1731 research outputs found
Sort by
Purification and detection of cancer-related miRNAs in microdevices
No full textMicroRNAs (miRNAs) are short non-coding RNAs, whose primary function consists in mRNA silencing. Mature miRNAs are found in the cytoplasm as single-stranded molecules but there is growing evidence that miRNAs can be excreted by cells, mainly encapsulated inside exosomes, in almost all body fluids. It has also been shown that the level of expression of some of these circulating miRNAs (e.g. miR-21) varies significantly under pathological conditions such as in the presence of cancer. Circulating miRNAs are therefore emerging as promising non-invasive diagnostic and prognostic tumour biomarkers. Nevertheless, current methods for the purification of circulating miRNAs are challenging, mainly due to low body fluid concentration, variability, and quantification limits. This thesis aimed at developing and studying an innovative miniaturised strategy for the purification and detection of cancer-related circulating miRNAs. The employment of microdevices could provide a faster, simpler and low-cost alternative to the current laboratory procedures for the analysis of extracellular miRNAs. The solid-state miRNA purification method shown here is based on the introduction of chemical and morphological modifications on the surface of an adequate substrate (silicon, PDMS). In particular, surface functionalisation with organic molecules carrying charged functional groups was employed to establish specific interactions with the electrical charged moieties of miRNAs. Modulation of the charge density and morphology will be allowed by the additional introduction of neutral organosilanes characterised by different chain length.
In this thesis, a detailed chemical and morphological characterisation of the modified planar surfaces is presented and correlated with the capacity to selectively purify miRNAs from a complex biological sample. The most efficient condition was implemented on a PDMS microdevice and further coupled with a sensitive detection technique (RT-qPCR). The performances of our purification system will be eventually tested with both synthetic miRNAs and biological samples
Public R&D Policy Impact Evaluation:Propensity Score Matching and Structural Modeling Estimations
Get PDFThis dissertation is about public research and development (R&D) subsidies to support private firms doing innovative activities and quantitative impact evaluation of the policy on total factor productivity (TFP) change and additional R&D effort. Public R&D subsidization as a public R&D policy, beside different types of public interventions, has been widely used by governments to stimulate private R&D. These policies aim to fill the gap between the private and social rates of returns by encouraging business enterprises to spend on additional R&D, produce more innovation output and inventions, or change their innovative behavior. These changes can be carried out either individually or in collaboration with other entities. One ultimate goal of R&D policy is increasing the total factor productivity and relative performance both at firm and aggregate levels. This study deals with direct place-based public R&D subsidies and empirically measures the effects of this type of public incentives on productivity growth and R&D input additionality. In order to evaluate the policy effect, a quasi-experimental counterfactual setting for subsidized (treated) and non-subsidized (non-treated) firms can be framed thank to the characteristics and mechanism of the local R&D program in the Province of Trento in Italy. The average treatment effect of the policy on target variables is measured for subsidized units (Average treatment effect on treated: ATET) and for the whole population of the firms (Average treatment effect: ATE), using techniques capable of tackling the problems of endogeneity and selection bias which arise in empirical evaluation studies.
Propensity score matching (PSM) and structural modeling methodologies are used to measure the effects of the R&D subsidies on target variables, TFP change and additional R&D expenditure, respectively. The former approach is non-parametric and does not assume a functional form for the effect of policy on R&D and productivity change, while the latter models the optimizing behavior of the firm (agent) and the public agency, searching for an equilibrium in a pre-determined game theoretical framework. Although the PSM method takes advantage of no pre-defined structure assumption, however and in contrary, the structural model with simultaneous equations, takes into account the effect of unobservables on subsidized firms’ selection procedure, beside R&D spillovers effect.
In order to design the evaluation framework to estimate ATE and ATET on the target variable of interest (TFP change), we have built a firm-level panel dataset (maximum 5 years of information) constructed by combination and merge of datasets related to public (provincial) R&D policy, firms’ characteristics, firms’ R&D activities and TFP change measures. The time span of the dataset allows us to capture the effects in both short-term and long run, consequently tracing the short and long term effects of the R&D program. This helps us to consider the usual longer effect lag an innovation policy entails, specifically on a target variable such as productivity and a treatment such as innovation incentive, which the effects may take time to be realized in comparison with other types of outcomes and investment policies. The dataset represents the outcome of a long process of combining and merging various datasets related to firms’ financial statements and balance sheet (AIDA: Italian company information and business intelligence) and APIAE’s R&D policy information provided by ISPAT.
TFP change and its decompositions, technical efficiency change and technological frontier change are realized using Malmquist Data Envelopment Analysis (DEA) method. DEA takes a system approach towards the firm as decision making unit (DMU) and only applies the input(s) and output(s) measures to calculate the relative (in)efficiency of the firms. Malmquist method based on index theory, captures the (in)efficiency change and the technological frontier movement within a time interval. TFP change measures are calculated by CRS output-oriented DEA dual model using a new package introduced in STATA software and merged into the reference dataset described previously.
To sum up, after the formation and construction of dataset by combining and merging different datasets, treatment effect analysis is carried out using PSM nearest neighbor and kernel estimators. The balancing property satisfaction on pre-treatment observable factors (age and size in our setting) is primarily investigated and propensity distribution graphs have been also provided. Taking into account the dataset features, R&D subsidies effect is measured for manufacturing and ICT industries (using 4 techniques to measure both ATE and ATET), beside low-medium technology and high-tech industries classifications (Both ATE and ATET). Moreover, the subsidies effect on TFP measures have also been measured for different categories of selection procedures. Results show heterogenous and mixed effect of R&D subsidies based on different settings of evaluation (sectors and selection categories), targeted outcome, PSM method (different PSM algorithms for nearest neighbor and kernel) and time of the effect (short-term or long run). The complete results have been discussed in detail in the related sections in chapter three.
To address the effect of unobservable factors, beside spillover effect on R&D subsidies allocation and the effect on outcome, a structural model is estimated using a cross-sectional dataset. The dataset is formed by merging R&D policy-related (linked to Provincial Law LP 6/99 enforced by provincial agency for the promotion of economic activities :APIAE) dataset and firms’ determinants provided by ISPAT (Statistical institute of Province of Trento).This approach complements the drawbacks due to estimation using PSM methodology. However, the pre-defined functional form for equations is a limitation of this approach. The structural model applied includes application decision, selection (subsidies allocation) and R&D investment equations to be turned into econometric equations for empirical estimation. The context and dataset features allow for different empirical modifications with respect to the benchmark model applied. The results determine the effect of firm (project) characteristics on all stages of the subsidization game. Size, age, exporting status, board size and sector are main factors being investigated. The results show not only there is no additional R&D expenditure, but also some crowding out of subsidies occurs. The base model is determined in such a format which makes it possible to evaluate the spillover effect and spillover rate of R&D spending as well. The results show that on average half (50%) of each euro spent on R&D spill overs.
The results shed light on the effects and impacts of a place-based R&D policy on TFP change ,R&D additionality and spillovers, while suggesting policy implications to the local public authorities. Furthermore, the design and process of impact evaluation using two different complementary approaches in a new context on a different target variable (TFP change in addition to classical input additionality variable) can be referred and applied in any policy evaluation related studies.
In the following, chapter one deals with the theoretical and empirical reasons for the existence of different public R&D policies based on Schumpeterian growth theory, spillovers effect and tackling market failure. It further provides a review of R&D and innovative activity indices at different levels of analysis (regional, national and international) and reviews the literature of empirical innovation policy evaluation studies related to the effect of R&D policy on additionality.
The review concerns both micro and macro perspectives in approaching public R&D policy and the impact of the policy on additionalities and TFP growth. Studies in R&D policy usually concern either the macro growth accounting approach and measure the effect of R&D policies on aggregate growth indices regardless of pointing out to micro foundation effects leading to the aggregate level changes or they only focus on the micro-econometric firm-level evaluation without addressing the relationship between firms’ additional R&D activities and the economic growth. Moreover, the R&D activities expenditure and growth indices at international, EU, national (Italy) and regional (Trento Province) have also been briefly pointed out and tracked over time, to realize the practical importance of R&D incentives.
In order to introduce and spot the areas this research addresses, the traditional market failure and the logic and reasons behind public R&D policies (aimed at increasing positive externalities and R&D spillovers) and subsequently different innovation policy instruments and their interaction with firms’ R&D decision making have been reviewed. This provides a comprehensive perspective over the importance and the forms of R&D policies.
