A null mutation in the gene encoding a type I interferon receptor component eliminates antiproliferative and antiviral responses to interferons alpha and beta and alters macrophage responses.

To examine the in vivo role(s) of type I interferons (IFNs) and to determine the role of a component of the type I IFN receptor (IFNAR1) in mediating responses to these IFNs, we generated mice with a null mutation (-/-) in the IFNAR1 gene. Despite compelling evidence for modulation of cell proliferation and differentiation by type I IFNs, there were no gross signs of abnormal fetal development or morphological changes in adult IFNAR1-/- mice. However, abnormalities of hemopoietic cells were detected in IFNAR1 -/- mice. Elevated levels of myeloid lineage cells were detected in peripheral blood and bone marrow by staining with Mac-1 and Gr-1 antibodies. Furthermore, bone marrow macrophages from IFNAR1 -/- mice showed abnormal responses to colony-stimulating factor 1 and lipopolysaccharide. IFNAR1 -/- mice were highly susceptible to viral infection: viral titers were undetected 24 hr after infection of IFNAR1 +/+ mice but were extremely high in organs of IFNAR1 -/- mice, demonstrating that the type I IFN system is a major acute antiviral defence. In cell lines derived from IFNAR1 -/- mice, there was no signaling in response to IFN-alpha or -beta as measured by induction of 2'-5' oligoadenylate synthetase, antiviral, or antiproliferative responses. Importantly, these studies demonstrate that type I IFNs function in the development and responses of myeloid lineage cells, particularly macrophages, and that the IFNAR1 receptor component is essential for antiproliferative and antiviral responses to IFN-alpha and -beta.

A detergent-free method for purifying caveolae membrane from tissue culture cells.

Current methods for purifying caveolae from tissue culture cells take advantage of the Triton X-100 insolubility of this membrane domain. To circumvent the use of detergents, we have developed a method that depends upon the unique buoyant density of caveolae membrane. The caveolae fractions that we obtain are highly enriched in caveolin. As a consequence we are able to identify caveolae-associated proteins that had previously gone undetected. Moreover, resident caveolae proteins that are soluble in Triton X-100 are retained during the isolation.

Stars and brown dwarfs in the σ Orionis cluster (Research Note) III. OSIRIS/GTC low-resolution spectroscopy of variable sources

Context. Although many studies have been performed so far, there are still dozens of low-mass stars and brown dwarfs in the young σ Orionis open cluster without detailed spectroscopic characterisation. Aims. We look for unknown strong accretors and disc hosts that were undetected in previous surveys. Methods. We collected low-resolution spectroscopy (R ~ 700) of ten low-mass stars and brown dwarfs in σ Orionis with OSIRIS at the Gran Telescopio Canarias under very poor weather conditions. These objects display variability in the optical, infrared, Hα, and/or X-rays on time scales of hours to years. We complemented our spectra with optical and near-/mid-infrared photometry. Results. For seven targets, we detected lithium in absorption, identified Hα, the calcium doublet, and forbidden lines in emission, and/or determined spectral types for the first time. We characterise in detail a faint, T Tauri-like brown dwarf with an 18 h-period variability in the optical and a large Hα equivalent width of –125  ±  15 Å, as well as two M1-type, X-ray-flaring, low-mass stars, one with a warm disc and forbidden emission lines, the other with a previously unknown cold disc with a large inner hole. Conclusions. New unrevealed strong accretors and disc hosts, even below the substellar limit, await discovery among the list of known σ Orionis stars and brown dwarfs that are variable in the optical and have no detailed spectroscopic characterisation yet.

