A probable Keplerian disk feeding an optically revealed massive young star

The canonical picture of star formation involves disk-mediated accretion, with Keplerian accretion disks and associated bipolar jets primarily observed in nearby, low-mass young stellar objects (YSOs). Recently, rotating gaseous structures and Keplerian disks have been detected around several massive (M > 8 M ⊙) YSOs (MYSOs)1–4, including several disk-jet systems5–7. All the known MYSO systems are in the Milky Way, and all are embedded in their natal material. Here we report the detection of a rotating gaseous structure around an extragalactic MYSO in the Large Magellanic Cloud. The gas motion indicates that there is a radial flow of material falling from larger scales onto a central disk-like structure. The latter exhibits signs of Keplerian rotation, so that there is a rotating toroid feeding an accretion disk and thus the growth of the central star. The system is in almost all aspects comparable to Milky Way high-mass YSOs accreting gas from a Keplerian disk. The key difference between this source and its Galactic counterparts is that it is optically revealed rather than being deeply embedded in its natal material as is expected of such a massive young star. We suggest that this is the consequence of the star having formed in a low-metallicity and low-dust content environment. Thus, these results provide important constraints for models of the formation and evolution of massive stars and their circumstellar disks

Interleukin-1β sequesters hypoxia inducible factor 2α to the primary cilium.

BACKGROUND: The primary cilium coordinates signalling in development, health and disease. Previously we have shown that the cilium is essential for the anabolic response to loading and the inflammatory response to interleukin-1β (IL-1β). We have also shown the primary cilium elongates in response to IL-1β exposure. Both anabolic phenotype and inflammatory pathology are proposed to be dependent on hypoxia-inducible factor 2 alpha (HIF-2α). The present study tests the hypothesis that an association exists between the primary cilium and HIFs in inflammatory signalling. RESULTS: Here we show, in articular chondrocytes, that IL-1β-induces primary cilia elongation with alterations to cilia trafficking of arl13b. This elongation is associated with a transient increase in HIF-2α expression and accumulation in the primary cilium. Prolyl hydroxylase inhibition results in primary cilia elongation also associated with accumulation of HIF-2α in the ciliary base and axoneme. This recruitment and the associated cilia elongation is not inhibited by blockade of HIFα transcription activity or rescue of basal HIF-2α expression. Hypomorphic mutation to intraflagellar transport protein IFT88 results in limited ciliogenesis. This is associated with increased HIF-2α expression and inhibited response to prolyl hydroxylase inhibition. CONCLUSIONS: These findings suggest that ciliary sequestration of HIF-2α provides negative regulation of HIF-2α expression and potentially activity. This study indicates, for the first time, that the primary cilium regulates HIF signalling during inflammation

Metals detected by ICP/MS in wound tissue of war injuries without fragments in Gaza

<p>Abstract</p> <p>Background</p> <p>The amount and identity of metals incorporated into "weapons without fragments" remain undisclosed to health personnel. This poses a long-term risk of assumption and contributes to additional hazards for victims because of increased difficulties with clinical management. We assessed if there was evidence that metals are embedded in "wounds without fragments" of victims of the Israeli military operations in Gaza in 2006 and 2009.</p> <p>Methods</p> <p>Biopsies of "wounds without fragments" from clinically classified injuries, amputation (A), charred (C), burns (B), multiple piercing wounds by White Phosphorus (WP) (M), were analyzed by ICP/MS for content in 32 metals.</p> <p>Results</p> <p>Toxic and carcinogenic metals were detected in folds over control tissues in wound tissues from all injuries: in A and C wounds (Al, Ti, Cu, Sr, Ba, Co, Hg, V, Cs and Sn), in M wounds (Al, Ti, Cu, Sr, Ba, Co and Hg) and in B wounds (Co, Hg, Cs, and Sn); Pb and U in wounds of all classes; B, As, Mn, Rb, Cd, Cr, Zn in wounds of all classes, but M; Ni was in wounds of class A. Kind and amounts of metals correlate with clinical classification of injuries, exposing a specific metal signature, similar for 2006 and 2009 samples.</p> <p>Conclusions</p> <p>The presence of toxic and carcinogenic metals in wound tissue is indicative of the presence in weapon inducing the injury. Metal contamination of wounds carries unknown long term risks for survivors, and can imply effects on populations from environmental contamination. We discuss remediation strategies, and believe that these data suggest the need for epidemiological and environmental surveys.</p