Chapter two primarily discusses about the effect of R&D subsidies on TFP change. The discussion addresses the relationship between R&D and total factor productivity (TFP) as a channel which subsidies may affect TFP. In addition, other channels and interactions which can explain the effect of R&D subsidies on TFP change and the components of TFP change, will be investigated and discussed. Afterwards, in line with the review of the previous chapter, the empirical literature of studies dealing with evaluation of the effect of R&D subsidies on TFP (as a different outcome variable from additionality variables discussed in the previous chapter) will be reviewed. This theoretical background helps us to shape the R&D policy evaluation framework to investigate the direct casual impact of R&D subsidization policy on target outcomes including TFP change (Chapter 3) and R&D expenditure (Chapter 4). Finally, taking into account the evaluation framework, we hypothesize the research questions based on the theoretical concepts and literature review discussed through the previous and current chapters.
Chapter three measures the effect of the provincial R&D subsidies on technical efficiency and technological frontier change as the decomposing elements of productivity change. It empirically measures the impact of R&D subsidies on productivity change using counterfactual treatment effect analysis. Malmquist Productivity Index (MPI) based on the non-parametric method of Data Envelopment Analysis (CRS output-oriented dual DEA model) is applied to measure the productivity change and the disentangled elements of productivity change. The chapter has contributed to the literature in some different aspects.
The main focus of this chapter is measuring the effects of R&D subsidies on decomposing elements of TFP, technical efficiency and technological frontier change. In the whole literature, there is only one other similar work in which the effects of R&D subsidies on TFP decomposed components have been assessed. There are few other papers in which they measure the impact of other type of investment subsidies (mainly capital subsidies) on targeted variables of TFP decompositions. However, they all use a parametric approach to measure the TFP components in contrary to non-parametric Malmquist DEA method applied in our study making no predefined assumption about the production function.
The subsidies effect evaluation is implemented using both PSM nearest neighbor and kernel methods (to check the robustness) to measure the average treatment effect of R&D subsidies on subsidized (treated) and all (the population) firms labeled as ATET (average treatment effect on treated) and ATE (Average treatment effect), respectively. The analysis is mainly carried out in manufacturing and ICT sectors as two main sectors in which R&D incentives allocations occur. The elaboration on classification of firms in different main industries based on ATECO 2007 system of firms’ economic activity coding has been carried out. It has also been defined and described in detail how 6-digit industry code is categorized into sectors.
Another important feature of this study different with a considerable share of empirical literature, is construction of a panel dataset on subsidies allocation and firms’ characteristics which allows us to capture the effect of the policy both in short term and long run (maximum of 5 years). Moreover, the effect of the evaluation based on two different types of selection and allocation procedures (automatic, evaluative (combined with negotiation method) is implemented.
The limitations of this chapter imposed by the methodology used, are excluding the effect of unobservable factors on selection process and not taking into account the spillovers effect. Consequently, Chapter’s four structural modeling puts effort to overcome these restrictions and suggest a complementary approach.
Chapter four empirically estimates an equilibrium oriented structural game model to investigate the relationship between firms’ characteristics with application cost (application decision equation), spillover rate (subsidization equation) and R&D investment (investment equation). The chapter reviews, modifies and estimates a structural model describing the mechanism through which the R&D subsidization policy influences R&D activity and the R&D spillover rate. The empirical contribution of this chapter is proposing a simplified model of a reference 4-staged game model with a Nash Bayesian Equilibrium (NBE), based on the contextual setting of the region under study and data availability. The advantage of using this structural model is the ability to assume spillovers effect. This optimization approach relaxes the incapability of evaluation approach used in Chapter three to assume the presence of spillover effect due to the violation of Stable Unit Treatment Value Assumption (SUTVA). Moreover, chapter four takes into account the effect of unobservables on selection procedure and targeted variable, while in chapter three the unobservables are assumed uncorrelated with selection (subsidy) variable and the outcome. Nevertheless, opposed to structural modelling, the method used in chapter three does not assume any parametric form to evaluate the impact. Hence, chapter three and chapter four complement each other in measuring the impact of R&D policy on targeted variables.
