The Size and Origin of Metal-enriched Regions in the Intergalactic Medium from Spectra of Binary Quasars

We present tomography of the circum-galactic metal distribution at redshift 1.7-4.5 derived from echellete spectroscopy of binary quasars. We find C IV systems at similar redshifts in paired sightlines more often than expected for sightline-independent redshifts. As the separation of the sightlines increases from 36 kpc to 907 kpc, the amplitude of this clustering decreases. At the largest separations, the C IV systems cluster similar to the Lyman-break galaxies studied by Adelberger et al. in 2005. The C IV systems are significantly less correlated than these galaxies, however, at separations less than R_1 0.42 ± 0.15 h^( –1) comoving Mpc. Measured in real space, i.e., transverse to the sightlines, this length scale is significantly smaller than the break scale estimated previously from the line-of-sight correlation function in redshift space by Scannapieco et al. in 2006. Using a simple model, we interpret the new real-space measurement as an indication of the typical physical size of enriched regions. We adopt this size for enriched regions and fit the redshift-space distortion in the line-of-sight correlation function. The fitted velocity kick is consistent with the peculiar velocity of galaxies as determined by the underlying mass distribution and places an upper limit on the average outflow (or inflow) speed of metals. The implied timescale for dispersing metals is larger than the typical stellar ages of Lyman-break galaxies, and we argue that enrichment by galaxies at z > 4.3 played a greater role in dispersing metals. To further constrain the growth of enriched regions, we discuss empirical constraints on the evolution of the C IV correlation function with cosmic time. This study demonstrates the potential of tomography for measuring the metal enrichment history of the circum-galactic medium

Statistical Searches for Microlensing Events in Large, Non-Uniformly Sampled Time-Domain Surveys: A Test Using Palomar Transient Factory Data

Many photometric time-domain surveys are driven by specific goals, such as searches for supernovae or transiting exoplanets, which set the cadence with which fields are re-imaged. In the case of the Palomar Transient Factory (PTF), several sub-surveys are conducted in parallel, leading to non-uniform sampling over its $\sim$$20,000 \mathrm{deg}^2$ footprint. While the median $7.26 \mathrm{deg}^2$ PTF field has been imaged $\sim$40 times in \textit{R}-band, $\sim$$2300 \mathrm{deg}^2$ have been observed $>$100 times. We use PTF data to study the trade-off between searching for microlensing events in a survey whose footprint is much larger than that of typical microlensing searches, but with far-from-optimal time sampling. To examine the probability that microlensing events can be recovered in these data, we test statistics used on uniformly sampled data to identify variables and transients. We find that the von Neumann ratio performs best for identifying simulated microlensing events in our data. We develop a selection method using this statistic and apply it to data from fields with $>$10 $R$-band observations, $1.1\times10^9$ light curves, uncovering three candidate microlensing events. We lack simultaneous, multi-color photometry to confirm these as microlensing events. However, their number is consistent with predictions for the event rate in the PTF footprint over the survey's three years of operations, as estimated from near-field microlensing models. This work can help constrain all-sky event rate predictions and tests microlensing signal recovery in large data sets, which will be useful to future time-domain surveys, such as that planned with the Large Synoptic Survey Telescope.Comment: 13 pages, 14 figures; accepted for publication in ApJ. fixed author lis

Transverse Sizes of CIV Absorption Systems Measured from Multiple QSO Sightlines

We present tomography of the circum-galactic metal distribution at redshift 1.7 to 4.5 derived from echellete spectroscopy of binary quasars. We find CIV systems at similar redshifts in paired sightlines more often than expected for sightline-independent redshifts. As the separation of the sightlines increases from 36 kpc to 907 kpc, the amplitude of this clustering decreases. At the largest separations, the CIV systems cluster similar to Lyman-break galaxies (Adelberger et al. 2005a). The CIV systems are significantly less correlated than these galaxies, however, at separations less than R_1 ~ 0.42 +/- 0.15 h-1 comoving Mpc. Measured in real space, i.e., transverse to the sightlines, this length scale is significantly smaller than the break scale estimated from the line-of-sight correlation function in redshift space (Scannapieco et al. 2006a). Using a simple model, we interpret the new real-space measurement as an indication of the typical physical size of enriched regions. We adopt this size for enriched regions and fit the redshift-space distortion in the line-of-sight correlation function. The fitted velocity kick is consistent with the peculiar velocity of galaxies as determined by the underlying mass distribution and places an upper limit on the outflow (or inflow) speed of metals. The implied time scale for dispersing metals is larger than the typical stellar ages of Lyman-break galaxies (Shapley et al. 2001), and we argue that enrichment by galaxies at z > 4.3 played a greater role in dispersing metals. To further constrain the growth of enriched regions, we discuss empirical constraints on the evolution of the CIV correlation function with cosmic time. This study demonstrates the potential of tomography for measuring the metal enrichment history of the circum-galactic medium.Comment: 22 pages, 15 figures, 1 tabl

Tailored vs. Standardized Internet-Based Cognitive Behavior Therapy for Depression and Comorbid Symptoms: A Randomized Controlled Trial

Background and Aims:Major depression can be treated by means of cognitive behavior therapy, delivered via the Internet as guided self-help. Individually tailored guided self-help treatments have shown promising results in the treatment of anxiety disorders. This randomized controlled trial tested the efficacy of an Internet-based individually tailored guided selfhelp treatment which specifically targeted depression with comorbid symptoms. The treatment was compared both to standardized (non-tailored) Internet-based treatment and to an active control group in the form of a monitored online discussion group. Both guided self-help treatments were based on cognitive behavior therapy and lasted for 10 weeks. The discussion group consisted of weekly discussion themes related to depression and the treatment of depression. Methods:A total of 121 participants with diagnosed major depressive disorder and with a range of comorbid symptoms were randomized to three groups. The tailored treatment consisted of a prescribed set of modules targeting depression as well as comorbid problems. The standardized treatment was a previously tested guided self-help program for depression. Results:From pre-treatment to post-treatment, both treatment groups improved on measures of depression, anxiety and quality of life. The results were maintained at a 6-month follow-up. Subgroup analyses showed that the tailored treatment was more effective than the standardized treatment among participants with higher levels of depression at baseline and more comorbidity, both in terms of reduction of depressive symptoms and on recovery rates. In the subgroup with lower baseline scores of depression, few differences were seen between treatments and the discussion group. Conclusions:This study shows that tailored Internet-based treatment for depression is effective and that addressing comorbidity by tailoring may be one way of making guided self-help treatments more effective than standardized approaches in the treatment of more severe depression

Ovarian cancer risk factors by tumor aggressiveness : An analysis from the Ovarian Cancer Cohort Consortium

Ovarian cancer risk factors differ by histotype; however, within subtype, there is substantial variability in outcomes. We hypothesized that risk factor profiles may influence tumor aggressiveness, defined by time between diagnosis and death, independent of histology. Among 1.3 million women from 21 prospective cohorts, 4,584 invasive epithelial ovarian cancers were identified and classified as highly aggressive (death in = 35 vs. 20 to <25 kg/m(2), 1.93 [1.46-2.56] and current smoking (vs. never, 1.30 [1.07-1.57]) were associated with increased risk of highly aggressive disease. Results were similar within histotypes. Ovarian cancer risk factors may be directly associated with subtypes defined by tumor aggressiveness, rather than through differential effects on histology. Studies to assess biological pathways are warranted.Peer reviewe

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk

Identification of a BRCA2-Specific modifier locus at 6p24 related to breast cancer risk

Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9×10−8). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer

Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10-8, HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10-8, HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10-8, HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific associat

An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.Peer reviewe

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality