BMI1 and KAP1 interaction and function: BMI1 capped by KAP1?

The Polycomb-repressive complex 1 (PRC1) protein BMI1 is of major importance in the epigenetic regulation of gene expression. The repression of important tumour suppressor genes (such a P16INK4a and P14ARF) by means of chromatin remodeling has marked BMI1 as a proto-oncoprotein. We previously found evidence that posttranslational modification by phosphorylation may be implicated in the stability and functioning of BMI1. Furthermore, we found that KAP1, through direct interaction with BMI1, may be implicated in regulation of BMI1 functioning. I here begin to elucidate how phosphorylation affects BMI1 and how KAP1 regulates BMI1. Several U2OS or TIG3ER cell lines were created that overexpressed BMI1 wild type and mutants that either contain phospho-mimic or phospho-null mutations. shRNA’s were used to effectively knockdown KAP1 expression. The effect of BMI1 mutant overexpression and/or KAP1 knock down on proliferation was measured under cell stress conditions induced by arsenite, selenite or etoposide. The effect of KAP1 knock down and mutant KAP1 lacking the RingFinger domain (KAP1-DeltaRF) on sub-cellular localization was assessed in U2OS cells. Finally functional interaction between KAP1 and PRC1 was measured by analysis of transcriptional induction of the PRC1-target gene ATF3 upon mitogenic stimulation. BMI1 overexpression partially rescues arsenite induced senescence; this rescue activity is affected by its phosphorylation status. KAP1 knockdown increases the effect of BMI1 overexpression on proliferation under arsenite induced cell stress but ablates the differences observed between different BMI1 phospho-mutants. KAP1 induced increases of ATF3 induction point towards a functional interaction between KAP1 and PRC1. My experiments provide experimental indication that BMI1 affects proliferation under arsenite induced cell stress condition. This effect was enhanced by KAP1 knockdown suggesting that KAP1 inhibits the pro-proliferative effects of BMI1. Increased ATF3 induction in the presence of KAP1-DeltaRF mutant protein suggests that the KAP1 negatively controls expression of ATF3 in a RF-dependent manner. Further research is required to elucidate the exact molecular mechanisms underlying the function interaction of BMI1 and KAP1.

Efficient Gravitational Wave Searches with Pulsar Timing Arrays using Hamiltonian Monte Carlo

Pulsar timing arrays (PTAs) detect low-frequency gravitational waves (GWs) by looking for correlated deviations in pulse arrival times. Current Bayesian searches use Markov Chain Monte Carlo (MCMC) methods, which struggle to sample the large number of parameters needed to model the PTA and GW signals. As the data span and number of pulsars increase, this problem will only worsen. An alternative Monte Carlo sampling method, Hamiltonian Monte Carlo (HMC), utilizes Hamiltonian dynamics to produce sample proposals informed by first-order gradients of the model likelihood. This in turn allows it to converge faster to high dimensional distributions. We implement HMC as an alternative sampling method in our search for an isotropic stochastic GW background, and show that this method produces equivalent statistical results to similar analyses run with standard MCMC techniques, while requiring 100-200 times fewer samples. We show that the speed of HMC sample generation scales as $\mathcal{O}(N_\mathrm{psr}^{5/4})$ where $N_\mathrm{psr}$ is the number of pulsars, compared to $\mathcal{O}(N_\mathrm{psr}^2)$ for MCMC methods. These factors offset the increased time required to generate a sample using HMC, demonstrating the value of adopting HMC techniques for PTAs.Comment: 9 pages, 5 figures, submitted to Physical Review

Are we there yet? Time to detection of nanohertz gravitational waves based on pulsar-timing array limits

Decade-long timing observations of arrays of millisecond pulsars have placed highly constraining upper limits on the amplitude of the nanohertz gravitational-wave stochastic signal from the mergers of supermassive black hole binaries (~10^(−15) strain at f = 1 yr^(−1)). These limits suggest that binary merger rates have been overestimated, or that environmental influences from nuclear gas or stars accelerate orbital decay, reducing the gravitational-wave signal at the lowest, most sensitive frequencies. This prompts the question whether nanohertz gravitational waves (GWs) are likely to be detected in the near future. In this Letter, we answer this question quantitatively using simple statistical estimates, deriving the range of true signal amplitudes that are compatible with current upper limits, and computing expected detection probabilities as a function of observation time. We conclude that small arrays consisting of the pulsars with the least timing noise, which yield the tightest upper limits, have discouraging prospects of making a detection in the next two decades. By contrast, we find large arrays are crucial to detection because the quadrupolar spatial correlations induced by GWs can be well sampled by many pulsar pairs. Indeed, timing programs that monitor a large and expanding set of pulsars have an ~80% probability of detecting GWs within the next 10 years, under assumptions on merger rates and environmental influences ranging from optimistic to conservative. Even in the extreme case where 90% of binaries stall before merger and environmental coupling effects diminish low-frequency gravitational-wave power, detection is delayed by at most a few years

Model-based asymptotically optimal dispersion measure correction for pulsar timing

In order to reach the sensitivity required to detect gravitational waves, pulsar timing array experiments need to mitigate as much noise as possible in timing data. A dominant amount of noise is likely due to variations in the dispersion measure. To correct for such variations, we develop a statistical method inspired by the maximum likelihood estimator and optimal filtering. Our method consists of two major steps. First, the spectral index and amplitude of dispersion measure variations are measured via a time-domain spectral analysis. Second, the linear optimal filter is constructed based on the model parameters found in the first step, and is used to extract the dispersion measure variation waveforms. Compared to current existing methods, this method has better time resolution for the study of short timescale dispersion variations, and generally produces smaller errors in waveform estimations. This method can process irregularly sampled data without any interpolation because of its time-domain nature. Furthermore, it offers the possibility to interpolate or extrapolate the waveform estimation to regions where no data is available. Examples using simulated data sets are included for demonstration.Comment: 15 pages, 15 figures, submitted 15th Sept. 2013, accepted 2nd April 2014 by MNRAS. MNRAS, 201