Probing large-scale wind structures in Vela X–1 using off-states with INTEGRAL

Vela X–1 is the prototype of the class of wind-fed accreting pulsars in high-mass X-ray binaries hosting a supergiant donor. We have analysed in a systematic way 10 years of INTEGRAL data of Vela X–1 (22–50 keV) and we found that when outside the X-ray eclipse, the source undergoes several luminosity drops where the hard X-rays luminosity goes below ∼3 × 1035 erg s−1, becoming undetected by INTEGRAL. These drops in the X-ray flux are usually referred to as ‘off-states’ in the literature. We have investigated the distribution of these off-states along the Vela X–1 ∼ 8.9 d orbit, finding that their orbital occurrence displays an asymmetric distribution, with a higher probability to observe an off-state near the pre-eclipse than during the post-eclipse. This asymmetry can be explained by scattering of hard X-rays in a region of ionized wind, able to reduce the source hard X-ray brightness preferentially near eclipse ingress. We associate this ionized large-scale wind structure with the photoionization wake produced by the interaction of the supergiant wind with the X-ray emission from the neutron star. We emphasize that this observational result could be obtained thanks to the accumulation of a decade of INTEGRAL data, with observations covering the whole orbit several times, allowing us to detect an asymmetric pattern in the orbital distribution of off-states in Vela X–1.

The little-studied cluster Berkeley 90 I. LS III +46 11: a very massive O3.5 If* + O3.5 If* binary

Context. It appears that most (if not all) massive stars are born in multiple systems. At the same time, the most massive binaries are hard to find owing to their low numbers throughout the Galaxy and the implied large distances and extinctions. Aims. We want to study LS III +46 11, identified in this paper as a very massive binary; another nearby massive system, LS III +46 12; and the surrounding stellar cluster, Berkeley 90. Methods. Most of the data used in this paper are multi-epoch high S/N optical spectra, although we also use Lucky Imaging and archival photometry. The spectra are reduced with dedicated pipelines and processed with our own software, such as a spectroscopic-orbit code, CHORIZOS, and MGB. Results. LS III +46 11 is identified as a new very early O-type spectroscopic binary [O3.5 If* + O3.5 If*] and LS III +46 12 as another early O-type system [O4.5 V((f))]. We measure a 97.2-day period for LS III +46 11 and derive minimum masses of 38.80 ± 0.83 M⊙ and 35.60 ± 0.77 M⊙ for its two stars. We measure the extinction to both stars, estimate the distance, search for optical companions, and study the surrounding cluster. In doing so, a variable extinction is found as well as discrepant results for the distance. We discuss possible explanations and suggest that LS III +46 12 may be a hidden binary system where the companion is currently undetected.

On the formation and evolution of the first Be star in a black hole binary MWC 656

We find that the formation of MWC 656 (the first Be binary containing a black hole) involves a common envelope phase and a supernova explosion. This result supports the idea that a rapidly rotating Be star can emerge out of a common envelope phase, which is very intriguing because this evolutionary stage is thought to be too fast to lead to significant accretion and spin up of the B star. We predict ∼10–100 of B-BH binaries to currently reside in the Galactic disc, among which around 1/3 contain a Be star, but there is only a small chance to observe a system with parameters resembling MWC 656. If MWC 656 is representative of intrinsic Galactic Be-BH binary population, it may indicate that standard evolutionary theory needs to be revised. This would pose another evolutionary problem in understanding black hole (BH) binaries, with BH X-ray novae formation issue being the prime example. Future evolution of MWC 656 with an ∼5 M⊙ BH and with an ∼13 M⊙ main-sequence companion on an ∼60 d orbit may lead to the formation of a coalescing BH–NS (neutron star) system. The estimated Advanced LIGO/Virgo detection rate of such systems is up to ∼0.2 yr−1. This empirical estimate is a lower limit as it is obtained with only one particular evolutionary scenario, the MWC 656 binary. This is only a third such estimate available (after Cyg X-1 and Cyg X-3), and it lends additional support to the existence of so far undetected BH–NS binaries.

The Goodness of Simultaneous Fits in ISIS

In a previous work, we introduced a tool for analyzing multiple datasets simultaneously, which has been implemented into ISIS. This tool was used to fit many spectra of X-ray binaries. However, the large number of degrees of freedom and individual datasets raise an issue about a good measure for a simultaneous fit quality. We present three ways to check the goodness of these fits: we investigate the goodness of each fit in all datasets, we define a combined goodness exploiting the logical structure of a simultaneous fit, and we stack the fit residuals of all datasets to detect weak features. These tools are applied to all RXTE-spectra from GRO 1008−57, revealing calibration features that are not detected significantly in any single spectrum. Stacking the residuals from the best-fit model for the Vela X-1 and XTE J1859+083 data evidences fluorescent emission lines that would have gone undetected otherwise.

