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Molecular and functional characterization of the Odorant Receptor2 (OR2) in the tiger mosquito Aedes albopictus.
No full textIn mosquitoes, olfactory system plays a crucial role in many behaviors, including nectar feeding, host preference selection, searching for the right place to lay eggs. A.albopicus, known also as tiger mosquito, is an anthropophilic species which in the last years, due to a strong ecological plasticity, has spread throughout the world and all over Italy with a high abundance in man-made environments. Although long considered a secondary vector of viruses, the potentiality of its vectorial capacity is very dangerous and may constitute the foundation for a public health alert. Nevertheless, to date, for this mosquito nothing is known at molecular level. Based on the idea that an improved understanding of the olfactory system of mosquitoes may help in developing control methods that interfere with its behavior, recently we have undertaken a study aimed to characterize the A. albopictus Odorant Receptors. During my PhD work, I focused my attention on the identification, cloning and functional characterization of the A. albopictus OR2 ortholog. My data indicate that A. albopictus OR2 (AalOR2) shares a high degree of identity with the other mosquito OR2 orthologs characterized to date, confirming that OR2 is one of the most conserved mosquito ORs; furthermore, AalOR2 is expressed in the olfactory appendages of larvae and adults and its expression increases after a blood meal, as determined by a semi-quantitative RT-PCR.
Interestingly, this is the first report of an up-regulation of an OR in response to a blood meal; this increase could suggest a role of AalOR2 in searching oviposition right places. AalOR2, such as the other orthologs, is narrowly tuned to indole, a ubiquitous volatile compound that has been linked to host seeking, and oviposition. The de-orphaning of AalOR2 has been obtained, with same results, through Ca2+ imaging assay in HEK293 cells, and “in vivo” experiments using the Single Sensillum Recording (SSR) in an engineered neuron of the fruitfly Drosophila melanogaster that express AalOR2.
Furthermore, by using this technique, I was able to identify also a molecule, (-)Menthone, that produced an inhibitory effect on this Odorant Receptor. In summary, this work led to the cloning and de-orphaning of the first Odorant Receptor in A. albopictus, that may be used as potential molecular target for developing environmentally friendly strategies to control mosquito populations
On reputation evaluation in 2.0 communities.
No full textCurrent technology has disappointed many members of WEB2.0 communities by its slow and tough adaptability to specific usersʼ skills and competences. Most of the largest WEB2.0 communities rely on the work of their members to create the resources they are built on, a business model known under the acronym UGC (User Generated Contents), which is today very popular yet still very simple and immature. Presently the vast majority of the communities that relay on UGCs lack an accurate ranking system for their most proficient members and almost none of them provide an effective rewarding mechanism.
Sometimes they do provide means to cooperatively evaluate and classify the available resources, but very few of these mechanisms take in account the competence of the voters.
Although rough, the current technology seems sufficient to confer to some cooperative web communities a discrete success, which for the most part is due to their core-members passion and commitment. Unfortunately deficiencies like the ones described can involve that, over time, only a small amount of the members keep committed and willing to produce resources of a certain quality. This tendency leads to the situation in which, although the community grows in terms of numbers, in proportion its value decreases.
Considering the fast diffusion of web2.0 communities and the new emerging Enterprise2.0 communities phenomena, this problem needs no longer to be underestimated. 2.0 communities should start thinking about new means to raise their quality standards in order to stay effective and successful over time.
Providing communities with concrete rewarding systems like remunerative ones could fix the problem, nevertheless this approach rarely and loosely has been implemented so far.
The reason is that the task involves several and not trivial side problems, such as the necessity of an advanced ranking mechanisms to evaluate the members.
This method should be able to consider complex factors like competence and commitment, but at the same time it should be easily understandable and shared by the members of the community. In order to make sure that the members share and agree with the rating system it must involve their collaboration, which is a non trivial problem, especially in Entrprise2.0 communities.
For the aforementioned reasons I propose as a means to overcome the problem a method based on reputation rather than competence and commitment, which is named Reputation Community Evaluation (RCE). This new approach is not based solely on quantitative measurements but relies on an algorithm which exploits the community member reputations to evaluate the resources and the members themselves. In this method the reputation of the single member grows or decreases according to its activity in the community and the evaluations received from the other members over a certain period of time. All members opinions/votes are themselves weighted accordingly to the single member reputation. This approach makes possible to put in place new kinds of business models, which aim to use users reputations as a digital currency inside Web 2.0 or Enterprise 2.0 communities
Funzione e ruolo nel sistema penale del processo per reati sessuali: luci e ombre dopo la legge n. 38/2009.
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Comprendere il dissenso: aporie del realismo e pragmatica universale tra H. Putnam e J. Habermas.
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The X-ray behaviour of Fermi/LAT pulsars.
