CK1ε Is Required for Breast Cancers Dependent on β-Catenin Activity

Background: Aberrant $\beta$-catenin signaling plays a key role in several cancer types, notably colon, liver and breast cancer. However approaches to modulate $\beta$-catenin activity for therapeutic purposes have proven elusive to date. Methodology: To uncover genetic dependencies in breast cancer cells that harbor active $\beta$-catenin signaling, we performed RNAi-based loss-of-function screens in breast cancer cell lines in which we had characterized $\beta$-catenin activity. Here we identify CSNK1E, the gene encoding casein kinase 1 epsilon (CK1$\varepsilon$) as required specifically for the proliferation of breast cancer cells with activated $\beta$-catenin and confirm its role as a positive regulator of $\beta$-catenin-driven transcription. Furthermore, we demonstrate that breast cancer cells that harbor activated $\beta$-catenin activity exhibit enhanced sensitivity to pharmacological blockade of Wnt/$\beta$-catenin signaling. We also find that expression of CK1$\varepsilon$ is able to promote oncogenic transformation of human cells in a $\beta$-catenin-dependent manner. Conclusions/Significance: These studies identify CK1$\varepsilon$ as a critical contributor to activated $\beta$-catenin signaling in cancer and suggest it may provide a potential therapeutic target for cancers that harbor active $\beta$-catenin. More generally, these observations delineate an approach that can be used to identify druggable synthetic lethal interactions with signaling pathways that are frequently activated in cancer but are difficult to target with the currently available small molecule inhibitors

The Leptonic Higgs as a Messenger of Dark Matter

We propose that the leptonic cosmic ray signals seen by PAMELA and ATIC result from the annihilation or decay of dark matter particles via states of a leptonic Higgs doublet to $\tau$ leptons, linking cosmic ray signals of dark matter to LHC signals of the Higgs sector. The states of the leptonic Higgs doublet are lighter than about 200 GeV, yielding large $\bar{\tau} \tau$ and $\bar{\tau} \tau \bar{\tau} \tau$ event rates at the LHC. Simple models are given for the dark matter particle and its interactions with the leptonic Higgs, for cosmic ray signals arising from both annihilations and decays in the galactic halo. For the case of annihilations, cosmic photon and neutrino signals are on the verge of discovery.Comment: 34 pages, 9 figures, minor typos corrected, references adde

LHC String Phenomenology

We argue that it is possible to address the deeper LHC Inverse Problem, to gain insight into the underlying theory from LHC signatures of new physics. We propose a technique which may allow us to distinguish among, and favor or disfavor, various classes of underlying theoretical constructions using (assumed) new physics signals at the LHC. We think that this can be done with limited data $(5-10 fb^{-1})$, and improved with more data. This is because of two reasons -- a) it is possible in many cases to reliably go from (semi)realistic microscopic string construction to the space of experimental observables, say, LHC signatures. b) The patterns of signatures at the LHC are sensitive to the structure of the underlying theoretical constructions. We illustrate our approach by analyzing two promising classes of string compactifications along with six other string-motivated constructions. Even though these constructions are not complete, they illustrate the point we want to emphasize. We think that using this technique effectively over time can eventually help us to meaningfully connect experimental data to microscopic theory.Comment: 50 Pages, 13 Figures, 3 Tables, v2: minor changes, references adde

Condensed Matter Theory of Dipolar Quantum Gases

Recent experimental breakthroughs in trapping, cooling and controlling ultracold gases of polar molecules, magnetic and Rydberg atoms have paved the way toward the investigation of highly tunable quantum systems, where anisotropic, long-range dipolar interactions play a prominent role at the many-body level. In this article we review recent theoretical studies concerning the physics of such systems. Starting from a general discussion on interaction design techniques and microscopic Hamiltonians, we provide a summary of recent work focused on many-body properties of dipolar systems, including: weakly interacting Bose gases, weakly interacting Fermi gases, multilayer systems, strongly interacting dipolar gases and dipolar gases in 1D and quasi-1D geometries. Within each of these topics, purely dipolar effects and connections with experimental realizations are emphasized.Comment: Review article; submitted 09/06/2011. 158 pages, 52 figures. This document is the unedited author's version of a Submitted Work that was subsequently accepted for publication in Chemical Reviews, copyright American Chemical Society after peer review. To access the final edited and published work, a link will be provided soo

