ABSTRACT Quasar emission lines are often shifted from the systemic velocity due to various dynamical and radiative processes in the line-emitting region. The level of these velocity shifts depends ...both on the line species and on quasar properties. We study velocity shifts for the line peaks (not the centroids) of various narrow and broad quasar emission lines relative to systemic using a sample of 849 quasars from the Sloan Digital Sky Survey Reverberation Mapping (SDSS-RM) project. The coadded (from 32 epochs) spectra of individual quasars have sufficient signal-to-noise ratio (S/N) to measure stellar absorption lines to provide reliable systemic velocity estimates, as well as weak narrow emission lines. The large dynamic range in quasar luminosity (∼2 dex) of the sample allowed us to explore potential luminosity dependence of the velocity shifts. We derive average line peak velocity shifts as a function of quasar luminosity for different lines, and quantify their intrinsic scatter. We further quantify how well the peak velocity can be measured as a function of continuum S/N, and demonstrate that there is no systematic bias in the velocity measurements when S/N is degraded to as low as ∼3 per SDSS pixel ( ). Based on the observed line shifts, we provide empirical guidelines on redshift estimation from O ii , O iii , Ne v , Mg ii, C iii, He ii , broad Hβ, C iv, and Si iv, which are calibrated to provide unbiased systemic redshifts in the mean, but with increasing intrinsic uncertainties of 46, 56, 119, 205, 233, 242, 400, 415, and 477 , in addition to the measurement uncertainties. These results demonstrate the infeasibility of measuring quasar redshifts to better than with only broad lines.
This guideline is structured to provide a clinical framework stratified by cancer severity to facilitate care decisions and guide the specifics of implementing the selected management options. The ...summary presented represents Part I of the two-part series dedicated to Clinically Localized Prostate Cancer: AUA/ASTRO/SUO Guideline discussing risk stratification and care options by cancer severity.
The systematic review utilized in the creation of this guideline was completed by the Agency for Healthcare Research and Quality and through additional supplementation by ECRI Institute. This review included articles published between January 2007 and March 2014 with an update search conducted through August 2016. When sufficient evidence existed, the body of evidence for a particular treatment was assigned a strength rating of A (high), B (moderate), or C (low) for support of Strong, Moderate, or Conditional Recommendations. Additional information is provided as Clinical Principles and Expert Opinions (table 2 in supplementary unabridged guideline, http://jurology.com/).
The AUA (American Urological Association), ASTRO, and SUO (Society of Urologic Oncology) formulated an evidence-based guideline based on a risk stratified clinical framework for the management of localized prostate cancer.
This guideline attempts to improve a clinician’s ability to treat patients diagnosed with localized prostate cancer, but higher quality evidence in future trials will be essential to improve the level of care for these patients. In all cases, patient preferences should be considered when choosing a management strategy.
This guideline is structured to provide a clinical framework stratified by cancer severity to facilitate care decisions and guide the specifics of implementing the selected management options. The ...summary presented herein represents Part II of the two-part series dedicated to Clinically Localized Prostate Cancer: AUA/ASTRO/SUO Guideline discussing risk stratification and care options by cancer severity. Please refer to Part I for discussion of specific care options and outcome expectations and management.
The systematic review utilized in the creation of this guideline was completed by the Agency for Healthcare Research and Quality and through additional supplementation by ECRI Institute. This review included articles published between January 2007 and March 2014 with an update search conducted through August 2016. When sufficient evidence existed, the body of evidence for a particular treatment was assigned a strength rating of A (high), B (moderate), or C (low) for support of Strong, Moderate, or Conditional Recommendations. Additional information is provided as Clinical Principles and Expert Opinions (table 2 in supplementary unabridged guideline, http://jurology.com/).
The AUA (American Urological Association), ASTRO, and SUO (Society of Urologic Oncology) formulated an evidence-based guideline based on a risk stratified clinical framework for the management of localized prostate cancer.
This guideline attempts to improve a clinician’s ability to treat patients diagnosed with localized prostate cancer, but higher quality evidence in future trials will be essential to improve the level of care for these patients. In all cases, patient preferences should be considered when choosing a management strategy.
Peripheral inflammation is often associated with major depressive disorder (MDD), and immunological biomarkers of depression remain a focus of investigation.
We used microarray data on whole blood ...from two independent case-control studies of MDD: the GlaxoSmithKline–High-Throughput Disease-specific target Identification Program GSK-HiTDiP study (113 patients and 57 healthy control subjects) and the Janssen–Brain Resource Company study (94 patients and 100 control subjects). Genome-wide differential gene expression analysis (18,863 probes) resulted in a p value for each gene in each study. A Bayesian method identified the largest p-value threshold (q = .025) associated with twice the number of genes differentially expressed in both studies compared with the number of coincidental case-control differences expected by chance.