No full textMore than 40 years after the discovery of Isolated Neutron Stars, the comprehension of their physics is still rather poor. This thesis is based on a program of multiwavelength observations of pulsars which yielded new and important pieces of information about the overall proprieties of this class of sources.
The thesis is organized as follows:
- In chapter 1 we give a very brief overview of the current status of the under-standing of Isolated Neutron Stars. We also talk about the Fermi revolution that occurred in the last three years, focusing on the Fermi contribution to the knowledge of neutron stars. Then, we describe the results led by the synergy between X-ray and °-ray bands.
- In chapter 2 we give a detailed description of X-ray analyses we did and surprising results we obtained for two different radio-quiet pulsars. Such neutron stars, J0007+7303 and J0357+3205, can be considered ”extreme” in the Fermi pulsars’ zoo due to their energetics and ages. Both the X-ray observations and analyses are very different so that they can be considered as the standing-up examples of all the following analyses.
- In chapter 3 we describe the analysis we done in the X-ray band and briefly report the obtained spectra of each pulsar and its nebula, if present. Then, we study the X-ray and °-ray pulsars’ luminosities as a function of their rotational energies and ages in order to find any relationship between these values and any difference between the two populations of radio-quiet and radio-loud pulsars.
- In chapter 4 we report the ”identity card” of all Fermi pulsars, the detailed description of the analyses done and results obtained for each pulsar.
Finally, in appendix we report our accepted proposals of the most significative X-ray observations used in this thesis plus the article on the X-ray behaviour of Fermi/LAT pulsars we published on the Astrophyisical Journal
Advanced manufacturing techniques for X-ray and VHE gamma-ray astronomical mirrors.
No full textThe main theme of this thesis is on the development of the technologies for the future X-ray astronomy telescopes and specifically for the New Hard X-ray Mission and eROSITA (Spectrum-RG) missions. Other important next future X-ray missions, currently under advanced study and/or manufacturing are NuSTAR (USA), ASTRO-H (Japan) and GEMS (USA).
The New Hard X-ray Mission (NHXM) is being developed in Italy as an evolution of the original HEXIT-SAT project and is now the hard x-ray project of reference for the Italian high energy community. NHXM is meant to provide a real breakthrough on a number of hot astrophysical issues, by exploiting the most advanced technology in broad-band (0.2 – 80 keV) high angular resolution (<20 arc seconds HEW) grazing incidence mirrors and spectroscopic detectors, together with the use of a high efficiency imaging polarimeter. Such issues can be summarized in two main headings:
● making the census of the population of black holes in the Universe and probing the physics of accretion in the most diverse conditions;
● investigating the particle acceleration mechanisms at work in different contexts, and the effects of radiative transfer in highly magnetized plasmas and strong gravitational fields.
These topics were identified as top priority in the study commissioned by the Italian Space Agency (ASI) in 2004 to the Italian scientific community with contracts involving Thales-Alenia Space Italy (TAS-I, Turin), the Media Lario Technologies (MLT, Lecco) company and the INAF institution. NHXM benefits from the phase A study of the canceled French-Italian-German SIMBOL-X mission (2007-2008) and has been recently subjected to a scientific phase B study financed by ASI. Media Lario Technologies company received a contract from ASI in 2009 for a Technology Development Program (ASI-TDP) aiming at improving the technology readiness level with also in-house adoption of hardware for the metrology/manufacturing of the multilayer x-ray optics.
Spectrum-RG is a Russian - German x-ray astrophysical observatory scheduled for lunch in 2013. German Space Agency (DLR) is responsible for the development of the key mission instrument - the x-ray grazing incident mirror telescope eROSITA. The second experiment is ART-XC - an x-ray mirror telescope with a harder response than eROSITA, which is being developed by Russia (IKI, Moscow and VNIIEF, Sarov). The name eROSITA stands for extended Roentgen Survey with an Imaging Telescope Array. The general design of the eROSITA x-ray telescope is derived from that of ABRIXAS: a bundle of 7 mirror modules with short focal lengths make up a compact telescope which is ideal for survey observations. Similar designs had been proposed for the missions DUO and ROSITA but were not realized. Compared to those, however, the effective area in the soft x-ray band has now much increased by adding 27 additional outer mirror shells to the original 27 ones of each mirror module. The requirement on the on-axis resolution has also been confined, namely to 15 arc seconds HEW. For these reasons the prefix “extended” to the original name “ROSITA” had been added. The scientific motivation for this extension is founded in the ambitious goal to detect about 100000 clusters of galaxies which trace the large scale structure of the Universe in space and time.
