AKT1/BRCA1 in the control of homologous recombination and genetic stability: the missing link between hereditary and sporadic breast cancers

Endogenous replicative stress could be one trigger leading to tumor initiation: indeed, activation of the DNA damage response (DDR), considered the result of replicative stress, is observed in pre-cancerous cells; moreover, in hereditary breast cancers, almost all of the genes affected relate to the DDR. The most frequently mutated gene in hereditary breast cancers, BRCA1, is essential for homologous recombination (HR), a fundamental process for maintaining genome stability that permits the reactivation of blocked replication forks. Recent studies have established links between DDR and the oncogenic kinase AKT1, which is upregulated in about 50% of sporadic breast cancers. More specifically, the activation of AKT1 shows a deficient phenotype in BRCA1 and HR, revealing molecular similarities between hereditary and sporadic breast cancers. However, these results reveal a paradox regarding the physiological role of AKT1: in non-tumor cells, AKT1 promotes cellular proliferation, but consequently endangers genome integrity during replication if HR is inhibited. Since HR could itself lead to genetic instability, we propose that, under physiological conditions, moderate activation of AKT1 does not inhibit but prevents an excess of HR. The regulation of AKT1 would represent a fine transitory system for controlling HR and maintaining genomic integrity

The DNA polymerase λ is required for the repair of non-compatible DNA double strand breaks by NHEJ in mammalian cells

DNA polymerase lambda (polλ) is a recently identified DNA polymerase whose cellular function remains elusive. Here we show, that polλ participates at the molecular level in a chromosomal context, in the repair of DNA double strand breaks (DSB) via non-homologous end joining (NHEJ) in mammalian cells. The expression of a catalytically inactive form of polλ (polλDN) decreases the frequency of NHEJ events in response to I-Sce-I-induced DSB whereas inactivated forms of its homologues polβ and polμ do not. Only events requiring DNA end processing before ligation are affected; this defect is associated with large deletions arising in the vicinity of the induced DSB. Furthermore, polλDN-expressing cells exhibit increased sensitization and genomic instability in response to ionizing radiation similar to that of NHEJ-defective cells. Our data support a requirement for polλ in repairing a subset of DSB in genomic DNA, thereby contributing to the maintenance of genetic stability mediated by the NHEJ pathway

Constrained caloric curves and phase transition for hot nuclei

Simulations based on experimental data obtained from multifragmenting quasi-fused nuclei produced in central $^{129}$Xe + $^{nat}$Sn collisions have been used to deduce event by event freeze-out properties in the thermal excitation energy range 4-12 AMeV [Nucl. Phys. A809 (2008) 111]. From these properties and the temperatures deduced from proton transverse momentum fluctuations, constrained caloric curves have been built. At constant average volumes caloric curves exhibit a monotonic behaviour whereas for constrained pressures a backbending is observed. Such results support the existence of a first order phase transition for hot nuclei.Comment: 14 pages, 5 figures, accepted in Physics Letters

Black Hole Spectroscopy: Testing General Relativity through Gravitational Wave Observations

Assuming that general relativity is the correct theory of gravity in the strong field limit, can gravitational wave observations distinguish between black hole and other compact object sources? Alternatively, can gravitational wave observations provide a test of one of the fundamental predictions of general relativity? Here we describe a definitive test of the hypothesis that observations of damped, sinusoidal gravitational waves originated from a black hole or, alternatively, that nature respects the general relativistic no-hair theorem. For astrophysical black holes, which have a negligible charge-to-mass ratio, the black hole quasi-normal mode spectrum is characterized entirely by the black hole mass and angular momentum and is unique to black holes. In a different theory of gravity, or if the observed radiation arises from a different source (e.g., a neutron star, strange matter or boson star), the spectrum will be inconsistent with that predicted for general relativistic black holes. We give a statistical characterization of the consistency between the noisy observation and the theoretical predictions of general relativity, together with a numerical example.Comment: 19 pages, 7 figure

