Active galactic nuclei (AGNs) that show strong rest-frame optical/UV variability in their blue continuum and broad line emission are classified as changing-look AGN, or at higher luminosities, ...changing-look quasars (CLQs). These surprisingly large and sometimes rapid transitions challenge accepted models of quasar physics and duty cycles, offer several new avenues for study of quasar host galaxies, and open a wider interpretation of the cause of differences between broad and narrow-line AGN. To better characterize extreme quasar variability, we present follow-up spectroscopy as part of a comprehensive search for CLQs across the full Sloan Digital Sky Survey (SDSS) footprint using spectroscopically confirmed quasars from the SDSS DR7 catalog. Our primary selection requires large-amplitude ( mag, mag) variability over any of the available time baselines probed by the SDSS and Pan-STARRS 1 surveys. We employ photometry from the Catalina Sky Survey to verify variability behavior in CLQ candidates where available, and confirm CLQs using optical spectroscopy from the William Herschel, MMT, Magellan, and Palomar telescopes. For our adopted signal-to-noise ratio threshold on variability of broad Hβ emission, we find 17 new CLQs, yielding a confirmation rate of 20%. These candidates are at lower Eddington ratio relative to the overall quasar population, which supports a disk-wind model for the broad line region. Based on our sample, the CLQ fraction increases from 10% to roughly half as the continuum flux ratio between repeat spectra at 3420 increases from 1.5 to 6. We release a catalog of more than 200 highly variable candidates to facilitate future CLQ searches.
Neuroactive metabolites of the kynurenine pathway (KP) of tryptophan degradation have been implicated in the pathophysiology of neurodegenerative disorders, including Huntington's disease (HD)
1. A ...central hallmark of HD is neurodegeneration caused by a polyglutamine expansion in the huntingtin (htt) protein
2. Here we exploit a transgenic
Drosophila melanogaster model of HD to interrogate the therapeutic potential of KP manipulation. We observe that genetic and pharmacological inhibition of kynurenine 3-monooxygenase (KMO) increases levels of the neuroprotective metabolite kynurenic acid (KYNA) relative to the neurotoxic metabolite 3-hydroxykynurenine (3-HK) and ameliorates neurodegeneration. We also find that genetic inhibition of tryptophan 2,3-dioxygenase (TDO), the first and rate-limiting step in the pathway, leads to a similar neuroprotective shift toward KYNA synthesis. Importantly, we demonstrate that the feeding of KYNA and 3-HK to HD model flies directly modulates neurodegeneration, underscoring the causative nature of these metabolites. This study provides the first genetic evidence that inhibition of KMO and TDO activity protects against neurodegenerative disease in an animal model, indicating that strategies targeted at two key points within the KP may have therapeutic relevance in HD, and possibly other neurodegenerative disorders.
► Mutant htt flies are sensitized to increased flux through the central KP ► Genetic inhibition of KMO or TDO is neuroprotective ► KMO inhibitors ameliorate neurodegeneration ► Neurodegeneration is directly modulated by 3-HK and KYNA
Despite their factor of ∼108 difference in black hole mass, several lines of evidence suggest possible similarities between black hole accretion flows in active galactic nuclei (AGN) and Galactic ...X-ray binaries. However, it is still unclear whether the geometry of the disk-corona system in X-ray binaries directly scales up to AGN and whether this analogy still holds in different accretion states. We test this AGN/X-ray binary analogy by comparing the observed correlations between the UV-to-X-ray spectral index ( OX) and Eddington ratio in AGN to those predicted from observations of X-ray binary outbursts. This approach probes the geometry of their disk-corona systems as they transition between different accretion states. We use new Chandra X-ray and ground-based rest-UV observations of faded "changing-look" quasars to extend this comparison to lower Eddington ratios of <10−2, where observations of X-ray binaries predict a softening of OX in AGN. We find that the observed correlations between the OX and Eddington ratio of AGN displays a remarkable similarity to accretion state transitions in prototypical X-ray binary outbursts, including an inversion of this correlation at a critical Eddington ratio of ∼10−2. Our results suggest that the structures of black hole accretion flows directly scale across a factor of ∼108 in black hole mass and across different accretion states, enabling us to apply theoretical models of X-ray binaries to explain AGN phenomenology.
We present a detailed characterization of the 849 broad-line quasars from the Sloan Digital Sky Survey Reverberation Mapping (SDSS-RM) project. Our quasar sample covers a redshift range of 0.1 < z < ...4.5 and is flux-limited to iPSF < 21.7 without any other cuts on quasar properties. The main sample characterization includes: (1) spectral measurements of the continuum and broad emission lines for individual objects from the coadded first-season spectroscopy in 2014, (2) identification of broad and narrow absorption lines in the spectra, and (3) optical variability properties for continuum and broad lines from multi-epoch spectroscopy. We provide improved systemic redshift estimates for all quasars and demonstrate the effects of the signal-to-noise ratio on the spectral measurements. We compile measured properties for all 849 quasars along with supplemental multi-wavelength data for subsets of our sample from other surveys. The SDSS-RM sample probes a diverse range in quasar properties and shows well-detected continuum and broad-line variability for many objects from first-season monitoring data. The compiled properties serve as the benchmark for follow-up work based on SDSS-RM data. The spectral fitting tools are made public along with this work.