Growth delay of human bladder cancer cells by Prostate Stem Cell Antigen downregulation is associated with activation of immune signaling pathways

<p>Abstract</p> <p>Background</p> <p>Prostate stem cell antigen (PSCA) is a glycosylphosphatidylinositol (GPI) anchored protein expressed not only in prostate but also in pancreas and bladder cancer as shown by immunohistochemistry and mRNA analysis. It has been targeted by monoclonal antibodies in preclinical animal models and more recently in a clinical trial in prostate cancer patients. The biological role played in tumor growth is presently unknown. In this report we have characterized the contribution of PSCA expression to tumor growth.</p> <p>Methods</p> <p>A bladder cell line was engineered to express a doxycycline (dox) regulated shRNA against PSCA. To shed light on the PSCA biological role in tumor growth, microarray analysis was carried out as a function of PSCA expression. Expression of gene set of interest was further analyzed by qPCR</p> <p>Results</p> <p>Down regulation of the PSCA expression was associated with reduced cell proliferation <it>in vitro </it>and <it>in vivo</it>. Mice bearing subcutaneous tumors showed a reduced tumor growth upon treatment with dox, which effectively induced shRNA against PSCA as revealed by GFP expression. Pathway analysis of deregulated genes suggests a statistical significant association between PSCA downregulation and activation of genes downstream of the IFNα/β receptor.</p> <p>Conclusions</p> <p>These experiments established for the first time a correlation between the level of PSCA expression and tumor growth and suggest a role of PSCA in counteracting the natural immune response.</p

Crystal Structure of Reovirus Attachment Protein σ1 in Complex with Sialylated Oligosaccharides

Many viruses attach to target cells by binding to cell-surface glycans. To gain a better understanding of strategies used by viruses to engage carbohydrate receptors, we determined the crystal structures of reovirus attachment protein σ1 in complex with α-2,3-sialyllactose, α-2,6-sialyllactose, and α-2,8-di-siallylactose. All three oligosaccharides terminate in sialic acid, which serves as a receptor for the reovirus serotype studied here. The overall structure of σ1 resembles an elongated, filamentous trimer. It contains a globular head featuring a compact β-barrel, and a fibrous extension formed by seven repeating units of a triple β-spiral that is interrupted near its midpoint by a short α -helical coiled coil. The carbohydrate-binding site is located between β-spiral repeats two and three, distal from the head. In all three complexes, the terminal sialic acid forms almost all of the contacts with σ1 in an identical manner, while the remaining components of the oligosaccharides make little or no contacts. We used this structural information to guide mutagenesis studies to identify residues in σ1 that functionally engage sialic acid by assessing hemagglutination capacity and growth in murine erythroleukemia cells, which require sialic acid binding for productive infection. Our studies using σ1 mutant viruses reveal that residues 198, 202, 203, 204, and 205 are required for functional binding to sialic acid by reovirus. These findings provide insight into mechanisms of reovirus attachment to cell-surface glycans and contribute to an understanding of carbohydrate binding by viruses. They also establish a filamentous, trimeric carbohydrate-binding module that could potentially be used to endow other trimeric proteins with carbohydrate-binding properties

Heart valve disease: investigation by cardiovascular magnetic resonance

Cardiovascular magnetic resonance (CMR) has become a valuable investigative tool in many areas of cardiac medicine. Its value in heart valve disease is less well appreciated however, particularly as echocardiography is a powerful and widely available technique in valve disease. This review highlights the added value that CMR can bring in valve disease, complementing echocardiography in many areas, but it has also become the first-line investigation in some, such as pulmonary valve disease and assessing the right ventricle. CMR has many advantages, including the ability to image in any plane, which allows full visualisation of valves and their inflow/outflow tracts, direct measurement of valve area (particularly for stenotic valves), and characterisation of the associated great vessel anatomy (e.g. the aortic root and arch in aortic valve disease). A particular strength is the ability to quantify flow, which allows accurate measurement of regurgitation, cardiac shunt volumes/ratios and differential flow volumes (e.g. left and right pulmonary arteries). Quantification of ventricular volumes and mass is vital for determining the impact of valve disease on the heart, and CMR is the 'Gold standard' for this. Limitations of the technique include partial volume effects due to image slice thickness, and a low ability to identify small, highly mobile objects (such as vegetations) due to the need to acquire images over several cardiac cycles. The review examines the advantages and disadvantages of each imaging aspect in detail, and considers how CMR can be used optimally for each valve lesion

