A common variant associated with dyslexia reduces expression of the KIAA0319 gene

This work was supported by the Wellcome Trust (MYD, SP, TSS, JCK, RWM, PC, SB, and APM), the Intramural Research Programs of the National Human Genome Research Institute (MYD and EDG) and National Cancer Institute (MPO), and the NIH/Ox-Cam Graduate Partnership Program (MYD).Numerous genetic association studies have implicated the KIAA0319 gene on human chromosome 6p22 in dyslexia susceptibility. The causative variant(s) remains unknown but may modulate gene expression, given that (1) a dyslexia-associated haplotype has been implicated in the reduced expression of KIAA0319, and (2) the strongest association has been found for the region spanning exon 1 of KIAA0319. Here, we test the hypothesis that variant(s) responsible for reduced KIAA0319 expression resides on the risk haplotype close to the gene's transcription start site. We identified seven single-nucleotide polymorphisms on the risk haplotype immediately upstream of KIAA0319 and determined that three of these are strongly associated with multiple reading-related traits. Using luciferase-expressing constructs containing the KIAA0319 upstream region, we characterized the minimal promoter and additional putative transcriptional regulator regions. This revealed that the minor allele of rs9461045, which shows the strongest association with dyslexia in our sample (max p-value = 0.0001), confers reduced luciferase expression in both neuronal and non-neuronal cell lines. Additionally, we found that the presence of this rs9461045 dyslexia-associated allele creates a nuclear protein-binding site, likely for the transcriptional silencer OCT-1. Knocking down OCT-1 expression in the neuronal cell line SHSY5Y using an siRNA restores KIAA0319 expression from the risk haplotype to nearly that seen from the non-risk haplotype. Our study thus pinpoints a common variant as altering the function of a dyslexia candidate gene and provides an illustrative example of the strategic approach needed to dissect the molecular basis of complex genetic traits.PostprintPeer reviewe

The spectral variability and magnetic field characteristics of the Of?p star HD 148937

We report magnetic and spectroscopic observations and modeling of the Of?p star HD 148937 within the context of the MiMeS LP at the CFHT. Thirty-two high signal-to-noise ratio circularly polarised (Stokes V) spectra and 13 unpolarised (Stokes I) spectra of HD 148937 were acquired in 2009 and 2010. A definite detection of a Stokes V Zeeman signature is obtained in the grand mean of all observations (in both LSD mean profiles and individual spectral lines). The longitudinal magnetic field inferred from the Stokes V LSD profiles is consistently negative, in contrast to the essentially zero field strength measured from the diagnostic null profiles. A period search of equivalent width measurements confirms the previously-reported 7.03 d variability period. The variation of equivalent widths is not strictly periodic: we present evidence for evolution of the amount or distribution of circumstellar plasma. Interpreting the 7.03 d period as the stellar rotational period within the context of the ORM, we have phased the equivalent widths and longitudinal field measurements. The longitudinal field measurements show a weak sinusoidal variation of constant sign, with extrema out of phase with the H{\alpha} variation by about 0.25 cycles. The inferred magnetic configuration confirms the suggestion of Naz\'e et al (2010), who proposed that the weaker variability of HD 148937 as compared to other members of this class is a consequence of the stellar geometry. Based on the derived magnetic properties and published wind characteristics, we find a wind magnetic confinement parameter \eta\ast \simeq 20 and rotation parameter W = 0.12, supporting a picture in which the Halpha emission and other line variability have their origin in an oblique, rigidly rotating magnetospheric structure resulting from a magnetically channeled wind. (Abridged.)Comment: 13 pages, MNRAS. Version 2, small change to Fig. 1

The writing on the wall: the concealed communities of the East Yorkshire horselads

This paper examines the graffiti found within late nineteenth and early-twentieth century farm buildings in the Wolds of East Yorkshire. It suggests that the graffiti were created by a group of young men at the bottom of the social hierarchy - the horselads – and was one of the ways in which they constructed a distinctive sense of communal identity, at a particular stage in their lives. Whilst it tells us much about changing agricultural regimes and social structures, it also informs us about experiences and attitudes often hidden from official histories and biographies. In this way, the graffiti are argued to inform our understanding, not only of a concealed community, but also about their hidden histor

Discovery Of A Magnetic Field In The Rapidly Rotating O-Type Secondary Of The Colliding-Wind Binary HD 47129 (Plaskett\u27s Star)