Une nouvelle méthode pour estimer la torsion géométrique en scoliose idiopathique de l’adolescent

La scoliose idiopathique de l’adolescent (SIA) est une déformation tridimensionnelle (3D) de la colonne vertébrale. Pour la plupart des patients atteints de SIA, aucun traitement chirurgical n’est nécessaire. Lorsque la déformation devient sévère, un traitement chirurgical visant à réduire la déformation est recommandé. Pour déterminer la sévérité de la SIA, l’imagerie la plus utilisée est une radiographie postéroantérieure (PA) ou antéro-postérieure (AP) du rachis. Plusieurs indices sont disponibles à partir de cette modalité d’imagerie afin de quantifier la déformation de la SIA, dont l’angle de Cobb. La conduite thérapeutique est généralement basée sur cet indice. Cependant, les indices disponibles à cette modalité d’imagerie sont de nature bidimensionnelle (2D). Celles-ci ne décrivent donc pas entièrement la déformation dans la SIA dû à sa nature tridimensionnelle (3D). Conséquemment, les classifications basées sur les indices 2D souffrent des mêmes limitations. Dans le but décrire la SIA en 3D, la torsion géométrique a été étudiée et proposée par Poncet et al. Celle-ci mesure la tendance d’une courbe tridimensionnelle à changer de direction. Cependant, la méthode proposée est susceptible aux erreurs de reconstructions 3D et elle est calculée localement au niveau vertébral. L’objectif de cette étude est d’évaluer une nouvelle méthode d’estimation de la torsion géométrique par l’approximation de longueurs d’arcs locaux et par paramétrisation de courbes dans la SIA. Une première étude visera à étudier la sensibilité de la nouvelle méthode présentée face aux erreurs de reconstructions 3D du rachis. Par la suite, deux études cliniques vont présenter la iv torsion géométrique comme indice global et viseront à démontrer l’existence de sous-groupes non-identifiés dans les classifications actuelles et que ceux-ci ont une pertinence clinique. La première étude a évalué la robustesse de la nouvelle méthode d’estimation de la torsion géométrique chez un groupe de patient atteint de la SIA. Elle a démontré que la nouvelle technique est robuste face aux erreurs de reconstructions 3D du rachis. La deuxième étude a évalué la torsion géométrique utilisant cette nouvelle méthode dans une cohorte de patient avec des déformations de type Lenke 1. Elle a démontré qu’il existe deux sous-groupes, une avec des valeurs de torsion élevées et l’autre avec des valeurs basses. Ces deux sous-groupes possèdent des différences statistiquement significatives, notamment au niveau du rachis lombaire avec le groupe de torsion élevée ayant des valeurs d’orientation des plans de déformation maximales (PMC) en thoraco-lombaire (TLL) plus élevées. La dernière étude a évalué les résultats chirurgicaux de patients ayant une déformation Lenke 1 sous-classifiées selon les valeurs de torsion préalablement. Cette étude a pu démontrer des différences au niveau du PMC au niveau thoraco-lombaire avec des valeurs plus élevées en postopératoire chez les patients ayant une haute torsion. Ces études présentent une nouvelle méthode d’estimation de la torsion géométrique et présentent cet indice quantitativement. Elles ont démontré l’existence de sous-groupes 3D basés sur cet indice ayant une pertinence clinique dans la SIA, qui n’étaient pas identifiés auparavant. Ce projet contribue dans la tendance actuelle vers le développement d’indices 3D et de classifications 3D pour la scoliose idiopathique de l’adolescent.

