Activity of Genes with Functions in Human Williams-Beuren Syndrome Is Impacted by Mobile Element Insertions in the Gray Wolf Genome.

In canines, transposon dynamics have been associated with a hyper-social behavioral syndrome, although the functional mechanism has yet to be described. We investigate the epigenetic and transcriptional consequences of these behavior-associated mobile element insertions (MEIs) in dogs and Yellowstone gray wolves. We posit that the transposons themselves may not be the causative feature; rather, their transcriptional regulation may exert the functional impact. We survey four outlier transposons associated with hyper-sociability, with the expectation that they are targeted for epigenetic silencing. We predict hyper-methylation of MEIs, suggestive that the epigenetic silencing of and not the MEIs themselves may be driving dysregulation of nearby genes. We found that transposon-derived sequences are significantly hyper-methylated, regardless of their copy number or species. Further, we have assessed transcriptome sequence data and found evidence that MEIs impact the expression levels of six genes (WBSCR17, LIMK1, GTF2I, WBSCR27, BAZ1B, and BCL7B), all of which have known roles in human Williams-Beuren syndrome due to changes in copy number, typically hemizygosity. Although further evidence is needed, our results suggest that a few insertions alter local expression at multiple genes, likely through a cis-regulatory mechanism that excludes proximal methylation

Universal Pulse Shape Scaling Function and Exponents: A Critical Test for Avalanche Models applied to Barkhausen Noise

In order to test if the universal aspects of Barkhausen noise in magnetic materials can be predicted from recent variants of the non-equilibrium zero temperature Random Field Ising Model (RFIM), we perform a quantitative study of the universal scaling function derived from the Barkhausen pulse shape in simulations and experiment. Through data collapses and scaling relations we determine the critical exponents $\tau$ and $1/\sigma\nu z$ in both simulation and experiment. Although we find agreement in the critical exponents, we find differences between theoretical and experimental pulse shape scaling functions as well as between different experiments.Comment: 19 pages (in preprint format), 5 figures, 1 tabl

Health-related quality of life in KEYNOTE-010 : a phase II/III study of pembrolizumab versus docetaxel in patients with previously treated advanced, programmed death ligand 1-expressing NSCLC

Introduction: In the phase II/III KEYNOTE-010 study (ClinicalTrials.gov, NCT01905657), pembrolizumab significantly prolonged overall survival over docetaxel in patients with previously treated, programmed death ligand 1-expressing (tumor proportion score >= 1%), advanced NSCLC. Health-related quality of life (HRQoL) results are reported here. Methods: Patients were randomized 1:1:1 to pembrolizumab 2 or 10 mg/kg every 3 weeks or docetaxel 75 mg/m(2) every 3 weeks. HRQoL was assessed using European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLC) Core 30 (C30), EORTC QLQ-Lung Cancer 13 (LC13), and EuroQoL-5D. Key analyses included mean baseline-to-week-12 change in global health status (GHS)/quality of life (QoL) score, functioning and symptom domains, and time to deterioration in a QLQ-LC13 composite endpoint of cough, dyspnea, and chest pain. Results: Patient reported outcomes compliance was high across all three instruments. Pembrolizumab was associated with better QLQ-C30 GHS/QoL scores from baseline to 12 weeks than docetaxel, regardless of pembrolizumab dose or tumor proportion score status (not significant). Compared with docetaxel, fewer pembrolizumab-treated patients had "deteriorated" status and more had "improved" status in GHS/QoL. Nominally significant improvement was reported in many EORTC symptom domains with pembrolizumab, and nominally significant worsening was reported with docetaxel. Significant prolongation in true time to deterioration for the QLQ-LC13 composite endpoint emerged for pembrolizumab 10 mg/kg compared to docetaxel (nominal two-sided p = 0.03), but not for the 2-mg/kg dose. Conclusions: These findings suggest that HRQoL and symptoms are maintained or improved to a greater degree with pembrolizumab than with docetaxel in this NSCLC patient population. (C) 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Planet Hunters. V. A Confirmed Jupiter-Size Planet in the Habitable Zone and 42 Planet Candidates from the Kepler Archive Data

We report the latest Planet Hunter results, including PH2 b, a Jupiter-size (R_PL = 10.12 \pm 0.56 R_E) planet orbiting in the habitable zone of a solar-type star. PH2 b was elevated from candidate status when a series of false positive tests yielded a 99.9% confidence level that transit events detected around the star KIC 12735740 had a planetary origin. Planet Hunter volunteers have also discovered 42 new planet candidates in the Kepler public archive data, of which 33 have at least three transits recorded. Most of these transit candidates have orbital periods longer than 100 days and 20 are potentially located in the habitable zones of their host stars. Nine candidates were detected with only two transit events and the prospective periods are longer than 400 days. The photometric models suggest that these objects have radii that range between Neptune to Jupiter. These detections nearly double the number of gas giant planet candidates orbiting at habitable zone distances. We conducted spectroscopic observations for nine of the brighter targets to improve the stellar parameters and we obtained adaptive optics imaging for four of the stars to search for blended background or foreground stars that could confuse our photometric modeling. We present an iterative analysis method to derive the stellar and planet properties and uncertainties by combining the available spectroscopic parameters, stellar evolution models, and transiting light curve parameters, weighted by the measurement errors. Planet Hunters is a citizen science project that crowd-sources the assessment of NASA Kepler light curves. The discovery of these 43 planet candidates demonstrates the success of citizen scientists at identifying planet candidates, even in longer period orbits with only two or three transit events.Comment: 35 pages, 11 figures, 6 tables, accepted and published on ApJ ApJ, 776, 1

SARS-CoV-2 Viral Load in Saliva Rises Gradually and to Moderate Levels in Some Humans

Transmission of SARS-CoV-2 in community settings often occurs before symptom onset, therefore testing strategies that can reliably detect people in the early phase of infection are urgently needed. Early detection of SARS-CoV-2 infection is especially critical to protect vulnerable populations who require frequent interactions with caretakers. Rapid COVID-19 tests have been proposed as an attractive strategy for surveillance, however a limitation of most rapid tests is their low sensitivity. Low-sensitivity tests are comparable to high sensitivity tests in detecting early infections when two assumptions are met: (1) viral load rises quickly (within hours) after infection and (2) viral load reaches and sustains high levels (>10⁵ - 10⁶ RNA copies/mL). However, there are no human data testing these assumptions. In this study, we document a case of presymptomatic household transmission from a healthy college student to his brother and father. Participants prospectively provided twice-daily saliva samples. Samples were analyzed by RT-qPCR and RT-ddPCR and we measured the complete viral load profiles throughout the course of infection of the brother and father. This study provides evidence that in at least some human cases of SARS-CoV-2, viral load rises slowly (over days, not hours) and not to such high levels to be detectable reliably by any low-sensitivity test. Additional viral load profiles from different samples types across a broad demographic must be obtained to describe the early phase of infection and determine which testing strategies will be most effective for identifying SARS-CoV-2 infection before transmission can occur

The Association of Intensive Blood Pressure Treatment and Non-Fatal Cardiovascular or Serious Adverse Events in Older Adults With Mortality: Mediation Analysis in Sprint

AIMS: Randomized clinical trials of hypertension treatment intensity evaluate the effects on incident major adverse cardiovascular events (MACEs) and serious adverse events (SAEs). Occurrences after a non-fatal index event have not been rigorously evaluated. The aim of this study was to evaluate the association of intensive (\u3c120 \u3emmHg) to standard (\u3c140 \u3emmHg) blood pressure (BP) treatment with mortality mediated through a non-fatal MACE or non-fatal SAE in 9361 participants in the Systolic Blood Pressure Intervention Trial. METHODS AND RESULTS: Logistic regression and causal mediation modelling to obtain direct and mediated effects of intensive BP treatment. Primary outcome was all-cause mortality (ACM). Secondary outcomes were cardiovascular (CVM) and non-CV mortality (non-CVM). The direct effect of intensive treatment was a lowering of ACM [odds ratio (OR) 0.75, 95% confidence interval (CI): 0.60-0.94]. The MACE-mediated effect substantially attenuated (OR 0.96, 95% CI: 0.92-0.99) ACM, while the SAE-mediated effect was associated with increased (OR 1.03, 95% CI: 1.01-1.05) ACM. Similar patterns were noted for intensive BP treatment on CVM and non-CVM. We also noted that SAE incidence was 3.9-fold higher than MACE incidence (13.7 vs. 3.5%), and there were a total of 365 (3.9%) ACM cases, with non-CVM being 2.6-fold higher than CVM [2.81% (263/9361) vs. 1.09% (102/9361)]. The SAE to MACE and non-CVM to CVM preponderance was found across all age groups, with the ≥80-year age group having the highest differences. CONCLUSION: The current analytic techniques demonstrated that intensive BP treatment was associated with an attenuated mortality benefit when it was MACE-mediated and possibly harmful when it was SAE-mediated. Current cardiovascular trial reporting of treatment effects does not allow expansion of the lens to focus on important occurrences after the index event

Resistance to autosomal dominant Alzheimer's disease in an APOE3 Christchurch homozygote: a case report.

We identified a PSEN1 (presenilin 1) mutation carrier from the world's largest autosomal dominant Alzheimer's disease kindred, who did not develop mild cognitive impairment until her seventies, three decades after the expected age of clinical onset. The individual had two copies of the APOE3 Christchurch (R136S) mutation, unusually high brain amyloid levels and limited tau and neurodegenerative measurements. Our findings have implications for the role of APOE in the pathogenesis, treatment and prevention of Alzheimer's disease

The Product and System Specificities of Measuring Curation Impact

Using three datasets archived at the National Center for Atmospheric Research (NCAR), we describe the creation of a ‘data usage index’ for curation-specific impact assessments. Our work is focused on quantitatively evaluating climate and weather data used in earth and space science research, but we also discuss the application of this approach to other research data contexts. We conclude with some proposed future directions for metric-based work in data curation