Endothelial cell Nrf2-KO attenuates endothelial function and skeletal muscle antioxidant capacity

INTRODUCTION: Endothelial cells line the inner surface of blood vessels and play a major role in modulating blood flow and gas exchange. Endothelial dysfunction is thought to be a contributor to cardiovascular disease development, and it is well-accepted that excessive reactive oxygen species (harmful molecules) likely contribute to endothelial dysfunction. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) is considered the master regulator of cellular protection in response to elevated reactive oxygen species. Therefore, Nrf2 may be a potential therapeutic target to protect against endothelial dysfunction. However, the roles of endothelial cell-specific Nrf2 on endothelial function are not known. The purpose of this study was to investigate the impacts of endothelial cell-specific Nrf2 deletion on vascular function (endothelium-dependent and endothelium-independent vasodilation) and skeletal muscle antioxidant status. METHODS: Leg arteries were harvested from 6-mo old C57BL/6 mice (WT, n = 6) and endothelial cell-specific Nrf2-knockout mice (Tie2-Cre-Nrf2 floxed-KO, n = 6). Endothelium-dependent vasodilation was assessed in response to flow (30 uL·min-1) and acetylcholine (ACh, 10-7-10-3 M) with and without Nω-Nitro-L-arginine methyl ester (L-NAME), and endothelium-independent vasodilation was assessed with sodium nitroprusside (SNP, 10-9-10-4 M) using videomicroscopy. Skeletal muscle antioxidant protein expression for glutathione peroxidase-1 (GPX-1) and catalase (CAT) was assessed by immunoblotting. RESULTS: Endothelium-dependent vasodilation was lower in Nrf2-KO compared to WT induced by flow (WT: 34.8±2.9%, Nrf2-KO: 20.7±3.7%, P-3M, WT: 68.3±8.2%, Nrf2-KO: 44.5±7.1%, PP-3 M, 19.1±4.4%, PP=0.28) or ACh (10-3 M, 37.7±7.0%, P = 0.16). Endothelium-independent vasodilation was not different (SNP 10-4 M, WT: 92.7±3.6%, Nrf2-KO: 81.9± 0.2%, P=0.157). In addition, GPX-1 was lower in Nrf2-KO mice (WT: 0.47±0.06, Nrf2-KO: 0.001±0.003, PP=0.08). CONCLUSIONS: Endothelial cell Nrf2 may play a key role in endothelial-mediated vasodilatory function. The nitric oxide synthase inhibitor L-NAME attenuated endothelial-mediated vasodilation in WT but not in endothelial cell Nrf2-KO. Furthermore, endothelial cell Nrf2 may play a role in skeletal muscle antioxidant homeostasis, which suggests potential systemic implications of endothelial cell Nrf2 deletion. These results collectively suggest that the endothelial cell Nrf2 system is linked to endothelial dysfunction and changes in the skeletal muscle redox environment, likely through nitric oxide- and oxidative stress-related mechanisms

Attachment styles and personal growth following romantic breakups: The mediating roles of distress, rumination, and tendency to rebound

© 2013 Marshall et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article has been made available through the Brunel Open Access Publishing Fund.The purpose of this research was to examine the associations of attachment anxiety and avoidance with personal growth following relationship dissolution, and to test breakup distress, rumination, and tendency to rebound with new partners as mediators of these associations. Study 1 (N = 411) and Study 2 (N = 465) measured attachment style, breakup distress, and personal growth; Study 2 additionally measured ruminative reflection, brooding, and proclivity to rebound with new partners. Structural equation modelling revealed in both studies that anxiety was indirectly associated with greater personal growth through heightened breakup distress, whereas avoidance was indirectly associated with lower personal growth through inhibited breakup distress. Study 2 further showed that the positive association of breakup distress with personal growth was accounted for by enhanced reflection and brooding, and that anxious individuals’ greater personal growth was also explained by their proclivity to rebound. These findings suggest that anxious individuals’ hyperactivated breakup distress may act as a catalyst for personal growth by promoting the cognitive processing of breakup-related thoughts and emotions, whereas avoidant individuals’ deactivated distress may inhibit personal growth by suppressing this cognitive work

