For more than 50 years geneticists have assumed that variations in phenotypic expression are caused by alterations in genotype. Recent evidence shows that ‘simple’ mendelian disorders or monogenic ...traits are often far from simple, exhibiting phenotypic variation (variable expressivity) that cannot be explained entirely by a gene or allelic alteration. In certain cases of androgen insensitivity syndrome caused by identical mutations in the androgen receptor gene, phenotypic variability is caused by somatic mosaicism, that is, somatic mutations that occur only in certain androgen-sensitive cells. Recently, more than 30 other genetic conditions that exhibit variable expressivity have been linked to somatic mosaicism. Somatic mutations have also been identified in diseases such as prostate and colorectal cancer. Therefore, the concept of somatic mutations and mosaicism is likely to have far reaching consequences for genetics, in particular in areas such as genetic counseling.
The physiological interplay of androgen and estrogen action in endocrine tissues is well recognized. The biochemical processes responsible for this interplay have yet to be fully defined. We have ...demonstrated that the androgen receptor (AR) and estrogen receptor-alpha (ERα) can interact directly using the yeast and mammalian two-hybrid systems. These interactions occurred between the C-terminal ERα ligand-binding domain and either the N-terminal AR transactivational domain or the full-length AR. Estrogen receptor-beta (ERβ) did not interact with the AR. DNA cotransfection studies employing AR, ERα and ERβ expression vectors and AR- or ER-reporter gene constructs were used to identify and measure potential functional effects of AR–ER interaction. Coexpression of ERα with AR decreased AR transactivation by 35%; coexpression of AR with ERα decreased ERα transactivation by 74%. Coexpression of AR and ERβ did not significantly modulate AR or ERβ transactivation. In summary, we have shown that specific domains of AR and ERα physically interact and have demonstrated the functional consequences of such interaction. These results may help explain the nature of the physiological interplay between androgens and estrogens.
This work aim to prepare a program of studies on nuclear physics and astrophysics, which will be conducted at the new ELI-NP Laser facility, which actually is under construction in Bucharest, ...Romania. For the arguments treated, such activity has required also a multidisciplinary approach and knowledge in the fields of nuclear physics, astrophysics, laser and plasma physics join with also some competences on solid state physics related to the radiation detection. A part of this work has concerned to the experimental test, which have been performed in several laboratories and in order to study and increase the level of knowledge on the different parts of the project. In particular have been performed studies on the laser matter interaction at the ILIL laboratory of Pisa Italy and at the LENS laboratory in Catania, where (by using different experimental set-ups) has been investigated some key points concerning the production of the plasma stream. Test has been performed on several target configurations in terms of: composition, structure and size. All the work has been devoted to optimize the conditions of target in order to have the best performance on the production yields and on energies distribution of the inner plasma ions. A parallel activity has been performed in order to study the two main detectors, which will constitute the full detections system, which will be installed at the ELI-NP facility.
An experimental campaign aiming to investigate the acceleration mechanisms through laser–matter interaction in nanosecond domain has been carried out at the LENS (Laser Energy for Nuclear Science) ...laboratory of INFN-LNS, Catania. Pure Al targets were irradiated by 6ns laser pulses at different pumping energies, up to 2J. Advanced diagnostics tools were used to characterize the plasma plume and ion production. We show the preliminary results of this experimental campaign, and especially the ones showing the production of multicharged ions having very narrow energy spreads.
The neurodegenerative diseases Huntington disease, dentatorubropallidoluysian atrophy, spinocerebellar atrophy type 3, and spinal bulbar muscular atrophy are caused by expansion of a polyglutamine ...tract within their respective gene products. There is increasing evidence that generation of truncated proteins containing an expanded polyglutamine tract may be a key step in the pathogenesis of these disorders. We now report that, similar to huntingtin, atrophin-1, ataxin-3, and the androgen receptor are cleaved in apoptotic extracts. Furthermore, each of these proteins is cleaved by one or more purified caspases, cysteine proteases involved in apoptotic death. The CAG length does not modulate susceptibility to cleavage of any of the full-length proteins. Our results suggest that by generation of truncated polyglutamine-containing proteins, caspase cleavage may represent a common step in the pathogenesis of each of these neurodegenerative diseases.
The proteasome is the primary subcellular organelle responsible for protein degradation. It is a dynamic assemblage of 34 core subunits and many differentially expressed, transiently interacting, ...modulatory proteins. This paper describes a novel affinity chromatography method for the purification of functional human holoproteasome complexes using mild conditions. Human proteasomes purified by this simple procedure maintained the ability to proteolytically process synthetic peptide substrates and degrade ubiquitinated parkin. Furthermore, the entire purification fraction was analyzed by mass spectrometry in order to identify proteasomal proteins and putative proteasome-interacting proteins. The mild purification conditions maintained transient physical interactions between holoproteasomes and a number of known modulatory proteins. In addition, several classes of putative interacting proteins co-purified with the proteasomes, including proteins with a role in the ubiquitin proteasome system for protein degradation or DNA repair. These results demonstrate the efficacy of using this affinity purification strategy for isolating functional human proteasomes and identifying proteins that may physically interact with human proteasomes.
The new detector CHIMERA, in its final 4π configuration, has been installed at Laboratori Nazionali del Sud (LNS) in Catania in January 2003. Beams of different energies ranging from protons to Au ...ions were delivered by the Tandem and the Super Conducting Cyclotron for nuclear reaction studies, in agreement with the approval of the Scientific Advisory Committee of LNS. Recent experimental results confirm very low energy thresholds of the trigger (below 0.5 MeV/nucleon), ensured within a wide dynamical range. Good characteristics of identification of light charged particles and heavy fragments have been obtained by using three detection techniques: Δ
E-E, Δ
E-time of flight, and the Pulse-Shape discrimination method. We present results of recent analysis concerning the production of intermediate mass fragments (IMF) in semi-peripheral collisions. Our results combined with theoretical Boltzmann-Nordheim-Vlasov simulations clearly demonstrate the presence of very fast processes of IMF production in the overlapping region of the target and projectile nuclei during re-separation, i.e. in the time scale comparable with the collision time. Evidence for slower, sequential-like production of IMF's is also shown.
Expansion of the long (CAG; glutamine)n repeat in the first exon of the X-linked human androgen receptor gene (hAR) causes spinal and bulbar muscular atrophy, frequently in association with mild ...androgen insensitivity. The relevant normal motor neurons are preferentially stimulated by androgen, however no motor neuron disorder occurs with any other known AR mutation, including those that cause complete androgen insensitivity. We have found that a polyglutamine (Gln) expanded AR transactivates an androgen-responsive reporter gene subnormally. Other groups have reported that a poly Gln-deleted AR transactivates normally. A parsimonious interpretation of all these facts is that poly Gln expansion causes the AR to lose a function that is necessary for full androgen sensitivity and to gain a function that is selectively motor neuronotoxic.
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