The introduction of duplex Doppler ultrasound almost half a century ago signified a revolutionary advance in the ability to assess limb blood flow in humans. It is now widely used to assess blood ...flow under a variety of experimental conditions to study skeletal muscle resistance vessel function. Despite its pervasive adoption, there is substantial variability between studies in relation to experimental protocols, procedures for data analysis, and interpretation of findings. This guideline results from a collegial discussion among physiologists and pharmacologists, with the goal of providing general as well as specific recommendations regarding the conduct of human studies involving Doppler ultrasound-based measures of resistance vessel function in skeletal muscle. Indeed, the focus is on methods used to assess resistance vessel function and not upstream conduit artery function (i.e., macrovasculature), which has been expertly reviewed elsewhere. In particular, we address topics related to experimental design, data collection, and signal processing as well as review common procedures used to assess resistance vessel function, including postocclusive reactive hyperemia, passive limb movement, acute single limb exercise, and pharmacological interventions.
Given the importance of flexible use of different COVID-19 vaccines within the same schedule to facilitate rapid deployment, we studied mixed priming schedules incorporating an adenoviral-vectored ...vaccine (ChAdOx1 nCoV-19 ChAd, AstraZeneca), two mRNA vaccines (BNT162b2 BNT, Pfizer–BioNTech, and mRNA-1273 m1273, Moderna) and a nanoparticle vaccine containing SARS-CoV-2 spike glycoprotein and Matrix-M adjuvant (NVX-CoV2373 NVX, Novavax).
Com-COV2 is a single-blind, randomised, non-inferiority trial in which adults aged 50 years and older, previously immunised with a single dose of ChAd or BNT in the community, were randomly assigned (in random blocks of three and six) within these cohorts in a 1:1:1 ratio to receive a second dose intramuscularly (8–12 weeks after the first dose) with the homologous vaccine, m1273, or NVX. The primary endpoint was the geometric mean ratio (GMR) of serum SARS-CoV-2 anti-spike IgG concentrations measured by ELISA in heterologous versus homologous schedules at 28 days after the second dose, with a non-inferiority criterion of the GMR above 0·63 for the one-sided 98·75% CI. The primary analysis was on the per-protocol population, who were seronegative at baseline. Safety analyses were done for all participants who received a dose of study vaccine. The trial is registered with ISRCTN, number 27841311.
Between April 19 and May 14, 2021, 1072 participants were enrolled at a median of 9·4 weeks after receipt of a single dose of ChAd (n=540, 47% female) or BNT (n=532, 40% female). In ChAd-primed participants, geometric mean concentration (GMC) 28 days after a boost of SARS-CoV-2 anti-spike IgG in recipients of ChAd/m1273 (20 114 ELISA laboratory units ELU/mL 95% CI 18 160 to 22 279) and ChAd/NVX (5597 ELU/mL 4756 to 6586) was non-inferior to that of ChAd/ChAd recipients (1971 ELU/mL 1718 to 2262) with a GMR of 10·2 (one-sided 98·75% CI 8·4 to ∞) for ChAd/m1273 and 2·8 (2·2 to ∞) for ChAd/NVX, compared with ChAd/ChAd. In BNT-primed participants, non-inferiority was shown for BNT/m1273 (GMC 22 978 ELU/mL 95% CI 20 597 to 25 636) but not for BNT/NVX (8874 ELU/mL 7391 to 10 654), compared with BNT/BNT (16 929 ELU/mL 15 025 to 19 075) with a GMR of 1·3 (one-sided 98·75% CI 1·1 to ∞) for BNT/m1273 and 0·5 (0·4 to ∞) for BNT/NVX, compared with BNT/BNT; however, NVX still induced an 18-fold rise in GMC 28 days after vaccination. There were 15 serious adverse events, none considered related to immunisation.
Heterologous second dosing with m1273, but not NVX, increased transient systemic reactogenicity compared with homologous schedules. Multiple vaccines are appropriate to complete primary immunisation following priming with BNT or ChAd, facilitating rapid vaccine deployment globally and supporting recognition of such schedules for vaccine certification.
UK Vaccine Task Force, Coalition for Epidemic Preparedness Innovations (CEPI), and National Institute for Health Research. NVX vaccine was supplied for use in the trial by Novavax.
To test the influence of multiple factors on cochlear implant (CI) speech performance in quiet and in noise for postlinguistically deaf adults, and to design a model of predicted auditory performance ...with a CI as a function of the significant factors.
Retrospective multi-centre study.
Data from 2251 patients implanted since 2003 in 15 international centres were collected. Speech scores in quiet and in noise were converted into percentile ranks to remove differences between centres. The influence of 15 pre-, per- and postoperative factors, such as the duration of moderate hearing loss (mHL), the surgical approach (cochleostomy or round window approach), the angle of insertion, the percentage of active electrodes, and the brand of device were tested. The usual factors, duration of profound HL (pHL), age, etiology, duration of CI experience, that are already known to have an influence, were included in the statistical analyses.
