Characterization of a disease-associated mutation affecting a putative splicing regulatory element in intron 6b of the cystic fibrosis transmembrane conductance regulator (CFTR) gene

Cystic fibrosis (CF) is a common recessive disorder caused by >1600 mutations in the CF transmembrane conductance regulator (CFTR) gene. About 13% of CFTR mutations are classified as “splicing mutations,” but for almost 40% of these, their role in affecting the pre-mRNA splicing of the gene is not yet defined. In this work, we describe a new splicing mutation detected in three unrelated Italian CF patients. By DNA analyses and mRNA studies, we identified the c.1002–1110_1113delTAAG mutation localized in intron 6b of the CFTR gene. At the mRNA level, this mutation creates an aberrant inclusion of a sequence of 101 nucleotides between exons 6b and 7. This sequence corresponds to a portion of intron 6b and resembles a cryptic exon because it is characterized by an upstream ag and a downstream gt sequence, which are most probably recognized as 5′- and 3′-splice sites by the spliceosome. Through functional analysis of this splicing defect, we show that this mutation abolishes the interaction of the splicing regulatory protein heterogeneous nuclear ribonucleoprotein A2/B1 with an intronic splicing regulatory element and creates a new recognition motif for the SRp75 splicing factor, causing activation of the cryptic exon. Our results show that the c.1002–1110_1113delTAAG mutation creates a new intronic splicing regulatory element in intron 6b of the CFTR gene exclusively recognized by SRp75

Performance of Optically Readout GEM-based TPC with a 55Fe source

Optical readout of large Time Projection Chambers (TPCs) with multiple Gas Electron Multipliers (GEMs) amplification stages has shown to provide very interesting performances for high energy particle tracking. Proposed applications for low-energy and rare event studies, such as Dark Matter search, ask for demanding performance in the keV energy range. The performance of such a readout was studied in details as a function of the electric field configuration and GEM gain by using a $^{55}$Fe source within a 7 litre sensitive volume detector developed as a part of the R\&D for the CYGNUS project. Results reported in this paper show that the low noise level of the sensor allows to operate with a 2~keV threshold while keeping a rate of fake-events lesser than 10 per year. In this configuration, a detection efficiency well above 95\% along with an energy resolution ($\sigma$) of 18\% is obtained for the 5.9 keV photons, demonstrating the very promising capabilities of this technique

Italian carbonatite system: From mantle to ore-deposit

A new discovery of carbonatites at Pianciano, Ficoreto and Forcinelle in the Roman Region demonstrates that Italian carbonatites are not just isolated, mantle xenoliths-bearing, primitive diatremic rocks but also evolved subtype fluor-calciocarbonatite (F ~ 10 wt%) associated with fluor ore (F ~ 30 wt%). New data constrain a multi-stage petrogenetic process, 1-orthomagmatic, 2-carbothermal, 3-hydrothermal. Petrography and geochemistry are conducive to processes of immiscibility and decarbonation, rather than assimilation and crystal fractionation. A CO2-rich, ultra-alkaline magma is inferred to produce immiscible melilite leucitite and carbonatite melts, at lithospheric mantle depths. At the crustal level and in the presence of massive CO2 exsolution, decarbonation reactions may be the dominant processes. Decarbonation consumes dolomite and produces calcite and periclase, which, in turn, react with silica to produce forsterite and Ca silicates (monticellite, melilite, andradite). Under carbothermal conditions, carbonate breakdown releases Sr, Ba and LREE; F and S become concentrated in residual fluids, allowing precipitation of fluorite and barite, as well as celestine and anhydrite. Fluor-calciocarbonatite is the best candidate to exsolve fluids able to deposit fluor ore, which has a smaller volume. At the hydrothermal stage, REE concentration and temperature dropping allow the formation of LREEF2+ and LREECO3+ ligands, which control the precipitation of interstitial LREE fluorcarbonate and silicates: (bastnäsite-(Ce), Ce(CO3)F and britholite-(Ce), (Ce,Ca)5(SiO4,PO4)3(OH,F). Vanadates such as wakefieldite-(Ce), CeVO4, vanadinite, Pb5(VO4)3Cl and coronadite Pb(Mn4+ 6 Mn3+ 2)O16 characterise the matrix. At temperatures of ≤100 °C analcime, halloysite, quartz, barren calcite, and zeolites (K-Ca) precipitate in expansion fractures, veins and dyke aureoles. © 2019 The Authors689909IGM SD RAS 0330-2016-0005The HiTech AlkCarb European Union Horizon 2020 project grant-agreement number 689909 supported this research. Mineralogical studies was also partly supported by the Russian State assignment project IGM SD RAS 0330-2016-0005

