Thrombin-induced events in non-platelet cells are mediated by the unique proteolytic mechanism established for the cloned platelet thrombin receptor.

We recently isolated a cDNA clone encoding a functional platelet thrombin receptor that defined a unique mechanism of receptor activation. Thrombin cleaves its receptor's extracellular amino terminal extension, unmasking a new amino terminus that functions as a tethered peptide ligand and activates the receptor. A novel peptide mimicking this new amino terminus was a full agonist for platelet secretion and aggregation, suggesting that this unusual mechanism accounts for platelet activation by thrombin. Does this mechanism also mediate thrombin's assorted actions on non-platelet cells? We now report that the novel thrombin receptor agonist peptide reproduces thrombin-induced events (specifically, phosphoinositide hydrolysis and mitogenesis) in CCL-39 hamster lung fibroblasts, a naturally thrombin-responsive cell line. Moreover, these thrombin-induced events could be recapitulated in CV-1 cells, normally poorly responsive to thrombin, after transfection with human platelet thrombin receptor cDNA. Our data show that important thrombin-induced cellular events are mediated by the same unusual mechanism of receptor activation in both platelets and fibroblasts, very likely via the same or very similar receptors

Expression of Protease-Activated Receptor 1 and 2 and Anti-Tubulogenic Activity of Protease-Activated Receptor 1 in Human Endothelial Colony-Forming Cells

Endothelial colony-forming cells (ECFCs) are obtained from the culture of human peripheral blood mononuclear cell (hPBMNC) fractions and are characterised by high proliferative and pro-vasculogenic potential, which makes them of great interest for cell therapy. Here, we describe the detection of protease-activated receptor (PAR) 1 and 2 amongst the surface proteins expressed in ECFCs. Both receptors are functionally coupled to extracellular signal-regulated kinase (ERK) 1 and 2, which become activated and phosphorylated in response to selective PAR1- or PAR2-activating peptides. Specific stimulation of PAR1, but not PAR2, significantly inhibits capillary-like tube formation by ECFCs in vitro, suggesting that tubulogenesis is negatively regulated by proteases able to stimulate PAR1 (e.g. thrombin). The activation of ERKs is not involved in the regulation of tubulogenesis in vitro, as suggested by use of the MEK inhibitor PD98059 and by the fact that PAR2 stimulation activates ERKs without affecting capillary tube formation. Both qPCR and immunoblotting showed a significant downregulation of vascular endothelial growth factor 2 (VEGFR2) in response to PAR1 stimulation. Moreover, the addition of VEGF (50–100 ng/ml) but not basic Fibroblast Growth Factor (FGF) (25–100 ng/ml) rescued tube formation by ECFCs treated with PAR1-activating peptide. Therefore, we propose that reduction of VEGF responsiveness resulting from down-regulation of VEGFR2 is underlying the anti-tubulogenic effect of PAR1 activation. Although the role of PAR2 remains elusive, this study sheds new light on the regulation of the vasculogenic activity of ECFCs and suggests a potential link between adult vasculogenesis and the coagulation cascade

Exoplanet Catalogues

One of the most exciting developments in the field of exoplanets has been the progression from 'stamp-collecting' to demography, from discovery to characterisation, from exoplanets to comparative exoplanetology. There is an exhilaration when a prediction is confirmed, a trend is observed, or a new population appears. This transition has been driven by the rise in the sheer number of known exoplanets, which has been rising exponentially for two decades (Mamajek 2016). However, the careful collection, scrutiny and organisation of these exoplanets is necessary for drawing robust, scientific conclusions that are sensitive to the biases and caveats that have gone into their discovery. The purpose of this chapter is to discuss and demonstrate important considerations to keep in mind when examining or constructing a catalogue of exoplanets. First, we introduce the value of exoplanetary catalogues. There are a handful of large, online databases that aggregate the available exoplanet literature and render it digestible and navigable - an ever more complex task with the growing number and diversity of exoplanet discoveries. We compare and contrast three of the most up-to-date general catalogues, including the data and tools that are available. We then describe exoplanet catalogues that were constructed to address specific science questions or exoplanet discovery space. Although we do not attempt to list or summarise all the published lists of exoplanets in the literature in this chapter, we explore the case study of the NASA Kepler mission planet catalogues in some detail. Finally, we lay out some of the best practices to adopt when constructing or utilising an exoplanet catalogue.Comment: 14 pages, 6 figures. Invited review chapter, to appear in "Handbook of Exoplanets", edited by H.J. Deeg and J.A. Belmonte, section editor N. Batalh