Phase-coherent mapping of gravitational-wave backgrounds using ground-based laser interferometers

We extend the formalisms developed in Gair et al. and Cornish and van Haasteren to create maps of gravitational-wave backgrounds using a network of ground-based laser interferometers. We show that in contrast to pulsar timing arrays, which are insensitive to half of the gravitational-wave sky (the curl modes), a network of ground-based interferometers is sensitive to both the gradient and curl components of the background. The spatial separation of a network of interferometers, or of a single interferometer at different times during its rotational and orbital motion around the Sun, allows for recovery of both components. We derive expressions for the response functions of a laser interferometer in the small-antenna limit, and use these expressions to calculate the overlap reduction function for a pair of interferometers. We also construct maximum-likelihood estimates of the + and x-polarization modes of the gravitational-wave sky in terms of the response matrix for a network of ground-based interferometers, evaluated at discrete times during Earth's rotational and orbital motion around the Sun. We demonstrate the feasibility of this approach for some simple simulated backgrounds (a single point source and spatially-extended distributions having only grad or curl components), calculating maximum-likelihood sky maps and uncertainty maps based on the (pseudo)inverse of the response matrix. The distinction between this approach and standard methods for mapping gravitational-wave power is also discussed.Comment: 22 pages, 11 figure

On detection of the stochastic gravitational-wave background using the Parkes pulsar timing array

We search for the signature of an isotropic stochastic gravitational-wave background in pulsar timing observations using a frequency-domain correlation technique. These observations, which span roughly 12 yr, were obtained with the 64-m Parkes radio telescope augmented by public domain observations from the Arecibo Observatory. A wide range of signal processing issues unique to pulsar timing and not previously presented in the literature are discussed. These include the effects of quadratic removal, irregular sampling, and variable errors which exacerbate the spectral leakage inherent in estimating the steep red spectrum of the gravitational-wave background. These observations are found to be consistent with the null hypothesis, that no gravitational-wave background is present, with 76 percent confidence. We show that the detection statistic is dominated by the contributions of only a few pulsars because of the inhomogeneity of this data set. The issues of detecting the signature of a gravitational-wave background with future observations are discussed.Comment: 12 pages, 8 figures, 7 tables, accepted for publication in MNRA

Placing limits on the stochastic gravitational-wave background using European Pulsar Timing Array data

Direct detection of low-frequency gravitational waves ($10^{-9} - 10^{-8}$ Hz) is the main goal of pulsar timing array (PTA) projects. One of the main targets for the PTAs is to measure the stochastic background of gravitational waves (GWB) whose characteristic strain is expected to approximately follow a power-law of the form $h_c(f)=A (f/\hbox{yr}^{-1})^{\alpha}$, where $f$ is the gravitational-wave frequency. In this paper we use the current data from the European PTA to determine an upper limit on the GWB amplitude $A$ as a function of the unknown spectral slope $\alpha$ with a Bayesian algorithm, by modelling the GWB as a random Gaussian process. For the case $\alpha=-2/3$, which is expected if the GWB is produced by supermassive black-hole binaries, we obtain a 95% confidence upper limit on $A$ of $6\times 10^{-15}$, which is 1.8 times lower than the 95% confidence GWB limit obtained by the Parkes PTA in 2006. Our approach to the data analysis incorporates the multi-telescope nature of the European PTA and thus can serve as a useful template for future intercontinental PTA collaborations.Comment: 14 pages, 8 figures, 3 tables, mnras accepte

The effects of LIGO detector noise on a 15-dimensional Markov-chain Monte-Carlo analysis of gravitational-wave signals

Gravitational-wave signals from inspirals of binary compact objects (black holes and neutron stars) are primary targets of the ongoing searches by ground-based gravitational-wave (GW) interferometers (LIGO, Virgo, and GEO-600). We present parameter-estimation results from our Markov-chain Monte-Carlo code SPINspiral on signals from binaries with precessing spins. Two data sets are created by injecting simulated GW signals into either synthetic Gaussian noise or into LIGO detector data. We compute the 15-dimensional probability-density functions (PDFs) for both data sets, as well as for a data set containing LIGO data with a known, loud artefact ("glitch"). We show that the analysis of the signal in detector noise yields accuracies similar to those obtained using simulated Gaussian noise. We also find that while the Markov chains from the glitch do not converge, the PDFs would look consistent with a GW signal present in the data. While our parameter-estimation results are encouraging, further investigations into how to differentiate an actual GW signal from noise are necessary.Comment: 11 pages, 2 figures, NRDA09 proceeding

Evading the pulsar constraints on the cosmic string tension in supergravity inflation

The cosmic string is a useful probe of the early Universe and may give us a clue to physics at high energy scales where any artificial particle accelerators cannot reach. Although one of the most promising tools is the cosmic microwave background, the constraint from gravitational waves is becoming so stringent that one may not hope to detect its signatures in the cosmic microwave background. In this paper, we construct a scenario that contains cosmic strings observable in the cosmic microwave background while evading the constraint imposed by the recent pulsar timing data. We argue that cosmic strings with relatively large tension are allowed by delaying the onset of the scaling regime. We also show that this scenario is naturally realized in the context of chaotic inflation in supergravity, where the phase transition is governed by the Hubble induced mass.Comment: 24pages, 3 figures, published in JCA