Spectral Variability of Quasars in the Sloan Digital Sky Survey. I: Wavelength Dependence

Sloan Digital Sky Survey (SDSS) repeat spectroscopic observations have resulted in multiple-epoch spectroscopy for roughly 2500 quasars observed more than 50 days apart. From this sample, we identify 315 quasars that have varied significantly between observations. We create an ensemble difference spectrum (bright phase minus faint phase) covering rest-frame wavelengths from 1000 to 6000 Angstroms. This average difference spectrum is bluer than the average single-epoch quasar spectrum; a power-law fit to the difference spectrum yields a spectral index alpha_lambda = -2.00, compared to an index of alpha_lambda = -1.35 for the single-epoch spectrum. The strongest emission lines vary only 30% as much as the continuum. Due to the lack of variability of the lines, measured photometric color is not always bluer in brighter phases, but depends on redshift and the filters used. Lastly, the difference spectrum is bluer than the ensemble quasar spectrum only for lambda_rest < 2500 Angstroms, indicating that the variability cannot result from a simple scaling of the average quasar spectrum.Comment: 47 pages, 14 figures, 3 tables, accepted for publication in Ap

Bioengineered small extracellular vesicles deliver multiple SARS‐CoV‐2 antigenic fragments and drive a broad immunological response

The COVID‐19 pandemic highlighted the clear risk that zoonotic viruses pose to global health and economies. The scientific community responded by developing several efficacious vaccines which were expedited by the global need for vaccines. The emergence of SARS‐CoV‐2 breakthrough infections highlights the need for additional vaccine modalities to provide stronger, long‐lived protective immunity. Here we report the design and preclinical testing of small extracellular vesicles (sEVs) as a multi‐subunit vaccine. Cell lines were engineered to produce sEVs containing either the SARS‐CoV‐2 Spike receptor‐binding domain, or an antigenic region from SARS‐CoV‐2 Nucleocapsid, or both in combination, and we tested their ability to evoke immune responses in vitro and in vivo. B cells incubated with bioengineered sEVs were potent activators of antigen‐specific T cell clones. Mice immunised with sEVs containing both sRBD and Nucleocapsid antigens generated sRBD‐specific IgGs, nucleocapsid‐specific IgGs, which neutralised SARS‐CoV‐2 infection. sEV‐based vaccines allow multiple antigens to be delivered simultaneously resulting in potent, broad immunity, and provide a quick, cheap, and reliable method to test vaccine candidates

A genome-wide association meta-analysis of self-reported allergy identifies shared and allergy-specific susceptibility loci

Allergic disease is very common and carries substantial public-health burdens. We conducted a meta-analysis of genome-wide associations with self-reported cat, dust-mite and pollen allergies in 53,862 individuals. We used generalized estimating equations to model shared and allergy-specific genetic effects. We identified 16 shared susceptibility loci with association P < 5 × 10-8, including 8 loci previously associated with asthma, as well as 4p14 near TLR1, TLR6 and TLR10 (rs2101521, P = 5.3 × 10 -21); 6p21.33 near HLA-C and MICA (rs9266772, P = 3.2 × 10 -12); 5p13.1 near PTGER4 (rs7720838, P = 8.2 × 10 -11); 2q33.1 in PLCL1 (rs10497813, P = 6.1 × 10-10), 3q28 in LPP (rs9860547, P = 1.2 × 10-9); 20q13.2 in NFATC2 (rs6021270, P = 6.9 × 10-9), 4q27 in ADAD1 (rs17388568, P = 3.9 × 10-8); and 14q21.1 near FOXA1 and TTC6 (rs1998359, P = 4.8 × 10-8). We identified one locus with substantial evidence of differences in effects across allergies at 6p21.32 in the class II human leukocyte antigen (HLA) region (rs17533090, P = 1.7 × 10-12), which was strongly associated with cat allergy. Our study sheds new light on the shared etiology of immune and autoimmune disease

Age-associated B cells predict impaired humoral immunity after COVID-19 vaccination in patients receiving immune checkpoint blockade

