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

The BL Lac objects OQ 530 and S5 0716+714. Simultaneous observations in the X-rays, radio, optical and TeV bands

We present the results of the BeppoSAX observations of two BL Lacs, OQ 530 and S5 0716+714, as part of a ToO program for the simultaneous observation at radio, optical, X-ray and TeV energies. Both sources are detected in the LECS and MECS, with S5 0716+714 visible also in the PDS band, up to about 60 keV. The X-ray spectra of both sources are better fitted by a double power-law model, with a steep soft X-ray component flattening at harder energies, with breaks at 0.3 and 1.5 keV, respectively. The concave shape of the spectra in both objects is consistent with soft X-rays being produced by the synchrotron and harder X-rays by the inverse Compton processes. Also the X-ray variability properties confirm this scenario, in particular for S5 0716+714 our observation shows variations by about a factor 3 over one hour below 3 keV and no variability above. Their simultaneous broad band energy spectral distributions can be successfully interpreted within the frame of a homogeneous synchrotron and inverse Compton model, including a possible contribution from an external source of seed photons with the different spectral states of S5 0716+714 being reproduced by changing the injected power. The resulting parameters are fully consistent with the two sources being intermediate objects within the "sequence" scenario proposed for blazars.Comment: 10 pages, 8 figures, accepted by A&

Swift observations of IBL and LBL objects

BL Lacs are an enigmatic class of active galactic nuclei (AGNs), characterized by the non-thermal continuum typically attributed to synchrotron and inverse Compton emission. Depending on the frequency location of the maxima of these components, they are subdivided into three subclasses LBLs, IBLs, and HBLs. We present the results of a set of observations of eight BL Lac objects of LBL and IBL type performed by the XRT and UVOT detectors onboard the Swift satellite between January 2005 and November 2006. We are mainly interested in measuring the spectral parameters, and particularly the steepness between the UV and the X-ray band, useful for determining the classification of these sources. We compare the behavior of these sources with previous XMM-Newton, BeppoSAX obser- vations and with historical data in the X-ray and in the optical band. We are also interested in classifying the sources in our sample on the basis of the observations and comparing them with their classification presented in literature. We performed X-ray spectral analysis of observed BL Lac objects using a simple powerlaw and in a few cases the log-parabolic model. We also combined the UV emission with the low energy X-ray data to We used observational data to classify sources in our sample and derived parameters of their spectral energy distribution. We found that for the IBLs X-rays low states show features of the high energy component, usually interpreted as due to inverse Compton emission. Sources in our sample exhibit a range of temporal UV and X-ray behaviors, some objects having clear and neat correlated UV and X-ray variations (e.g. ON231) and other objects showing no clear (e.g. AO 0235+164) UV and X-ray correlation. Finally, we also note that our estimates of spectral curvature are in the range of that measured for the HBLs.Comment: 10 pages, 7 figures, published in A&

Swift detection of all previously undetected blazars in a micro-wave flux-limited sample of WMAP foreground sources

Almost the totality of the bright foreground sources in the WMAP CMB maps are blazars, a class of sources that show usually also X-ray emission. However, 23 objects in a flux-limited sample of 140 blazars of the WMAP catalog (first year) were never reported before as X-ray sources. We present here the results of 41 Swift observations which led to the detection of all these 23 blazars in the 0.3-10 keV band. We conclude that all micro-wave selected blazars are X-ray emitters and that the distribution of the micro-wave to X-ray spectral slope $\alpha_{mu x}$ of LBL blazars is very narrow, confirming that the X-ray flux of most blazars is a very good estimator of their micro-wave emission. The X-ray spectral shape of all the objects that were observed long enough to allow spectral analysis is flat and consistent with inverse Compton emission within the commonly accepted view where the radiation from blazars is emitted in a Sychrotron-Inverse-Compton scenario. We predict that all blazars and most radio galaxies above the sensitivity limit of the WMAP and of the Planck CMB missions are X-ray sources detectable by the present generation of X-ray satellites. An hypothetical all-sky soft X-ray survey with sensitivity of approximately $10^{-15}$ erg/s would be crucial to locate and remove over 100,000 blazars from CMB temperature and polarization maps and therefore accurately clean the primordial CMB signal from the largest population of extragalactic foreground contaminants.Comment: 13 pages, 4 figures, 5 tables, A&A in pres