CYGNO: a gaseous TPC with optical readout for dark matter directional search

The CYGNO project has the goal to use a gaseous TPC with optical readout to detect dark matter and solar neutrinos with low energy threshold and directionality. The CYGNO demonstrator will consist of 1 m 3 volume filled with He:CF 4 gas mixture at atmospheric pressure. Optical readout with high granularity CMOS sensors, combined with fast light detectors, will provide a detailed reconstruction of the event topology. This will allow to discriminate the nuclear recoil signal from the background, mainly represented by low energy electron recoils induced by radioactivity. Thanks to the high reconstruction efficiency, CYGNO will be sensitive to low mass dark matter, and will have the potential to overcome the neutrino floor, that ultimately limits non-directional dark matter searches

First evidence of luminescence in a He/CF4_4 gas mixture induced by non-ionizing electrons

Optical readout of Gas Electron Multipliers (GEM) provides very interesting performances and has been proposed for different applications in particle physics. In particular, thanks to its good efficiency in the keV energy range, it is being developed for low-energy and rare event studies, such as Dark Matter search. So far, the optical approach exploits the light produced during the avalanche processes in GEM channels. Further luminescence in the gas can be induced by electrons accelerated by a suitable electric field. The CYGNO collaboration studied this process with a combined use of a triple-GEM structure and a grid in an He/CF$_4$ (60/40) gas mixture at atmospheric pressure. Results reported in this paper allow to conclude that with an electric field of about 11~kV/cm a photon production mean free path of about 1.0~cm was found

Performance of an Optically Read-Out Time Projection Chamber with ultra-relativistic electrons

The Time Projection Chamber (TPC) is an ideal candidate to finely study the charged particle ionization in a gaseous medium. Large volumes TPCs can be readout with a suitable number of channels offering a complete 3D reconstruction of an ultra-relativistic charged particle track, that is the sequence of its energy releases in the TPC gas volume. Moreover, He-based TPCs are very promising to study keV energy particles as nuclear recoils, opening the possibility for directional searches of Dark Matter (DM) and the study of Solar Neutrinos (SN). In this paper we report the analysis of the data acquired with a small TPC prototype (named LEMOn) built by the CYGNO collaboration that was exposed to a beam of 450 MeV electrons at the Beam Test Facility of National Laboratories of Frascati. LEMOn is operated with a He-CF4 mixture at atmospheric pressure and is based on a Gas Electron Multipliers amplification stage that produces visible light collected by a sub-millimeter position resolution scientific CMOS camera. This type of readout - in conjunction with a fast light detection - allows a 3D reconstruction of the electrons tracks. The electrons are leaving a trail of segments of ionizations corresponding to a few keV energy release each. Their study leads to predict a keV energy threshold and 1-10 mm longitudinal and 0.1-0.3 mm transverse position resolution for nuclear recoils, very promising for the application of optically readout TPC to DM searches and SN measurements

Y-Chromosome Based Evidence for Pre-Neolithic Origin of the Genetically Homogeneous but Diverse Sardinian Population: Inference for Association Scans

The island of Sardinia shows a unique high incidence of several autoimmune diseases with multifactorial inheritance, particularly type 1 diabetes and multiple sclerosis. The prior knowledge of the genetic structure of this population is fundamental to establish the optimal design for association studies in these diseases. Previous work suggested that the Sardinians are a relatively homogenous population, but some reports were contradictory and data were largely based on variants subject to selection. For an unbiased assessment of genetic structure, we studied a combination of neutral Y-chromosome variants, 21 biallelic and 8 short tandem repeats (STRs) in 930 Sardinian males. We found a high degree of interindividual variation but a homogenous distribution of the detected variability in samples from three separate regions of the island. One haplogroup, I-M26, is rare or absent outside Sardinia and is very common (0.37 frequency) throughout the island, consistent with a founder effect. A Bayesian full likelihood analysis (BATWING) indicated that the time from the most recent common ancestor (TMRCA) of I-M26, was 21.0 (16.0–25.5) thousand years ago (KYA) and that the population began to expand 14.0 (7.8–22.0) KYA. These results suggest a largely pre-Neolithic settlement of the island with little subsequent gene flow from outside populations. Consequently, Sardinia is an especially attractive venue for case-control genome wide association scans in common multifactorial diseases. Concomitantly, the high degree of interindividual variation in the current population facilitates fine mapping efforts to pinpoint the aetiologic polymorphisms

The Development of Mouse APECED Models Provides New Insight into the Role of AIRE in Immune Regulation

Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy is a rare recessive autoimmune disorder caused by a defect in a single gene called AIRE (autoimmune regulator). Characteristics of this disease include a variable combination of autoimmune endocrine tissue destruction, mucocutaneous candidiasis and ectodermal dystrophies. The development of Aire-knockout mice has provided an invaluable model for the study of this disease. The aim of this review is to briefly highlight the strides made in APECED research using these transgenic murine models, with a focus on known roles of Aire in autoimmunity. The findings thus far are compelling and prompt additional areas of study which are discussed