Age-associated B cells (ABC) accumulate with age and in individuals with different immunological disorders, including cancer patients treated with immune checkpoint blockade and those with inborn errors of immunity. Here, we investigate whether ABCs from different conditions are similar and how they impact the longitudinal level of the COVID-19 vaccine response. Single-cell RNA sequencing indicates that ABCs with distinct aetiologies have common transcriptional profiles and can be categorised according to their expression of immune genes, such as the autoimmune regulator (AIRE). Furthermore, higher baseline ABC frequency correlates with decreased levels of antigen-specific memory B cells and reduced neutralising capacity against SARS-CoV-2. ABCs express high levels of the inhibitory FcγRIIB receptor and are distinctive in their ability to bind immune complexes, which could contribute to diminish vaccine responses either directly, or indirectly via enhanced clearance of immune complexed-antigen. Expansion of ABCs may, therefore, serve as a biomarker identifying individuals at risk of suboptimal responses to vaccination

Accelerated waning of the humoral response to COVID-19 vaccines in obesity

Funding: EAVE II is funded by the Medical Research Council (MRC) (MC_PC_19075) with the support of BREATHE—The Health Data Research Hub for Respiratory Health (MC_PC_19004), which is funded through the UK Research and Innovation Industrial Strategy Challenge Fund and delivered through Health Data Research UK. This research is part of the Data and Connectivity National Core Study, led by Health Data Research UK in partnership with the Office for National Statistics and funded by UK Research and Innovation (grant MC_PC_20058) and National Core Studies–Immunity. Additional support was provided through Public Health Scotland, the Scottish Government Director-General Health and Social Care and the University of Edinburgh. The SCORPIO study was supported by the MRC (MR/W020564/1, a core award to J.E.T.; MC_UU_0025/12 and MR/T032413/1, awards to N.J.M.) and the Medical Research Foundation (MRF-057-0002-RG-THAV-C0798). Additional support was provided by NHS Blood and Transplant (WPA15-02 to N.J.M.), the Wellcome Trust (Institutional Strategic Support Fund 204845/Z/16/Z to N.J.M.), Addenbrooke’s Charitable Trust (900239 to N.J.M.) and the NIHR Cambridge Biomedical Research Centre and NIHR BioResource. M.A.L is supported by the Biotechnology and Biological Sciences Research Council (BBSRC) (BBS/E/B/000C0427 and BBS/E/B/000C0428) and is a Lister Institute Fellow and an EMBO Young Investigator. I.M.H. is supported by a Cambridge Institute for Medical Research PhD studentship. H.J.S. is supported by a Sir Henry Dale Fellowship, jointly funded by the Wellcome Trust and the Royal Society (109407), and a BBSRC institutional program grant (BBS/E/B/000C0433). I.S.F. is supported by the Wellcome Trust (207462/Z/17/Z), the Botnar Fondation, the Bernard Wolfe Health Neuroscience Endowment and an NIHR Senior Investigator Award.Obesity is associated with an increased risk of severe Coronavirus Disease 2019 (COVID-19) infection and mortality. COVID-19 vaccines reduce the risk of serious COVID-19 outcomes; however, their effectiveness in people with obesity is incompletely understood. We studied the relationship among body mass index (BMI), hospitalization and mortality due to COVID-19 among 3.6 million people in Scotland using the Early Pandemic Evaluation and Enhanced Surveillance of COVID-19 (EAVE II) surveillance platform. We found that vaccinated individuals with severe obesity (BMI > 40 kg/m2) were 76% more likely to experience hospitalization or death from COVID-19 (adjusted rate ratio of 1.76 (95% confidence interval (CI), 1.60–1.94). We also conducted a prospective longitudinal study of a cohort of 28 individuals with severe obesity compared to 41 control individuals with normal BMI (BMI 18.5–24.9 kg/m2). We found that 55% of individuals with severe obesity had unquantifiable titers of neutralizing antibody against authentic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus compared to 12% of individuals with normal BMI (P = 0.0003) 6 months after their second vaccine dose. Furthermore, we observed that, for individuals with severe obesity, at any given anti-spike and anti-receptor-binding domain (RBD) antibody level, neutralizing capacity was lower than that of individuals with a normal BMI. Neutralizing capacity was restored by a third dose of vaccine but again declined more rapidly in people with severe obesity. We demonstrate that waning of COVID-19 vaccine-induced humoral immunity is accelerated in individuals with severe obesity. As obesity is associated with increased hospitalization and mortality from breakthrough infections, our findings have implications for vaccine prioritization policies.Publisher PDFPeer reviewe

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection

Longitudinal analysis reveals that delayed bystander CD8+ T cell activation and early immune pathology distinguish severe COVID-19 from mild disease.

