Separase prevents genomic instability by controlling replication fork speed

Proper chromosome segregation is crucial for preserving genomic integrity, and errors in this process cause chromosome mis-segregation, which may contribute to cancer development. Sister chromatid separation is triggered by Separase, an evolutionary conserved protease that cleaves the cohesin complex, allowing the dissolution of sister chromatid cohesion. Here we provide evidence that Separase participates in genomic stability maintenance by controlling replication fork speed. We found that Separase interacted with the replication licensing factors MCM2-7, and genome-wide data showed that Separase co-localized with MCM complex and cohesin. Unexpectedly, the depletion of Separase increased the fork velocity about 1.5-fold and caused a strong acetylation of cohesin's SMC3 subunit and altered checkpoint response. Notably, Separase silencing triggered genomic instability in both HeLa and human primary fibroblast cells. Our results show a novel mechanism for fork progression mediated by Separase and thus the basis for genomic instability associated with tumorigenesis

X-ray irradiated protoplanetary disk atmospheres II: Predictions from models in hydrostatic equilibrium

We present new models for the X-ray photoevaporation of circumstellar discs which suggest that the resulting mass loss (occurring mainly over the radial range 10-40 AU) may be the dominant dispersal mechanism for gas around low mass pre-main sequence stars, contrary to the conclusions of previous workers. Our models combine use of the MOCASSIN Monte Carlo radiative transfer code and a self-consistent solution of the hydrostatic structure of the irradiated disc. We estimate the resulting photoevaporation rates assuming sonic outflow at the surface where the gas temperature equals the local escape temperature and derive mass loss rates of ~10^{-9} M_sun/yr, typically a factor 2-10 times lower than the corresponding rates in our previous work (Ercolano et al., 2008) where we did not adjust the density structure of the irradiated disc. The somewhat lower rates, and the fact that mass loss is concentrated towards slightly smaller radii, result from the puffing up of the heated disc at a few AU which partially screens the disc at tens of AU. (.....) We highlight the fact that X-ray photoevaporation has two generic advantages for disc dispersal compared with photoevaporation by extreme ultraviolet (EUV) photons that are only modestly beyond the Lyman limit: the demonstrably large X-ray fluxes of young stars even after they have lost their discs and the fact that X-rays are effective at penetrating much larger columns of material close to the star (abridged).Comment: Accepted for publication in ApJ, 12 pages, 11 figure

Separase prevents genomic instability by controlling replication fork speed

Proper chromosome segregation is crucial for preserving genomic integrity, and errors in this process cause chromosome mis-segregation, which may contribute to cancer development. Sister chromatid separation is triggered by Separase, an evolutionary conserved protease that cleaves the cohesin complex, allowing the dissolution of sister chromatid cohesion. Here we provide evidence that Separase participates in genomic stability maintenance by controlling replication fork speed. We found that Separase interacted with the replication licensing factors MCM2-7, and genome-wide data showed that Separase co-localized with MCM complex and cohesin. Unexpectedly, the depletion of Separase increased the fork velocity about 1.5-fold and caused a strong acetylation of cohesin's SMC3 subunit and altered checkpoint response. Notably, Separase silencing triggered genomic instability in both HeLa and human primary fibroblast cells. Our results show a novel mechanism for fork progression mediated by Separase and thus the basis for genomic instability associated with tumorigenesis

X-ray Photoevaporation-starved T Tauri Accretion

X-ray luminosities of accreting T Tauri stars are observed to be systematically lower than those of non-accretors. There is as yet no widely accepted physical explanation for this effect, though it has been suggested that accretion somehow suppresses, disrupts or obscures coronal X-ray activity. Here, we suggest that the opposite might be the case: coronal X-rays modulate the accretion flow. We re-examine the X-ray luminosities of T Tauri stars in the Orion Nebula Cluster and find that not only are accreting stars systematically fainter, but that there is a correlation between mass accretion rate and stellar X-ray luminosity. We use the X-ray heated accretion disk models of Ercolano et al. to show that protoplanetary disk photoevaporative mass loss rates are strongly dependent on stellar X-ray luminosity and sufficiently high to be competitive with accretion rates. X-ray disk heating appears to offer a viable mechanism for modulating the gas accretion flow and could be at least partially responsible for the observed correlation between accretion rates and X-ray luminosities of T Tauri stars.Comment: 4 pages 3 figures, ApJ Letters, in pres

