NEW INSIGHTS ON THE AGAMOUS SUBFAMILY GENES IN ORYZA SATIVA

More than 30 years of plant biology have assessed the tight relationship existing between MADS-box genes and plant development and reproduction. Transcription factors of the MADS-box family have been associated with crucial processes throughout the whole life plant: germination, hormonal signalling, vegetative growth, transition from vegetative to reproductive phase, flower, fruit and seed development, embryogenesis. MADS-box are key regulators of the gene networks behind all of these processes; therefore, they have been (and continue to be) the subject of a number of molecular and functional studies which aim to add more and more details on the overall picture of how plants are made. Among MADS-box, the AGAMOUS subfamily plays a fundamental role in plant reproduction; genes belonging to this subfamily have been associated with reproductive organ development and seed and fruit development in many different species. During evolution, the AGAMOUS subfamily underwent various events of duplication which led to the presence, in the extant plant species, of multiple AGAMOUS-like genes, often acquiring different functions thanks to subfunctionalization and neofunctionalization. The aim of this thesis is to shed some more light upon the AGAMOUS-like genes present in rice (Oryza sativa). In the first part, we demonstrate how the alternative splicing of a single aminoacid in rice AGAMOUS ortholog OsMADS3 can alter its functionality, as proven by the different ability of the two isoforms to interact with other MADS-box proteins and by the different phenotype generated by their ectopic expression in A. thaliana. In the second part, we present preliminary data about the role of rice AGAMOUS subfamily genes in controlling rice seed development. AGAMOUS-like genes have been associated with fruit and seed development in various species, but functional characterization experiments are difficult to perform on fruit plants because of their long life cycle; thus, rice represent the perfect model species to start with. Our experiments show that in multiple mutants in AGAMOUS-like genes fertility and seed development are severely impaired

Budget Impact Model of Omalizumab In The Treatment of Chronic Spontaneous Urticaria In Italy

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Cost-effectiveness analysis of alectinib versus crizotinib in first-line treatment of anaplastic lymphoma kinase-positive advanced non-small cell lung cancer:

In the randomized, active-controlled, multicenter Phase III open-label ALEX trial, alectinib showed superior efficacy and lower toxicity compared with crizotinib in the primary treatment of anaplastic lymphoma kinase-positive non-small cell lung cancer (ALK-positive NSCLC). The aim of this economic evaluation was to assess the cost-utility of alectinib versus crizotinib from the perspective of the Italian National Health Service (INHS). A partitioned survival model with three health states (progression-free, post-progression, and death) was used. The clinical data (progression-free survival, overall survival and time to progression) was based on the ALEX trial. Utility values were derived from EQ-5D scores evaluated in the ALEX trial and literature. Costs included drug treatments, progression-free, post-progression and supportive care. Direct medical costs and benefits (quality-adjusted life-years, QALYs) were discounted at a 3.0% annual rate. Uncertainty was assessed using deterministic and probabilistic sensitivity analyses. Treatment with alectinib versus crizotinib led to a gain of 2.82 life-years, 1.86 QALYs, and incremental costs of €58,276, resulting in an incremental cost-utility ratio of €31,353 per QALY. The deterministic analysis showed that the most critical parameters in the model were the cost of post-progression and utility scores. From the probabilistic sensitivity analysis, alectinib had a 64.5% probability of being cost-effective at a willingness-to-pay threshold of €40,000 per QALY. Compared with crizotinib, alectinib increased the length of the progression-free state and the QALYs. The incremental overall cost increase was reflective of longer treatment durations in the progression-free state. Compared with crizotinib, alectinib can be considered a valid cost-utility option in the treatment of naive patients with ALK-positive NSCLC

Internal shocks in relativistic outflows: collisions of magnetized shells

(Abridged): We study the collision of magnetized irregularities (shells) in relativistic outflows in order to explain the origin of the generic phenomenology observed in the non-thermal emission of both blazars and gamma-ray bursts. We focus on the influence of the magnetic field on the collision dynamics, and we further investigate how the properties of the observed radiation depend on the strength of the initial magnetic field and on the initial internal energy density of the flow. The collisions of magnetized shells and the radiation resulting from these collisions are calculated using the 1D relativistic magnetohydrodynamics code MRGENESIS. The interaction of the shells with the external medium prior to their collision is also determined using an exact solver for the corresponding 1D relativistic magnetohydrodynamic Riemann problem. Our simulations show that two magnetization parameters - the ratio of magnetic energy density and thermal energy density, \alpha_B, and the ratio of magnetic energy density and mass-energy density, \sigma - play an important role in the pre-collision phase, while the dynamics of the collision and the properties of the light curves depend mostly on the magnetization parameter \sigma. The interaction of the shells with the external medium changes the flow properties at their edges prior to the collision. For sufficiently dense shells moving at large Lorentz factors (\simgt 25) these properties depend only on the magnetization parameter \sigma. Internal shocks in GRBs may reach maximum efficiencies of conversion of kinetic into thermal energy between 6% and 10%, while in case of blazars, the maximum efficiencies are \sim 2%.Comment: 17 pages, 18 figures. 2 new references have been added. Accepted for publication in Astronomy and Astrophysic