The kinetics of the immune changes in COVID-19 across severity groups have not been rigorously assessed. Using immunophenotyping, RNA sequencing and serum cytokine analysis, we analyzed serial samples from 207 SARS-CoV2-infected individuals with a range of disease severities over 12 weeks from symptom onset. An early robust bystander CD8+ T cell immune response, without systemic inflammation, characterized asymptomatic or mild disease. Hospitalized individuals had delayed bystander responses and systemic inflammation that was already evident near symptom onset, indicating that immunopathology may be inevitable in some individuals. Viral load did not correlate with this early pathological response, but did correlate with subsequent disease severity. Immune recovery is complex, with profound persistent cellular abnormalities in severe disease correlating with altered inflammatory responses, with signatures associated with increased oxidative phosphorylation replacing those driven by cytokines tumor necrosis factor (TNF) and interleukin (IL)- 6. These late immunometabolic and immune defects may have clinical implication

XNAzymes targeting the SARS-CoV-2 genome inhibit viral infection

The unprecedented emergence and spread of SARS-CoV-2, the coronavirus responsible for the COVID-19 pandemic, underscores the need for diagnostic and therapeutic technologies that can be rapidly tailored to novel threats. Here, we show that site-specific RNA endonuclease XNAzymes – artificial catalysts composed of single-stranded synthetic xeno-nucleic acid oligonucleotides (in this case 2’-deoxy-2’-fluoro--D-arabino nucleic acid) – may be designed, synthesised and screened within days, enabling the discovery of a range of enzymes targeting SARS-CoV-2 ORF1ab, ORF7b, spike- and nucleocapsid-encoding RNA. Three of these are further engineered to self-assemble into a catalytic nanostructure with enhanced biostability. This XNA nanostructure is capable of cleaving genomic SARS-CoV-2 RNA under physiological conditions, and when transfected into cells inhibits infection with authentic SARS-CoV-2 virus by RNA knockdown. These results demonstrate the potential of XNAzymes to provide a platform for the rapid generation of antiviral reagents.Collaborator Nicholas Matheson is supported by: MRC (TSF ref. MR/T032413/1) NHSBT (grant ref. WPA15-02) The Addenbrooke’s Charitable Trust (grant ref. 900239) NIHR Cambridge BRC

Hydrodynamic Models of Line-Driven Accretion Disk Winds III: Local Ionization Equilibrium

We present time-dependent numerical hydrodynamic models of line-driven accretion disk winds in cataclysmic variable systems and calculate wind mass-loss rates and terminal velocities. The models are 2.5-dimensional, include an energy balance condition with radiative heating and cooling processes, and includes local ionization equilibrium introducing time dependence and spatial dependence on the line radiation force parameters. The radiation field is assumed to originate in an optically thick accretion disk. Wind ion populations are calculated under the assumption that local ionization equilibrium is determined by photoionization and radiative recombination, similar to a photoionized nebula. We find a steady wind flowing from the accretion disk. Radiative heating tends to maintain the temperature in the higher density wind regions near the disk surface, rather than cooling adiabatically. For a disk luminosity L (sub disk) = solar luminosity, white dwarf mass M(sub wd) = 0.6 solar mass, and white dwarf radii R(sub wd) = 0.01 solar radius, we obtain a wind mass-loss rate of M(sub wind) = 4 x 10(exp -12) solar mass yr(exp -1) and a terminal velocity of approximately 3000 km per second. These results confirm the general velocity and density structures found in our earlier constant ionization equilibrium adiabatic CV wind models. Further we establish here 2.5D numerical models that can be extended to QSO/AGN winds where the local ionization equilibrium will play a crucial role in the overall dynamics