The empirical evaluations and results of both final chapters are explained and concluded in the related essays. Moreover, the features and contribution of chapters will be restated in the abstract at the beginning of each chapter
Le Minos dans le Corpus Platonicum
Get PDFLa thèse propose une analyse du Minos, court dialogue du Corpus Platonicum considéré comme apocryphe à partir du XIXème siècle. Ce dialogue pose la question de la définition de la loi et fait l’éloge de la figure de Minos en tant que roi et législateur. En le resituant dans son contexte historique au-delà de toute question d’authenticité, l’étude se propose de restituer au dialogue son organicité et son unité, qui lui sont niées par les études qui considèrent le dialogue comme le sous-produit d’un imitateur. L’étude se compose de trois noyaux. D’abord, une étude sémantique de l’argumentation, fondée sur des jeux étymologisants entre nomos, nomizein, dianemein, nemein, nomeus, permet à la fois de retracer l’unité et la subtilité de l’argumentation du dialogue et d’entamer une réflexion sur l’étymologie comme méthode argumentative utilisée par Platon et attestée dans d’autres dialogues apocryphes. Ensuite, une étude des trois définitions de la loi présentes dans le dialogue mène à une discussion sur les ressemblances et les différences entre le Minos et les grands dialogues politiques du corpus, République, Politique et Lois. Enfin, l’étude de l’éloge du roi Minos permet de voir les éléments communs au Minos et aux Lettres et de situer le dialogue dans un contexte précis : au IVème siècle, lorsque surgit un nouvel intérêt pour les figures monarchiques, et en particulier dans le contexte de l’Académie ancienne. L’éloge qui fait de la figure de Minos (perçu comme un tyran dans la société athénienne) un roi-législateur fondateur des meilleures lois grecques apparaît comme un manifeste de l’entreprise des réformes des tyrannies commencée par Platon et continuée par les Académiciens après sa mort. Les trois analyses aboutissent toutes à la même conclusion : le Minos peut être considéré comme l’une des premières exégèses des dialogues politiques de Platon dans le cadre de l’Académie. Cette exégèse présuppose une « lecture » de la lettre figée des dialogues authentiques et en reprend les concepts, les images et les méthodes dans une forme qui en est déjà une fixation et une schématisation, dans un contexte politique sensible au renouveau de la figure royale. Enfin, la ressemblance entre le Minos et nombre de fragments attribués à Archytas permet de considérer le Minos comme un hypo-texte fondamental dans la formation des écrits politiques pseudo-pythagoriciens
Social predispositions and underlying neural mechanisms in chicks (Gallus gallus domesticus)
Get PDFThe detection of animate creatures, being social companions, preys or predators, is fundamental for survival and social interaction among vertebrates. Social predispositions are a set of unlearnt rudimental knowledge about animate beings, helping animals to structure sensory experience immediately after birth. An animal can detect the presence of a living being relying on both dynamic as well as static cues. Immediately after hatching visually naïve chicks for instance, spontaneously prefer biological motion patterns as well as face-like stimuli. Similar evidence has been collected on human adults and infants. In the present work, we aimed to investigate both dynamic and static cues eliciting spontaneous social attraction in visually naïve chicks and the relative neural correlates using an immunohistochemical staining of the immediate early gene product c-Fos as a neuronal activity marker. In a first behavioural study, visually naïve chicks demonstrated to have an innate preference for visible speed changes, cues of self-propulsion (implying an internal energy source to the moving object). In a second study, we found an involvement of septum and preoptic area of the hypothalamus in the perception of this predisposed animate motion cues. Septum is an evolutionarily well-conserved part of the limbic system. Together with preoptic area, they are key nodes of the social decision-making network rich in sex-steroid hormone receptors and involved in various adult social behaviours. This is the first evidence of the involvement of these areas in the perception of elementary animate cues in unexperienced newborn animals. In a third study, we successfully replicated a previous work, finding chicks’ spontaneous preference for a naturalistic configuration of features (stuffed fowl) vs. an artificial one (similar fowl cut in pieces and reassembled scrambled on a box). Here we found a differential involvement of intermediate medial mesopallium in the perception of static configuration of features. Intermediate medial mesopallium is a telencephalic region known to be involved in learning the features of the imprinting object. As an interesting by-product of these studies, we found a recurrent asymmetry in c-fos expression in favour of the left hemisphere. Previous literature showed that light exposure of the egg in a critical embryonic time window stimulate selectively the left hemisphere of chicks and influence future brain and behavioural lateralisation. Intriguingly, the asymmetries we observed in our experiments were in chicks hatched from dark incubated eggs. We devised an experiment to understand how the spontaneous level of c-Fos in the two hemispheres could be modulated by embryonic light exposure. Preliminary results suggest a spontaneous higher c-fos expression in the left hemisphere regardless of embryonic light stimulation. These results adds to previous existing knowledge about the organisation of chicks brain immediately after hatching and pave the way for future studies on neural correlates of social predispositions in vertebrates
Improving air quality assessment over complex terrain by optimizing meteorological and pollutant transport modeling
Get PDFThe Alpine region is a sensitive area to air pollution, as it presents specific characteristics, which expose it to a greater environmental burden with respect to flat areas. During the last decades, the scientific community has developed many different modeling tools to tackle the problem of air pollution. This issue demands at least three distinct procedures: the modeling of the meteorological fields, the modeling of the transport and dispersion of the pollutants and the modeling of the emitting sources. Each of these procedures performs differently across different space and time scales and carries its own strengths and weaknesses, which affect results in terms of pollutant dispersion patterns. The present work focuses on testing and improving different modeling tools at a local scale, over very complex topography, where most of them are brought to work at the limit of their applicability, but they are still the best available tools to face the problem. Different case studies are used in this research in order to evaluate strengths and deficiencies of the models and, where possible, to improve their performance. The experimental datasets used for this purpose come from both previously performed field campaigns and specifically designed campaigns, including meteorological and air quality observations. The performance of Land Surface Models within the Weather Research and Forecasting Model is evaluated and improved, focusing on their ability in reproducing near-ground variables, with specific attention to the frequent ground thermal inversion occurring in the mountainous areas. The performance of dispersion models recommended for applications over complex terrain is also tested and their results are compared with unique measurements (PM10 vertical profiles and tracer gas ground concentration), under challenging wintertime conditions. Atmospheric turbulence parameterizations are also analyzed, in order to understand their role and effects in a modeling chain for dispersion assessment purposes
Characterisation of Silicon Photomultipliers for the detection of Near Ultraviolet and Visible light
Get PDFLight measurements are widely used in physics experiments and medical applications. It is possible to nd many of them in High{Energy Physics, Astrophysics and Astroparticle Physics experiments and in the PET or SPECT medical techniques. Two different types of light detectors are usually used: thermal detectors and photoelectric effect based detectors. Among the rst type detectors, the Bolometer is the most widely used and developed. Its invention dates back in the nineteenth century. It represents a good choice to detect optical power in far infrared and microwave wavelength regions but it does not have single photon detection capability. It is usually used in the rare events Physics experiments. Among the photoelectric effect based detectors, the Photomultiplier Tube (PMT) is the most important nowadays for the detection of low-level light
flux. It was invented in the late thirties and it has
the single photon detection capability and a good quantum efficiency (QE) in the near-ultraviolet (NUV) and visible regions. Its drawbacks are the high bias voltage requirement, the diculty to employ it in strong magnetic field environments and its fragility.
Other widely used light detectors are the Solid-State detectors, in particular the silicon based ones. They were developed in the last sixty years to become a good alternative to the PMTs. The silicon photodetectors can be divided into three types depending on the operational bias voltage and, as a consequence, their internal gain: photodiodes, avalanche photodiodes (APDs) and Geiger-mode detectors, Single Photon Avalanche Diodes (SPADs). The first type detector does not have internal gain, thus its signal is proportional to the number of incoming photons that are converted in electron-hole pairs. The detector and the read-out circuit noises limit the detector sensitivity to, at least, some hundreds of photons. The APD exploits the impact ionisation effect to have an internal gain up to some hundreds or more. The internal gain allows the detector to improve the performance with respect to a similar area photodiode reducing the sensitivity limit to some tens of photons. Operating the APDs with a bias voltage larger than the breakdown one, the Geiger-mode operation range can be reached. In this case, the detectors have a very high gain, in the order of (10^5-10^7), but their signal is not proportional to the number of the incoming photons, it is always the same. The SPAD (or GM-APD) is a typical Geiger-mode silicon detector. It has the single photon detection capability as the PMT, due to the high gain, but its signal is digital: it is fired or not by the incoming photons. The capability to give a signal proportional to the number of photons is lost in a SPAD. To recover this property, a matrix of independent SPADs connected in parallel is built. These matrices are called Silicon Photomultipliers, SiPMs (or Multi-Pixel Photon Counters, MPPCs).