Securing combined Fog-to-Cloud systems: challenges and directions

Nowadays, fog computing is emerged for providing computational power closer to the users. Fog computing brings real-time processing, lowlatency, geo-distributed and etc. Although, fog computing do not come to compete cloud computing, it comes to collaborate. Recently, Fog-To-Cloud (F2C) continuum system is introduced to provide hierarchical computing system and facilitates fog-cloud collaboration. This F2C continuum system might encounter security issues and challenges due to their hierarchical and distributed nature. In this paper, we analyze attacks in different layer of F2C system and identify most potential security requirements and challenges for the F2C continuum system. Finally, we introduce the most remarkable efforts and trends for bringing secure F2C system.This work is supported by the H2020 projects mF2C (730929). It is also supported by the Spanish Ministry of Economy and Competitiveness and the European Regional Development Fund both under contract RTI2018-094532-B-100.Peer ReviewedPostprint (author's final draft

The large-scale environment of thermonuclear and core-collapse supernovae

The new generation of wide-field time-domain surveys has made it feasible to study the clustering of supernova (SN) host galaxies in the large-scale structure (LSS) for the first time. We investigate the LSS environment of SN populations, using 106 dark matter density realisations with a resolution of ∼3.8 Mpc, constrained by the 2M+ + galaxy survey. We limit our analysis to redshift z < 0.036, using samples of 498 thermonuclear and 782 core-collapse SNe from the Zwicky Transient Facility’s Bright Transient Survey and Census of the Local Universe catalogues. We detect clustering of SNe with high significance; the observed clustering of the two SNe populations is consistent with each other. Further, the clustering of SN hosts is consistent with that of the Sloan Digital Sky Survey (SDSS) Baryon Oscillation Spectroscopic Survey DR12 spectroscopic galaxy sample in the same redshift range. Using a tidal shear classifier, we classify the LSS into voids, sheets, filaments, and knots. We find that both SNe and SDSS galaxies are predominantly found in sheets and filaments. SNe are significantly under-represented in voids and over-represented in knots compared to the volume fraction in these structures. This work opens the potential for using forthcoming wide-field deep SN surveys as a complementary LSS probe

The Koala: A Fast Blue Optical Transient with Luminous Radio Emission from a Starburst Dwarf Galaxy at z=0.27

We present ZTF18abvkwla (the "Koala"), a fast blue optical transient discovered in the Zwicky Transient Facility (ZTF) One-Day Cadence (1DC) Survey. ZTF18abvkwla has a number of features in common with the groundbreaking transient AT 2018cow: blue colors at peak ($g-r\approx -0.5$ mag), a short rise time from half-max of under two days, a decay time to half-max of only three days, a high optical luminosity (${M}_{g,\mathrm{peak}}\approx -20.6$ mag), a hot (gsim40,000 K) featureless spectrum at peak light, and a luminous radio counterpart. At late times (${\rm{\Delta }}t\gt 80\,\mathrm{days}$), the radio luminosity of ZTF18abvkwla ($\nu {L}_{\nu }\gtrsim {10}^{40}\,\mathrm{erg}\,{{\rm{s}}}^{-1}$ at 10 $\mathrm{GHz}$, observer-frame) is most similar to that of long-duration gamma-ray bursts (GRBs). The host galaxy is a dwarf starburst galaxy ($M\approx 5\times {10}^{8}\,{M}_{\odot }$, $\mathrm{SFR}\approx 7\,{M}_{\odot }\,{\mathrm{yr}}^{-1}$) that is moderately metal-enriched ($\mathrm{log}[{\rm{O}}/{\rm{H}}]\approx 8.5$), similar to the hosts of GRBs and superluminous supernovae. As in AT2018cow, the radio and optical emission in ZTF18abvkwla likely arise from two separate components: the radio from fast-moving ejecta (${\rm{\Gamma }}\beta c\gt 0.38c$) and the optical from shock-interaction with confined dense material (<0.07 M ⊙ in $\sim {10}^{15}\,\mathrm{cm}$). Compiling transients in the literature with ${t}_{\mathrm{rise}}\lt 5\,\mathrm{days}$ and ${M}_{\mathrm{peak}}\lt -20$ mag, we find that a significant number are engine-powered, and suggest that the high peak optical luminosity is directly related to the presence of this engine. From 18 months of the 1DC survey, we find that transients in this rise-luminosity phase space are at least two to three orders of magnitude less common than CC SNe. Finally, we discuss strategies for identifying such events with future facilities like the Large Synoptic Survey Telescope, as well as prospects for detecting accompanying X-ray and radio emission