We report the detection of a strong, organized magnetic field in the secondary component of the massive O8III/I+O7.5V/III double-lined spectroscopic binary system HD 47129 (Plaskett\u27s star) in the context of the Magnetism in Massive Stars survey. Eight independent Stokes V observations were acquired using the Echelle SpectroPolarimetric Device for the Observations of Stars (ESPaDOnS) spectropolarimeter at the Canada-France-Hawaii Telescope and the Narval spectropolarimeter at the Telescope Bernard Lyot. Using least-squares deconvolution we obtain definite detections of signal in Stokes V in three observations. No significant signal is detected in the diagnostic null (N) spectra. The Zeeman signatures are broad and track the radial velocity of the secondary component; we therefore conclude that the rapidly rotating secondary component is the magnetized star. Correcting the polarized spectra for the line and continuum of the (sharp-lined) primary, we measured the longitudinal magnetic field from each observation. The longitudinal field of the secondary is variable and exhibits extreme values of -810 +/- 150 and +680 +/- 190 G, implying a minimum surface dipole polar strength of 2850 +/- 500 G. In contrast, we derive an upper limit (3 sigma) to the primary\u27s surface magnetic field of 230 G. The combination of a strong magnetic field and rapid rotation leads us to conclude that the secondary hosts a centrifugal magnetosphere fed through a magnetically confined wind. We revisit the properties of the optical line profiles and X-ray emission - previously interpreted as a consequence of colliding stellar winds - in this context. We conclude that HD 47129 represents a heretofore unique stellar system - a close, massive binary with a rapidly rotating, magnetized component - that will be a rich target for further study

Visual/infrared interferometry of Orion Trapezium stars: Preliminary dynamical orbit and aperture synthesis imaging of the Theta 1 Orionis C system

Located in the Orion Trapezium cluster, Theta 1 Orionis C is one of the youngest and nearest high-mass stars (O5-O7) and also known to be a close binary system. Using new multi-epoch visual and near-infrared bispectrum speckle interferometric observations obtained at the BTA 6 m telescope, and IOTA near-infrared long-baseline interferometry, we trace the orbital motion of the Theta 1 Ori C components over the interval 1997.8 to 2005.9, covering a significant arc of the orbit. Besides fitting the relative position and the flux ratio, we apply aperture synthesis techniques to our IOTA data to reconstruct a model-independent image of the Theta 1 Ori C binary system. The orbital solutions suggest a high eccentricity (e approx. 0.91) and short-period (P approx. 10.9 yrs) orbit. As the current astrometric data only allows rather weak constraints on the total dynamical mass, we present the two best-fit orbits. From these orbital solutions one can be favoured, implying a system mass of 48 M_sun and a distance to the Trapezium cluster of 434 pc. When also taking the measured flux ratio and the derived location in the HR-diagram into account, we find good agreement for all observables, assuming a spectral type of O5.5 for Theta 1 Ori C1 (M=34.0 M_sun) and O9.5 for C2 (M=15.5 M_sun). We find indications that the companion C2 is massive itself, which makes it likely that its contribution to the intense UV radiation field of the Trapezium cluster is non-negligible. Furthermore, the high eccentricity of the preliminary orbit solution predicts a very small physical separation during periastron passage (approx. 1.5 AU, next passage around 2007.5), suggesting strong wind-wind interaction between the two O stars.Comment: 13 pages, 9 figures, Accepted for publication in Astronomy & Astrophysic

A highly efficient human pluripotent stem cell microglia model displays a neuronal-co-culture-specific expression profile and inflammatory response

Microglia are increasingly implicated in brain pathology, particularly neurodegenerative disease, with many genes implicated in Alzheimer's, Parkinson's, and motor neuron disease expressed in microglia. There is, therefore, a need for authentic, efficient in vitro models to study human microglial pathological mechanisms. Microglia originate from the yolk sac as MYB-independent macrophages, migrating into the developing brain to complete differentiation. Here, we recapitulate microglial ontogeny by highly efficient differentiation of embryonic MYB-independent iPSC-derived macrophages then co-culture them with iPSC-derived cortical neurons. Co-cultures retain neuronal maturity and functionality for many weeks. Co-culture microglia express key microglia-specific markers and neurodegenerative disease-relevant genes, develop highly dynamic ramifications, and are phagocytic. Upon activation they become more ameboid, releasing multiple microglia-relevant cytokines. Importantly, co-culture microglia downregulate pathogen-response pathways, upregulate homeostatic function pathways, and promote a more anti-inflammatory and pro-remodeling cytokine response than corresponding monocultures, demonstrating that co-cultures are preferable for modeling authentic microglial physiology