In a typical SiPM, the output signal is the sum of the SPAD ones, thus, although the digital nature of the SPAD signal, it is analogue and ranges from zero to the maximum number of cells composing the matrix. The detector response can be considered linear if the number of incoming photons is much smaller than the total number of cells because the probability that two photons arrive on the same cell is negligible. Main features of the SiPMs are the low bias voltage (<100 V typically), a high Photo-Detection Efficiency (PDE) in NUV and visible range (usually larger than the PMT QE), compactness, insensitivity to magnetic elds and high internal gain. The noise sources are the Dark Count Rate (DCR), the optical Cross-talk (CT) and the Afterpulsing (AP). The first is called primary noise and mainly depends, at room temperature, on the thermal generation of electron-hole pairs that can travel to the high-field region triggering a cell. The others are collectively called correlated noise because they can happen only after a primary signal, caused both by a photon or by a spontaneous carrier generation. In this thesis, the focus is on the characterisation of one SiPM technology produced in Fondazione Bruno Kessler (FBK) in Trento, Italy, named NUV-SiPMs. This technology, implementing the p-on-n concept, showed, from the beginning, a high PDE spectrum peaked in the NUV to violet region exceeding the 30 %, a very low DCR, typically below 100 KHz/mm^2 in the operating voltage range, and a total correlated noise probability under the
50 %. In the last years, the technology was developed modifying the silicon wafer substrate properties, reducing the delayed correlated noise probabilities, and adopting the so-called High-Density concept. In this last version, named NUV-HD, a new layout, with a narrower border region around the cell active area and deep trenches to electrically and optically isolate the cells, is employed. The first improvement has a direct influence on the PDE because it increases the Fill Factor (FF), the ratio between the active to the total cell area. The second layout change reduces the probability that a secondary photon can travel from a cell to a neighbouring one, reducing the cross-talk probability. Possible applications of the NUV-HD devices are: medical application (e.g. the Time of Flight PET, ToF-PET, scanners), the rare events Physics experiments (e.g. NEXT and DarkSide) and Astroparticle Physiscs experiments (e.g. the Cherenkov Telescope Array Observatory, CTA). The ToF-PET scanners are promising medical techniques with the goal of improving the spatial resolution of the classical PET scanners measuring the gamma rays time of flight. For this reason, these scanners require very fast photodetectors with coincidence time resolution (CTR) less or equal to 100 ps. NEXT and DarkSide are low temperature experiments with the main goal of observe rare events as the neutrinoless double beta decay and the Dark Matter particles. Due to the signal rarity, the detector noise requirements are very stringent. CTA will be a future ground-based Imaging Atmospheric Cherenkov Telescope (IACT) observatory, with the goal to track very high energy cosmic gamma rays, up to hundreds of TeV, to their galactic sources. It will consist of two matrices of telescopes of different type and size, each one having a camera. In the small size telescopes, the possibility to use the SiPMs to build the camera is under investigation. Since the cosmic gamma rays are detected through the secondary Cherenkov photons, produced by the accelerated electrons in the Earth atmosphere, the camera photosensors must have a very high detection efficiency from 300 nm to 600 nm, and, possibly, a low sensitivity in the NIR region to reject the night sky background. In addition, they must have good timing properties and high granularity.