An M Theory Solution to the Strong CP Problem and Constraints on the Axiverse

We give an explicit realization of the "String Axiverse" discussed in Arvanitaki et. al \cite{Arvanitaki:2009fg} by extending our previous results on moduli stabilization in $M$ theory to include axions. We extend the analysis of \cite{Arvanitaki:2009fg} to allow for high scale inflation that leads to a moduli dominated pre-BBN Universe. We demonstrate that an axion which solves the strong-CP problem naturally arises and that both the axion decay constants and GUT scale can consistently be around $2\times 10^{16}$ GeV with a much smaller fine tuning than is usually expected. Constraints on the Axiverse from cosmological observations, namely isocurvature perturbations and tensor modes are described. Extending work of Fox et. al \cite{Fox:2004kb}, we note that {\it the observation of tensor modes at Planck will falsify the Axiverse completely.} Finally we note that Axiverse models whose lightest axion has mass of order $10^{-15}$ eV and with decay constants of order $5\times 10^{14}$ GeV require no (anthropic) fine-tuning, though standard unification at $10^{16}$ GeV is difficult to accommodate.Comment: 16 pages, 8 figures, v2 References adde

Neutrino Masses, Baryon Asymmetry, Dark Matter and the Moduli Problem : A Complete Framework

Recent developments in string theory have led to "realistic" string compactifications which lead to moduli stabilization while generating a hierarchy between the Electroweak and Planck scales at the same time. However, this seems to suggest a rethink of our standard notions of cosmological evolution after the end of inflation and before the beginning of BBN. We argue that within classes of realistic string compactifications, there generically exists a light modulus with a mass comparable to that of the gravitino which generates a large late-time entropy when it decays. Therefore, all known mechanisms of generating the baryon asymmetry of the Universe in the literature have to take this fact into account. In this work, we find that it is still possible to naturally generate the observed baryon asymmetry of the Universe as well as light left-handed neutrino masses from a period of Affleck-Dine(AD) leptogenesis shortly after the end of inflation, in classes of realistic string constructions with a minimal extension of the MSSM below the unification scale (consisting only of right-handed neutrinos) and satisfying certain microscopic criteria described in the text. The consequences are as follows. The lightest left-handed neutrino is required to be virtually massless. The moduli (gravitino) problem can be naturally solved in this framework both within gravity and gauge mediation. The observed upper bound on the relic abundance constrains the moduli-matter and moduli-gravitino couplings since the DM is produced non-thermally within this framework. Finally, although not a definite prediction, the framework naturally allows a light right-handed neutrino and sneutrinos around the electroweak scale which could have important implications for DM as well as the LHC.Comment: 41 pages, no figures, journal version adde

Electroweak Baryogenesis and Dark Matter with an approximate R-symmetry

It is well known that R-symmetric models dramatically alleviate the SUSY flavor and CP problems. We study particular modifications of existing R-symmetric models which share the solution to the above problems, and have interesting consequences for electroweak baryogenesis and the Dark Matter (DM) content of the universe. In particular, we find that it is naturally possible to have a strongly first-order electroweak phase transition while simultaneously relaxing the tension with EDM experiments. The R-symmetry (and its small breaking) implies that the gauginos (and the neutralino LSP) are pseudo-Dirac fermions, which is relevant for both baryogenesis and DM. The singlet superpartner of the U(1)_Y pseudo-Dirac gaugino plays a prominent role in making the electroweak phase transition strongly first-order. The pseudo-Dirac nature of the LSP allows it to behave similarly to a Dirac particle during freeze-out, but like a Majorana particle for annihilation today and in scattering against nuclei, thus being consistent with current constraints. Assuming a standard cosmology, it is possible to simultaneously have a strongly first-order phase transition conducive to baryogenesis and have the LSP provide the full DM relic abundance, in part of the allowed parameter space. However, other possibilities for DM also exist, which are discussed. It is expected that upcoming direct DM searches as well as neutrino signals from DM annihilation in the Sun will be sensitive to this class of models. Interesting collider and Gravity-wave signals are also briefly discussed.Comment: 50 pages, 10 figure