Geochemistry of Apatite from rapid cooled samples

Apatite (U-Th-Sm)/He (AHe) thermochronology is increasingly used for reconstructing geodynamic processes of the upper crust and the surface. Results of AHe thermochronology, however, are often in conflict with apatite fission track (AFT) thermochronology, yielding an inverted age-relationship with AHe dates older than AFT dates of the same samples. This effect is mainly explained by radiation damage of apatite, either impeding He diffusion or causing non-thermal annealing of fission tracks. So far, systematic age inversions have only been described for old and slowly cooled terranes, whereas for young and rapidly cooled samples 'too old' AHe dates are usually explained by the presence of undetected U and/or Th-rich micro-inclusions. We report apatite (U-Th-Sm)/He results for rapidly cooled volcanogenic samples deposited in a deep ocean environment with a relatively simple post-depositional thermal history. Robust age constraints are provided independently through sample biostratigraphy. All studied apatites have low U contents (< 5 ppm on average). While AFT dates are largely in agreement with deposition ages, most AHe dates are too old. For leg 43, where deposition age of sampled sediment is 26.5-29.5 Ma, alpha-corrected average AHe dates are up to 45 Ma, indicating overestimations of AHe dates up to 50%. This is explained by He implantation from surrounding host U-Th rich sedimentary components and it is shown that AHe dates can be "corrected" by mechanically abrading the outer part of grains. We recommend that particularly for low U-Th-apatites the possibility of He implantation should be carefully checked before considering the degree to which the alpha-ejection correction should be applied.

Barriers and Facilitators to Treatment among Newly Diagnosed Hypertensive Patients in Nepal: a Qualitative Study

Thesis (Master's)--University of Washington, 2016-06

The Hi content of compact groups of galaxies

The Hi content of Hickson Compact Groups in the southern hemisphere is measured using data from the Hi Parkes All-Sky Survey (HIPASS), and dedicated observations using the narrow band filter on the Multibeam instrument on the Parkes telescope. The expected Hi mass of these groups was estimated using the luminosity, diameter, and morphological types of the member galaxies, calibrated from published data. Taking careful account of non-detection limits, the results show that the compact group population that has been detected by these observations has an Hi content similar to that of galaxies in the reference field sample. The upper limits for the undetected groups lie within the normal range; improvement of these limits will require a large increase in sensitivity.

Effect of early marine diagenesis on coral reconstructions of surface-ocean 13C/12C and carbonate saturation state

Recent research suggests that future decreases in the carbonate saturation state of surface seawater associated with the projected build-up of atmospheric CO2 could cause a global decline in coral reef-building capacity. Whether significant reductions in coral calcification are underway is a matter of considerable debate. Multicentury records of skeletal calcification extracted from massive corals have the potential to reconstruct the progressive effect of anthropogenic changes in carbonate saturation on coral reefs. However, early marine aragonite cements are commonly precipitated from pore waters in the basal portions of massive coral skeletons and, if undetected, could result in apparent nonlinear reductions in coral calcification toward the present. To address this issue, we present records of coral skeletal density, extension rate, calcification rate, δ13C, and δ18O for well preserved and diagenetically altered coral cores spanning ∼1830-1994 A.D. at Ningaloo Reef Marine Park, Western Australia. The record for the pristine coral shows no significant decrease in skeletal density or δ13C indicative of anthropogenic changes in carbonate saturation state or δ13C of surface seawater (oceanic Suess effect). In contrast, progressive addition of early marine inorganic aragonite toward the base of the altered coral produces an apparent ∼25% decrease in skeletal density toward the present, which misleadingly matches the nonlinear twentieth century decrease in coral calcification predicted by recent modeling and experimental studies. In addition, the diagenetic aragonite is enriched in 13C, relative to coral aragonite, resulting in a nonlinear decrease in δ13C toward the present that mimics the decrease in δ13C expected from the oceanic Suess effect. Taken together, these diagenetic changes in skeletal density and δ13C could be misinterpreted to reflect changes in surface-ocean carbonate saturation state driven by the twentieth century build-up of atmospheric CO2. Copyright 2004 by the American Geophysical Union.

