The pulsar spectral index distribution

The flux density spectra of radio pulsars are known to be steep and, to first order, described by a power-law relationship of the form S_{\nu} \propto \nu^{\alpha}, where S_{\nu} is the flux density at some frequency \nu and \alpha is the spectral index. Although measurements of \alpha have been made over the years for several hundred pulsars, a study of the intrinsic distribution of pulsar spectra has not been carried out. From the result of pulsar surveys carried out at three different radio frequencies, we use population synthesis techniques and a likelihood analysis to deduce what underlying spectral index distribution is required to replicate the results of these surveys. We find that in general the results of the surveys can be modelled by a Gaussian distribution of spectral indices with a mean of -1.4 and unit standard deviation. We also consider the impact of the so-called "Gigahertz-peaked spectrum" pulsars. The fraction of peaked spectrum sources in the population with significant turn-over at low frequencies appears to be at most 10%. We demonstrate that high-frequency (>2 GHz) surveys preferentially select flatter-spectrum pulsars and the converse is true for lower-frequency (<1 GHz) surveys. This implies that any correlations between \alpha and other pulsar parameters (for example age or magnetic field) need to carefully account for selection biases in pulsar surveys. We also expect that many known pulsars which have been detected at high frequencies will have shallow, or positive, spectral indices. The majority of pulsars do not have recorded flux density measurements over a wide frequency range, making it impossible to constrain their spectral shapes. We also suggest that such measurements would allow an improved description of any populations of pulsars with 'non-standard' spectra.Comment: 8 pages, 5 figures. Accepted by MNRA

Pulsar scintillation studies with LOFAR I. The census

Interstellar scintillation (ISS) of pulsar emission can be used both as a probe of the ionized interstellar medium (IISM) and cause corruptions in pulsar timing experiments. Of particular interest are so-called scintillation arcs which can be used to measure time-variable interstellar scattering delays directly, potentially allowing high-precision improvements to timing precision.The primary aim of this study is to carry out the first sizeable and self-consistent census of diffractive pulsar scintillation and scintillation-arc detectability at low frequencies, as a primer for larger-scale IISM studies and pulsar-timing related propagation studies with the LOw-Frequency ARray (LOFAR) High Band Antennae (HBA)

Gravitational-radiation losses from the pulsar-white-dwarf binary PSR J1141-6545

Pulsars in close binary orbit around another neutron star or a massive white dwarf make ideal laboratories for testing the predictions of gravitational radiation and self-gravitational effects. We report new timing measurements of the pulsar-white-dwarf binary PSR J1141-6545, providing strong evidence that such asymmetric systems have gravitational wave losses that are consistent with general relativity. The orbit is found to be decaying at a rate of $1.04\pm0.06$ times the general relativistic prediction and the Shapiro delay is consistent with the orbital inclination angle derived from scintillation measurements. The system provides a unique test-bed for tensor-scalar theories of gravity; our current measurements place stringent constraints in the theory space, with a limit of $\alpha_0^2 < 2.1 \times 10^{-5}$ for weakly non-linear coupling and an asymptotic limit of $\alpha_0^2 < 3.4 \times 10^{-6}$ for strongly non-linear coupling, where $\alpha_0$ is the linear coupling strength of matter to an underlying scalar field. This asymptotic limit is nearly three times smaller than the Cassini bound ($\alpha_0^2 \approx 10^{-5}$).Comment: 4 pages, 2 figures, To Appear in Physical Review

Periodic interstellar scintillation variations of PSRs~J0613−-0200 and J0636+5128 associated with the Local Bubble shell

Annual variations of interstellar scintillation can be modelled to constrain parameters of the ionized interstellar medium. If a pulsar is in a binary system, then investigating the orbital parameters is possible through analysis of the orbital variation of scintillation. In observations carried out from 2011 January to 2020 August by the European Pulsar Timing Array radio telescopes, PSRs~J0613$-$0200 and J0636+5128 show strong annual variations in their scintillation velocity, while the former additionally exhibits an orbital fluctuation. Bayesian theory and Markov-chain-Monte-Carlo methods are used to interpret these periodic variations. We assume a thin and anisotropic scattering screen model, and discuss the mildly and extremely anisotropic scattering cases. PSR~J0613$-$0200 is best described by mildly anisotropic scattering, while PSR~J0636+5128 exhibits extremely anisotropic scattering. We measure the distance, velocity and degree of anisotropy of the scattering screen for our two pulsars, finding that scattering screen distances from Earth for PSRs~J0613$-$0200 and J0636+5128 are 316$^{+28}_{-20}$\,pc and 262$^{+96}_{-38}$\,pc, respectively. The positions of these scattering screens are coincident with the shell of the Local Bubble towards both pulsars. These associations add to the growing evidence of the Local Bubble shell as a dominant region of scattering along many sightlines.Comment: Accepted by SCIENCE CHINA Physics, Mechanics & Astronomy ( SCPMA

The relativistic pulsar-white dwarf binary PSR J1738+0333 II. The most stringent test of scalar-tensor gravity

(abridged) We report the results of a 10-year timing campaign on PSR J1738+0333, a 5.85-ms pulsar in a low-eccentricity 8.5-hour orbit with a low-mass white dwarf companion (...) The measurements of proper motion and parallax allow for a precise subtraction of the kinematic contribution to the observed orbital decay; this results in a significant measurement of the intrinsic orbital decay: (-25.9 +/- 3.2) \times 10^{-15} s/s. This is consistent with the orbital decay from the emission of gravitational waves predicted by general relativity, (-27.7 +1.5/-1.9) \times 10^{-15} s/s (...). This agreement introduces a tight upper limit on dipolar gravitational wave emission, a prediction of most alternative theories of gravity for asymmetric binary systems such as this. We use this limit to derive the most stringent constraints ever on a wide class of gravity theories, where gravity involves a scalar field contribution. When considering general scalar-tensor theories of gravity, our new bounds are more stringent than the best current solar-system limits over most of the parameter space, and constrain the matter-scalar coupling constant {\alpha}_0^2 to be below the 10^{-5} level. For the special case of the Jordan-Fierz-Brans-Dicke, we obtain the one-sigma bound {\alpha}_0^2 < 2 \times 10^{-5}, which is within a factor two of the Cassini limit. We also use our limit on dipolar gravitational wave emission to constrain a wide class of theories of gravity which are based on a generalization of Bekenstein's Tensor-Vector-Scalar gravity (TeVeS), a relativistic formulation of Modified Newtonian Dynamics (MOND).Comment: Accepted for publication in MNRAS. 18 pages in emulate MNRAS format, 9 figures and 1 tabl

Occupational exposure to gases/fumes and mineral dust affect DNA methylation levels of genes regulating expression

Many workers are daily exposed to occupational agents like gases/fumes, mineral dust or biological dust, which could induce adverse health effects. Epigenetic mechanisms, such as DNA methylation, have been suggested to play a role. We therefore aimed to identify differentially methylated regions (DMRs) upon occupational exposures in never-smokers and investigated if these DMRs associated with gene expression levels. To determine the effects of occupational exposures independent of smoking, 903 never-smokers of the LifeLines cohort study were included. We performed three genome-wide methylation analyses (Illumina 450 K), one per occupational exposure being gases/fumes, mineral dust and biological dust, using robust linear regression adjusted for appropriate confounders. DMRs were identified using comb-p in Python. Results were validated in the Rotterdam Study (233 never-smokers) and methylation-expression associations were assessed using Biobank-based Integrative Omics Study data (n = 2802). Of the total 21 significant DMRs, 14 DMRs were associated with gases/fumes and 7 with mineral dust. Three of these DMRs were associated with both exposures (RPLP1 and LINC02169 (2x)) and 11 DMRs were located within transcript start sites of gene expression regulating genes. We replicated two DMRs with gases/fumes (VTRNA2-1 and GNAS) and one with mineral dust (CCDC144NL). In addition, nine gases/fumes DMRs and six mineral dust DMRs significantly associated with gene expression levels. Our data suggest that occupational exposures may induce differential methylation of gene expression regulating genes and thereby may induce adverse health effects. Given the millions of workers that are exposed daily to occupational exposures, further studies on this epigenetic mechanism and health outcomes are warranted

Controlling bias and inflation in epigenome- and transcriptome-wide association studies using the empirical null distribution

We show that epigenome- and transcriptome-wide association studies (EWAS and TWAS) are prone to significant inflation and bias of test statistics, an unrecognized phenomenon introducing spurious findings if left unaddressed. Neither GWAS-based methodology nor state-of-the-art confounder adjustment methods completely remove bias and inflation. We propose a Bayesian method to control bias and inflation in EWAS and TWAS based on estimation of the empirical null distribution. Using simulations and real data, we demonstrate that our method maximizes power while properly controlling the false positive rate. We illustrate the utility of our method in large-scale EWAS and TWAS meta-analyses of age and smoking

Mendelian randomization integrating GWAS and eQTL data reveals genetic determinants of complex and clinical traits

Genome-wide association studies (GWAS) have identified thousands of variants associated with complex traits, but their biological interpretation often remains unclear. Most of these variants overlap with expression QTLs, indicating their potential involvement in regulation of gene expression. Here, we propose a transcriptome-wide summary statistics-based Mendelian Randomization approach (TWMR) that uses multiple SNPs as instruments and multiple gene expression traits as exposures, simultaneously. Applied to 43 human phenotypes, it uncovers 3,913 putatively causal gene-trait associations, 36% of which have no genome-wide significant SNP nearby in previous GWAS. Using independent association summary statistics, we find that the majority of these loci were missed by GWAS due to power issues. Noteworthy among these links is educational attainment-associated BSCL2, known to carry mutations leading to a Mendelian form of encephalopathy. We also find pleiotropic causal effects suggestive of mechanistic connections. TWMR better accounts for pleiotropy and has the potential to identify biological mechanisms underlying complex traits

Refining Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorder Genetic Loci by Integrating Summary Data From Genome-wide Association, Gene Expression, and DNA Methylation Studies

Background: Recent genome-wide association studies (GWASs) identified the first genetic loci associated with attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). The next step is to use these results to increase our understanding of the biological mechanisms involved. Most of the identified variants likely influence gene regulation. The aim of the current study is to shed light on the mechanisms underlying the genetic signals and prioritize genes by integrating GWAS results with gene expression and DNA methylation (DNAm) levels. Methods: We applied summary-data–based Mendelian randomization to integrate ADHD and ASD GWAS data with fetal brain expression and methylation quantitative trait loci, given the early onset of these disorders. We also analyzed expression and methylation quantitative trait loci datasets of adult brain and blood, as these provide increased statistical power. We subsequently used summary-data–based Mendelian randomization to investigate if the same variant influences both DNAm and gene expression levels. Results: We identified multiple gene expression and DNAm levels in fetal brain at chromosomes 1 and 17 that were associated with ADHD and ASD, respectively, through pleiotropy at shared genetic variants. The analyses in brain and blood showed additional associated gene expression and DNAm levels at the same and additional loci, likely because of increased statistical power. Several of the associated genes have not been identified in ADHD and ASD GWASs before. Conclusions: Our findings identified the genetic variants associated with ADHD and ASD that likely act through gene regulation. This facilitates prioritization of candidate genes for functional follow-up studies

DNA methylation signatures of aggression and closely related constructs : A meta-analysis of epigenome-wide studies across the lifespan

DNA methylation profiles of aggressive behavior may capture lifetime cumulative effects of genetic, stochastic, and environmental influences associated with aggression. Here, we report the first large meta-analysis of epigenome-wide association studies (EWAS) of aggressive behavior (N = 15,324 participants). In peripheral blood samples of 14,434 participants from 18 cohorts with mean ages ranging from 7 to 68 years, 13 methylation sites were significantly associated with aggression (alpha = 1.2 x 10(-7); Bonferroni correction). In cord blood samples of 2425 children from five cohorts with aggression assessed at mean ages ranging from 4 to 7 years, 83% of these sites showed the same direction of association with childhood aggression (r = 0.74, p = 0.006) but no epigenome-wide significant sites were found. Top-sites (48 at a false discovery rate of 5% in the peripheral blood meta-analysis or in a combined meta-analysis of peripheral blood and cord blood) have been associated with chemical exposures, smoking, cognition, metabolic traits, and genetic variation (mQTLs). Three genes whose expression levels were associated with top-sites were previously linked to schizophrenia and general risk tolerance. At six CpGs, DNA methylation variation in blood mirrors variation in the brain. On average 44% (range = 3-82%) of the aggression-methylation association was explained by current and former smoking and BMI. These findings point at loci that are sensitive to chemical exposures with potential implications for neuronal functions. We hope these results to be a starting point for studies leading to applications as peripheral biomarkers and to reveal causal relationships with aggression and related traits.Peer reviewe