Endothelial-specific Nox2 overexpression increases vascular superoxide and macrophage recruitment in ApoE−/− mice

AIMS: Vascular disease states are associated with endothelial dysfunction and increased production of reactive oxygen species derived from NADPH oxidases. However, it remains unclear whether a primary increase in superoxide production specifically in the endothelium alters the initiation or progression of atherosclerosis. METHODS AND RESULTS: Mice overexpressing Nox2 specifically in the endothelium (Nox2-Tg) were crossed with ApoE(-/-) mice to produce Nox2-Tg ApoE(-/-) mice and ApoE(-/-) littermates. Endothelial overexpression of Nox2 in ApoE(-/-) mice did not alter blood pressure, but significantly increased vascular superoxide production compared with ApoE(-/-) littermates, measured using both lucigenin chemiluminescence and 2-hydroxyethidium production (ApoE(-/-), 19.9 ± 6.3 vs. Nox2-Tg ApoE(-/-), 47.0 ± 7.0 nmol 2-hydroxyethidium/aorta, P< 0.05). Increased endothelial superoxide production increased endothelial levels of vascular cell adhesion protein 1 and enhanced macrophage recruitment in early lesions in the aortic roots of 9-week-old mice, indicating increased atherosclerotic plaque initiation. However, endothelial-specific Nox2 overexpression did not alter native or angiotensin II-driven atherosclerosis in either the aortic root or the descending aorta. CONCLUSION: Endothelial-targeted Nox2 overexpression in ApoE(-/-) mice is sufficient to increase vascular superoxide production and increase macrophage recruitment possible via activation of endothelial cells. However, this initial increase in macrophage recruitment did not alter the progression of atherosclerosis. These results indicate that Nox-mediated reactive oxygen species signalling has important cell-specific and distinct temporal roles in the initiation and progression of atherosclerosis

Constraining the X-ray - Infrared spectral index of second-timescale flares from SGR1935+2154 with Palomar Gattini-IR

The Galactic magnetar SGR1935+2154 has been reported to produce the first known example of a bright millisecond duration radio burst (FRB 200428) similar to the cosmological population of fast radio bursts (FRBs), bolstering the association of FRBs to active magnetars. The detection of a coincident bright X-ray burst has revealed the first observed multi-wavelength counterpart of a FRB. However, the search for similar emission at optical wavelengths has been hampered by the high inferred extinction on the line of sight. Here, we present results from the first search for second-timescale emission from the source at near-infrared wavelengths using the Palomar Gattini-IR observing system in J-band, made possible by a recently implemented detector read-out mode that allowed for short exposure times of 0.84 s with 99.9% observing efficiency. With a total observing time of 12 hours (47728 images) on source, we place median $3\,\sigma$ limits on the second-timescale emission of $< 20$ mJy (13.1 AB mag). We present non-detection limits from epochs of four simultaneous X-ray bursts detected by the Insight-{\it HXMT} and {\it NuSTAR} telescopes during our observing campaign. The limits translate to an extinction corrected fluence limit of $< 125$ Jy ms for an estimated extinction of $A_J = 2.0$ mag. These limits provide the most stringent constraints to date on the fluence of flares at frequencies of $\sim 10^{14}$ Hz, and constrain the ratio of the near-infrared (NIR) fluence to that of coincident X-ray bursts to $R_{\rm NIR} < 2.5 \times 10^{-2}$. Our observations were sensitive enough to easily detect a near-infrared counterpart of FRB 200428 if the NIR emission falls on the same power law as that observed across its radio to X-ray spectrum. The non-detection of NIR emission around the coincident X-ray bursts constrains the fluence index of the brightest burst to be steeper than $0.35$.Comment: 10 pages, 4 figures, submitted to ApJL. Comments welcom

RGS1 regulates myeloid cell accumulation in atherosclerosis and aortic aneurysm rupture through altered chemokine signalling

Chemokine signalling drives monocyte recruitment in atherosclerosis and aortic aneurysms. The mechanisms that lead to retention and accumulation of macrophages in the vascular wall remain unclear. Regulator of G-Protein Signalling-1 (RGS1) deactivates G-protein signalling, reducing the response to sustained chemokine stimulation. Here we show that Rgs1 is upregulated in atherosclerotic plaque and aortic aneurysms. Rgs1 reduces macrophage chemotaxis and desensitizes chemokine receptor signalling. In early atherosclerotic lesions, Rgs1 regulates macrophage accumulation and is required for the formation and rupture of Angiotensin II-induced aortic aneurysms, through effects on leukocyte retention. Collectively, these data reveal a role for Rgs1 in leukocyte trafficking and vascular inflammation and identify Rgs1, and inhibition of chemokine receptor signalling as potential therapeutic targets in vascular disease

Palomar Gattini-IR: Survey overview, data processing system, on-sky performance and first results

Palomar Gattini-IR is a new wide-field, near-infrared (NIR) robotic time domain survey operating at Palomar Observatory. Using a 30 cm telescope mounted with a H2RG detector, Gattini-IR achieves a field of view (FOV) of 25 sq. deg. with a pixel scale of 8.”7 in J-band. Here, we describe the system design, survey operations, data processing system and on-sky performance of Palomar Gattini-IR. As a part of the nominal survey, Gattini-IR scans ≈7500 square degrees of the sky every night to a median 5σ depth of 15.7 AB mag outside the Galactic plane. The survey covers ≈15,000 square degrees of the sky visible from Palomar with a median cadence of 2 days. A real-time data processing system produces stacked science images from dithered raw images taken on sky, together with point-spread function (PSF)-fit source catalogs and transient candidates identified from subtractions within a median delay of ≈4 hr from the time of observation. The calibrated data products achieve an astrometric accuracy (rms) of ≈0.”7 with respect to Gaia DR2 for sources with signal-to-noise ratio > 10, and better than ≈0.”35 for sources brighter than ≈12 Vega mag. The photometric accuracy (rms) achieved in the PSF-fit source catalogs is better than ≈3% for sources brighter than ≈12 Vega mag and fainter than the saturation magnitude of ≈8.5 Vega mag, as calibrated against the Two Micron All Sky Survey catalog. The detection efficiency of transient candidates injected into the images is better than 90% for sources brighter than the 5σ limiting magnitude. The photometric recovery precision of injected sources is 3% for sources brighter than 13 mag, and the astrometric recovery rms is ≈0.”9. Reference images generated by stacking several field visits achieve depths of ≳16.5 AB mag over 60% of the sky, while it is limited by confusion in the Galactic plane. With a FOV ≈40× larger than any other existing NIR imaging instrument, Gattini-IR is probing the reddest and dustiest transients in the local universe such as dust obscured supernovae in nearby galaxies, novae behind large columns of extinction within the galaxy, reddened microlensing events in the Galactic plane and variability from cool and dust obscured stars. We present results from transients and variables identified since the start of the commissioning period

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment