Lithium chloride modulates chondrocyte primary cilia and inhibits Hedgehog signaling

This work was supported in part by funding from the AO Foundation (project S-12-15K) and the Medical Research Council (Swindon, United Kingdom) (MR/L002876/1). C.A.P. was supported by the Royal Society of New Zealand through a James Cook Research Fellowshi

Arterial oxygen content is precisely maintained by graded erythrocytotic responses in settings of high/normal serum iron levels, and predicts exercise capacity: an observational study of hypoxaemic patients with pulmonary arteriovenous malformations.

Oxygen, haemoglobin and cardiac output are integrated components of oxygen transport: each gram of haemoglobin transports 1.34 mls of oxygen in the blood. Low arterial partial pressure of oxygen (PaO2), and haemoglobin saturation (SaO2), are the indices used in clinical assessments, and usually result from low inspired oxygen concentrations, or alveolar/airways disease. Our objective was to examine low blood oxygen/haemoglobin relationships in chronically compensated states without concurrent hypoxic pulmonary vasoreactivity.165 consecutive unselected patients with pulmonary arteriovenous malformations were studied, in 98 cases, pre/post embolisation treatment. 159 (96%) had hereditary haemorrhagic telangiectasia. Arterial oxygen content was calculated by SaO2 x haemoglobin x 1.34/100.There was wide variation in SaO2 on air (78.5-99, median 95)% but due to secondary erythrocytosis and resultant polycythaemia, SaO2 explained only 0.1% of the variance in arterial oxygen content per unit blood volume. Secondary erythrocytosis was achievable with low iron stores, but only if serum iron was high-normal: Low serum iron levels were associated with reduced haemoglobin per erythrocyte, and overall arterial oxygen content was lower in iron deficient patients (median 16.0 [IQR 14.9, 17.4]mls/dL compared to 18.8 [IQR 17.4, 20.1]mls/dL, p<0.0001). Exercise tolerance appeared unrelated to SaO2 but was significantly worse in patients with lower oxygen content (p<0.0001). A pre-defined athletic group had higher Hb:SaO2 and serum iron:ferritin ratios than non-athletes with normal exercise capacity. PAVM embolisation increased SaO2, but arterial oxygen content was precisely restored by a subsequent fall in haemoglobin: 86 (87.8%) patients reported no change in exercise tolerance at post-embolisation follow-up.Haemoglobin and oxygen measurements in isolation do not indicate the more physiologically relevant oxygen content per unit blood volume. This can be maintained for SaO2 ≥78.5%, and resets to the same arterial oxygen content after correction of hypoxaemia. Serum iron concentrations, not ferritin, seem to predict more successful polycythaemic responses

Who Watches the Watchmen? An Appraisal of Benchmarks for Multiple Sequence Alignment

Multiple sequence alignment (MSA) is a fundamental and ubiquitous technique in bioinformatics used to infer related residues among biological sequences. Thus alignment accuracy is crucial to a vast range of analyses, often in ways difficult to assess in those analyses. To compare the performance of different aligners and help detect systematic errors in alignments, a number of benchmarking strategies have been pursued. Here we present an overview of the main strategies--based on simulation, consistency, protein structure, and phylogeny--and discuss their different advantages and associated risks. We outline a set of desirable characteristics for effective benchmarking, and evaluate each strategy in light of them. We conclude that there is currently no universally applicable means of benchmarking MSA, and that developers and users of alignment tools should base their choice of benchmark depending on the context of application--with a keen awareness of the assumptions underlying each benchmarking strategy.Comment: Revie

Ischaemic strokes in patients with pulmonary arteriovenous malformations and hereditary hemorrhagic telangiectasia: associations with iron deficiency and platelets.

<div><p>Background</p><p>Pulmonary first pass filtration of particles marginally exceeding ∼7 µm (the size of a red blood cell) is used routinely in diagnostics, and allows cellular aggregates forming or entering the circulation in the preceding cardiac cycle to lodge safely in pulmonary capillaries/arterioles. Pulmonary arteriovenous malformations compromise capillary bed filtration, and are commonly associated with ischaemic stroke. Cohorts with CT-scan evident malformations associated with the highest contrast echocardiographic shunt grades are known to be at higher stroke risk. Our goal was to identify within this broad grouping, which patients were at higher risk of stroke.</p><p>Methodology</p><p>497 consecutive patients with CT-proven pulmonary arteriovenous malformations due to hereditary haemorrhagic telangiectasia were studied. Relationships with radiologically-confirmed clinical ischaemic stroke were examined using logistic regression, receiver operating characteristic analyses, and platelet studies.</p><p>Principal Findings</p><p>Sixty-one individuals (12.3%) had acute, non-iatrogenic ischaemic clinical strokes at a median age of 52 (IQR 41–63) years. In crude and age-adjusted logistic regression, stroke risk was associated not with venous thromboemboli or conventional neurovascular risk factors, but with low serum iron (adjusted odds ratio 0.96 [95% confidence intervals 0.92, 1.00]), and more weakly with low oxygen saturations reflecting a larger right-to-left shunt (adjusted OR 0.96 [0.92, 1.01]). For the same pulmonary arteriovenous malformations, the stroke risk would approximately double with serum iron 6 µmol/L compared to mid-normal range (7–27 µmol/L). Platelet studies confirmed overlooked data that iron deficiency is associated with exuberant platelet aggregation to serotonin (5HT), correcting following iron treatment. By MANOVA, adjusting for participant and 5HT, iron or ferritin explained 14% of the variance in log-transformed aggregation-rate (p = 0.039/p = 0.021).</p><p>Significance</p><p>These data suggest that patients with compromised pulmonary capillary filtration due to pulmonary arteriovenous malformations are at increased risk of ischaemic stroke if they are iron deficient, and that mechanisms are likely to include enhanced aggregation of circulating platelets.</p></div