The main scientific goals are:
● to detect the hot intergalactic medium of 50-100 thousand galaxy clusters and groups and hot gas in filaments between clusters to map out the large scale structure in the Universe for the study of cosmic structure evolution;
● to detect systematically all obscured accreting Black Holes in nearby galaxies and many (up to 3 Million) new, distant active galactic nuclei;
● to study in detail the physics of galactic x-ray source populations, like pre-main sequence stars, supernova remnants and x-ray binaries.
Max-Planck-Institute für extraterrestrische Physik (MPE) is the scientific institute responsible for the eROSITA Payload. Media Lario Technologies (MLT) is the industrial enabler for the manufacturing of the Optical Payload for eROSITA - including the flight quality mandrels, and it is currently in the C/D Phase of the project.
The research activity described in this thesis has been carried out at Media Lario Technologies company and at the Brera Astronomical Observatory under the supervision of INAF-OAB researchers Dott. Giovanni Pareschi and Dott. Gianpiero Tagliaferri. The research activity of the author of this thesis is focused on the development of an advance polishing technique for the mandrels to be used as masters in the mirrors replication by electroforming. The goal is to implement a process where the mandrels can be manufactured with a high accuracy (< 6 arc seconds HEW) and low roughness (< 0.2 nm rms) within a consistent short time. In the contest of the eROSITA and NHXM (projects currently running in MLT) the author participated as technical/scientific responsible, investigating innovative mandrels manufacturing technologies (e.g. Single Point Diamond Turning, shape corrective polishing) representing an evolution of the standard approach used so far. In this frame the author has also contributed to the adoption of a customized deterministic polishing machine and a customized 3D metrology device for the mandrel geometrical characterization.
An additional research activity, performed by the author at Media Lario Technologies company and at the Brera Astronomical Observatory, is focused on the development of lightweight glass mirrors manufactured via cold-slumping technique for Imaging Atmospheric Cherenkov Telescopes (IACT). Very High Energy (VHE) gamma rays, with photon energies in the TeV range, can be detected by ground based experiments. In fact, such high energy photons interact high in the upper atmosphere and generate an air shower of secondary particles. These particles emit the so-called Cherenkov light, a faint blue light. The mirror elements here developed have a sandwich-like structure where the reflecting and backing facets are composed by glass sheets with an interposed honeycomb aluminum core. This effort found application at the world’s largest IACT, the 17m MAGIC II telescope (currently operating in Roque de los Muchachos - La Palma, Canary Islands), where 112 mirrors (~ 1 squared meter each), manufactured with the newly developed cold-slumping technique here described, are installed
The NK cells phenotype and function in resected non small cell lung cancer: differences between squamous and adenocarcinoma.
No full textThe tumor microenvironment has come to light as a key player in carcinogenesis and progression. Tumors affect many host cell types, in particular immune cells. The immune system appears to select particularly fit tumor cells in the process of immuno-editing, while the tumor cells influence the polarization of immune cells towards phenotypes that favor tumor growth and vascularization. Here we investigated the phenotype of tumor infiltrating natural killer (NK) cells, focusing on angiogenesis associated cytokines and activities in patient-derived material from non-small cell lung cancer (NSCLC). Samples from the tumor and adjacent normal issues, as well as peripheral blood and lung samples as well as from non-oncologic patients with bullous emphysema were collected and rapidly processed to obtain single cell suspensions. Flow cytometry (FC) analyses were performed to evaluate specific markers (CD3, CD56, CD16) to identify NK cell subsets. We observed that in the NSCLC samples, the CD56+CD16- NK phenotype, associated with cytokine production, predominated in the tumor samples while the CD56dimCD16+ cytotoxic phenotype dominated in the adjacent normal tissues and in lung tissue derived from non-oncologic patients. This was independent of tumor histotype and smoking status. We examined the angiogenic potential of tumor infiltrating NK cells by intracellular staining for production of VEGF, PlGF, IL-8 (CXCL8), IFNand other markers. The CD56+CD16- subset was clearly associated with production of angiogenic cytokines in all samples. However, patients with squamous carcinoma histotypes showed remarkably and significantly higher production of angiogenic factors in tumor infiltrating, adjacent tissue and especially in peripheral blood CD56+CD16- NK cells than patients with adenocarcinomas. Following surgical intervention, these levels were reduced in disease-free patients. Moreover, supernatants derived from the tumor infiltrating CD56+CD16- NK cells were able to induce endothelial cell chemotaxis and formation of capillary-like structures in vitro; this was particularly evident for NK cells isolated from squamous cell carcinomas. Our data suggest that squamous NSCLC tumors have a significant systemic effect on NK cells, enhancing angiogenic cytokine production in a manner dependent on the presence of disease. NK cells appear to participate in tumor neovascularization and could represent a peripheral marker for disease progression, angiogenesis and response to therapies in some tumor subsets
DSDM (Digital Slide Dynamic Morphometry): targeting tumor budding in colorectal cancer.
