent on cow behaviour, as it is observed for other systems, and that
RTLS is suitable to determine the occupancy level of the different functional
areas of the barn, compute cow behavioural indices, and track each animal
of the herd.
An automatic and real-time software tool for the visual analysis of the
cows location data in free-stall barns acquired by the RTLS was designed and
developed. A visual representation used for visualizing two dimensional data
of each cow using colours was implemented as a functionality of this tool.
The different colour and colour intensity denoted the difference in sample
density at a location. Measurement of the instant speed of each cow over the
time, represented through an interactive graph, was another functionality
implemented in this software.
The results obtained by a use case of this software tool, which was carried
out in order to acquire useful informations related to the occurrence of estrus,
showed that a pattern, related to the behaviour of the cow analyzed, can be
identified when the state of estrus occurs. Moreover, since it was designed
to monitor cow behavior in real time, it offers the ability, by adding new
control modules, to notify any inconvenience through alert messages as a
result of changes in dairy cow behaviour and, therefore, it is possible to alert
the farmer in real time
Le complicanze chirurgiche de trapianto renale. La laparoscopia può essere d'aiuto?
No full textL incidenza delle complicanze chirurgiche del trapianto renale è notevolmente diminuita nel corso degli ultimi anni; e questo non solo grazie all evoluzione dei mezzi diagnostici e ad una migliore conoscenza dei farmaci immunosoppressori ma anche grazie all evoluzione delle tecniche chirurgiche. Le complicanze più comuni si verificano nella maggior parte dei casi nel precoce periodo postoperatorio, mentre altre si manifestano diversi anni dopo.
L'inizio della moderna urologia è segnata da due tappe fondamentali, la prima nefrectomia laparoscopica per via transperitoneale che risal agli inizi degli anni Novanta, descritta da Clayman e la prima nefrectomia eseguita per via retroperitoneale eseguita nel 1993 da Gaur con accesso diretto senza passare attraverso la cavità peritoneale. Oggi la nefrectomia laparoscopica è un intervento largamente diffuso in quasi tutti i Centri che praticano routinariamente la chirurgia laparoscopica. Dopo una prima fase di incertezze, legata ad una ancora non ben nota conoscenza dei risultati a distanza, oggi questa procedura è indicata anche per patologie oncologiche.
La tecnica della nefrectomia laparoscopica su donatore vivente ha rivoluzionato il trapianto renale, infatti permette, riducendo la morbilità chirurgica pur mantenendo le possibilità di un buon risultato nel ricevente, di aumentare il numero dei donatori. Questa tecnica divenuta il metodo di prelievo di riferimento nei centri di trapianti in tutto il mondo, non presenta controindicazioni assolute.
Scopo della tesi sarà attraverso una revisione della letteratura, individuare l'evidenza clinica delle complicanze chirurgiche dopo prelievo renale rispetto alle precedenti tecniche con particolare attenzione ai diversi aspetti relativi sia al donatore che al ricevente in termini di morbilità e di mortalità.
Sulla base di una attenta analisi dell'esperienza clinica si è focalizzata l'attenzione sui problemi tecnici legati al prelievo del rene, sulla comparsa di linfoceli, sulle complicanze vascolari, urinarie e su quelle di ordine generale.
La casistica osservata include pazienti (maschi e femmine) di età media tra i 20-70 anni sottoposti ad intervento chirurgico eseguito per complicanze dopo prelievo renale laparoscopico e non, nel periodo che va dal 2003 al 2013.
Sono stati raccolti e analizzati vari fattori, quali la tecnica operatoria precedentemente utilizzata, il tipo di complicanze, l'anno del prelievo, il tipo di trattamento effettuato per complicanze e il periodo post operatori