Submillimeter Studies of Prestellar Cores and Protostars: Probing the Initial Conditions for Protostellar Collapse

Improving our understanding of the initial conditions and earliest stages of protostellar collapse is crucial to gain insight into the origin of stellar masses, multiple systems, and protoplanetary disks. Observationally, there are two complementary approaches to this problem: (1) studying the structure and kinematics of prestellar cores observed prior to protostar formation, and (2) studying the structure of young (e.g. Class 0) accreting protostars observed soon after point mass formation. We discuss recent advances made in this area thanks to (sub)millimeter mapping observations with large single-dish telescopes and interferometers. In particular, we argue that the beginning of protostellar collapse is much more violent in cluster-forming clouds than in regions of distributed star formation. Major breakthroughs are expected in this field from future large submillimeter instruments such as Herschel and ALMA.Comment: 12 pages, 9 figures, to appear in the proceedings of the conference "Chemistry as a Diagnostic of Star Formation" (C.L. Curry & M. Fich eds.

Gravitational Waves from Gravitational Collapse

Gravitational wave emission from the gravitational collapse of massive stars has been studied for more than three decades. Current state of the art numerical investigations of collapse include those that use progenitors with realistic angular momentum profiles, properly treat microphysics issues, account for general relativity, and examine non--axisymmetric effects in three dimensions. Such simulations predict that gravitational waves from various phenomena associated with gravitational collapse could be detectable with advanced ground--based and future space--based interferometric observatories.Comment: 68 pages including 13 figures; revised version accepted for publication in Living Reviews in Relativity (http://www.livingreviews.org

From z>6 to z~2: Unearthing Galaxies at the Edge of the Dark Ages

Galaxies undergoing formation and evolution can now be observed over a time baseline of some 12 Gyr. An inherent difficulty with high-redshift observations is that the objects are very faint and the best resolution (HST) is only ~0.5 kpc. Such studies thereby combine in a highly synergistic way with the great detail that can be obtained for nearby galaxies. 3 new developments are highlighted. First is the derivation of stellar masses for galaxies from SEDs using HST and now Spitzer data, and dynamical masses from both sub-mm observations of CO lines and near-IR observations of optical lines like Halpha. A major step has been taken with evidence that points to the z~2-3 LBGs having masses that are a few x 10^10 Msolar. Second is the discovery of a population of evolved red galaxies at z~2-3 which appear to be the progenitors of the more massive early-type galaxies of today, with dynamical masses around a few x 10^11 Msolar. Third are the remarkable advances that have occurred in characterizing dropout galaxies to z~6 and beyond, < 1 Gyr from recombination. The HST ACS has played a key role here, with the dropout technique being applied to i & z images in several deep ACS fields, yielding large samples of these objects. This has allowed a detailed determination of their properties and meaningful comparisons against lower-z samples. The use of cloning techniques has overcome many of the strong selection biases affecting the study of these objects. A clear trend of size with redshift has been identified, and its impact on the luminosity density and SFR estimated. There is a significant though modest decrease in the SFR from z~2.5 to z~6. The latest data also allow for the first robust determination of the LF at z~6. Finally, the latest UDF ACS and NICMOS data has resulted in the detection of some galaxies at z~7-8.Comment: 18 pages, 8 figures. To appear in Penetrating Bars through Masks of Cosmic Dust: The Hubble Tuning Fork Strikes a New Note, eds. D. Block, K. Freeman, R. Groess, I. Puerari, & E.K. Block (Dordrecht: Kluwer), in pres