Nasal Host Response-Based Screening for Undiagnosed Respiratory Viruses: A Pathogen Surveillance and Detection Study

BACKGROUND: Symptomatic patients who test negative for common viruses are an important possible source of unrecognised or emerging pathogens, but metagenomic sequencing of all samples is inefficient because of the low likelihood of finding a pathogen in any given sample. We aimed to determine whether nasopharyngeal CXCL10 screening could be used as a strategy to enrich for samples containing undiagnosed viruses. METHODS: In this pathogen surveillance and detection study, we measured CXCL10 concentrations from nasopharyngeal swabs from patients in the Yale New Haven health-care system, which had been tested at the Yale New Haven Hospital Clinical Virology Laboratory (New Haven, CT, USA). Patients who tested negative for a panel of respiratory viruses using multiplex PCR during Jan 23-29, 2017, or March 3-14, 2020, were included. We performed host and pathogen RNA sequencing (RNA-Seq) and analysis for viral reads on samples with CXCL10 higher than 1 ng/mL or CXCL10 testing and quantitative RT-PCR (RT-qPCR) for SARS-CoV-2. We used RNA-Seq and cytokine profiling to compare the host response to infection in samples that were virus positive (rhinovirus, seasonal coronavirus CoV-NL63, or SARS-CoV-2) and virus negative (controls). FINDINGS: During Jan 23-29, 2017, 359 samples were tested for ten viruses on the multiplex PCR respiratory virus panel (RVP). 251 (70%) were RVP negative. 60 (24%) of 251 samples had CXCL10 higher than 150 pg/mL and were identified for further analysis. 28 (47%) of 60 CXCL10-high samples were positive for seasonal coronaviruses. 223 (89%) of 251 samples were PCR negative for 15 viruses and, of these, CXCL10-based screening identified 32 (13%) samples for further analysis. Of these 32 samples, eight (25%) with CXCL10 concentrations higher than 1 ng/mL and sufficient RNA were selected for RNA-Seq. Microbial RNA analysis showed the presence of influenza C virus in one sample and revealed RNA reads from bacterial pathobionts in four (50%) of eight samples. Between March 3 and March 14, 2020, 375 (59%) of 641 samples tested negative for 15 viruses on the RVP. 32 (9%) of 375 samples had CXCL10 concentrations ranging from 100 pg/mL to 1000 pg/mL and four of those were positive for SARS-CoV-2. CXCL10 elevation was statistically significant, and a distinguishing feature was found in 28 (8%) of 375 SARS-CoV-2-negative samples versus all four SARS-CoV-2-positive samples (p=4·4 × 10 INTERPRETATION: These results confirm CXCL10 as a robust nasopharyngeal biomarker of viral respiratory infection and support host response-based screening followed by metagenomic sequencing of CXCL10-high samples as a practical approach to incorporate clinical samples into pathogen discovery and surveillance efforts. FUNDING: National Institutes of Health, the Hartwell Foundation, the Gruber Foundation, Fast Grants for COVID-19 research from the Mercatus Center, and the Huffman Family Donor Advised Fund

MWA rapid follow-up of gravitational wave transients: prospects for detecting prompt radio counterparts

We present and evaluate the prospects for detecting coherent radio counterparts to gravitational wave (GW) events using Murchison Widefield Array (MWA) triggered observations. The MWA rapid-response system, combined with its buffering mode ($\sim4$ minutes negative latency), enables us to catch any radio signals produced from seconds prior to hours after a binary neutron star (BNS) merger. The large field of view of the MWA ($\sim1000\,\text{deg}^2$ at 120\,MHz) and its location under the high sensitivity sky region of the LIGO-Virgo-KAGRA (LVK) detector network, forecast a high chance of being on-target for a GW event. We consider three observing configurations for the MWA to follow up GW BNS merger events, including a single dipole per tile, the full array, and four sub-arrays. We then perform a population synthesis of BNS systems to predict the radio detectable fraction of GW events using these configurations. We find that the configuration with four sub-arrays is the best compromise between sky coverage and sensitivity as it is capable of placing meaningful constraints on the radio emission from 12.6\% of GW BNS detections. Based on the timescales of four BNS merger coherent radio emission models, we propose an observing strategy that involves triggering the buffering mode to target coherent signals emitted prior to, during or shortly following the merger, which is then followed by continued recording for up to three hours to target later time post-merger emission. We expect MWA to trigger on $\sim5\text{--}22$ BNS merger events during the LVK O4 observing run, which could potentially result in two detections of predicted coherent emission.Comment: Accepted for publication in PAS

Predicting the Impact of Long-Term Temperature Changes on the Epidemiology and Control of Schistosomiasis: A Mechanistic Model

, the causative agent of schistosomiasis in humans.The model showed that the impact of temperature on disease prevalence and abundance is not straightforward; the mean infection burden in humans increases up to 30°C, but then crashes at 35°C, primarily due to increased mortalities of the snail intermediate host. In addition, increased temperatures changed the dynamics of disease from stable, endemic infection to unstable, epidemic cycles at 35°C. However, the prevalence of infection was largely unchanged by increasing temperatures. Temperature increases also affected the response of the model to changes in each parameter, indicating certain control strategies may become less effective with local temperature changes. At lower temperatures, the most effective single control strategy is to target the adult parasites through chemotherapy. However, as temperatures increase, targeting the snail intermediate hosts, for example through molluscicide use, becomes more effective. will not respond to increased temperatures in a linear fashion, and the optimal control strategy is likely to change as temperatures change. It is only through a mechanistic approach, incorporating the combined effects of temperature on all stages of the life-cycle, that we can begin to predict the consequences of climate change on the incidence and severity of such diseases

The Seventh Data Release of the Sloan Digital Sky Survey

This paper describes the Seventh Data Release of the Sloan Digital Sky Survey (SDSS), marking the completion of the original goals of the SDSS and the end of the phase known as SDSS-II. It includes 11663 deg^2 of imaging data, with most of the roughly 2000 deg^2 increment over the previous data release lying in regions of low Galactic latitude. The catalog contains five-band photometry for 357 million distinct objects. The survey also includes repeat photometry over 250 deg^2 along the Celestial Equator in the Southern Galactic Cap. A coaddition of these data goes roughly two magnitudes fainter than the main survey. The spectroscopy is now complete over a contiguous area of 7500 deg^2 in the Northern Galactic Cap, closing the gap that was present in previous data releases. There are over 1.6 million spectra in total, including 930,000 galaxies, 120,000 quasars, and 460,000 stars. The data release includes improved stellar photometry at low Galactic latitude. The astrometry has all been recalibrated with the second version of the USNO CCD Astrograph Catalog (UCAC-2), reducing the rms statistical errors at the bright end to 45 milli-arcseconds per coordinate. A systematic error in bright galaxy photometr is less severe than previously reported for the majority of galaxies. Finally, we describe a series of improvements to the spectroscopic reductions, including better flat-fielding and improved wavelength calibration at the blue end, better processing of objects with extremely strong narrow emission lines, and an improved determination of stellar metallicities. (Abridged)Comment: 20 pages, 10 embedded figures. Accepted to ApJS after minor correction

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

Combining genomic and epidemiological data to compare the transmissibility of SARS-CoV-2 variants Alpha and Iota.

SARS-CoV-2 variants shaped the second year of the COVID-19 pandemic and the discourse around effective control measures. Evaluating the threat posed by a new variant is essential for adapting response efforts when community transmission is detected. In this study, we compare the dynamics of two variants, Alpha and Iota, by integrating genomic surveillance data to estimate the effective reproduction number (Rt) of the variants. We use Connecticut, United States, in which Alpha and Iota co-circulated in 2021. We find that the Rt of these variants were up to 50% larger than that of other variants. We then use phylogeography to show that while both variants were introduced into Connecticut at comparable frequencies, clades that resulted from introductions of Alpha were larger than those resulting from Iota introductions. By monitoring the dynamics of individual variants throughout our study period, we demonstrate the importance of routine surveillance in the response to COVID-19

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