ALMA CO Observations of Gamma-Ray Supernova Remnant N132D in the Large Magellanic Cloud: Possible Evidence for Shocked Molecular Clouds Illuminated by Cosmic-Ray Protons

N132D is the brightest gamma-ray supernova remnant (SNR) in the Large Magellanic Cloud (LMC). We carried out 12CO(J = 1-0, 3-2) observations toward the SNR using the Atacama Large Millimeter/submillimeter Array (ALMA) and Atacama Submillimeter Telescope Experiment. We find diffuse CO emission not only at the southern edge of the SNR as previously known, but also inside the X-ray shell. We spatially resolved nine molecular clouds using ALMA with an angular resolution of 5'', corresponding to a spatial resolution of ~1 pc at the distance of the LMC. Typical cloud sizes and masses are ~2.0 pc and ~100 M ⊙, respectively. High intensity ratios of CO J = 3-2/1-0 > 1.5 are seen toward the molecular clouds, indicating that shock heating has occurred. Spatially resolved X-ray spectroscopy reveals that thermal X-rays in the center of N132D are produced not only behind a molecular cloud but also in front of it. Considering the absence of a thermal component associated with the forward shock toward one molecular cloud located along the line of sight to the center of the remnant, this suggests that this particular cloud is engulfed by shock waves and is positioned on the near side of the remnant. If the hadronic process is the dominant contributor to the gamma-ray emission, the shock-engulfed clouds play a role as targets for cosmic rays. We estimate the total energy of cosmic-ray protons accelerated in N132D to be ~0.5-3.8 x 1049 erg as a conservative lower limit, which is similar to that observed in Galactic gamma-ray SNRs.This work is supported in part by a Shiseido Female Researcher Science Grant (A.B.). P.S. is supported by the Australian Government Research Training Program (AGRTP) Scholarship. C.L. acknowledges funding from the National Science Foundation Graduate Research Fellowship under grant DGE1745303. K.T. was supported by NAOJ ALMA Scientific Research grant No. 2016-03B. M.S. acknowledges support by the Deutsche Forschungsgemeinschaft through the Heisenberg professor grants SA 2131/5-1 and 12-1. We are also grateful to the anonymous referee for useful comments which helped the authors to improve the pape

Patterns and functional implications of rare germline variants across 12 cancer types

Large-scale cancer sequencing data enable discovery of rare germline cancer susceptibility variants. Here we systematically analyse 4,034 cases from The Cancer Genome Atlas cancer cases representing 12 cancer types. We find that the frequency of rare germline truncations in 114 cancer-susceptibility-associated genes varies widely, from 4% (acute myeloid leukaemia (AML)) to 19% (ovarian cancer), with a notably high frequency of 11% in stomach cancer. Burden testing identifies 13 cancer genes with significant enrichment of rare truncations, some associated with specific cancers (for example, RAD51C, PALB2 and MSH6 in AML, stomach and endometrial cancers, respectively). Significant, tumour-specific loss of heterozygosity occurs in nine genes (ATM, BAP1, BRCA1/2, BRIP1, FANCM, PALB2 and RAD51C/D). Moreover, our homology-directed repair assay of 68 BRCA1 rare missense variants supports the utility of allelic enrichment analysis for characterizing variants of unknown significance. The scale of this analysis and the somatic-germline integration enable the detection of rare variants that may affect individual susceptibility to tumour development, a critical step toward precision medicine

Interactive impact of ethnic distance and cultural familiarity on the perceived effects of free trade agreements

Past research on free trade agreements (FTAs) mostly uses an economic perspective to assess their impact on the level of trade and investments between nations. As a result, there is a distinct paucity of research on the perceptions of employees and managers in organizations affected by FTAs, towards the likely outcomes of those FTAs. We address this gap by using the context of recently signed China-Australia free trade agreement (ChAFTA) to develop a multidimensional scale for the perceived advantages and disadvantages of FTAs. Drawing on social identity theory and the similarly-attraction paradigm we also show direct and interactive effects of perceived ethnic distance (between home and partner country) and cultural familiarity (with the FTA partner country) on these perceived outcomes of FTAs. Our findings highlight the need to look beyond the economic perspective and consider a much broader range of perceived outcomes of FTAs