An association between anti-platelet drug use and reduced cancer prevalence in diabetic patients: results from the Vermont Diabetes Information System Study

<p>Abstract</p> <p>Background</p> <p>Diabetes is associated with an increased risk of several malignancies. Both diabetic patients and patients with cancer have an increase in platelet reactivity and platelet activation has recently emerged as a potential mediator of cancer progression. Drug therapies, such as aspirin, that reduce platelet reactivity reduce both cardiovascular and cancer risk.</p> <p>Methods</p> <p>We performed a cross-sectional analysis to assess the association between history of cancer and current anti-platelet drug use in a primary care population of adults with diabetes enrolled in the Vermont Diabetes Information System.</p> <p>Results</p> <p>Self-reported characteristics, medical history, and a complete medication list were recorded on 1007 diabetic adults. Fifty percent of diabetic patients used an anti-platelet drug. In unadjusted analysis, no association was seen between anti-platelet drug use and cancer history (OR = 0.93; <it>P </it>= .70). Platelet inhibitor use was associated with a decreased patient-reported history of malignancy in a multivariate logistic regression adjusted for age, sex, body mass index, comorbidity, and number of medications (OR = 0.66; CI 0.44-0.99; <it>P </it>= .045). Similar odds of association were seen in both males and females, and for aspirin and non-aspirin platelet inhibitor therapy.</p> <p>Conclusions</p> <p>Our data suggest an association between anti-platelet drug use and reduced cancer prevalence in patients with diabetes. Given the potentially large implications of our observations in the diabetic population, further studies are required to determine if this association is causal.</p

Optical biosensor differentiates signaling of endogenous PAR1 and PAR2 in A431 cells

<p>Abstract</p> <p>Background</p> <p>Protease activated receptors (PARs) consist of a family of four G protein-coupled receptors. Many types of cells express several PARs, whose physiological significance is mostly unknown.</p> <p>Results</p> <p>Here, we show that non-invasive resonant waveguide grating (RWG) biosensor differentiates signaling of endogenous protease activated receptor subtype 1 (PAR₁) and 2 (PAR₂) in human epidermoid carcinoma A431 cells. The biosensor directly measures dynamic mass redistribution (DMR) resulted from ligand-induced receptor activation in adherent cells. In A431, both PAR₁and PAR₂agonists, but neither PAR₃nor PAR₄agonists, trigger dose-dependent Ca²⁺mobilization as well as G_q-type DMR signals. Both Ca²⁺flux and DMR signals display comparable desensitization patterns upon repeated stimulation with different combinations of agonists. However, PAR₁and PAR₂exhibit distinct kinetics of receptor re-sensitization. Furthermore, both trypsin- and thrombin-induced Ca²⁺flux signals show almost identical dependence on cell surface cholesterol level, but their corresponding DMR signals present different sensitivities.</p> <p>Conclusion</p> <p>Optical biosensor provides an alternative readout for examining receptor activation under physiologically relevant conditions, and differentiates the signaling of endogenous PAR₁and PAR₂in A431.</p