A linear mixed model approach to gene expression-tumor aneuploidy association studies.

Aneuploidy, defined as abnormal chromosome number or somatic DNA copy number, is a characteristic of many aggressive tumors and is thought to drive tumorigenesis. Gene expression-aneuploidy association studies have previously been conducted to explore cellular mechanisms associated with aneuploidy. However, in an observational setting, gene expression is influenced by many factors that can act as confounders between gene expression and aneuploidy, leading to spurious correlations between the two variables. These factors include known confounders such as sample purity or batch effect, as well as gene co-regulation which induces correlations between the expression of causal genes and non-causal genes. We use a linear mixed-effects model (LMM) to account for confounding effects of tumor purity and gene co-regulation on gene expression-aneuploidy associations. When applied to patient tumor data across diverse tumor types, we observe that the LMM both accounts for the impact of purity on aneuploidy measurements and identifies a new association between histone gene expression and aneuploidy

Black Hole Production at the Large Hadron Collider

Black hole production at the Large Hadron Collider (LHC) is an interesting consequence of TeV-scale gravity models. The predicted values, or lower limits, for the fundamental Planck scale and number of extra dimensions will depend directly on the accuracy of the black hole production cross-section. We give a range of lower limits on the fundamental Planck scale that could be obtained at LHC energies. In addition, we examine the effects of parton electric charge on black hole production using the trapped-surface approach of general relativity. Accounting for electric charge of the partons could reduce the black hole cross-section by one to four orders of magnitude at the LHC.Comment: CTP Symposium on Supersymmetry at LHC: Theoretical and Experimental Perspectives at the British University in Egypt 11-14 March 200

Microcanonical treatment of black hole decay at the Large Hadron Collider

This study of corrections to the canonical picture of black hole decay in large extra dimensions examines the effects of back-reaction corrected and microcanonical emission at the LHC. We provide statistical interpretations of the different multiparticle number densities in terms of black hole decay to standard model particles. Provided new heavy particles of mass near the fundamental Planck scale are not discovered, differences between these corrections and thermal decay will be insignificant at the LHC.Comment: small additions and clarifications, format for J. Phys.

Mitigation of off-target toxicity in CRISPR-Cas9 screens for essential non-coding elements.

Pooled CRISPR-Cas9 screens are a powerful method for functionally characterizing regulatory elements in the non-coding genome, but off-target effects in these experiments have not been systematically evaluated. Here, we investigate Cas9, dCas9, and CRISPRi/a off-target activity in screens for essential regulatory elements. The sgRNAs with the largest effects in genome-scale screens for essential CTCF loop anchors in K562 cells were not single guide RNAs (sgRNAs) that disrupted gene expression near the on-target CTCF anchor. Rather, these sgRNAs had high off-target activity that, while only weakly correlated with absolute off-target site number, could be predicted by the recently developed GuideScan specificity score. Screens conducted in parallel with CRISPRi/a, which do not induce double-stranded DNA breaks, revealed that a distinct set of off-targets also cause strong confounding fitness effects with these epigenome-editing tools. Promisingly, filtering of CRISPRi libraries using GuideScan specificity scores removed these confounded sgRNAs and enabled identification of essential regulatory elements

No-Bang Quantum State of the Cosmos

A quantum state of the entire cosmos (universe or multiverse) is proposed which is the equal mixture of the Giddings-Marolf states that are asymptotically single de Sitter spacetimes in both past and future and are regular on the throat or neck of minimal three-volume. That is, states are excluded that have a big bang or big crunch or which split into multiple asymptotic de Sitter spacetimes. (For simplicity, transitions between different values of the cosmological constant are assumed not to occur, though different positive values are allowed.) The entropy of this mixed state appears to be of the order of the three-fourths power of the Bekenstein-Hawking A/4 entropy of de Sitter spacetime. Most of the component pure states do not have rapid inflation, but when an inflaton is present and the states are weighted by the volume at the end of inflation, a much smaller number of states may dominate and give a large amount of inflation and hence may agree with observations.Comment: 18 pages, LaTeX, updated with a few new qualifications and reference

