Homozygosity at variant MLH1 can lead to secondary mutation in NF1, neurofibromatosis type I and early onset leukemia

Cataloged from PDF version of article.Heterozygous germ-line variants of DNA mismatch repair (MMR) genes predispose individuals to hereditary non-polyposis colorectal cancer. Several independent reports have shown that individuals constitutionally homozygous for MMR allelic variants develop early onset hematological malignancies often associated to features of neurofibromatosis type 1 (NF1) syndrome. The genetic mechanism of NF1 associated to MMR gene deficiency is not fully known. We report here that a child with this form of NF1 displays a heterozygous NF1 gene mutation (c.3721C > T), in addition to a homozygous MLH1 gene mutation (c.676C > T) leading to a truncated MLH1 protein (p.R226X). The parents did not display NF1 features nor the NF1 mutation. This new NF1 gene mutation is recurrent and predicts a truncated neurofibromin (p.R1241X) lacking its GTPase activating function, as well as all C-terminally located functional domains. Our findings suggest that NF1 disease observed in individuals homozygous for deleterious MMR variants may be due to a concomitant NF1 gene mutation. The presence of both homozygous MLH1 and heterozygous NF1 mutation in the child studied here also provides a mechanistic explanation for early onset malignancies that are observed in affected individuals. It also provides a model for cooperation between genetic alterations in human carcinogenesis. © 2007 Elsevier B.V. All rights reserved

Characterizing the cosmological gravitational wave background: Anisotropies and non-Gaussianity

A future detection of the stochastic gravitational wave background (SGWB) with gravitational wave (GW) experiments is expected to open a new window on early universe cosmology and on the astrophysics of compact objects. In this paper we study SGWB anisotropies, that can offer new tools to discriminate between different sources of GWs. In particular, the cosmological SGWB inherits its anisotropies both (i) at its production and (ii) during its propagation through our perturbed universe. Concerning (i), we show that it typically leads to anisotropies with order one dependence on frequency. We then compute the effect of (ii) through a Boltzmann approach, including contributions of both large-scale scalar and tensor linearized perturbations. We also compute for the first time the three-point function of the SGWB energy density, which can allow one to extract information on GW non-Gaussianity with interferometers. Finally, we include nonlinear effects associated with long wavelength scalar fluctuations, and compute the squeezed limit of the 3-point function for the SGWB density contrast. Such limit satisfies a consistency relation, conceptually similar to that found in the literature for the case of cosmic microwave background perturbations

Anisotropies and non-Gaussianity of the cosmological gravitational wave background

The stochastic gravitational wave background (SGWB) is expected to be a key observable for gravitational wave (GW) interferometry. Its detection will open a new window to early Universe cosmology and to the astrophysics of compact objects. Using a Boltzmann approach, we study the angular anisotropies of the GW energy density, which is an important tool to disentangle the different cosmological and astrophysical contributions to the SGWB. Anisotropies in the cosmological background are imprinted both at its production and by GW propagation through the large-scale scalar and tensor perturbations of the Universe. The first contribution is not present in the cosmic microwave background radiation (as the Universe is not transparent to photons before recombination), causing an order 1 dependence of the anisotropies on frequency. Moreover, we provide a new method to characterize the cosmological SGWB through its possible deviation from Gaussian statistics. In particular, the SGWB will become a new probe of the primordial non-Gaussianity of the large-scale cosmological perturbations

Gravitational wave anisotropies from primordial black holes

An observable stochastic background of gravitational waves is generated whenever primordial black holes are created in the early universe thanks to a small-scale enhancement of the curvature perturbation. We calculate the anisotropies and non-Gaussianity of such stochastic gravitational waves background which receive two contributions, the first at formation time and the second due to propagation effects. The former contribution can be generated if the distribution of the curvature perturbation is characterized by a local and scale-invariant shape of non-Gaussianity. Under such an assumption, we conclude that a sizeable magnitude of anisotropy and non-Gaussianity in the gravitational waves would suggest that primordial black holes may not comply the totality of the dark matter.An observable stochastic background of gravitational waves is generated whenever primordial black holes are created in the early universe thanks to a small-scale enhancement of the curvature perturbation. We calculate the anisotropies and non-Gaussianity of such stochastic gravitational waves background which receive two contributions, the first at formation time and the second due to propagation effects. The former contribution can be generated if the distribution of the curvature perturbation is characterized by a local and scale-invariant shape of non-Gaussianity. Under such an assumption, we conclude that a sizeable magnitude of anisotropy and non-Gaussianity in the gravitational waves would suggest that primordial black holes may not comply the totality of the dark matter

Probing anisotropies of the Stochastic Gravitational Wave Background with LISA

We investigate the sensitivity of the Laser Interferometer Space Antenna (LISA) to the anisotropies of the Stochastic Gravitational Wave Background (SGWB). We first discuss the main astrophysical and cosmological sources of SGWB which are characterized by anisotropies in the GW energy density, and we build a Signal-to-Noise estimator to quantify the sensitivity of LISA to different multipoles. We then perform a Fisher matrix analysis of the prospects of detectability of anisotropic features with LISA for individual multipoles, focusing on a SGWB with a power-law frequency profile. We compute the noise angular spectrum taking into account the specific scan strategy of the LISA detector. We analyze the case of the kinematic dipole and quadrupole generated by Doppler boosting an isotropic SGWB. We find that β ΩGW ∼ 2 × 10-11 is required to observe a dipolar signal with LISA. The detector response to the quadrupole has a factor ∼ 103 β relative to that of the dipole. The characterization of the anisotropies, both from a theoretical perspective and from a map-making point of view, allows us to extract information that can be used to understand the origin of the SGWB, and to discriminate among distinct superimposed SGWB sources