Protoplanetary disc evolution and dispersal: the implications of X-ray photoevaportion

(Abridged) We explore the role of X-ray photoevaporation in the evolution and dispersal of viscously evolving T-Tauri discs. We show that the X-ray photoevaporation wind rates scale linearly with X-ray luminosity, such that the observed range of X-ray luminosities for solar-type T-Tauri stars (10e28-10e31 erg\s) gives rise to vigorous disc winds with rates of order 10e-10-10e-7 M_sun/yr. We use the wind solutions from radiation-hydrodynamic models, coupled to a viscous evolution model to construct a population synthesis model so that we may study the physical properties of evolving discs and so-called `transition discs'. Current observations of disc lifetimes and accretion rates can be matched by our model assuming a viscosity parameter alpha = 2.5e-3. Our models confirm that X-rays play a dominant role in the evolution and dispersal of protoplanetary discs giving rise to the observed diverse population of inner hole `transition' sources which include those with massive outer discs, those with gas in their inner holes and those with detectable accretion signatures. To help understand the nature of observed transition discs we present a diagnostic diagram based on accretion rates versus inner hole sizes that demonstrate that, contrary to recent claims, many of the observed accreting and non accreting transition discs can easily be explained by X-ray photoevaporation. Finally, we confirm the conjecture of Drake et al. (2009), that accretion is suppressed by the X-rays through `photoevaporation starved accretion' and predict this effect can give rise to a negative correlation between X-ray luminosity and accretion rate, as reported in the Orion data.Comment: Figure 12 and 13 have been updated. In the original version the results from an unused model run were plotted by mistak

Theoretical spectra of photoevaporating protoplanetary discs: An atlas of atomic and low-ionisation emission lines

We present a calculation of the atomic and low-ionisation emission line spectra of photoevaporating protoplanetary discs. Line luminosities and profiles are obtained from detailed photoionisation calculations of the disc and wind structures surrounding young active solar-type stars. The disc and wind density and velocity fields were obtained from the recently developed radiation-hydrodynamic models of Owen et al., that include stellar X-ray and EUV irradiation of protoplanetary discs at various stages of clearing, from primordial sources to inner hole sources of various hole sizes. Our models compare favourably with currently available observations, lending support to an X-ray driven photoevaporation model for disc dispersal. In particular, we find that X-rays drive a warm, predominantly neutral flow where the OI 6300A line can be produced by neutral hydrogen collisional excitation. Our models can, for the first time, provide a very good match to both luminosities and profiles of the low-velocity component of the OI 6300A line and other forbidden lines observed by Hartigan et al., which covered a large sample of T-Tauri stars. We find that the OI 6300A and the NeII 12.8um lines are predominantly produced in the X-ray-driven wind and thus appear blue-shifted by a few km/s for some of the systems when observed at non-edge-on inclinations. We note however that blue-shifts are only produced under certain conditions: X-ray luminosity, spectral shape and inner hole size all affect the location of the emitting region and the physical conditions in the wind. We caution therefore that while a blueshifted line is a tell-tale sign of an outflow, the lack of a blueshift should not be necessarily interpreted as a lack of outflow.Comment: 18 pages, 7 figures, accepted to be published in MNRAS - changes in the revised version: reference list update

Morphometric, histopathological and molecular findings of Macracanthorhynchus hirudinaceus infection in wild boar (Sus scrofa) from continental Italy

