Accurate measurement of gene copy number for human alpha-defensin DEFA1A3

Background: Multi-allelic copy number variants include examples of extensive variation between individuals in the copy number of important genes, most notably genes involved in immune function. The definition of this variation, and analysis of its impact on function, has been hampered by the technical difficulty of large-scale but accurate typing of genomic copy number. The copy-variable alpha-defensin locus DEFA1A3 on human chromosome 8 commonly varies between 4 and 10 copies per diploid genome, and presents considerable challenges for accurate high-throughput typing. Results: In this study, we developed two paralogue ratio tests and three allelic ratio measurements that, in combination, provide an accurate and scalable method for measurement of DEFA1A3 gene number. We combined information from different measurements in a maximum-likelihood framework which suggests that most samples can be assigned to an integer copy number with high confidence, and applied it to typing 589 unrelated European DNA samples. Typing the members of three-generation pedigrees provided further reassurance that correct integer copy numbers had been assigned. Our results have allowed us to discover that the SNP rs4300027 is strongly associated with DEFA1A3 gene copy number in European samples. Conclusions: We have developed an accurate and robust method for measurement of DEFA1A3 copy number. Interrogation of rs4300027 and associated SNPs in Genome-Wide Association Study SNP data provides no evidence that alpha-defensin copy number is a strong risk factor for phenotypes such as Crohn’s disease, type I diabetes, HIV progression and multiple sclerosis

The DetectDeviatingCells algorithm was a useful addition to the toolkit for cellwise error detection in observational data

OBJECTIVE: We evaluated the error detection performance of the DetectDeviatingCells (DDC) algorithm, which flags data anomalies at observation (casewise) and variable (cellwise) level in continuous variables. We compared its performance to other approaches in a simulated dataset. STUDY DESIGN AND SETTING: We simulated height and weight data for hypothetical individuals aged 2-20 years. We changed a proportion of height values according to pre-determined error patterns. We applied the DDC algorithm and other error-detection approaches (descriptive statistics, plots, fixed-threshold rules, classic and robust Mahalanobis distance) and we compared error detection performance with sensitivity, specificity, likelihood ratios, predictive values and ROC curves. RESULTS: At our chosen thresholds, error detection specificity was excellent across all scenarios for all methods and sensitivity was higher for multivariable and robust methods. The DDC algorithm performance was similar to other robust multivariable methods. Analysis of ROC curves suggested that all methods had comparable performance for gross errors (e.g. wrong measurement unit), but the DDC algorithm outperformed the others for more complex error patterns (e.g. transcription errors that are still plausible, although extreme). CONCLUSIONS: The DDC algorithm has the potential to improve error detection processes for observational data

Convergent approach to persistent atrial fibrillation ablation:long-term single-centre safety and efficacy

Background:Efforts to maintain sinus rhythm in patients with persistent atrial fibrillation (PsAF) remain challenging, with suboptimal long-term outcomes.Methods:All patients undergoing convergent PsAF ablation at our centre were retrospectively analysed. The Atricure Epi-Sense® system was used to perform surgical radiofrequency ablation of the LA posterior wall followed by endocardial ablation.Results:A total of 24 patients underwent convergent PsAF ablation, and 21 (84%) of them were male with a median age of 63. Twelve (50%) patients were obese. In total, 71% of patients had a severely dilated left atrium, and the majority (63%) had preserved left ventricular function. All were longstanding persistent. Eighteen (75%) patients had an AF duration of >2 years. There were no endocardial procedure complications. At 36 months, all patients were alive with no new stroke/transient ischaemic attack (TIA). Freedom from documented AF at 3, 6, 12, 18, 24, and 36 months was 83%, 78%, 74%, 74%, 74%, and 61%, respectively. There were no major surgical complications, with five minor complications recorded comprising minor wound infection, pericarditic pain, and hernia.Conclusions:Our data suggest that convergent AF ablation is effective with excellent immediate and long-term safety outcomes in a real-world cohort of patients with a significant duration of AF and evidence of established atrial remodelling. Convergent AF ablation appears to offer a safe and effective option for those who are unlikely to benefit from existing therapeutic strategies for maintaining sinus rhythm, and further evaluation of this exciting technique is warranted. Our cohort is unique within the published literature both in terms of length of follow-up and very low rate of adverse events

The Disk Substructures at High Angular Resolution Project (DSHARP). III. Spiral Structures in the Millimeter Continuum of the Elias 27, IM Lup, and WaOph 6 Disks

We present an analysis of Atacama Large Millimeter/submillimeter Array 1.25 mm continuum observations of spiral structures in three protoplanetary disks from the Disk Substructures at High Angular Resolution Project. See full text for full abstract

Intratumor Heterogeneity of the Estrogen Receptor and the Long-term Risk of Fatal Breast Cancer.

Background:Breast cancer patients with estrogen receptor (ER)-positive disease have a continuous long-term risk for fatal breast cancer, but the biological factors influencing this risk are unknown. We aimed to determine whether high intratumor heterogeneity of ER predicts an increased long-term risk (25 years) of fatal breast cancer. Methods:The STO-3 trial enrolled 1780 postmenopausal lymph node-negative breast cancer patients randomly assigned to receive adjuvant tamoxifen vs not. The fraction of cancer cells for each ER intensity level was scored by breast cancer pathologists, and intratumor heterogeneity of ER was calculated using Rao's quadratic entropy and categorized into high and low heterogeneity using a predefined cutoff at the second tertile (67%). Long-term breast cancer-specific survival analyses by intra-tumor heterogeneity of ER were performed using Kaplan-Meier and multivariable Cox proportional hazard modeling adjusting for patient and tumor characteristics. Results:A statistically significant difference in long-term survival by high vs low intratumor heterogeneity of ER was seen for all ER-positive patients (P < .001) and for patients with luminal A subtype tumors (P = .01). In multivariable analyses, patients with high intratumor heterogeneity of ER had a twofold increased long-term risk as compared with patients with low intratumor heterogeneity (ER-positive: hazard ratio [HR] = 1.98, 95% confidence interval [CI] = 1.31 to 3.00; luminal A subtype tumors: HR = 2.43, 95% CI = 1.18 to 4.99). Conclusions:Patients with high intratumor heterogeneity of ER had an increased long-term risk of fatal breast cancer. Interestingly, a similar long-term risk increase was seen in patients with luminal A subtype tumors. Our findings suggest that intratumor heterogeneity of ER is an independent long-term prognosticator with potential to change clinical management, especially for patients with luminal A tumors

The Disk Substructures at High Angular Resolution Project (DSHARP). II. Characteristics of Annular Substructures

The Disk Substructures at High Angular Resolution Project (DSHARP) used ALMA to map the 1.25 mm continuum of protoplanetary disks at a spatial resolution of ~5 au. We present a systematic analysis of annular substructures in the 18 single-disk systems targeted in this survey. No dominant architecture emerges from this sample; instead, remarkably diverse morphologies are observed. Annular substructures can occur at virtually any radius where millimeter continuum emission is detected and range in widths from a few astronomical units to tens of astronomical units. Intensity ratios between gaps and adjacent rings range from near-unity to just a few percent. In a minority of cases, annular substructures coexist with other types of substructures, including spiral arms (3/18) and crescent-like azimuthal asymmetries (2/18). No clear trend is observed between the positions of the substructures and stellar host properties. In particular, the absence of an obvious association with stellar host luminosity (and hence the disk thermal structure) suggests that substructures do not occur preferentially near major molecular snowlines. Annular substructures like those observed in DSHARP have long been hypothesized to be due to planet–disk interactions. A few disks exhibit characteristics particularly suggestive of this scenario, including substructures in possible mean-motion resonance and double gap features reminiscent of hydrodynamical simulations of multiple gaps opened by a planet in a low-viscosity disk

Association of Plasma CD163 Concentration with De Novo–Onset Chronic Graft-versus-Host Disease

