35 research outputs found

    The first high-resolution observations of 37.7-, 38.3- and 38.5-GHz methanol masers

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    We have used the Australia Telescope Compact Array (ATCA) to undertake the first high angular resolution observations of 37.7-GHz (7−2−8−1E7_{-2} - 8_{-1}E) methanol masers towards a sample of eleven high-mass star formation regions which host strong 6.7-GHz methanol masers. The 37.7-GHz methanol sites are coincident to within the astrometric uncertainty (0.4 arcseconds) with the 6.7-GHz methanol masers associated with the same star formation region. However, spatial and spectral comparison of the 6.7- and 37.7-GHz maser emission within individual sources shows that the 37.7-GHz masers are less often, or to a lesser degree co-spatial than are the 12.2-GHz and 6.7-GHz masers. We also made sensitive, high angular resolution observations of the 38.3- and 38.5-GHz class II methanol transitions (62−53A−6_{2} - 5_{3}A^{-} and 62−53A+6_{2} - 5_{3}A^{+}, respectively) and the 36.2-GHz (4−1−30E4_{-1} - 3_{0}E) class I methanol transition towards the same sample of eleven sources. The 37.7-, 38.3- and 38.5-GHz methanol masers are unresolved in the current observations, which implies a lower limit on the brightness temperature of the strongest masers of more than 10610^6K. We detected the 38.3-GHz methanol transition towards 7 sources, 5 of which are new detections and detected the 38.5-GHz transition towards 6 sources, 4 of which are new detections. We detected 36.2-GHz class I methanol masers towards all eleven sources, 6 of these are new detections for this transition, of which 4 sources do not have previously reported class I methanol masers from any transition.Comment: Accepted for publication in MNRAS, 34 pages, 20 figure

    αvβ3 and α5β1 integrin recycling pathways dictate downstream Rho kinase signaling to regulate persistent cell migration

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    Accumulating evidence suggests that integrin recycling regulates cell migration. However, the lack of reagents to selectively target the trafficking of individual heterodimers, as opposed to endocytic transport as a whole, has made it difficult to define the contribution made by particular recycling pathways to directional cell movement. We show that autophosphorylation of protein kinase D1 (PKD1) at Ser916 is necessary for its association with αvβ3 integrin. Expression of PKD1916A or the use of mutants of β3 that do not bind to PKD1 selectively inhibits short-loop, Rab4-dependent recycling of αvβ3, and this suppresses the persistence of fibroblast migration. However, we report that short-loop recycling does not directly contribute to fibroblast migration by moving αvβ3 to the cell front, but by antagonizing α5β1 recycling, which, in turn, influences the cell's decision to migrate with persistence or to move randomly

    Neuropilin-1/GIPC1 Signaling Regulates α5β1 Integrin Traffic and Function in Endothelial Cells

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    Neuropilin 1 (Nrp1) is a coreceptor for vascular endothelial growth factor A165 (VEGF-A165, VEGF-A164 in mice) and semaphorin 3A (SEMA3A). Nevertheless, Nrp1 null embryos display vascular defects that differ from those of mice lacking either VEGF-A164 or Sema3A proteins. Furthermore, it has been recently reported that Nrp1 is required for endothelial cell (EC) response to both VEGF-A165 and VEGF-A121 isoforms, the latter being incapable of binding Nrp1 on the EC surface. Taken together, these data suggest that the vascular phenotype caused by the loss of Nrp1 could be due to a VEGF-A164/SEMA3A-independent function of Nrp1 in ECs, such as adhesion to the extracellular matrix. By using RNA interference and rescue with wild-type and mutant constructs, we show here that Nrp1 through its cytoplasmic SEA motif and independently of VEGF-A165 and SEMA3A specifically promotes α5β1-integrin-mediated EC adhesion to fibronectin that is crucial for vascular development. We provide evidence that Nrp1, while not directly mediating cell spreading on fibronectin, interacts with α5β1 at adhesion sites. Binding of the homomultimeric endocytic adaptor GAIP interacting protein C terminus, member 1 (GIPC1), to the SEA motif of Nrp1 selectively stimulates the internalization of active α5β1 in Rab5-positive early endosomes. Accordingly, GIPC1, which also interacts with α5β1, and the associated motor myosin VI (Myo6) support active α5β1 endocytosis and EC adhesion to fibronectin. In conclusion, we propose that Nrp1, in addition to and independently of its role as coreceptor for VEGF-A165 and SEMA3A, stimulates through its cytoplasmic domain the spreading of ECs on fibronectin by increasing the Rab5/GIPC1/Myo6-dependent internalization of active α5β1. Nrp1 modulation of α5β1 integrin function can play a causal role in the generation of angiogenesis defects observed in Nrp1 null mice

    Endosomal integrin signals for survival.

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    The mechanisms underlying integrin-dependent signalling are a topic of continued study. Endocytosed integrins are now shown to drive assembly of signalling complexes on the cytoplasmic face of endocytic membranes to promote cancer cell survival and increase metastatic capacity following cell detachment

    A newly-discovered young massive star cluster at the end of the Galactic Bar

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    We present a near-infrared study of the candidate star cluster Mercer 81, located at the centre of the G338.4+0.1 HII region, and close to the TeV gamma-ray source HESS 1640-465. Using HST/NICMOS imaging and VLT/ISAAC spectroscopy we have detected a compact and highly extincted cluster of stars, though the bright stars in the centre of the field are in fact foreground objects. The cluster contains nine stars with strong Paschen-alpha emission, one of which we identify as a Wolf-Rayet (WR) star, as well as an A-type supergiant. The line-of-sight extinction is very large, AV∼45A_{V}\sim 45, illustrating the challenges of locating young star clusters in the Galactic Plane. From a quantitative analysis of the WR star we argue for a cluster age of 3.7−0.5+0.4^{+0.4}_{-0.5}\,Myr, and, assuming that all emission-line stars are WRs, a cluster mass of \ga 10^4\msun. A kinematic analysis of the cluster's surrounding HII-region shows that the cluster is located in the Galactic disk at a distance of 11±\pm2\,kpc. This places the cluster close to where the far end of the Bar intersects the Norma spiral arm. This cluster, as well as the nearby cluster [DBS2003]179, represent the first detections of active star cluster formation at this side of the Bar, in contrast to the near side which is well known to have recently undergone a ∼106\sim 10^6\msun\ starburst episode.Comment: 12 pages, 9 figures. Accepted for publication in MNRA

    Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

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    Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes

    Large expert-curated database for benchmarking document similarity detection in biomedical literature search

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    Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

    Whole-genome sequencing reveals host factors underlying critical COVID-19