Photoperiod Regulates Corticosterone Rhythms by Altered Adrenal Sensitivity via Melatonin-Independent Mechanisms in Fischer 344 Rats and C57BL/6J Mice

Most species living in temperate zones adapt their physiology and behavior to seasonal changes in the environment by using the photoperiod as a primary cue. The mechanisms underlying photoperiodic regulation of stress-related functions are not well understood. In this study, we analyzed the effects of photoperiod on the hypothalamic-pituitary-adrenal axis in photoperiod-sensitive Fischer 344 rats. We first examined how photoperiod affects diurnal variations in plasma concentrations of adrenocorticotropic hormone (ACTH) and corticosterone. ACTH levels did not exhibit diurnal variations under long- and short-day conditions. On the other hand, corticosterone levels exhibited a clear rhythm under short-day condition with a peak during dark phase. This peak was not observed under long-day condition in which a significant rhythm was not detected. To analyze the mechanisms responsible for the photoperiodic regulation of corticosterone rhythms, ACTH was intraperitoneally injected at the onset of the light or dark phase in dexamethasone-treated rats maintained under long- and short-day conditions. ACTH induced higher corticosterone levels in rats examined at dark onset under short-day condition than those maintained under long-day condition. Next, we asked whether melatonin signals are involved in photoperiodic regulation of corticosterone rhythms, and rats were intraperitoneally injected with melatonin at late afternoon under long-day condition for 3 weeks. However, melatonin injections did not affect the corticosterone rhythms. In addition, photoperiodic changes in the amplitude of corticosterone rhythms were also observed in melatonin-deficient C57BL/6J mice, in which expression profiles of several clock genes and steroidgenesis genes in adrenal gland were modified by the photoperiod. Our data suggest that photoperiod regulates corticosterone rhythms by altered adrenal sensitivity through melatonin-independent mechanisms that may involve the adrenal clock

Infusing Sodium Bicarbonate Suppresses Hydrogen Peroxide Accumulation and Superoxide Dismutase Activity in Hypoxic-Reoxygenated Newborn Piglets

The effectiveness of sodium bicarbonate (SB) has recently been questioned although it is often used to correct metabolic acidosis of neonates. The aim of the present study was to examine its effect on hemodynamic changes and hydrogen peroxide (H(2)O(2)) generation in the resuscitation of hypoxic newborn animals with severe acidosis.Newborn piglets were block-randomized into a sham-operated control group without hypoxia (n = 6) and two hypoxia-reoxygenation groups (2 h normocapnic alveolar hypoxia followed by 4 h room-air reoxygenation, n = 8/group). At 10 min after reoxygenation, piglets were given either i.v. SB (2 mEq/kg), or saline (hypoxia-reoxygenation controls) in a blinded, randomized fashion. Hemodynamic data and blood gas were collected at specific time points and cerebral cortical H(2)O(2) production was continuously monitored throughout experimental period. Plasma superoxide dismutase and catalase and brain tissue glutathione, superoxide dismutase, catalase, nitrotyrosine and lactate levels were assayed.Two hours of normocapnic alveolar hypoxia caused cardiogenic shock with metabolic acidosis (PH: 6.99 ± 0.07, HCO(3)(-): 8.5 ± 1.6 mmol/L). Upon resuscitation, systemic hemodynamics immediately recovered and then gradually deteriorated with normalization of acid-base imbalance over 4 h of reoxygenation. SB administration significantly enhanced the recovery of both pH and HCO(3-) recovery within the first hour of reoxygenation but did not cause any significant effect in the acid-base at 4 h of reoxygenation and the temporal hemodynamic changes. SB administration significantly suppressed the increase in H(2)O(2) accumulation in the brain with inhibition of superoxide dismutase, but not catalase, activity during hypoxia-reoxygenation as compared to those of saline-treated controls.Despite enhancing the normalization of acid-base imbalance, SB administration during resuscitation did not provide any beneficial effects on hemodynamic recovery in asphyxiated newborn piglets. SB treatment also reduced the H(2)O(2) accumulation in the cerebral cortex without significant effects on oxidative stress markers presumably by suppressing superoxide dismutase but not catalase activity