Chronic graft-versus-host disease (GVHD) is the leading cause of long-term morbidity and mortality after allogeneic hematopoietic cell transplantation. To identify prognostic plasma proteins associated with de novo– or quiescent-onset chronic GVHD (cGVHD), we performed a discovery and validation proteomic study. The total study cohort included 167 consecutive patients who had no clinical evidence of GVHD under minimum glucocorticoid administration and had available plasma samples obtained at 80 ± 14 days after transplantation. We first used high-throughput mass spectrometry to screen pooled plasma using 20 cases with subsequent cGVHD and 20 controls without it, and we identified 20 candidate proteins. We then measured 12 of the 20 candidate proteins by ELISA on the same individual samples and identified 4 proteins for further verification (LGALS3BP, CD5L, CD163, and TXN for de novo onset, and LGALS3BP and CD5L for quiescent onset). The verification cohort included 127 remaining patients. The cumulative incidence of de novo–onset cGVHD was higher in patients with higher plasma soluble CD163 concentrations at day 80 than those with lower concentrations (75% versus 40%, P = .018). The cumulative incidence of de novo– or quiescent-onset cGVHD did not differ statistically according to concentrations of the 3 other proteins at day 80. CD163 is a macrophage scavenger receptor and is elevated in oxidative conditions. These results suggest that monocyte or macrophage activation or increased oxidative stress may contribute to the pathogenesis of cGVHD

Spiral Density Waves in a Young Protoplanetary Disk

Gravitational forces are expected to excite spiral density waves in protoplanetary disks, disks of gas and dust orbiting young stars. However, previous observations that showed spiral structure were not able to probe disk midplanes, where most of the mass is concentrated and where planet formation takes place. Using the Atacama Large Millimeter/submillimeter Array we detected a pair of trailing symmetric spiral arms in the protoplanetary disk surrounding the young star Elias 2-27. The arms extend to the disk outer regions and can be traced down to the midplane. These millimeter-wave observations also reveal an emission gap closer to the star than the spiral arms. We argue that the observed spirals trace shocks of spiral density waves in the midplane of this young disk.Comment: This is our own version of the manuscript, the definitive version was published in Science (DOI: 10.1126/science.aaf8296) on September 30, 2016. Posted to the arxiv for non-commercial us

CSI 2264: Characterizing Accretion-Burst Dominated Light Curves for Young Stars in NGC 2264

Based on more than four weeks of continuous high cadence photometric monitoring of several hundred members of the young cluster NGC 2264 with two space telescopes, NASA's Spitzer and the CNES CoRoT (Convection, Rotation, and planetary Transits), we provide high quality, multi-wavelength light curves for young stellar objects (YSOs) whose optical variability is dominated by short duration flux bursts, which we infer are due to enhanced mass accretion rates. These light curves show many brief -- several hour to one day -- brightenings at optical and near-infrared (IR) wavelengths with amplitudes generally in the range 5-50% of the quiescent value. Typically, a dozen or more of these bursts occur in a thirty day period. We demonstrate that stars exhibiting this type of variability have large ultraviolet (UV) excesses and dominate the portion of the u-g vs. g-r color-color diagram with the largest UV excesses. These stars also have large Halpha equivalent widths, and either centrally peaked, lumpy Halpha emission profiles or profiles with blue-shifted absorption dips associated with disk or stellar winds. Light curves of this type have been predicted for stars whose accretion is dominated by Rayleigh-Taylor instabilities at the boundary between their magnetosphere and inner circumstellar disk, or where magneto-rotational instabilities modulate the accretion rate from the inner disk. Amongst the stars with the largest UV excesses or largest Halpha equivalent widths, light curves with this type of variability greatly outnumber light curves with relatively smooth sinusoidal variations associated with long-lived hot spots. We provide quantitative statistics for the average duration and strength of the accretion bursts and for the fraction of the accretion luminosity associated with these bursts.Comment: Accepted for publication in AJ. 39 pages; 6 tables; 25 figures, many of which are highly degraded to meet size limits. Please download the regular resolution version at http://web.ipac.caltech.edu/staff/amc/staufferetal2014.pd