The role of toll-like receptor 7 in the neuropathogenesis of retrovirus infection in neonates

Viral infections of the central nervous system (CNS) in infants are rare; however, they are associated with high morbidity and mortality rates. These virus infections often induce strong innate immune responses in the brain including: the production of cytokines and chemokines, the activation of astrocytes and microglia and the recruitment of macrophages. Innate immune responses are often initiated by toll-like receptors (TLR). Several studies have demonstrated that toll-like receptor 7 (TLR7) can be stimulated by single-stranded RNA from multiple viruses. In the current study, we examined the mechanism by which TLR7 contributes to neuroinflammation in the neonatal brain using a mouse model of polytropic retrovirus infection. We found that TLR7 deficiency had no effect on neurologic disease, viral replication, or induction of interferon beta mRNA. However, TLR7 deficiency significantly altered neuroinflammatory responses including proinflammatory cytokine production, astrocyte activation, and microglial/macrophage activation. To our knowledge, this is the first demonstration of the necessity of TLR7 for innate immune responses to retrovirus infection in vivo. Additionally, this indicates that the immune response to retrovirus in the CNS may not be essential for disease pathogenesis in neonates

The Grizzly, April 11, 2000

Vandalism: Running Rampant in Reimert and the Quad • UC Gets Medieval in Annual Sport Fest • PBK Lecture Informative and Hilarious • Phi Psi Educates UC Greeks on Pledging Do\u27s and Don\u27ts • Students Take Center Stage at Airband 2000 • Service Day Calls UC Community to Action • Basket Bingo Allows Others to Make-a-Wish • Putting a Finger on Sexuality • RHA Behind the Scenes • Election Preview: CAB, RHA, USGA and Class Elections • Letters to the Editor • Thoughts from a Sophomore Chat: If Tuition Increases, Scholarships Must • UC Artists Unveil Photography Exhibit • The Voice of UC College Choir • Team Effort Puts UC in the Lead • Bears Quest for NCAA Tournament Continues • Softball Ranked 18th in Nation • Tennis Team Continues to Struggle • Golf Ties for Second with F&M • Track and Field Improves at Osprey Open • Sports Profiles: Joe Sprague; Sue Sobolewskihttps://digitalcommons.ursinus.edu/grizzlynews/1465/thumbnail.jp

The GALAH Survey: Chemical tagging and chrono-chemodynamics of accreted halo stars with GALAH+ DR3 and GaiaGaia eDR3

© 2021 The Author(s) Published by Oxford University Press on behalf of Royal Astronomical Society. This is the accepted manuscript version of an article which has been published in final form at https://doi.org/10.1093/mnras/stab3504Since the advent of $Gaia$ astrometry, it is possible to identify massive accreted systems within the Galaxy through their unique dynamical signatures. One such system, $Gaia$-Sausage-Enceladus (GSE), appears to be an early "building block" given its virial mass $> 10^{10}\,\mathrm{M_\odot}$ at infall ($z\sim1-3$). In order to separate the progenitor population from the background stars, we investigate its chemical properties with up to 30 element abundances from the GALAH+ Survey Data Release 3 (DR3). To inform our choice of elements for purely chemically selecting accreted stars, we analyse 4164 stars with low-$\alpha$ abundances and halo kinematics. These are most different to the Milky Way stars for abundances of Mg, Si, Na, Al, Mn, Fe, Ni, and Cu. Based on the significance of abundance differences and detection rates, we apply Gaussian mixture models to various element abundance combinations. We find the most populated and least contaminated component, which we confirm to represent GSE, contains 1049 stars selected via [Na/Fe] vs. [Mg/Mn] in GALAH+ DR3. We provide tables of our selections and report the chrono-chemodynamical properties (age, chemistry, and dynamics). Through a previously reported clean dynamical selection of GSE stars, including $30 < \sqrt{J_R~/~\mathrm{kpc\,km\,s^{-1}}} < 55$, we can characterise an unprecedented 24 abundances of this structure with GALAH+ DR3. Our chemical selection allows us to prevent circular reasoning and characterise the dynamical properties of the GSE, for example mean $\sqrt{J_R~/~\mathrm{kpc\,km\,s^{-1}}} = 26_{-14}^{+9}$. We find only $(29\pm1)\%$ of the GSE stars within the clean dynamical selection region. Our methodology will improve future studies of accreted structures and their importance for the formation of the Milky Way.Peer reviewedFinal Accepted Versio

Exome chip analysis identifies low-frequency and rare variants in MRPL38 for white matter hyperintensities on brain MRI

International audienc

Clinical outcomes and response to treatment of patients receiving topical treatments for pyoderma gangrenosum: a prospective cohort study

Background: pyoderma gangrenosum (PG) is an uncommon dermatosis with a limited evidence base for treatment. Objective: to estimate the effectiveness of topical therapies in the treatment of PG. Methods: prospective cohort study of UK secondary care patients with a clinical diagnosis of PG suitable for topical treatment (recruited July 2009 to June 2012). Participants received topical therapy following normal clinical practice (mainly Class I-III topical corticosteroids, tacrolimus 0.03% or 0.1%). Primary outcome: speed of healing at 6 weeks. Secondary outcomes: proportion healed by 6 months; time to healing; global assessment; inflammation; pain; quality-of-life; treatment failure and recurrence. Results: Sixty-six patients (22 to 85 years) were enrolled. Clobetasol propionate 0.05% was the most commonly prescribed therapy. Overall, 28/66 (43.8%) of ulcers healed by 6 months. Median time-to-healing was 145 days (95% CI: 96 days, ∞). Initial ulcer size was a significant predictor of time-to-healing (hazard ratio 0.94 (0.88;80 1.00); p = 0.043). Four patients (15%) had a recurrence. Limitations: No randomised comparator Conclusion: Topical therapy is potentially an effective first-line treatment for PG that avoids possible side effects associated with systemic therapy. It remains unclear whether more severe disease will respond adequately to topical therapy alone

The Seventeenth Data Release of the Sloan Digital Sky Surveys: Complete Release of MaNGA, MaStar and APOGEE-2 Data

This paper documents the seventeenth data release (DR17) from the Sloan Digital Sky Surveys; the fifth and final release from the fourth phase (SDSS-IV). DR17 contains the complete release of the Mapping Nearby Galaxies at Apache Point Observatory (MaNGA) survey, which reached its goal of surveying over 10,000 nearby galaxies. The complete release of the MaNGA Stellar Library (MaStar) accompanies this data, providing observations of almost 30,000 stars through the MaNGA instrument during bright time. DR17 also contains the complete release of the Apache Point Observatory Galactic Evolution Experiment 2 (APOGEE-2) survey which publicly releases infra-red spectra of over 650,000 stars. The main sample from the Extended Baryon Oscillation Spectroscopic Survey (eBOSS), as well as the sub-survey Time Domain Spectroscopic Survey (TDSS) data were fully released in DR16. New single-fiber optical spectroscopy released in DR17 is from the SPectroscipic IDentification of ERosita Survey (SPIDERS) sub-survey and the eBOSS-RM program. Along with the primary data sets, DR17 includes 25 new or updated Value Added Catalogs (VACs). This paper concludes the release of SDSS-IV survey data. SDSS continues into its fifth phase with observations already underway for the Milky Way Mapper (MWM), Local Volume Mapper (LVM) and Black Hole Mapper (BHM) surveys

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

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

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

Implementation of corticosteroids in treating COVID-19 in the ISARIC WHO Clinical Characterisation Protocol UK:prospective observational cohort study

BACKGROUND: Dexamethasone was the first intervention proven to reduce mortality in patients with COVID-19 being treated in hospital. We aimed to evaluate the adoption of corticosteroids in the treatment of COVID-19 in the UK after the RECOVERY trial publication on June 16, 2020, and to identify discrepancies in care. METHODS: We did an audit of clinical implementation of corticosteroids in a prospective, observational, cohort study in 237 UK acute care hospitals between March 16, 2020, and April 14, 2021, restricted to patients aged 18 years or older with proven or high likelihood of COVID-19, who received supplementary oxygen. The primary outcome was administration of dexamethasone, prednisolone, hydrocortisone, or methylprednisolone. This study is registered with ISRCTN, ISRCTN66726260. FINDINGS: Between June 17, 2020, and April 14, 2021, 47 795 (75·2%) of 63 525 of patients on supplementary oxygen received corticosteroids, higher among patients requiring critical care than in those who received ward care (11 185 [86·6%] of 12 909 vs 36 415 [72·4%] of 50 278). Patients 50 years or older were significantly less likely to receive corticosteroids than those younger than 50 years (adjusted odds ratio 0·79 [95% CI 0·70–0·89], p=0·0001, for 70–79 years; 0·52 [0·46–0·58], p80 years), independent of patient demographics and illness severity. 84 (54·2%) of 155 pregnant women received corticosteroids. Rates of corticosteroid administration increased from 27·5% in the week before June 16, 2020, to 75–80% in January, 2021. INTERPRETATION: Implementation of corticosteroids into clinical practice in the UK for patients with COVID-19 has been successful, but not universal. Patients older than 70 years, independent of illness severity, chronic neurological disease, and dementia, were less likely to receive corticosteroids than those who were younger, as were pregnant women. This could reflect appropriate clinical decision making, but the possibility of inequitable access to life-saving care should be considered. FUNDING: UK National Institute for Health Research and UK Medical Research Council

The 16th Data Release of the Sloan Digital Sky Surveys: First Release from the APOGEE-2 Southern Survey and Full Release of eBOSS Spectra

This paper documents the 16th data release (DR16) from the Sloan Digital Sky Surveys (SDSS), the fourth and penultimate from the fourth phase (SDSS-IV). This is the first release of data from the Southern Hemisphere survey of the Apache Point Observatory Galactic Evolution Experiment 2 (APOGEE-2); new data from APOGEE-2 North are also included. DR16 is also notable as the final data release for the main cosmological program of the Extended Baryon Oscillation Spectroscopic Survey (eBOSS), and all raw and reduced spectra from that project are released here. DR16 also includes all the data from the Time Domain Spectroscopic Survey and new data from the SPectroscopic IDentification of ERosita Survey programs, both of which were co-observed on eBOSS plates. DR16 has no new data from the Mapping Nearby Galaxies at Apache Point Observatory (MaNGA) survey (or the MaNGA Stellar Library "MaStar"). We also preview future SDSS-V operations (due to start in 2020), and summarize plans for the final SDSS-IV data release (DR17)