Towards energy resolution at the statistical limit from a negative ion time projection chamber

We make a proof-of-principle demonstration that improved energy resolution can be obtained in a negative-ion time projection chamber, by individually counting each electron produced by ionizing radiation.Comment: Submitted to Nucl. Instr. Meth.

Bureau of Land Management

The authors wish to thank Steve Leonard and George Staidle, who authored Technical Reference 1737-5, Riparian and Wetland Classification Review, which provided the basis for this document. We also thank those who reviewed and commented on Technical Reference 1737-5: Paul Hansen, Bill Platts, Bud Kovalchik

Targeting Superficial or Nodular Basal Cell Carcinoma with Topically Formulated Small Molecule Inhibitor of Smoothened

Purpose: Inappropriate activation of the Hedgehog (Hh) signaling pathway in skin is critical for the development of basal cell carcinomas (BCC). We have investigated the anti-BCC efficacy of topically-applied CUR61414, an inhibitor of the Hh signal transduction molecule Smoothened. Experimental Design: In preclinical studies, we used a depilatory model to evaluate the ability of topical formulations of CUR61414 to repress Hh responsive cells found at the base of hair follicles in normal skin. We also tested the in vivo effects of topical CUR61414 on murine BCCs developed in $Ptch1^{ +/−}$ K14-CreER2 p53 fl/fl mice. In a phase I clinical study, we evaluated the safety, tolerability, and efficacy of a multidose regimen of CUR61414 (0.09%, 0.35%, 1.1%, and 3.1%) applied topically to human superficial or nodular BCCs for up to 28 days. Results: In mice, topical CUR61414 significantly inhibited skin Hh signaling, blocked the induction of hair follicle anagen, and shrank existing BCCs. However, we observed no clinical activity of this formulation in human superficial or nodular BCCs in a phase I clinical study. Conclusions: Our data highlight some of the challenges of translating preclinical experience into successful human results for a topical anticancer agent.Stem Cell and Regenerative Biolog

Real-Time Detection and Filtering of Radio Frequency Interference On-board a Spaceborne Microwave Radiometer: The CubeRRT Mission

The Cubesat Radiometer Radio frequency interference Technology validation mission (CubeRRT) was developed to demonstrate real-time on-board detection and filtering of radio frequency interference (RFI) for wide bandwidth microwave radiometers. CubeRRT’s key technology is its radiometer digital backend (RDB) that is capable of measuring an instantaneous bandwidth of 1 GHz and of filtering the input signal into an estimated total power with and without RFI contributions. CubeRRT’s on-board RFI processing capability dramatically reduces the volume of data that must be downlinked to the ground and eliminates the need for ground-based RFI processing. RFI detection is performed by resolving the input bandwidth into 128 frequency sub-channels, with the kurtosis of each sub-channel and the variations in power across frequency used to detect non-thermal contributions. RFI filtering is performed by removing corrupted frequency sub-channels prior to the computation of the total channel power. The 1 GHz bandwidth input signals processed by the RDB are obtained from the payload’s antenna (ANT) and radiometer front end (RFE) subsystems that are capable of tuning across RF center frequencies from 6 to 40 GHz. The CubeRRT payload was installed into a 6U spacecraft bus provided by Blue Canyon Technologies that provides spacecraft power, communications, data management, and navigation functions. The design, development, integration and test, and on-orbit operations of CubeRRT are described in this paper. The spacecraft was delivered on March 22nd, 2018 for launch to the International Space Station (ISS) on May 21st, 2018. Since its deployment from the ISS on July 13th, 2018, the CubeRRT RDB has completed more than 5000 hours of operation successfully, validating its robustness as an RFI processor. Although CubeRRT’s RFE subsystem ceased operating on September 8th, 2018, causing the RDB input thereafter to consist only of internally generated noise, CubeRRT’s key RDB technology continues to operate without issue and has demonstrated its capabilities as a valuable subsystem for future radiometry missions

Fine-mapping, novel loci identification, and SNP association transferability in a genome-wide association study of QRS duration in African Americans

The electrocardiographic QRS duration, a measure of ventricular depolarization and conduction, is associated with cardiovascular mortality. While single nucleotide polymorphisms (SNPs) associated with QRS duration have been identified at 22 loci in populations of European descent, the genetic architecture of QRS duration in non-European populations is largely unknown. We therefore performed a genome-wide association study (GWAS) meta-analysis of QRS duration in 13,031 African Americans from ten cohorts and a transethnic GWAS meta-analysis with additional results from populations of European descent. In the African American GWAS, a single genome-wide significant SNP association was identified (rs3922844, P = 4 × 10−14) in intron 16 of SCN5A, a voltage-gated cardiac sodium channel gene. The QRS-prolonging rs3922844 C allele was also associated with decreased SCN5A RNA expression in human atrial tissue (P = 1.1 × 10−4). High density genotyping revealed that the SCN5A association region in African Americans was confined to intron 16. Transethnic GWAS meta-analysis identified novel SNP associations on chromosome 18 in MYL12A (rs1662342, P = 4.9 × 10−8) and chromosome 1 near CD1E and SPTA1 (rs7547997, P = 7.9 × 10−9). The 22 QRS loci previously identified in populations of European descent were enriched for significant SNP associations with QRS duration in African Americans (P = 9.9 × 10−7), and index SNP associations in or near SCN5A, SCN10A, CDKN1A, NFIA, HAND1, TBX5 and SETBP1 replicated in African Americans. In summary, rs3922844 was associated with QRS duration and SCN5A expression, two novel QRS loci were identified using transethnic meta-analysis, and a significant proportion of QRS–SNP associations discovered in populations of European descent were transferable to African Americans when adequate power was achieved

Multi-ancestry sleep-by-SNP interaction analysis in 126,926 individuals reveals lipid loci stratified by sleep duration.

Both short and long sleep are associated with an adverse lipid profile, likely through different biological pathways. To elucidate the biology of sleep-associated adverse lipid profile, we conduct multi-ancestry genome-wide sleep-SNP interaction analyses on three lipid traits (HDL-c, LDL-c and triglycerides). In the total study sample (discovery + replication) of 126,926 individuals from 5 different ancestry groups, when considering either long or short total sleep time interactions in joint analyses, we identify 49 previously unreported lipid loci, and 10 additional previously unreported lipid loci in a restricted sample of European-ancestry cohorts. In addition, we identify new gene-sleep interactions for known lipid loci such as LPL and PCSK9. The previously unreported lipid loci have a modest explained variance in lipid levels: most notable, gene-short-sleep interactions explain 4.25% of the variance in triglyceride level. Collectively, these findings contribute to our understanding of the biological mechanisms involved in sleep-associated adverse lipid profiles

Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity.

Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels

Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity

The present work was largely supported by a grant from the US National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (R01HL118305). The full list of acknowledgments appears in the Supplementary Notes 3 and 4.Peer reviewedPublisher PD