Conditional Agreements For Innovative Therapies In Italy: The Case Of Pirfenidone

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Consistency with synchrotron emission in the bright GRB 160625B observed by Fermi

We present time-resolved spectral analysis of prompt emission from GRB 160625B, one of the brightest bursts ever detected by Fermi in its nine years of operations. Standard empirical functions fail to provide an acceptable fit to the GBM spectral data, which instead require the addition of a low-energy break to the fitting function. We introduce a new fitting function, called 2SBPL, consisting of three smoothly connected power laws. Fitting this model to the data, the goodness of the fits significantly improves and the spectral parameters are well constrained. We also test a spectral model that combines non-Thermal and thermal (black body) components, but find that the 2SBPL model is systematically favoured. The spectral evolution shows that the spectral break is located around Ebreak ~100 keV, while the usual νFν peak energy feature Epeak evolves in the 0.5-6 MeV energy range. The slopes below and above Ebreak are consistent with the values-0.67 and-1.5, respectively, expected from synchrotron emission produced by a relativistic electron population with a low-energy cut-off. If Ebreak is interpreted as the synchrotron cooling frequency, the implied magnetic field in the emitting region is ~10 Gauss, i.e. orders of magnitudes smaller than the value expected for a dissipation region located at ~1013-14 cm from the central engine. The low ratio between Epeak and Ebreak implies that the radiative cooling is incomplete, contrary to what is expected in strongly magnetized and compact emitting regions

In silico identification of new putative pathogenic variants in the NEU1 sialidase gene affecting enzyme function and subcellular localization

The NEU1 gene is the first identified member of the human sialidases, glycohydrolitic enzymes that remove the terminal sialic acid from oligosaccharide chains. Mutations in NEU1 gene are causative of sialidosis (MIM 256550), a severe lysosomal storage disorder showing autosomal recessive mode of inheritance. Sialidosis has been classified into two subtypes: sialidosis type I, a normomorphic, late-onset form, and sialidosis type II, a more severe neonatal or early-onset form. A total of 50 causative mutations are reported in HGMD database, most of which are missense variants. To further characterize the NEU1 gene and identify new functionally relevant protein isoforms, we decided to study its genetic variability in the human population using the data generated by two large sequencing projects: the 1000 Genomes Project (1000G) and the NHLBI GO Exome Sequencing Project (ESP). Together these two datasets comprise a cohort of 7595 sequenced individuals, making it possible to identify rare variants and dissect population specific ones. By integrating this approach with biochemical and cellular studies, we were able to identify new rare missense and frameshift alleles in NEU1 gene. Among the 9 candidate variants tested, only two resulted in significantly lower levels of sialidase activity (pC and c.700G>A. These two mutations give rise to the amino acid substitutions p.V217A and p.D234N, respectively. NEU1 variants including either of these two amino acid changes have 44% and 25% residual sialidase activity when compared to the wild-type enzyme, reduced protein levels and altered subcellular localization. Thus they may represent new, putative pathological mutations resulting in sialidosis type I. The in silico approach used in this study has enabled the identification of previously unknown NEU1 functional alleles that are widespread in the population and could be tested in future functional studies

Signatures of synchrotron emission and of electron acceleration in the X-ray spectra of Mrk 421

BL Lac objects undergo strong flux variations involving considerable changes in their spectral shapes. We specifically investigate the X-ray spectral evolution of Mrk 421 over a time span of about nine years. We aim at statistically describing and physically understanding the large spectral changes in X rays observed in Mrk 421 over this time span. We perform a homogeneous spectral analysis of a wide data set including archived observations with ASCA, BeppoSax, RXTE, as well as published and unpublished XMM-Newton data. The presence of uncertainties is taken into account in our correlation analysis. The significance of the correlations found and possible spurious effects are studied with Monte Carlo simulations. We find that the Mrk421 spectral energy distribution (SED) has a lower peak at energies that vary in the range, 0.1-10 keV while its X-ray spectrum is definitely curved. Parameterizing the X-ray spectra with a log-parabolic model, we find a positive correlation between the position and the height of the SED peak. In addition, we find a negative trend of the spectral curvature parameter vs. the SED peak energy. We show that these relations between the spectral parameters are consistent with statistical or stochastic acceleration of the emitting particles, and provide insight into the physical processes occurring in BL Lac nuclei.Comment: 11 pages, 5 fiures, Accepted for publication in A&