The overexpression of the protein tyrosine kinase, Focal adhesion kinase (FAK), in endothelial cells has implicated its requirement in angiogenesis and tumour growth, but how pericyte FAK regulates ...tumour angiogenesis is unknown. We show that pericyte FAK regulates tumour growth and angiogenesis in multiple mouse models of melanoma, lung carcinoma and pancreatic B-cell insulinoma and provide evidence that loss of pericyte FAK enhances Gas6-stimulated phosphorylation of the receptor tyrosine kinase, Axl with an upregulation of Cyr61, driving enhanced tumour growth. We further show that pericyte derived Cyr61 instructs tumour cells to elevate expression of the proangiogenic/protumourigenic transmembrane receptor Tissue Factor. Finally, in human melanoma we show that when 50% or more tumour blood vessels are pericyte-FAK negative, melanoma patients are stratified into those with increased tumour size, enhanced blood vessel density and metastasis. Overall our data uncover a previously unknown mechanism of tumour growth by pericytes that is controlled by pericyte FAK.
The SARS-CoV-2 coronavirus responsible for the global pandemic contains a novel furin cleavage site in the spike protein (S) that increases viral infectivity and syncytia formation in cells. Here, we ...show that
-glycosylation near the furin cleavage site is mediated by members of the GALNT enzyme family, resulting in decreased furin cleavage and decreased syncytia formation. Moreover, we show that
-glycosylation is dependent on the novel proline at position 681 (P681). Mutations of P681 seen in the highly transmissible alpha and delta variants abrogate
-glycosylation, increase furin cleavage, and increase syncytia formation. Finally, we show that GALNT family members capable of glycosylating S are expressed in human respiratory cells that are targets for SARS-CoV-2 infection. Our results suggest that host
-glycosylation may influence viral infectivity/tropism by modulating furin cleavage of S and provide mechanistic insight into the role of the P681 mutations found in the highly transmissible alpha and delta variants.
Abstract
The ground-based gamma-ray observatory Very Energetic Radiation Imaging Telescope Array System (VERITAS,
https://veritas.sao.arizona.edu/
) is sensitive to photons of astrophysical origin ...with energies in the range between ≈85 GeV and ≈30 TeV. The instrument consists of four 12 m diameter imaging Cherenkov telescopes operating at the Fred Lawrence Whipple Observatory in southern Arizona. VERITAS started four-telescope operations in 2007 and collects about 1100 hr of good-weather data per year. The VERITAS collaboration has published over 100 journal articles since 2008 reporting on gamma-ray observations of a large variety of objects: Galactic sources like supernova remnants, pulsar wind nebulae, and binary systems; extragalactic sources like star-forming galaxies, dwarf-spheroidal galaxies, and highly variable active galactic nuclei. This note presents VTSCat: the catalog of high-level data products from all VERITAS publications.
Latitudinal gradients in species interactions are widely cited as potential causes or consequences of global patterns of biodiversity. However, mechanistic studies documenting changes in interactions ...across broad geographic ranges are limited. We surveyed predation intensity on common prey (live amphipods and gastropods) in communities of eelgrass (Zostera marina) at 48 sites across its Northern Hemisphere range, encompassing over 37° of latitude and four continental coastlines. Predation on amphipods declined with latitude on all coasts but declined more strongly along western ocean margins where temperature gradients are steeper. Whereas in situ water temperature at the time of the experiments was uncorrelated with predation, mean annual temperature strongly positively predicted predation, suggesting a more complex mechanism than simply increased metabolic activity at the time of predation. This large-scale biogeographic pattern was modified by local habitat characteristics; predation declined with higher shoot density both among and within sites. Predation rates on gastropods, by contrast, were uniformly low and varied little among sites. The high replication and geographic extent of our study not only provides additional evidence to support biogeographic variation in predation intensity, but also insight into the mechanisms that relate temperature and biogeographic gradients in species interactions.
Cosmic-ray electrons and positrons (CREs) at GeV-TeV energies are a unique probe of our local Galactic neighborhood. CREs lose energy rapidly via synchrotron radiation and inverse-Compton scattering ...processes while propagating within the Galaxy, and these losses limit their propagation distance. For electrons with TeV energies, the limit is on the order of a kiloparsec. Within that distance, there are only a few known astrophysical objects capable of accelerating electrons to such high energies. It is also possible that the CREs are the products of the annihilation or decay of heavy dark matter (DM) particles. VERITAS, an array of imaging air Cherenkov telescopes in southern Arizona, is primarily utilized for gamma-ray astronomy but also simultaneously collects CREs during all observations. We describe our methods of identifying CREs in VERITAS data and present an energy spectrum, extending from 300 GeV to 5 TeV, obtained from approximately 300 hours of observations. A single power-law fit is ruled out in VERITAS data. We find that the spectrum of CREs is consistent with a broken power law, with a break energy at 710±40stat±140syst GeV.