Gravitational torques imply molecular gas inflow towards the nucleus of M 51

PublishedJournal Article© 2016 ESO.The transport of gas towards the centre of galaxies is critical for black hole feeding and, indirectly, it can control active galactic nucleus (AGN) feedback. We have quantified the molecular gas inflow in the central R< 1 kpc of M 51 to be 1 M⊙/yr, using a new gravitational torque map and the molecular gas traced by the Plateau de Bure Interferometer Arcsecond Whirlpool Survey (PAWS). The nuclear stellar bar is responsible for this gas inflow. We also used torque profiles to estimate the location of dynamical resonances, and the results suggest a corotation for the bar CRbar ∼ 20″, and a corotation for the spiral CRsp ∼ 100″. We demonstrate how important it is to correct 3.6 μm images for dust emission when gravitational torques are to be computed, and we examine further sources of uncertainty. Our observational measurement of gas inflow can be compared with nuclear molecular outflow rates and provide useful constraints for numerical simulations.The authors would like to thank the anonymous referee for a helpful report, as well as Daniela Calzetti, Nick Z. Scoville and Mari Polletta for making the HST/F190N mosaic available to us. We also appreciate valuable comments from Françoise Combes and Sebastian Haan. We acknowledge financial support to the DAGAL network from the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme FP7/2007- 2013/ under REA grant agreement number PITN-GA-2011-289313. M.Q. acknowledges the International Max Planck Research School for Astronomy and Cosmic Physics at the University of Heidelberg (IMPRS-HD). S.G.B. thanks support from Spanish grant AYA2012-32295. J.P. acknowledges support from the CNRS programme “Physique et Chimie du Milieu Interstellaire” (PCMI). M.Q., S.E.M., D.C. and A.H. acknowledge funding from the Deutsche Forschungsgemeinschaft (DFG) via grants SCHI 536/7-2,SCHI 536/5-1, and SCHI 536/7-1 as part of the priority program SPP 1573 “ISM-SPP: Physics of the Interstellar Medium”

Lack of correlation of stem cell markers in breast cancer stem cells

BACKGROUND: Various markers are used to identify the unique sub-population of breast cancer cells with stem cell properties. Whether these markers are expressed in all breast cancers, identify the same population of cells, or equate to therapeutic response is controversial. METHODS: We investigated the expression of multiple cancer stem cell markers in human breast cancer samples and cell lines in vitro and in vivo, comparing across and within samples and relating expression with growth and therapeutic response to doxorubicin, docetaxol and radiotherapy. RESULTS: CD24, CD44, ALDH and SOX2 expression, the ability to form mammospheres and side-population cells are variably present in human cancers and cell lines. Each marker identifies a unique rather than common population of cancer cells. In vivo, cells expressing these markers are not specifically localized to the presumptive stem cell niche at the tumour/stroma interface. Repeated therapy does not consistently enrich cells expressing these markers, although ER-negative cells accumulate. CONCLUSIONS: Commonly employed methods identify different cancer cell sub-populations with no consistent therapeutic implications, rather than a single population of cells. The relationships of breast cancer stem cells to clinical parameters will require identification of specific markers or panels for the individual cancer

Short GMC lifetimes: an observational estimate with the PdBI Arcsecond Whirlpool Survey (PAWS)

PublishedJournal ArticleWe describe and execute a novel approach to observationally estimate the lifetimes of giant molecular clouds (GMCs). We focus on the cloud population between the two main spiral arms in M51 (the inter-arm region) where cloud destruction via shear and star formation feedback dominates over formation processes. By monitoring the change in GMC number densities and properties across the inter-arm, we estimate the lifetime as a fraction of the inter-arm travel time. We find that GMC lifetimes in M51's inter-arm are finite and short, 20-30 Myr. Over most of the region under investigation shear appears to regulate the lifetime. As the shear timescale increases with galactocentric radius, we expect cloud destruction to switch primarily to feedback at larger radii. We identify a transition from shear- to feedback-dominated disruption, finding that shear is more efficient at dispersing clouds, whereas feedback transforms the population, e.g., by fragmenting high-mass clouds into lower mass pieces. Compared to the characteristic timescale for molecular hydrogen in M51, our short lifetimes suggest that gas can remain molecular while clouds disperse and reassemble. We propose that galaxy dynamics regulates the cycling of molecular material from diffuse to bound (and ultimately star-forming) objects, contributing to long observed molecular depletion times in normal disk galaxies. We also speculate that, in extreme environments like elliptical galaxies and concentrated galaxy centers, star formation can be suppressed when the shear timescale is short enough that some clouds will not survive to form stars.We thank the IRAM staff for their support during the observations with the Plateau de Bure interferometer and the 30 m telescope. S.E.M., D.C., and A.H. acknowledge funding from the Deutsche Forschungsgemeinschaft (DFG) via grants SCHI 536/7-2, SCHI 536/5-1, and SCHI 536/7-1 as part of the priority program SPP 1573 “ISM-SPP: Physics of the Interstellar Medium.” C.L.D. acknowledges funding from the European Research Council for the FP7 ERC starting grant project LOCALSTAR. T.A.T. acknowledges support from NASA grant number NNX10AD01G. J.P. acknowledges support from the CNRS program “Physique et Chimie du Milieu Interstellaire” (PCMI). M.Q. acknowledges financial support to the DAGAL network from the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme FP7/2007-2013/ under REA grant agreement number PITN-GA-2011-289313