Cosmological implications of the Higgs mass measurement

We assume the validity of the Standard Model up to an arbitrary high-energy scale and discuss what information on the early stages of the Universe can be extracted from a measurement of the Higgs mass. For Mh < 130 GeV, the Higgs potential can develop an instability at large field values. From the absence of excessive thermal Higgs field fluctuations we derive a bound on the reheat temperature after inflation as a function of the Higgs and top masses. Then we discuss the interplay between the quantum Higgs fluctuations generated during the primordial stage of inflation and the cosmological perturbations, in the context of landscape scenarios in which the inflationary parameters scan. We show that, within the large-field models of inflation, it is highly improbable to obtain the observed cosmological perturbations in a Universe with a light Higgs. Moreover, independently of the inflationary model, the detection of primordial tensor perturbations through the B-mode of CMB polarization and the discovery of a light Higgs can simultaneously occur only with exponentially small probability, unless there is new physics beyond the Standard Model.Comment: 28 LaTeX pages, 6 figure

Bax Crystal Structures Reveal How BH3 Domains Activate Bax and Nucleate Its Oligomerization to Induce Apoptosis

SummaryIn stressed cells, apoptosis ensues when Bcl-2 family members Bax or Bak oligomerize and permeabilize the mitochondrial outer membrane. Certain BH3-only relatives can directly activate them to mediate this pivotal, poorly understood step. To clarify the conformational changes that induce Bax oligomerization, we determined crystal structures of BaxΔC21 treated with detergents and BH3 peptides. The peptides bound the Bax canonical surface groove but, unlike their complexes with prosurvival relatives, dissociated Bax into two domains. The structures define the sequence signature of activator BH3 domains and reveal how they can activate Bax via its groove by favoring release of its BH3 domain. Furthermore, Bax helices α2–α5 alone adopted a symmetric homodimer structure, supporting the proposal that two Bax molecules insert their BH3 domain into each other’s surface groove to nucleate oligomerization. A planar lipophilic surface on this homodimer may engage the membrane. Our results thus define critical Bax transitions toward apoptosis

Is the evidence for dark energy secure?

Several kinds of astronomical observations, interpreted in the framework of the standard Friedmann-Robertson-Walker cosmology, have indicated that our universe is dominated by a Cosmological Constant. The dimming of distant Type Ia supernovae suggests that the expansion rate is accelerating, as if driven by vacuum energy, and this has been indirectly substantiated through studies of angular anisotropies in the cosmic microwave background (CMB) and of spatial correlations in the large-scale structure (LSS) of galaxies. However there is no compelling direct evidence yet for (the dynamical effects of) dark energy. The precision CMB data can be equally well fitted without dark energy if the spectrum of primordial density fluctuations is not quite scale-free and if the Hubble constant is lower globally than its locally measured value. The LSS data can also be satisfactorily fitted if there is a small component of hot dark matter, as would be provided by neutrinos of mass 0.5 eV. Although such an Einstein-de Sitter model cannot explain the SNe Ia Hubble diagram or the position of the `baryon acoustic oscillation' peak in the autocorrelation function of galaxies, it may be possible to do so e.g. in an inhomogeneous Lemaitre-Tolman-Bondi cosmology where we are located in a void which is expanding faster than the average. Such alternatives may seem contrived but this must be weighed against our lack of any fundamental understanding of the inferred tiny energy scale of the dark energy. It may well be an artifact of an oversimplified cosmological model, rather than having physical reality.Comment: 12 pages, 5 figures; to appear in a special issue of General Relativity and Gravitation, eds. G.F.R. Ellis et al; Changes: references reformatted in journal style - text unchange

Cosmic Rays: The Second Knee and Beyond

We conduct a review of experimental results on Ultra-High Energy Cosmic Rays (UHECR's) including measurements of the features of the spectrum, the composition of the primary particle flux and the search for anisotropy in event arrival direction. We find that while there is a general consensus on the features in the spectrum -- the Second Knee, the Ankle, and (to a lesser extent) the GZK Cutoff -- there is little consensus on the composition of the primaries that accompany these features. This lack of consensus on the composition makes interpretation of the agreed upon features problematic. There is also little direct evidence about potential sources of UHECRs, as early reports of arrival direction anisotropies have not been confirmed in independent measurements.Comment: 46 pages, 30 figures. Topical Review to appear in J. Physics