Dihadron and isolated direct photon-hadron angular correlations are measured in p þ ffiffiffi p collisions at s p ¼ 510 GeV. Correlations of charged hadrons of 0.7 < pT < 10 GeV=c with π0 mesons of 4 ...< pT < 15 GeV=c or isolated direct photons of 7 < pT < 15 GeV=c are used to study nonperturbative effects generated by initial-state partonic transverse momentum and final-state transverse momentum from fragmentation. The nonperturbative behavior is characterized by measuring the out-of-plane transverse momentum component pout perpendicular to the axis of the trigger particle, which is the high-pT direct photon or π0. Nonperturbative evolution effects are extracted from Gaussian fits to the away-side inclusivecharged- hadron yields for different trigger-particle transverse momenta (ptrig T ). The Gaussian widths and root mean square of pout are reported as a function of the interaction hard scale ptrig T to investigate possible transverse-momentum-dependent evolution differences between the π0-h and direct photon-h correlations and factorization breaking effects. The widths are found to decrease with ptrig T , which indicates that the Collins-Soper-Sterman soft factor is not driving the evolution with the hard scale in nearly back-to-back dihadron and direct photon-hadron production in p þ p collisions. This behavior is in contrast to Drell-Yan and semi-inclusive deep-inelastic scattering measurements.
A new radio census of neutron star X-ray binaries van den Eijnden, J; Degenaar, N; Russell, T D ...
Monthly notices of the Royal Astronomical Society,
11/2021, Volume:
507, Issue:
3
Journal Article
Peer reviewed
Open access
ABSTRACT
We report new radio observations of a sample of 36 neutron star (NS) X-ray binaries, more than doubling the sample in the literature observed at current-day sensitivities. These sources ...include 13 weakly magnetized (B < 1010 G) and 23 strongly magnetized (B ≥ 1010 G) NSs. 16 of the latter category reside in high-mass X-ray binaries, of which only two systems were radio-detected previously. We detect four weakly and nine strongly magnetized NSs; the latter are systematically radio fainter than the former and do not exceed LR ≈ 3 × 1028 erg s−1. In turn, we confirm the earlier finding that the weakly magnetized NSs are typically radio fainter than accreting stellar-mass black holes. While an unambiguous identification of the origin of radio emission in high-mass X-ray binaries is challenging, we find that in all but two detected sources (Vela X-1 and 4U 1700-37) the radio emission appears more likely attributable to a jet than the donor star wind. The strongly magnetized NS sample does not reveal a global correlation between X-ray and radio luminosity, which may be a result of sensitivity limits. Furthermore, we discuss the effect of NS spin and magnetic field on radio luminosity and jet power in our sample. No current model can account for all observed properties, necessitating the development and refinement of NS jet models to include magnetic field strengths up to 1013 G. Finally, we discuss jet quenching in soft states of NS low-mass X-ray binaries, the radio non-detections of all observed very-faint X-ray binaries in our sample, and future radio campaigns of accreting NSs.
Neuroblastomas are tumors of peripheral sympathetic neurons and are the most common solid tumor in children. To determine the genetic basis for neuroblastoma, we performed whole-genome sequencing (6 ...cases), exome sequencing (16 cases), genome-wide rearrangement analyses (32 cases) and targeted analyses of specific genomic loci (40 cases) using massively parallel sequencing. On average, each tumor had 19 somatic alterations in coding genes (range of 3-70). Among genes not previously known to be involved in neuroblastoma, chromosomal deletions and sequence alterations of the chromatin-remodeling genes ARID1A and ARID1B were identified in 8 of 71 tumors (11%) and were associated with early treatment failure and decreased survival. Using tumor-specific structural alterations, we developed an approach to identify rearranged DNA fragments in sera, providing personalized biomarkers for minimal residual disease detection and monitoring. These results highlight the dysregulation of chromatin remodeling in pediatric tumorigenesis and provide new approaches for the management of patients with neuroblastoma.
In a search with the Parkes radio telescope of 56 unidentified Fermi-Large Area Telescope (LAT) gamma-ray sources, we have detected 11 millisecond pulsars (MSPs), 10 of them discoveries, of which ...five were reported by Kerr et al. We did not detect radio pulsations from six other pulsars now known in these sources. We describe the completed survey, which included multiple observations of many targets conducted to minimize the impact of interstellar scintillation, acceleration effects in binary systems, and eclipses. We consider that 23 of the 39 remaining sources may still be viable pulsar candidates. We present timing solutions and polarimetry for five of the MSPs and gamma-ray pulsations for PSR J1903–7051 (pulsations for five others were reported in the second Fermi-LAT catalog of gamma-ray pulsars). Two of the new MSPs are isolated and five are in >1 day circular orbits with 0.2–0.3 M{sub ⊙} presumed white dwarf companions. PSR J0955–6150, in a 24 day orbit with a ≈0.25 M{sub ⊙} companion but eccentricity of 0.11, belongs to a recently identified class of eccentric MSPs. PSR J1036–8317 is in an 8 hr binary with a >0.14 M{sub ⊙} companion that is probably a white dwarf. PSR J1946–5403 is in a 3 hr orbit with a >0.02 M{sub ⊙} companion with no evidence of radio eclipses.
ABSTRACT
We investigate how different magnetohydrodynamic models of propagation of a weak (Mach number ∼1.2) shock in the core of a galaxy cluster affect its observational appearance, using the ...Perseus cluster as our fiducial model. In particular, we study how thermal conduction, both isotropic and anisotropic, and ion–electron temperature equilibration modify a weak shock. Strong thermal conduction is expected to produce an electron temperature precursor. Less prominent pressure and density precursors are formed as well. A longer equilibration time largely reduces the density precursor but does not change the electron temperature precursor much. When thermal conduction becomes anisotropic, the intracluster magnetic field imprints its characteristic spatial scale on the distortions of the shock induced by heat fluxes.
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