The cosmic radio dipole is of fundamental interest to studies of cosmology. Recent works have put forth open questions about the nature of the observed cosmic radio dipole. In the current work, we ...use simulated source count maps to test a linear and a quadratic estimator for possible biases in the estimated dipole amplitude with respect to the masking procedure. We find a superiority on the part of the quadratic estimator, which we used to analyse the TGSS-ADR1, WENSS, SUMSS, and NVSS radio source catalogues, spread over a decade of frequencies. We applied the same masking strategy to all four surveys to produce comparable results. In order to address the differences in the observed dipole amplitudes, we cross-matched the two surveys located at both ends of the analysed frequency range. For the linear estimator, we identified a general bias in the estimated dipole directions. The positional offsets of the quadratic estimator to the cosmic microwave background (CMB) dipole for skies with 10
7
simulated sources is found to be below one degree and the absolute accuracy of the estimated dipole amplitudes is better than 10
−3
. For the four radio source catalogues, we find an increasing dipole amplitude with decreasing frequency, which is consistent with results from the literature and the results of the cross-matched catalogue. We conclude that for all analysed surveys, the observed cosmic radio dipole amplitudes exceed the expectations derived from the CMB dipole, which cannot strictly be explained by a kinematic dipole alone.
Balancing selection occurs when multiple alleles are maintained in a population, which can result in their preservation over long evolutionary time periods. A characteristic signature of this ...long-term balancing selection is an excess number of intermediate frequency polymorphisms near the balanced variant. However, the expected distribution of allele frequencies at these loci has not been extensively detailed, and therefore existing summary statistic methods do not explicitly take it into account. Using simulations, we show that new mutations which arise in close proximity to a site targeted by balancing selection accumulate at frequencies nearly identical to that of the balanced allele. In order to scan the genome for balancing selection, we propose a new summary statistic, β, which detects these clusters of alleles at similar frequencies. Simulation studies show that compared with existing summary statistics, our measure has improved power to detect balancing selection, and is reasonably powered in non-equilibrium demographic models and under a range of recombination and mutation rates. We compute β on 1000 Genomes Project data to identify loci potentially subjected to long-term balancing selection in humans. We report two balanced haplotypes-localized to the genes WFS1 and CADM2-that are strongly linked to association signals for complex traits. Our approach is computationally efficient and applicable to species that lack appropriate outgroup sequences, allowing for well-powered analysis of selection in the wide variety of species for which population data are rapidly being generated.
A number of epidemiological and genetic studies have attempted to determine whether levels of circulating lipids are associated with risks of various cancers, including breast cancer (BC). However, ...it remains unclear whether a causal relationship exists between lipids and BC. If alteration of lipid levels also reduced risk of BC, this could present a target for disease prevention. This study aimed to assess a potential causal relationship between genetic variants associated with plasma lipid traits (high-density lipoprotein, HDL; low-density lipoprotein, LDL; triglycerides, TGs) with risk for BC using Mendelian randomization (MR).
Data from genome-wide association studies in up to 215,551 participants from the Million Veteran Program (MVP) were used to construct genetic instruments for plasma lipid traits. The effect of these instruments on BC risk was evaluated using genetic data from the BCAC (Breast Cancer Association Consortium) based on 122,977 BC cases and 105,974 controls. Using MR, we observed that a 1-standard-deviation genetically determined increase in HDL levels is associated with an increased risk for all BCs (HDL: OR odds ratio = 1.08, 95% confidence interval CI = 1.04-1.13, P < 0.001). Multivariable MR analysis, which adjusted for the effects of LDL, TGs, body mass index (BMI), and age at menarche, corroborated this observation for HDL (OR = 1.06, 95% CI = 1.03-1.10, P = 4.9 × 10-4) and also found a relationship between LDL and BC risk (OR = 1.03, 95% CI = 1.01-1.07, P = 0.02). We did not observe a difference in these relationships when stratified by breast tumor estrogen receptor (ER) status. We repeated this analysis using genetic variants independent of the leading association at core HDL pathway genes and found that these variants were also associated with risk for BCs (OR = 1.11, 95% CI = 1.06-1.16, P = 1.5 × 10-6), including locus-specific associations at ABCA1 (ATP Binding Cassette Subfamily A Member 1), APOE-APOC1-APOC4-APOC2 (Apolipoproteins E, C1, C4, and C2), and CETP (Cholesteryl Ester Transfer Protein). In addition, we found evidence that genetic variation at the ABO locus is associated with both lipid levels and BC. Through multiple statistical approaches, we minimized and tested for the confounding effects of pleiotropy and population stratification on our analysis; however, the possible existence of residual pleiotropy and stratification remains a limitation of this study.
We observed that genetically elevated plasma HDL and LDL levels appear to be associated with increased BC risk. Future studies are required to understand the mechanism underlying this putative causal relationship, with the goal of developing potential therapeutic strategies aimed at altering the cholesterol-mediated effect on BC risk.
Many diseases exhibit population-specific causal effect sizes with trans-ethnic genetic correlations significantly less than 1, limiting trans-ethnic polygenic risk prediction. We develop a new ...method, S-LDXR, for stratifying squared trans-ethnic genetic correlation across genomic annotations, and apply S-LDXR to genome-wide summary statistics for 31 diseases and complex traits in East Asians (average N = 90K) and Europeans (average N = 267K) with an average trans-ethnic genetic correlation of 0.85. We determine that squared trans-ethnic genetic correlation is 0.82× (s.e. 0.01) depleted in the top quintile of background selection statistic, implying more population-specific causal effect sizes. Accordingly, causal effect sizes are more population-specific in functionally important regions, including conserved and regulatory regions. In regions surrounding specifically expressed genes, causal effect sizes are most population-specific for skin and immune genes, and least population-specific for brain genes. Our results could potentially be explained by stronger gene-environment interaction at loci impacted by selection, particularly positive selection.
Spatial analysis in earth sciences is often based on the concept of spatial autocorrelation, expressed by W. Tobler as the first law of geography: “everything is related to everything else, but near ...things are more related than distant things." Here, we show that subsurface soil properties in permafrost tundra terrain exhibit tremendous spatial variability. We describe the subsurface variability of soil organic carbon (SOC) and ground ice content from the centimeter to the landscape scale in three typical tundra terrain types common across the Arctic region. At the soil pedon scale, that is, from centimeters to 1–2 m, variability is caused by cryoturbation and affected by tussocks, hummocks and nonsorted circles. At the terrain scale, from meters to tens of meters, variability is caused by different generations of ice‐wedges. Variability at the landscape scale, that is, ranging hundreds of meters, is associated with geomorphic disturbances and catenary shifts. The co‐occurrence and overlap of different processes and landforms creates a spatial structure unique to permafrost environments. The coefficient of variation of SOC at the pedon scale (21%–73%) exceeds that found at terrain (17%–66%) and even landscape scale (24%–67%). Such high values for spatial variation are otherwise found at regional to continental scale. Clearly, permafrost soils do not conform to Tobler's law, but are among the most variable soils on Earth. This needs to be accounted for in mapping and predictions of the permafrost carbon feedbacks through various ecosystem processes. We conclude that scale deserves special attention in permafrost regions.
Key Points
Tundra environments feature some of the world's most variable soils
The occurrence and overlap of different periglacial landforms and processes create a unique spatial structure in permafrost environments
Local scale variability in tundra soils can exceed landscape scale variability with important implications for Arctic carbon dynamics
Background
This study was performed to determine the ability to escalate drug doses in a 15‐week CHOP protocol in dogs with multicentric lymphoma.
Hypothesis
We hypothesized that at least 50% of dogs ...could successfully be escalated in at least 1 drug. Secondary aims were to establish objective response rate (ORR), progression‐free interval (PFI), and overall survival time (OST).
Animals
Thirty dogs with newly diagnosed multicentric lymphoma were prospectively treated with a 15‐week CHOP protocol.
Methods
This was a prospective cohort study. Drug doses that did not cause dose‐limiting adverse effects (AEs) were increased using a standardized escalation protocol. AEs and response were assessed using VCOG criteria. Serial blood samples were collected after the first dose of each drug for pharmacokinetic analysis.