To fully characterise the SiPM, measurements of signal properties, noise parameters and PDE are needed. The set-ups and analysis of the characterisation procedure are fully described. In particular, the optical set-up, with
its calibration procedures, and the analysis methods, with the definition of the possible uncertainty sources, are the central point of this work. During the dark characterisation, the SiPM is enclosed in a light-tight climatic chamber. An oscilloscope acquires and sends to a PC software millisecond-long SiPM waveforms. The software implements a Differential Leading Edge Discriminator
(DLED) algorithm to better distinguish the SiPM pulses with time separation larger than a few nanoseconds. This analysis allows to count the primary pulses, due to the thermal/tunnelling excitations, obtaining the DCR,
and measure the correlated noise probabilities. In addition, signal parameters as amplitude, gain and cell recharge time are measured. The PDE measurements require a set-up in which the number of impinging photons to the device is precisely known. For this reason, a compact set-up, consisting of an integrating sphere inside a light-tight box, a series of LEDs with peak wavelength ranging from NUV to NIR, fully characterised before use, a monochromator, equipped with a tungsten lamp, and a transparent optical fibre, was developed. Along with the set-up, a light calibration procedure, taking into account different uncertainty sources (LED wavelength shift, light uniformity at the device
position, etc.), was also developed. Three different analysis techniques can be used to obtain the technology PDE. Each technique has its own benets and error sources. The equivalence among the different methods is shown. Moreover, measuring the PDE on SPADs with the same layout of single SiPM cells, identical results are obtained. This fact shows the equivalence between the single cell device and its larger counterpart, opening the possibility to measure the PDE of a new technology on SPADs. This is a very important result because the SPAD is a simpler device, with lower correlated noise, because it has no CT, and negligible primary one, often less than 1 kHz. Measurements are more precise, faster and it is possible to apply larger bias voltage, obtaining more information on the technology in such conditions at which no SiPM can be tested any more.
A rst version NUV-HD technology characterisation is shown. In this version, the NUV-HD SiPMs have cell pitch ranging from 25 um to 40 um. A typical primary noise lower than 100 KHz/mm^2 and a delayed correlated noise probability less than 5 % are measured, up to 10 V of overvoltage. In the same bias voltage range, a direct CT probability lower than 45 % is measured in the largest cell devices (25 % in the smallest ones). The PDE spectrum has the expected shape with the maximum in the NUV-violet region. A maximum value exceeding the 60 % is measured in the largest cell devices (45 % in the smallest ones). To investigate possible variations of the measured features on the wafer, devices taken from different wafer points are measured and compared
finding no difference but the primary noise. This parameter shows a variation by a factor up to about three on the wafer level. To compare the different cell devices, all the measured parameters are plotted as a function of the peak PDE, about 400 nm. During this comparison, the smallest device reveals worse than the others having a larger noise, both primary and correlated, at the same PDE value. The other three devices are comparable within the measurement errors. From the PDE measurements, a comparison between the measured FF and the expected one, as dened by the design, is obtained. In the smallest cell device, this comparison shows an unexpected discrepancy leading to the possibility that the expected FF is larger than the effective one. This possibility is investigated in the last part of this thesis in which a complete study of the factors contributing to the PDE is shown. This study is performed on a new NUV-HD version employing a photodiode with equal dopant prole of the SiPMs, a circular SPAD having 100 % FF and a square one with 35 um cell size and a nominal FF equal to 81 %. A developed box model is used to describe the electric eld inside the cell. The calculated effective FF is always different from the expected one. The reason of the measured difference is the electric field transition from the constant high value to zero occurring at the active area border region. This partially efficient region has an effect similar to an added completely ineffective region of 1-1.5 um size inside the expected active area. The transition region effect is critical for the smallest cells because
it strongly reduces the effective FF with respect to the design one. The study of the factors contributing to the PDE of the NUV-HD SiPMs is very important. Through the obtained results, it is confirmed that the technology QE is just maximised in the wavelength range of interest, NUV to
blue, and, at the same wavelengths, the triggering probability saturation rate is very small allowing the detectors to reach the maximum PDE when biased with a few volts of overvoltage. This operating condition has also the effect to employ the detector having low noise, both primary and correlated one. The best solution to further improve the technology PDE is a redesign of the electric field border region to reduce the gap between the expected FF and the effective one. This is more important for the smallest cell devices in which the actual transition region effect reduces the PDE performance to about the 50-60 % of the expected values