No full textBackground: In histopathology, quantitative assessment of various morphologic features is based on published methods that were conceived on specific areas observed through the microscope and microscopical objective used. Failure to reproduce the same reference field size if using a different microscope may change the score assessed. When visualizing a digital slide on a computer screen, through a dedicated viewer, it is possible to select the adequate objective-magnification (zoom toolbar). However, the field of view is rectangular, different from the circular field area viewed by optical microscopy. In addition, the evaluation of the size of the selected area of the digital slide is not immediately evident and must be estimated with the draw functions of the viewer or the scale/axes grid.
Methods: Using the tools offered by ImageScope, the virtual slide viewer of Aperio Technologies (Vista, USA), a system was conceived to reproduce the various methods published for assessing tumor budding, an important prognostic factor in colorectal cancer. Each method, based on counting tumor budding within a specific area, was reproduced as a colored circle, corresponding to a graphic overlay layer. The various circles were grouped in a target-like shape and then exported and saved as an .xml file. A web page was created giving access to 100 whole-slide digital scans. When each digital slide was opened the file containing the target-like area had to be imported in order to move it onto a tumor budding “hot spot” and to perform the
measurements. Eighteen international experts in gastrointestinal pathology were invited to participate.
Results: Twelve investigators completed the task, the majority of them performing the multiple assessments of each case in less than 12 minutes.
Conclusions: The assessing system proposed appeared to be feasible for pathologists. It allows precise application of methods originally conceived for optical microscopy. The graphical layers that make the tool are freely moved within the digital slide: this system was named DSDM (Digital Slide Dynamic Morphometry). This telepathology extension has various potential applications and might be a useful tool for histopathological assessment of diagnostic parameters that need to be quantified
P53 family members regulate the Otx1 gene expression in differentiation of breast cancer stem cells and in mammary gland development.
No full textTp53, Tp63 and Tp73 family members encode for transcription factors which play a key role in
control of the genome integrity inducing cell-cycle arrest, senescence, apoptosis or cell
differentiation. They take a part in cell stress response and in tumor suppression (De Young MP
and Ellisen LW, 2007).
Wild type p53 protein is a growth modulator and its inactivation is a critical event in malignant
transformation (Gasco M, 2002).
It has been recently demonstrated that p53 has developmental and differentiation functions (Hu
W, 2008). Indeed an over-expression of p53 in tumor cells induces asymmetrical division
avoiding a self-renewal of cancer stem cells (CSCs) and promoting their differentiation (Cicalese
A, 2009).
In this study 43 human ductal and lobular invasive breast carcinomas have been analyzed for the
expression of p53, p63, p73 and a pool of non-clustered homeobox genes. The homeogenes play
a crucial role in embryogenesis, regulating cell differentiation and proliferation (Pagani IS,
2010). They are expressed in adult mammary gland and when deregulated, are involved in
breast cancer (Lewis MT, 2000).
We demonstrated that the Otx1 homeogene is transcribed in breast cancer, in CSCs
differentiation and in adult mammary gland development.
We established that the p53 and p73 proteins directly induce the Otx1 expression by acting on its
promoter. Otx1 has been described as a critical molecule for axon refinement in corticogenesis
(Zhang YA, 2002), and its activity in breast cancer suggests a synergistic function with p53 and
p73 in CSCs differentiation.
In adult mammary gland development the Otx1 expression is not regulated by p53, but is
correlated with the expression of Tp73 in lactation and in regression. This suggests that in
physiological conditions Otx1 is regulated by p73, while in the tumors p53 regulates its
expression
Molecular analysis of persistent enterovirus infections.
No full textHuman enteroviruses (HEVs) are etiological agents of different clinical entities varying from asymptomatic to mild, severe, or fatal diseases. There is now growing evidence that HEVs can cause or contribute to common chronic diseases. Even though a specific therapies are not yet available, a correct diagnosis is necessary both for diagnostic and epidemiologic purposes. Gene amplification methods and sequencing greatly facilitates the laboratory diagnosis of these conditions and allows discovering previously unsuspected etiopathogenetic associations.
In this work, three clinical conditions possibly associated with persistent HEV infections have been investigated: type 1 diabetes in children, the post-polio syndrome in adult patients, as well as clinical cases of inflammatory cardiomyopathy. New methods for HEVs detection have been developed based on bioinformatic studies of HEV sequence databases. These methods have been tested with reference virus strains as well as a wide range of clinical specimens. Our most sensitive assay is based on the detection and sequencing of the viral polymerase (3Dpol) coding region.
Different cohorts of patients have been investigated using classical virology and molecular methods. The studies allowed to conclude that HEVs can persist for long periods in humans and that these agents can be associated with endocrine, neurological, and cardiovascular conditions