Results
Of the 23 dogs with the opportunity to dose escalate, at least 1 drug was successfully escalated in 18 (78%). Vincristine was successfully escalated to 0.8 mg/m2 or higher in 11 dogs, cyclophosphamide to 300 mg/m2 or higher in 16 dogs, and doxorubicin to 35 mg/m2 or 1.4 mg/kg or higher in 9 dogs. Three of the 23 dogs (13%) were hospitalized at least once because of drug‐induced AEs. Neutropenia was the most common dose‐limiting toxicosis for all drugs. Peak doxorubicin concentrations were significantly lower in dogs where doxorubicin was successfully escalated. The objective response rate was 100%. The median progression free interval was 171 days. The median overall survival time was 254 days.
Conclusions
Drugs in the CHOP protocol can often be escalated safely with manageable AEs.
In a series of earlier papers, we developed expressions for ion and electron velocity distribution functions and their velocity moments at the passage over the solar wind termination shock. As we ...have shown there, with the introduction of appropriate particle invariants and the use of Liouville’s theorem one can get explicit solutions for the resulting total downstream pressure by adding up from partial pressure contributions of solar wind protons, solar wind electrons and pick-up protons. These expressions are the first step toward delivering the main contributions to the total plasma pressure in the downstream plasma flow and consistently determine the shock compression ratio. Here we start from these individual fluid pressures downstream of the shock and thereafter evaluate for the first time the shock-induced entropy production of the different fluids, when they are passing over the shock to the downstream side. As shown here, the resulting ion entropy production substantially deviates from earlier calculations using a pseudo-polytropic reaction of the ions to the shock compression, with polytropies selected to describe fluid-specific reactions at the shock passage similar to those seen by the Voyagers. From these latter models, ion entropy jumps are derived that depend on the pick-up ion abundance, while our calculations deliver an abundance-independent ion entropy production that only depends on the shock compression ratio and the tilt angle between the upstream magnetic field and the normal to the shock surface. We also show here that the thermodynamically permitted upper limit in the entropy production is only reached when strongly heated electrons are included in the entropy balance.
Accelerating climate change and increased economic and environmental interests in permafrost-affected regions have resulted in an acute need for more directed permafrost research. In June 2014, 88 ...early career researchers convened to identify future priorities for permafrost research. This multidisciplinary forum concluded that five research topics deserve greatest attention: permafrost landscape dynamics, permafrost thermal modeling, integration of traditional knowledge, spatial distribution of ground ice, and engineering issues. These topics underline the need for integrated research across a spectrum of permafrost-related domains and constitute a contribution to the Third International Conference on Arctic Research Planning (ICARP III).
In this paper we consider a multi-fluid plasma that describes the upstream solar wind at its passage over the solar wind termination shock. In one respect, the plasma at the shock reacts like a joint ...fluid that is described by a single compression ratio. This ratio depends on all upstream and downstream pressures of the magnetohydrodynamic (MHD) plasma. In another respect, the distinguished plasma fluids in their downstream properties show fluid-specific reactions, thet we describe by using additional kinetic information on the plasma constituents, such as the Liouville theorem, the conservation of typical particle invariants, and the species-specific influence of the electric shock ramp. We thus obtain the resulting distribution functions of the seperate fluid particles and their associated velocity moments for the downstream region, especially their separate fluid pressures. We show that the different fluid pressures in different forms depend on the shock compression ratio and on the tilt angle between the upstream magnetic field and the shock surface normal. The dominant downstream pressures are connected with the pick-up protons and with the solar wind electrons, one dominating under some given shock conditions, the other dominating under some other shock conditions. Since the downstream distributions of solar wind protons and pick-up protons partly overlap in velocity space, we look for a joint distribution of the joint proton population in the form of a joint Kappa distribution and find that the associated Kappa index and the “Gaussian velocity width” are functions of the pick-up ion abundance, of the joint compression ratio, and of the tilt angle. Owing to the strongly heated electrons the energy-per-mass density ratio of the downstream plasma turns out to be fairly different from all that was expected up to now. This might also give a hint as to why the heliosheath plasma flow lines seen by Voyagers are different from all MHD simulations so far.