String Consistency for Unified Model Building

We explore the use of real fermionization as a test case for understanding how specific features of phenomenological interest in the low-energy effective superpotential are realized in exact solutions to heterotic superstring theory. We present pedagogic examples of models which realize SO(10) as a level two current algebra on the world-sheet, and discuss in general how higher level current algebras can be realized in the tensor product of simple constituent conformal field theories. We describe formal developments necessary to compute couplings in models built using real fermionization. This allows us to isolate cases of spin structures where the standard prescription for real fermionization may break down.Comment: harvmac (available from xxx.lanl.gov), 30 pages (reduced format), if you are using harvmac for the first time, make sure to adjust the "site dependent options" at the beginning of the harvmac file. Shortened introduction and added table 3, listing the complete massless spectrum with U(1) charges of Model A. Version to appear in journa

Physics and Mathematics of Calogero particles

We give a review of the mathematical and physical properties of the celebrated family of Calogero-like models and related spin chains.Comment: Version to appear in Special Issue of Journal of Physics A: Mathematical and Genera

ABA Criminal Justice Section Task Force on College Due Process Rights and Victim Protections: Recommendations for Colleges and Universities in Resolving Allegations of Campus Sexual Misconduct

The Executive Committee of the ABA Criminal Justice Section commissioned the Task Force on College Due Process Rights and Victim Protections in November 2016. Immediately after, extensive efforts were made to find members that represented all interested parties: victims, the accused, universities, other stakeholders, and national experts. The Task Force was fully constituted in the winter of 2017, and it ended up including two voting members who were originally liaisons from the ABA Commission on Domestic and Sexual Violence and the ABA Section of Civil Rights and Social Justice. This elevation was made in recognition of their significant contributions

Revisiting Scalar and Pseudoscalar Couplings with Nucleons

Certain dark matter interactions with nuclei are mediated possibly by a scalar or pseudoscalar Higgs boson. The estimation of the corresponding cross sections requires a correct evaluation of the couplings between the scalar or pseudoscalar Higgs boson and the nucleons. Progress has been made in two aspects relevant to this study in the past few years. First, recent lattice calculations show that the strange-quark sigma term $\sigma_s$ and the strange-quark content in the nucleon are much smaller than what are expected previously. Second, lattice and model analyses imply sizable SU(3) breaking effects in the determination on the axial-vector coupling constant $g_A^8$ that in turn affect the extraction of the isosinglet coupling $g_A^0$ and the strange quark spin component $\Delta s$ from polarized deep inelastic scattering experiments. Based on these new developments, we re-evaluate the relevant nucleon matrix elements and compute the scalar and pseudoscalar couplings of the proton and neutron. We also find that the strange quark contribution in both types of couplings is smaller than previously thought.Comment: 17 pages, Sec. II is revised and the pion-nucleon sigma term extracted from the scattering data is discussed. Version to appear in JHE

COrE (Cosmic Origins Explorer) A White Paper

COrE (Cosmic Origins Explorer) is a fourth-generation full-sky, microwave-band satellite recently proposed to ESA within Cosmic Vision 2015-2025. COrE will provide maps of the microwave sky in polarization and temperature in 15 frequency bands, ranging from 45 GHz to 795 GHz, with an angular resolution ranging from 23 arcmin (45 GHz) and 1.3 arcmin (795 GHz) and sensitivities roughly 10 to 30 times better than PLANCK (depending on the frequency channel). The COrE mission will lead to breakthrough science in a wide range of areas, ranging from primordial cosmology to galactic and extragalactic science. COrE is designed to detect the primordial gravitational waves generated during the epoch of cosmic inflation at more than $3\sigma$ for $r=(T/S)>=10^{-3}$. It will also measure the CMB gravitational lensing deflection power spectrum to the cosmic variance limit on all linear scales, allowing us to probe absolute neutrino masses better than laboratory experiments and down to plausible values suggested by the neutrino oscillation data. COrE will also search for primordial non-Gaussianity with significant improvements over Planck in its ability to constrain the shape (and amplitude) of non-Gaussianity. In the areas of galactic and extragalactic science, in its highest frequency channels COrE will provide maps of the galactic polarized dust emission allowing us to map the galactic magnetic field in areas of diffuse emission not otherwise accessible to probe the initial conditions for star formation. COrE will also map the galactic synchrotron emission thirty times better than PLANCK. This White Paper reviews the COrE science program, our simulations on foreground subtraction, and the proposed instrumental configuration.Comment: 90 pages Latex 15 figures (revised 28 April 2011, references added, minor errors corrected