Although Macracanthorhynchus hirudinaceus is a neglected acanthocephalan of suids occasionally responsible for severe infections in humans, the spread of wild boar (Sus scrofa) populations in Europe could promote the circulation. Herein, we report the first morphometric, histological and molecular characterization of a severe M. hirudinaceus infection in a boar from continental Italy. The boar's intestine displayed granulomatous enteritis due to 24 helminths (14 females, 10 males), identified as adults of M. hirudinaceus by a combined morphometric/molecular approach. The phylogenetic analysis of the cox1 gene revealed a close relationship of the M. hirudinaceus sequence type found herein with those from Hungary and insular Italy. The high haplotype diversity and low nucleotide diversity of M. hirudinaceus specimens would suggest its rapid demographic expansion in the Mediterranean basin. More research is needed to assess the presence of M. hirudinaceus in susceptible beetle species and the role of boars in the epidemiology of infection

“I Wouldn’t Even Know What to Ask for”: Patients’ and Caregivers’ Experiences of Psychological Support for Huntington’s Disease in Italy

People with Huntington's disease (HD) often experience psychological difficulties linked with disease progression and the adjustment to living with a chronic condition, which are also frequently shared by their informal caregivers (e.g., partners). Although limited, the current literature on psychological care for people with HD shows that interventions have the potential to drive improvements in mental health and quality of life. However, the experience of accessing and receiving psychological support for HD remains unclear across several countries. This study adopted a qualitative design to explore the experiences of psychological support for HD from the perspectives of patients and caregivers living in Italy. Semi-structured interviews were carried out with 14 participants-7 patients with early-manifest HD and 7 partners acting as their caregivers. The resulting data were analysed through thematic analysis. Four overarching themes were identified: (1) the availability of psychological support for HD, (2) barriers to accessing psychological support, (3) enablers to accessing psychological support, and (4) the future development of public psychological provision for HD. In Italy, patients and caregivers perceive public psychological support for HD as unavailable or inadequate, and private therapy is often seen as unaffordable. Barriers such as distrust in public healthcare and preconceptions about therapy may limit access, while advice from HD organisations and seeking therapy for other reasons may act as enablers. A strong emphasis is put on the need for accessible public psychological support throughout all the stages of the condition

X-ray irradiated protoplanetary disk atmospheres I: Predicted emission line spectrum and photoevaporation

We present MOCASSIN 2D photoionisation and dust radiative transfer models of a prototypical T Tauri disk irradiated by X-rays from the young pre-main sequence star. The calculations demonstrate a layer of hot gas reaching temperatures of ~10^6 K at small radii and ~10^4 K at a distance of 1 AU. The gas temperatures decrease sharply with depth, but appear to be completely decoupled from dust temperatures down to a column depth of ~5*10^21 cm^-2. We predict that several fine-structure and forbidden lines of heavy elements, as well as recombination lines of hydrogen and helium, should be observable with current and future instrumentation, although optical lines may be smothered by the stellar spectrum. Predicted line luminosities are given for the the brightest collisionally excited lines (down to ~10^-8L_sun, and for recombination transitions from several levels of HI and HeI. The mass loss rate due to X-ray photoevaporation estimated from our models is of the order of 10^-8 M_sun yr^-1, implying a dispersal timescale of a few Myr for a disk of mass 0.027 M_sun, which is the mass of the disk structure model we employed. We discuss the limitations of our model and highlight the need for further calculations that should include the simultaneous solution of the 2D radiative transfer problem and the 1D hydrostatic equilibrium in the polar direction.Comment: 11 pages, 6 figures. Accepted for publication in Ap

OXavidin for Tissue Targeting Biotinylated Therapeutics

Avidin is a glycoprotein from hen egg white that binds biotin with very high affinity. Here we describe OXavidin, a product containing aldehyde groups, obtained by ligand-assisted sugar oxidation of avidin by sodium periodate. OXavidin chemically reacts with cellular and tissue proteins through Schiff's base formation thus residing in tissues for weeks while preserving the biotin binding capacity. The long tissue residence of OXavidin as well as that of OXavidin/biotinylated agent complex occurs in normal and neoplastic tissues and immunohistochemistry shows a strong and homogenous stromal localization. Once localized in tissue/tumor, OXavidin becomes an “artificial receptor” for intravenous injected biotin allowing tumor targeting with biotinylated therapeutics like radioisotopes or toxins. Moreover, present data also suggest that OXavidin might be useful for the homing of biotinylated cells. Overall, OXavidin exhibits a remarkable potential for many different therapeutic applications