Summary
Background
GNAQ and GNA11 mutant nonuveal melanoma represent a poorly characterized rare subgroup of melanoma with a gene mutation profile similar to uveal melanoma.
Objectives
To ...characterize these tumours in terms of clinical behaviour and genetic characteristics.
Methods
Patients with nonuveal GNAQ/11 mutated melanoma were identified from the prospective multicentre tumour tissue registry ADOREG, Tissue Registry in Melanoma (TRIM) and additional cooperating skin cancer centres. Extensive data on patient, tumour and treatment characteristics were collected retrospectively. Targeted sequencing was used to determine tumour mutational burden. Immunohistochemistry staining was performed for programmed death‐ligand 1 and BRCA1‐associated protein (BAP)1. Existing whole‐exome cutaneous and uveal melanoma data were analysed for mutation type and burden.
Results
We identified 18 patients with metastatic GNAQ/11 mutant nonuveal melanoma. Tumours had a lower tumour mutational burden and fewer ultraviolet signature mutations than cutaneous melanomas. In addition to GNAQ and GNA11 mutations (nine each), six splicing factor 3b subunit 1 (SF3B1), three eukaryotic translation initiation factor 1A X‐linked (EIF1AX) and four BAP1 mutations were detected. In contrast to uveal melanoma, GNAQ/11 mutant nonuveal melanomas frequently metastasized lymphatically and concurrent EIF1AX, SF3B1 and BAP1 mutations showed no apparent association with patient prognosis. Objective response to immunotherapy was poor with only one partial response observed in 10 treated patients (10%).
Conclusions
Our findings suggest that GNAQ/11 mutant nonuveal melanomas are a subtype of melanoma that is both clinically and genetically distinct from cutaneous and uveal melanoma. As they respond poorly to available treatment regimens, novel effective therapeutic approaches for affected patients are urgently needed.
What is already known about this topic?
The rare occurrence of GNAQ/11 mutations in nonuveal melanoma has been documented.
GNAQ/11 mutant nonuveal melanomas also harbour genetic alterations in EIF1AX, SF3B1 and BAP1 that are of prognostic relevance in uveal melanoma.
What does this study add?
GNAQ/11 mutant nonuveal melanomas show metastatic spread reminiscent of cutaneous melanoma, but not uveal melanoma.
GNAQ/11 mutant nonuveal melanomas have a low tumour mutational burden that is higher than uveal melanoma, but lower than cutaneous melanoma.
What is the translational message?
Primary GNAQ/11 mutant nonuveal melanomas are a subtype of melanoma that is clinically and genetically distinct from both cutaneous and uveal melanoma.
As metastatic GNAQ/11 mutant nonuveal melanomas respond poorly to available systemic therapies, including immune checkpoint inhibition, novel therapeutic approaches for these tumours are urgently needed.
Linked Comment: Rafei‐Shamsabadi. Br J Dermatol 2020; 183:806–807.
What is already known about this topic?
The rare occurrence of GNAQ/11 mutations in nonuveal melanoma has been documented.
GNAQ/11 mutant nonuveal melanomas also harbour genetic alterations in EIF1AX, SF3B1 and BAP1 that are of prognostic relevance in uveal melanoma.
What does this study add?
GNAQ/11 mutant nonuveal melanomas show metastatic spread reminiscent of cutaneous melanoma, but not uveal melanoma.
GNAQ/11 mutant nonuveal melanomas have a low tumour mutational burden that is higher than uveal melanoma, but lower than cutaneous melanoma.
What is the translational message?
Primary GNAQ/11 mutant nonuveal melanomas are a subtype of melanoma that is clinically and genetically distinct from both cutaneous and uveal melanoma.
As metastatic GNAQ/11 mutant nonuveal melanomas respond poorly to available systemic therapies, including immune checkpoint inhibition, novel therapeutic approaches for these tumours are urgently needed.
Linked Comment: Rafei‐Shamsabadi. Br J Dermatol 2020; 183:806–807.
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