A total of 165 genes were differentially expressed in both studies with concordant direction of fold change. The 90 genes overexpressed (or UP genes) in MDD were significantly enriched for immune response to infection, were concentrated in a module of the gene coexpression network associated with innate immunity, and included clusters of genes with correlated expression in monocytes, monocyte-derived dendritic cells, and neutrophils. In contrast, the 75 genes underexpressed (or DOWN genes) in MDD were associated with the adaptive immune response and included clusters of genes with correlated expression in T cells, natural killer cells, and erythroblasts. Consistently, the MDD patients with overexpression of UP genes also had underexpression of DOWN genes (correlation > .70 in both studies).
MDD was replicably associated with proinflammatory activation of the peripheral innate immune system, coupled with relative inactivation of the adaptive immune system, indicating the potential of transcriptional biomarkers for immunological stratification of patients with depression.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Abstract We present the first results from the Revealing Low-Luminosity Active Galactic Nuclei (ReveaLLAGN) survey, a JWST survey of seven nearby LLAGNs. We focus on two observations with the ...Mid-Infrared Instrument (MIRI)’s Medium-Resolution Spectrometer of the nuclei of NGC 1052 and Sombrero (NGC 4594/M104). We also compare these data to public JWST data of higher-luminosity AGNs, NGC 7319 and NGC 7469. JWST clearly separates the AGN spectrum from the galaxy light even in Sombrero, the faintest target in our survey; the AGN components have very red spectra. We find that the emission-line widths in both NGC 1052 and Sombrero increase with increasing ionization potential, with FWHM > 1000 km s −1 for lines with ionization potential ≳ 50 eV. These lines are also significantly blueshifted in both LLAGNs. The high-ionization-potential lines in NGC 7319 show neither broad widths nor significant blueshifts. Many of the lower-ionization-potential emission lines in Sombrero show significant blue wings extending >1000 km s −1 . These features and the emission-line maps in both galaxies are consistent with outflows along the jet direction. Sombrero has the lowest-luminosity high-ionization-potential lines (Ne v and O iv ) ever measured in the mid-infrared, but the relative strengths of these lines are consistent with higher-luminosity AGNs. On the other hand, the Ne v emission is much weaker relative to the Ne iii and Ne ii lines of higher-luminosity AGNs. These initial results show the great promise that JWST holds for identifying and studying the physical nature of LLAGNs.
ABSTRACT Reverberation mapping (RM) measurements of broad-line region (BLR) lags in quasars are important for directly measuring black hole masses in these distant objects, but so far there have been ...limited attempts and success given the practical difficulties of RM in this regime. Here we report preliminary results of 15 BLR lag measurements from the Sloan Digital Sky Survey Reverberation Mapping (SDSS-RM) project, a dedicated RM program with multi-object spectroscopy designed for RM over a wide redshift range. The lags are based on the 2014 spectroscopic light curves alone (32 epochs over six months) and focus on the Hβ and Mg ii broad lines in the 100 lowest-redshift ( ) quasars included in SDSS-RM; they represent a small subset of the lags that SDSS-RM (including 849 quasars to ) is expected to deliver. The reported preliminary lag measurements are for intermediate-luminosity quasars at , including nine Hβ lags and six Mg ii lags, for the first time extending RM results to this redshift-luminosity regime and providing direct quasar black hole mass estimates over approximately half of cosmic time. The Mg ii lags also increase the number of known Mg ii lags by several fold and start to explore the utility of Mg ii for RM at high redshift. The location of these new lags at higher redshifts on the observed BLR size-luminosity relationship is statistically consistent with previous Hβ results at . However, an independent constraint on the relationship slope at is not yet possible owing to the limitations in our current sample. Our results demonstrate the general feasibility and potential of multi-object RM for quasars.
Resistance to oncogene-targeted therapies involves discrete drug-tolerant persister cells, originally discovered through in vitro assays. Whether a similar phenomenon limits efficacy of programmed ...cell death 1 (PD-1) blockade is poorly understood. Here, we performed dynamic single-cell RNA-Seq of murine organotypic tumor spheroids undergoing PD-1 blockade, identifying a discrete subpopulation of immunotherapy persister cells (IPCs) that resisted CD8+ T cell-mediated killing. These cells expressed Snai1 and stem cell antigen 1 (Sca-1) and exhibited hybrid epithelial-mesenchymal features characteristic of a stem cell-like state. IPCs were expanded by IL-6 but were vulnerable to TNF-α-induced cytotoxicity, relying on baculoviral IAP repeat-containing protein 2 (Birc2) and Birc3 as survival factors. Combining PD-1 blockade with Birc2/3 antagonism in mice reduced IPCs and enhanced tumor cell killing in vivo, resulting in durable responsiveness that matched TNF cytotoxicity thresholds in vitro. Together, these data demonstrate the power of high-resolution functional ex vivo profiling to uncover fundamental mechanisms of immune escape from durable anti-PD-1 responses, while identifying IPCs as a cancer cell subpopulation targetable by specific therapeutic combinations.
