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

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

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

High-resolution coherency functionals for velocity analysis: an application for subbasalt seismic exploration

We tested the properties of three different coherency functionals for the velocity analysis of seismic data relative to subbasalt exploration. We evaluated the performance of the standard semblance algorithm and two high-resolution coherency functionals based on the use of analytic signals and of the covariance estimation along hyperbolic traveltime trajectories. Approximate knowledge of the wavelet was exploited to design appropriate filters that matched the primary reflections, thereby further improving the ability of the functionals to highlight the events of interest. The tests were carried out on two synthetic seismograms computed on models reproducing the geologic setting of basaltic intrusions and on common midpoint gathers from a 3D survey. Synthetic and field data had a very low signal-to-noise ratio, strong multiple contamination, and weak primary subbasalt signals. The results revealed that high-resolution coherency functionals were more suitable than semblance algorithms to detect primary signals and to distinguish them from multiples and other interfering events. This early discrimination between primaries and multiples could help to target specific signal enhancement and demultiple operations

Decaying shock studies of phase transitions in MgOSiO2 systems: implications for the Super-Earths interiors

We report an experimental study of the phase diagrams of periclase (MgO), enstatite (MgSiO3) and forsterite (Mg2SiO4) at high pressures. We investigated with laser driven decaying shocks the pressure/temperature curves of MgO, MgSiO3 and Mg2SiO4 between 0.2-1.2 TPa, 0.12-0.5 TPa and 0.2-0.85 TPa respectively. A melting signature has been observed in MgO at 0.47 TPa and 9860 K, while no phase changes were observed neither in MgSiO3 nor in Mg2SiO4. An increasing of reflectivity of MgO, MgSiO3 and Mg2SiO4 liquids have been detected at 0.55 TPa -12 760 K, 0.15 TPa - 7540 K, 0.2 TPa - 5800 K, respectively. In contrast to SiO2, melting and metallization of these compounds do not coincide implying the presence of poor electrically conducting liquids close to the melting lines. This has important implications for the generation of dynamos in Super-earths mantles

Different renal phenotypes in related adult males with Fabry disease with the same classic genotype

BACKGROUND: Fabry disease related patients with classical mutation usually exhibit similar severe phenotype especially concerning renal manifestation. METHODS: A dry blood spot screening (DBS) and the DNA analysis has been performed in a 48-year-old man (Patient 1) because of paresthesia. RESULTS: The DBS revealed absent leukocyte \u3b1-Gal A enzyme activity while DNA analysis identified the I354K mutation. Serum creatinine and e-GFR were in normal range and also albuminuria and proteinuria were absent. The brain MRI showed ischemic lesions and a diffuse focus of gliosis in the white matter, while the echocardiogram showed a left ventricular hypertrophy. The renal biopsy performed in the case index showed a massive deposition of zebra bodies. By a familiar investigation, it was recognized that his brother (Patient 2) died 2 years before from sudden death syndrome at the age of 49. He had suffered sporadic and undiagnosed pain at the extremities, a prior cataract, bilateral neurosensorial hearing loss and left ventricular hypertrophy on Echocardiogram. His previous laboratory examinations revealed a normal serum creatinine and the absence of proteinuria. Pedigree analysis of the brothers revealed a high disease burden among family members, with an affected cousin (Patient 3) who progressed early to end-stage renal disease (ESRD) that required renal transplantation. CONCLUSIONS: Here we describe the clinical history of three adult male members of the same family with the same genotype who manifested different presentation and progression of the disease, particularly concerning the renal involvement