Squeezed tensor non-Gaussianity in non-attractor inflation

We investigate primordial tensor non-Gaussianity in single field inflation, during a phase of non-attractor evolution when the spectrum of primordial tensor modes can be enhanced to a level detectable at interferometer scales. Making use of a tensor duality we introduced in arXiv:1808.10475, we analytically compute the full bispectrum of primordial tensor fluctuations during the non-attractor era. During this epoch the shape of the tensor bispectrum is enhanced in the squeezed limit, its amplitude can be amplified with respect to slow-roll models, and tensor non-Gaussianity can exhibit a scale dependence distinctive of our set-up. We prove that our results do not depend on the frame used for the calculations. Squeezed tensor non-Gaussianity induces a characteristic quadrupolar anisotropy on the power spectrum of the stochastic background of primordial tensor perturbations. As a step to make contact with gravitational wave experiments, we discuss the response function of a ground based Michelson interferometer to a gravitational wave background with such a feature.Comment: 34 pages, 4 figure

Quantum gravity phenomenology at the dawn of the multi-messenger era—A review

The exploration of the universe has recently entered a new era thanks to the multi-messenger paradigm, characterized by a continuous increase in the quantity and quality of experimental data that is obtained by the detection of the various cosmic messengers (photons, neutrinos, cosmic rays and gravitational waves) from numerous origins. They give us information about their sources in the universe and the properties of the intergalactic medium. Moreover, multi-messenger astronomy opens up the possibility to search for phenomenological signatures of quantum gravity. On the one hand, the most energetic events allow us to test our physical theories at energy regimes which are not directly accessible in accelerators; on the other hand, tiny effects in the propagation of very high energy particles could be amplified by cosmological distances. After decades of merely theoretical investigations, the possibility of obtaining phenomenological indications of Planck-scale effects is a revolutionary step in the quest for a quantum theory of gravity, but it requires cooperation between different communities of physicists (both theoretical and experimental). This review, prepared within the COST Action CA18108 “Quantum gravity phenomenology in the multi-messenger approach”, is aimed at promoting this cooperation by giving a state-of-the art account of the interdisciplinary expertise that is needed in the effective search of quantum gravity footprints in the production, propagation and detection of cosmic messengers.publishedVersio

EuCAPT White Paper: Opportunities and Challenges for Theoretical Astroparticle Physics in the Next Decade

Astroparticle physics is undergoing a profound transformation, due to a series of extraordinary new results, such as the discovery of high-energy cosmic neutrinos with IceCube, the direct detection of gravitational waves with LIGO and Virgo, and many others. This white paper is the result of a collaborative effort that involved hundreds of theoretical astroparticle physicists and cosmologists, under the coordination of the European Consortium for Astroparticle Theory (EuCAPT). Addressed to the whole astroparticle physics community, it explores upcoming theoretical opportunities and challenges for our field of research, with particular emphasis on the possible synergies among different subfields, and the prospects for solving the most fundamental open questions with multi-messenger observations.Comment: White paper of the European Consortium for Astroparticle Theory (EuCAPT). 135 authors, 400 endorsers, 133 pages, 1382 reference

Quantum gravity phenomenology at the dawn of the multi-messenger era -- A review

The exploration of the universe has recently entered a new era thanks to the multi-messenger paradigm, characterized by a continuous increase in the quantity and quality of experimental data that is obtained by the detection of the various cosmic messengers (photons, neutrinos, cosmic rays and gravitational waves) from numerous origins. They give us information about their sources in the universe and the properties of the intergalactic medium. Moreover, multi-messenger astronomy opens up the possibility to search for phenomenological signatures of quantum gravity. On the one hand, the most energetic events allow us to test our physical theories at energy regimes which are not directly accessible in accelerators; on the other hand, tiny effects in the propagation of very high energy particles could be amplified by cosmological distances. After decades of merely theoretical investigations, the possibility of obtaining phenomenological indications of Planck-scale effects is a revolutionary step in the quest for a quantum theory of gravity, but it requires cooperation between different communities of physicists (both theoretical and experimental). This review is aimed at promoting this cooperation by giving a state-of-the art account of the interdisciplinary expertise that is needed in the effective search of quantum gravity footprints in the production, propagation and detection of cosmic messengers

Cosmology with the Laser Interferometer Space Antenna

The Laser Interferometer Space Antenna (LISA) has two scientific objectives of cosmological focus: to probe the expansion rate of the universe, and to understand stochastic gravitational-wave backgrounds and their implications for early universe and particle physics, from the MeV to the Planck scale. However, the range of potential cosmological applications of gravitational wave observations extends well beyond these two objectives. This publication presents a summary of the state of the art in LISA cosmology, theory and methods, and identifies new opportunities to use gravitational wave observations by LISA to probe the universe