The Huntington's disease mutation is a CAG repeat expansion in the huntingtin gene that results in an expanded polyglutamine tract in the huntingtin protein. The CAG repeat is unstable and expansions ...of hundreds of CAGs have been detected in Huntington's disease post-mortem brains. The age of disease onset can be predicted partially from the length of the CAG repeat as measured in blood. Onset age is also determined by genetic modifiers, which in six cases involve variation in DNA mismatch repair pathways genes. Knocking-out specific mismatch repair genes in mouse models of Huntington's disease prevents somatic CAG repeat expansion. Taken together, these results have led to the hypothesis that somatic CAG repeat expansion in Huntington's disease brains is required for pathogenesis. Therefore, the pathogenic repeat threshold in brain is longer than (CAG)40, as measured in blood, and is currently unknown. The mismatch repair gene MSH3 has become a major focus for therapeutic development, as unlike other mismatch repair genes, nullizygosity for MSH3 does not cause malignancies associated with mismatch repair deficiency. Potential treatments targeting MSH3 currently under development include gene therapy, biologics and small molecules, which will be assessed for efficacy in mouse models of Huntington's disease. The zQ175 knock-in model carries a mutation of approximately (CAG)185 and develops early molecular and pathological phenotypes that have been extensively characterized. Therefore, we crossed the mutant huntingtin allele onto heterozygous and homozygous Msh3 knockout backgrounds to determine the maximum benefit of targeting Msh3 in this model. Ablation of Msh3 prevented somatic expansion throughout the brain and periphery, and reduction of Msh3 by 50% decreased the rate of expansion. This had no effect on the deposition of huntingtin aggregation in the nuclei of striatal neurons, nor on the dysregulated striatal transcriptional profile. This contrasts with ablating Msh3 in knock-in models with shorter CAG repeat expansions. Therefore, further expansion of a (CAG)185 repeat in striatal neurons does not accelerate the onset of molecular and neuropathological phenotypes. It is striking that highly expanded CAG repeats of a similar size in humans cause disease onset before 2 years of age, indicating that somatic CAG repeat expansion in the brain is not required for pathogenesis. Given that the trajectory for somatic CAG expansion in the brains of Huntington's disease mutation carriers is unknown, our study underlines the importance of administering treatments targeting somatic instability as early as possible.
We present composite broad-line region (BLR) reverberation mapping lag measurements for H , Hβ, He ii λ4686, and Mg ii for a sample of 144, z 1 quasars from the Sloan Digital Sky Survey Reverberation ...Mapping (SDSS-RM) project. Using only the 32-epoch spectroscopic light curves in the first six-month season of SDSS-RM observations, we compile correlation function measurements for individual objects and then coadd them to allow the measurement of the average lags for our sample at mean redshifts of 0.4 (for H ) and ∼0.65 (for the other lines). At similar quasar luminosities and redshifts, the sample-averaged lag decreases in the order of Mg ii, H , Hβ, and He ii. This decrease in lags is accompanied by an increase in the mean line width of the four lines, and is roughly consistent with the virialized motion for BLR gas in photoionization equilibrium. These are among the first RM measurements of stratified BLR structure at z > 0.3. Dividing our sample by luminosity, H shows clear evidence of increasing lags with luminosity, consistent with the expectation from the measured BLR size-luminosity relation based on Hβ. The other three lines do not show a clear luminosity trend in their average lags due to the limited dynamic range of luminosity probed and the poor average correlation signals in the divided samples, a situation that will be improved with the incorporation of additional photometric and spectroscopic data from SDSS-RM. We discuss the utility and caveats of composite lag measurements for large statistical quasar samples with reverberation mapping data.
The etiologies of newborn deaths in neonatal intensive care units usually remain unknown, even after genetic testing. Whole-genome sequencing, combined with artificial intelligence-based methods for ...predicting the effects of non-coding variants, provide an avenue for resolving these deaths. Using one such method, SpliceAI, we identified a maternally inherited deep intronic PKHD1 splice variant (chr6:52030169T>C), in trans with a pathogenic missense variant (p.Thr36Met), in a newborn who died of autosomal recessive polycystic kidney disease at age 2 days. We validated the deep intronic variant's impact in maternal urine-derived cells expressing PKHD1. Reverse transcription polymerase chain reaction followed by Sanger sequencing showed that the variant causes inclusion of 147bp of the canonical intron between exons 29 and 30 of PKHD1 into the mRNA, including a premature stop codon. Allele-specific expression analysis at a heterozygous site in the mother showed that the mutant allele completely suppresses canonical splicing. In an unrelated healthy control, there was no evidence of transcripts including the novel splice junction. We returned a diagnostic report to the parents, who underwent in vitro embryo selection.