The significant factors were: the pure tone average threshold of the better ear, the brand of device, the percentage of active electrodes, the use of hearing aids (HAs) during the period of pHL, and the duration of mHL.
A new model was designed showing a decrease of performance that started during the period of mHL, and became faster during the period of pHL. The use of bilateral HAs slowed down the related central reorganization that is the likely cause of the decreased performance.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A SARS-CoV-2 variant carrying the Spike protein amino acid change D614G has become the most prevalent form in the global pandemic. Dynamic tracking of variant frequencies revealed a recurrent pattern ...of G614 increase at multiple geographic levels: national, regional, and municipal. The shift occurred even in local epidemics where the original D614 form was well established prior to introduction of the G614 variant. The consistency of this pattern was highly statistically significant, suggesting that the G614 variant may have a fitness advantage. We found that the G614 variant grows to a higher titer as pseudotyped virions. In infected individuals, G614 is associated with lower RT-PCR cycle thresholds, suggestive of higher upper respiratory tract viral loads, but not with increased disease severity. These findings illuminate changes important for a mechanistic understanding of the virus and support continuing surveillance of Spike mutations to aid with development of immunological interventions.
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•A SARS-CoV-2 variant with Spike G614 has replaced D614 as the dominant pandemic form•The consistent increase of G614 at regional levels may indicate a fitness advantage•G614 is associated with lower RT PCR Cts, suggestive of higher viral loads in patients•The G614 variant grows to higher titers as pseudotyped virions
Korber et al. present evidence that there are now more SARS-CoV-2 viruses circulating in the human population globally that have the G614 form of the Spike protein versus the D614 form that was originally identified from the first human cases in Wuhan, China. Follow-up studies show that patients infected with G614 shed more viral nucleic acid compared with those with D614, and G614-bearing viruses show significantly higher infectious titers in vitro than their D614 counterparts.
We study the time lags between the continuum emission of quasars at different wavelengths, based on more than four years of multi-band (g, r, i, z) light curves in the Pan-STARRS Medium Deep Fields. ...As photons from different bands emerge from different radial ranges in the accretion disk, the lags constrain the sizes of the accretion disks. We select 240 quasars with redshifts of z 1 or z 0.3 that are relatively emission-line free. The light curves are sampled from day to month timescales, which makes it possible to detect lags on the scale of the light crossing time of the accretion disks. With the code JAVELIN, we detect typical lags of several days in the rest frame between the g band and the riz bands. The detected lags are ∼2-3 times larger than the light crossing time estimated from the standard thin disk model, consistent with the recently measured lag in NGC 5548 and microlensing measurements of quasars. The lags in our sample are found to increase with increasing luminosity. Furthermore, the increase in lags going from g − r to g − i and then to g − z is slower than predicted in the thin disk model, particularly for high-luminosity quasars. The radial temperature profile in the disk must be different from what is assumed. We also find evidence that the lags decrease with increasing line ratios between ultraviolet Fe ii lines and Mg ii, which may point to changes in the accretion disk structure at higher metallicity.
Rindopepimut is a vaccine targeting the tumor-specific EGF driver mutation, EGFRvIII. The ReACT study investigated whether the addition of rindopepimut to standard bevacizumab improved outcome for ...patients with relapsed, EGFRvIII-positive glioblastoma.
In this double-blind, randomized, phase II study (NCT01498328) conducted at 26 hospitals in the United States, bevacizumab-naïve patients with recurrent EGFRvIII-positive glioblastoma were randomized to receive rindopepimut or a control injection of keyhole limpet hemocyanin, each concurrent with bevacizumab. The primary endpoint was 6-month progression-free survival (PFS6) by central review with a one-sided significance of 0.2.
Between May 2012 and 2014, 73 patients were randomized (36 rindopepimut, 37 control). Rindopepimut toxicity included transient, low-grade local reactions. As primary endpoint, PFS6 was 28% (10/36) for rindopepimut compared with 16% (6/37) for control (
= 0.12, one-sided). Secondary and exploratory endpoints also favored the rindopepimut group including a statistically significant survival advantage HR, 0.53; 95% confidence interval (CI), 0.32-0.88; two-sided log-rank
= 0.01, a higher ORR 30% (9/30) vs. 18% (6/34;
= 0.38), median duration of response 7.8 months (95% CI, 3.5-22.2) vs. 5.6 (95% CI, 3.7-7.4), and ability to discontinue steroids for ≥6 months 33% (6/18) vs. 0% (0/19). Eighty percent of rindopepimut-treated patients achieved robust anti-EGFRvIII titers (≥1:12,800), which were associated with prolonged survival (HR = 0.17; 95% CI, 0.07-0.45;
< 0.0001).
Our randomized trial supports the potential for targeted immunotherapy among patients with GBM, but the therapeutic benefit requires validation due to the small sample size and potential heterogeneity of bevacizumab response among recurrent patients with GBM.
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