ETV7 can trigger breast cancer chemoresistance
Get PDFChemotherapy still represents the most common and sometimes the only possible therapeutic option for advanced breast cancer. Its efficacy is profoundly threatened by intrinsic or acquired chemoresistance, which, in some cases, can be unexpectedly promoted by the chemotherapeutic drugs used. ETV7, a poorly characterized ETS factor with no established roles in breast cancer so far, is reported here to be activated at the transcriptional level by chemotherapy and be able to promote breast cancer cells chemoresistance. This project proposes a novel drug resistance circuitry in breast cancer cells, specifically to Doxorubicin, governed by the ETV7 repressive action on DNAJC15, a gene whose low expression was previously associated with drug resistance in breast and ovarian cancer. Moreover, the impact of ETV7 in causing drug resistance is proved here to extend also to another type of drug, 5-Fluorouracil (5-FU), a chemotherapeutic agent commonly used in combination with Doxorubicin for breast cancer treatment. In this case, additional novel ETV7 targets (DPYD and DPEP1) were established and can represent important mediators for ETV7-mediated resistance to 5-FU. Additional relevant data, relative to biological implications for ETV7 in breast cancer progression, is provided here by the ETV7 ChIP-seq analysis, which reveals the first reported in vivo mapping of ETV7 occupancy. Through ChIP-seq novel ETV7 direct targets have been identified, some of them yet unexplored in breast cancer; notably, their expression revealed to be capable of predicting breast cancer patients outcome. Furthermore, a possible control exerted by ETV7 on the TGF-β pathway, discovered by enrichment analysis on ChIP-seq ETV7 targets, suggests a different and opposing role for ETV7 activation in either advanced stage cancers or normal and early stage breast cancers.
Taken collectively, the results from this project propose an important key role for ETV7 in triggering breast cancer multi-drug resistance phenotype in response to chemotherapy, by controlling the expression of specific targets
Twist of messenger Fate: novel mechanisms for TDP43 in modulating mRNA decay and alternative polyadenylation
Get PDFTDP43 is an ubiquitously expressed RNA-binding protein implicated in several aspects of RNA metabolism. It can shuttle between the nucleus and the cytoplasm; however, when it is mutated in some familial Amyotrophic Lateral Sclerosis (ALS) cases, it undergoes nuclear clearance and cytoplasmic accumulation, driving neuronal degeneration. The same phenotype is present in patients bearing ALS-inducing mutations in other genes and ALS sporadic patients, defining TDP43 proteinopathy as a common feature in this pathology. Why does it cause specific motor neuron death?
Our quantitative proteomics analysis of the TDP43 interactome revealed the interaction with components of the mRNA surveillance pathway, suggesting a still undiscovered function in nonsense-mediated decay. We demonstrated that TDP43 acts translation- and SMG1-dependently as a mRNA decay enhancer of specific transcripts by binding their 3’UTR. In particular, it leads to the down-regulation of transcripts with a long 3’UTR.
From our sequencing data of spinal cords from TDP43Q331K transgenic mouse model and of motor neuron-like NSC-34 cells silenced for TDP43 emerged that TDP43 plays another striking role in the 3’UTR, modulating mRNA alternative polyadenylation and promoting the generation of shorter transcripts. This finding is supported by the direct interaction of TDP43 with the cleavage stimulation factor, a core component of the polyadenylation machinery.
These results broaden our knowledge of the role of TDP43 in the post-transcriptional gene expression regulation. The impairment of these two biological processes by TDP43 proteinopathy could have implications in ALS pathogenesis, representing possible new targets for therapeutic approaches
The impact of reward and punishment on visual attention during naturalistic visual search: valence or salience?
No full textIn this thesis, I am going to address the issue of how both reward and punishment affect visual representation, by the use of a visual search paradigm performed in naturalistic scenes. More specifically, I am going to approach these two motivational forces by referring to their constituting dimensions, namely valence and salience. In fact, while being positioned in oppositely valenced space, these two outcomes share the burden of signaling stimuli with strong behavioral importance, coding therefore for motivational salience. After reviewing the main existing literature in this field (Chapter 1), I will describe a series of studies which examine how reward and punishment impact visual attention through the analysis of behavioral measures (Chapter 2) and fMRI activation (Chapter 3 and 4). The main idea resulting from these studies is that, in spite of what a rational approach to the problem would suggest, automatic visual attention does not process these two outcomes according to a salience, but rather through a valence pattern
Il Koinon dei Nesioti
No full textLa tesi indaga il Koinon dei Nesioti offrendo una storia politica, un'analisi istituzionale, economica e identitaria di questa federazione di età ellenistica