WEBT multiwavelength monitoring and XMM-Newton observations of BL Lacertae in 2007-2008. Unveiling different emission components

In 2007-2008 we carried out a new multiwavelength campaign of the Whole Earth Blazar Telescope (WEBT) on BL Lacertae, involving three pointings by the XMM-Newton satellite, to study its emission properties. The source was monitored in the optical-to-radio bands by 37 telescopes. The brightness level was relatively low. Some episodes of very fast variability were detected in the optical bands. The X-ray spectra are well fitted by a power law with photon index of about 2 and photoelectric absorption exceeding the Galactic value. However, when taking into account the presence of a molecular cloud on the line of sight, the data are best fitted by a double power law, implying a concave X-ray spectrum. The spectral energy distributions (SEDs) built with simultaneous radio-to-X-ray data at the epochs of the XMM-Newton observations suggest that the peak of the synchrotron emission lies in the near-IR band, and show a prominent UV excess, besides a slight soft-X-ray excess. A comparison with the SEDs corresponding to previous observations with X-ray satellites shows that the X-ray spectrum is extremely variable. We ascribe the UV excess to thermal emission from the accretion disc, and the other broad-band spectral features to the presence of two synchrotron components, with their related SSC emission. We fit the thermal emission with a black body law and the non-thermal components by means of a helical jet model. The fit indicates a disc temperature greater than 20000 K and a luminosity greater than 6 x 10^44 erg/s.Comment: 11 pages, 7 figures, accepted for publication in A&

Active wetting of epithelial tissues

Development, regeneration and cancer involve drastic transitions in tissue morphology. In analogy with the behavior of inert fluids, some of these transitions have been interpreted as wetting transitions. The validity and scope of this analogy are unclear, however, because the active cellular forces that drive tissue wetting have been neither measured nor theoretically accounted for. Here we show that the transition between 2D epithelial monolayers and 3D spheroidal aggregates can be understood as an active wetting transition whose physics differs fundamentally from that of passive wetting phenomena. By combining an active polar fluid model with measurements of physical forces as a function of tissue size, contractility, cell-cell and cell-substrate adhesion, and substrate stiffness, we show that the wetting transition results from the competition between traction forces and contractile intercellular stresses. This competition defines a new intrinsic lengthscale that gives rise to a critical size for the wetting transition in tissues, a striking feature that has no counterpart in classical wetting. Finally, we show that active shape fluctuations are dynamically amplified during tissue dewetting. Overall, we conclude that tissue spreading constitutes a prominent example of active wetting --- a novel physical scenario that may explain morphological transitions during tissue morphogenesis and tumor progression

The correlated optical and radio variability of BL Lacertae. WEBT data analysis 1994-2005

Since 1997, BL Lacertae has undergone a phase of high optical activity, with the occurrence of several prominent outbursts. Starting from 1999, the Whole Earth Blazar Telescope (WEBT) consortium has organized various multifrequency campaigns on this blazar, collecting tens of thousands of data points. One of the main issues in the study of this huge dataset has been the search for correlations between the optical and radio flux variations, and for possible periodicities in the light curves. The analysis of the data assembled during the first four campaigns (comprising also archival data to cover the period 1968-2003) revealed a fair optical-radio correlation in 1994-2003, with a delay of the hard radio events of ~100 days. Moreover, various statistical methods suggested the existence of a radio periodicity of ~8 years. In 2004 the WEBT started a new campaign to extend the dataset to the most recent observing seasons, in order to possibly confirm and better understand the previous results. In this campaign we have collected and assembled about 11000 new optical observations from twenty telescopes, plus near-IR and radio data at various frequencies. Here, we perform a correlation analysis on the long-term R-band and radio light curves. In general, we confirm the ~100-day delay of the hard radio events with respect to the optical ones, even if longer (~200-300 days) time lags are also found in particular periods. The radio quasi-periodicity is confirmed too, but the "period" seems to progressively lengthen from 7.4 to 9.3 years in the last three cycles. The optical and radio behaviour in the last forty years suggests a scenario where geometric effects play a major role. In particular, the alternation of enhanced and suppressed optical activity (accompanied by hard and soft radio events, respectively) canComment: 6 pages, 4 figure