Is pulse palpation helpful in detecting atrial fibrillation? A systematic review

Background Atrial fibrillation in the elderly is common and potentially life threatening. The classical sign of atrial fibrillation is an irregularly irregular pulse. Objective The objective of this research was to determine the accuracy of pulse palpation to detect atrial fibrillation. Methods We searched Medline, EMBASE, and the reference lists of review articles for studies that compared pulse palpation with the electrocardiogram (ECG) diagnosis of atrial fibrillation. Two reviewers independently assessed the search results to determine the eligibility of studies, extracted data, and assessed the quality of the studies. Results We identified 3 studies (2385 patients) that compared pulse palpation with ECG. The estimated sensitivity of pulse palpation ranged from 91% to 100%, while specificity ranged from 70% to 77%. Pooled sensitivity was 94% (95% confidence interval [CI], 84%-97%) and pooled specificity was 72% (95% CI 69%-75%). The pooled positive likelihood ratio was 3.39, while the pooled negative likelihood ratio was 0.10. Conclusions Pulse palpation has a high sensitivity but relatively low specificity for atrial fibrillation. It is therefore useful for ruling out atrial fibrillation. It may also be a useful screen to apply opportunistically for previously undetected atrial fibrillation. Assuming a prevalence of 3% for undetected atrial fibrillation in patients older than 65 years, and given the test's sensitivity and specificity, opportunistic pulse palpation in this age group would detect an irregular pulse in 30% of screened patients, requiring further testing with ECG. Among screened patients, 0.2% would have atrial fibrillation undetected with pulse palpation.

HLA and Genomewide Allele Sharing in Dizygotic Twins

Gametic selection during fertilization or the effects of specific genotypes on the viability of embryos may cause a skewed transmission of chromosomes to surviving offspring. A recent analysis of transmission distortion in humans reported significant excess sharing among full siblings. Dizygotic (DZ) twin pairs are a special case of the simultaneous survival of two genotypes, and there have been reports of DZ pairs with excess allele sharing around the HLA locus, a candidate locus for embryo survival. We performed an allele-sharing study of 1,592 DZ twin pairs from two independent Australian cohorts, of which 1,561 pairs were informative for linkage on chromosome 6. We also analyzed allele sharing in 336 DZ twin pairs from The Netherlands. We found no evidence of excess allele sharing, either at the HLA locus or in the rest of the genome. In contrast, we found evidence of a small but significant (P = .003 for the Australian sample) genomewide deficit in the proportion of two alleles shared identical by descent among DZ twin pairs. We reconciled conflicting evidence in the literature for excess genomewide allele sharing by performing a simulation study that shows how undetected genotyping errors can lead to an apparent deficit or excess of allele sharing among sibling pairs, dependent on whether parental genotypes are known. Our results imply that gene-mapping studies based on affected sibling pairs that include DZ pairs will not suffer from false-positive results due to loci involved in embryo survival.

Inhibition of transforming growth factor-beta 1 signaling attenuates ataxia telanglectasia mutated activity in response to genotoxic stress

Ionizing radiation causes DNA damage that elicits a cellular program of damage control coordinated by the kinase activity of ataxia telangiectasia mutated protein (ATM). Transforming growth factor beta (TGF beta)-1, which is activated by radiation, is a potent and pleiotropic mediator of physiologic and pathologic processes. Here we show that TGF beta inhibition impedes the canonical cellular DNA damage stress response. Irradiated Tgf beta 1 nail murine epithelial cells or human epithelial cells treated with a small-molecule inhibitor of TGF beta type I receptor kinase exhibit decreased phosphorylation of Chk2, Rad17, and p53; reduced gamma H2AX radiation-induced foci; and increased radiosensitivity compared with TGF beta competent cells. We determined that loss of TGF beta signaling in epithelial cells truncated ATM autophosphorylation and significantly reduced its kinase activity, without affecting protein abundance. Addition of TGF beta restored functional ATM and downstream DNA damage responses. These data reveal a heretofore undetected critical link between the microenvironment and ATM, which directs epithelial cell stress responses, cell fate, and tissue integrity. Thus, Tgf beta 1, in addition to its role in homoeostatic growth control, plays a complex role in regulating responses to genotoxic stress, the failure of which would contribute to the development of cancer; conversely, inhibiting TGF beta may be used to advantage in cancer therapy.