X-Ray Spectroscopy of Stars

(abridged) Non-degenerate stars of essentially all spectral classes are soft X-ray sources. Low-mass stars on the cooler part of the main sequence and their pre-main sequence predecessors define the dominant stellar population in the galaxy by number. Their X-ray spectra are reminiscent, in the broadest sense, of X-ray spectra from the solar corona. X-ray emission from cool stars is indeed ascribed to magnetically trapped hot gas analogous to the solar coronal plasma. Coronal structure, its thermal stratification and geometric extent can be interpreted based on various spectral diagnostics. New features have been identified in pre-main sequence stars; some of these may be related to accretion shocks on the stellar surface, fluorescence on circumstellar disks due to X-ray irradiation, or shock heating in stellar outflows. Massive, hot stars clearly dominate the interaction with the galactic interstellar medium: they are the main sources of ionizing radiation, mechanical energy and chemical enrichment in galaxies. High-energy emission permits to probe some of the most important processes at work in these stars, and put constraints on their most peculiar feature: the stellar wind. Here, we review recent advances in our understanding of cool and hot stars through the study of X-ray spectra, in particular high-resolution spectra now available from XMM-Newton and Chandra. We address issues related to coronal structure, flares, the composition of coronal plasma, X-ray production in accretion streams and outflows, X-rays from single OB-type stars, massive binaries, magnetic hot objects and evolved WR stars.Comment: accepted for Astron. Astrophys. Rev., 98 journal pages, 30 figures (partly multiple); some corrections made after proof stag

Bilateral inhibition of HAUSP deubiquitinase by a viral interferon regulatory factor protein

Herpesvirus-associated ubiquitin specific protease (HAUSP) regulates the stability of p53 and MDM2, implicating HAUSP as a therapeutic target for tuning p53-mediated anti-tumor activity. Here, we report the structural analysis of HAUSP with Kaposi’s sarcoma-associated herpesvirus vIRF4 and the discovery of two vIRF4-derived peptides, vif1 and vif2, as potent and selective HAUSP antagonists. This analysis reveals a bilateral belt-type interaction resulting in inhibition of HAUSP. The vif1 peptide binds the HAUSP TRAF domain, competitively blocking substrate binding, while the vif2 peptide binds both the HAUSP TRAF and catalytic domains, robustly suppressing its deubiquitination activity. Consequently, peptide treatments comprehensively blocked HAUSP, leading to p53-dependent cell cycle arrest and apoptosis in culture and tumor regression in xenograft mouse model. Thus, the virus has developed a unique molecular strategy to target the HAUSP-MDM2-p53 pathway, and these virus-derived short peptides represent biologically active HAUSP antagonists

Activation of endogenous p53 by combined p19Arf gene transfer and nutlin-3 drug treatment modalities in the murine cell lines B16 and C6

<p>Abstract</p> <p>Background</p> <p>Reactivation of p53 by either gene transfer or pharmacologic approaches may compensate for loss of p19Arf or excess mdm2 expression, common events in melanoma and glioma. In our previous work, we constructed the pCLPG retroviral vector where transgene expression is controlled by p53 through a p53-responsive promoter. The use of this vector to introduce p19Arf into tumor cells that harbor p53wt should yield viral expression of p19Arf which, in turn, would activate the endogenous p53 and result in enhanced vector expression and tumor suppression. Since nutlin-3 can activate p53 by blocking its interaction with mdm2, we explored the possibility that the combination of p19Arf gene transfer and nutlin-3 drug treatment may provide an additive benefit in stimulating p53 function.</p> <p>Methods</p> <p>B16 (mouse melanoma) and C6 (rat glioma) cell lines, which harbor p53wt, were transduced with pCLPGp19 and these were additionally treated with nutlin-3 or the DNA damaging agent, doxorubicin. Viral expression was confirmed by Western, Northern and immunofluorescence assays. p53 function was assessed by reporter gene activity provided by a p53-responsive construct. Alterations in proliferation and viability were measured by colony formation, growth curve, cell cycle and MTT assays. In an animal model, B16 cells were treated with the pCLPGp19 virus and/or drugs before subcutaneous injection in C57BL/6 mice, observation of tumor progression and histopathologic analyses.</p> <p>Results</p> <p>Here we show that the functional activation of endogenous p53wt in B16 was particularly challenging, but accomplished when combined gene transfer and drug treatments were applied, resulting in increased transactivation by p53, marked cell cycle alteration and reduced viability in culture. In an animal model, B16 cells treated with both p19Arf and nutlin-3 yielded increased necrosis and decreased BrdU marking. In comparison, C6 cells were quite susceptible to either treatment, yet p53 was further activated by the combination of p19Arf and nutlin-3.</p> <p>Conclusions</p> <p>To the best of our knowledge, this is the first study to apply both p19Arf and nutlin-3 for the stimulation of p53 activity. These results support the notion that a p53 responsive vector may prove to be an interesting gene transfer tool, especially when combined with p53-activating agents, for the treatment of tumors that retain wild-type p53.</p