JAK2V617F promotes replication fork stalling with disease-restricted impairment of the intra-S checkpoint response

Cancers result from the accumulation of genetic lesions, but the cellular consequences of driver mutations remain unclear, especially during the earliest stages of malignancy. The V617F mutation in the JAK2 non-receptor tyrosine kinase (JAK2V617F) is present as an early somatic event in most patients with myeloproliferative neoplasms (MPNs), and the study of these chronic myeloid malignancies provides an experimentally tractable approach to understanding early tumorigenesis. Introduction of exogenous JAK2V617F impairs replication fork progression and is associated with activation of the intra-S checkpoint, with both effects mediated by phosphatidylinositide 3-kinase (PI3K) signaling. Analysis of clonally derived JAK2V617F-positive erythroblasts from MPN patients also demonstrated impaired replication fork progression accompanied by increased levels of replication protein A (RPA)-containing foci. However, the associated intra-S checkpoint response was impaired in erythroblasts from polycythemia vera (PV) patients, but not in those from essential thrombocythemia (ET) patients. Moreover, inhibition of p53 in PV erythroblasts resulted in more gamma-H2Ax (γ-H2Ax)–marked double-stranded breaks compared with in like-treated ET erythroblasts, suggesting the defective intra-S checkpoint function seen in PV increases DNA damage in the context of attenuated p53 signaling. These results demonstrate oncogene-induced impairment of replication fork progression in primary cells from MPN patients, reveal unexpected disease-restricted differences in activation of the intra-S checkpoint, and have potential implications for the clonal evolution of malignancies

The curious nonexistence of Gaussian 2-designs

2-designs -- ensembles of quantum pure states whose 2nd moments equal those of the uniform Haar ensemble -- are optimal solutions for several tasks in quantum information science, especially state and process tomography. We show that Gaussian states cannot form a 2-design for the continuous-variable (quantum optical) Hilbert space L2(R). This is surprising because the affine symplectic group HWSp (the natural symmetry group of Gaussian states) is irreducible on the symmetric subspace of two copies. In finite dimensional Hilbert spaces, irreducibility guarantees that HWSp-covariant ensembles (such as mutually unbiased bases in prime dimensions) are always 2-designs. This property is violated by continuous variables, for a subtle reason: the (well-defined) HWSp-invariant ensemble of Gaussian states does not have an average state because the averaging integral does not converge. In fact, no Gaussian ensemble is even close (in a precise sense) to being a 2-design. This surprising difference between discrete and continuous quantum mechanics has important implications for optical state and process tomography.Comment: 9 pages, no pretty figures (sorry!

Noncommutative brane-world, (Anti) de Sitter vacua and extra dimensions

We investigate a curved brane-world, inspired by a noncommutative D3-brane, in a type IIB string theory. We obtain, an axially symmetric and a spherically symmetric, (anti) de Sitter black holes in 4D. The event horizons of these black holes possess a constant curvature and may be seen to be governed by different topologies. The extremal geometries are explored, using the noncommutative scaling in the theory, to reassure the attractor behavior at the black hole event horizon. The emerging two dimensional, semi-classical, black hole is analyzed to provide evidence for the extra dimensions in a curved brane-world. It is argued that the gauge nonlinearity in the theory may be redefined by a potential in a moduli space. As a result, D=11 and D=12 dimensional geometries may be obtained at the stable extrema of the potential.Comment: 17 pages, 1 figur

Epidemiologic Study of Dental Caries Experience and Between-Meal Eating Patterns

The relationship between dental caries and between-meal snacks was investigated in a study of 1,486 high school students. The participants completed a questionnaire on between-meal habits and then were given dental examinations. The lack of differences in dental caries between racial and geographic groups was not related to the frequency of sucrose-containing, between-meal snacks.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66591/2/10.1177_00220345730520022501.pd

Why Does Inflation Start at the Top of the Hill?

We show why the universe started in an unstable de Sitter state. The quantum origin of our universe implies one must take a `top down' approach to the problem of initial conditions in cosmology, in which the histories that contribute to the path integral, depend on the observable being measured. Using the no boundary proposal to specify the class of histories, we study the quantum cosmological origin of an inflationary universe in theories like trace anomaly driven inflation in which the effective potential has a local maximum. We find that an expanding universe is most likely to emerge in an unstable de Sitter state, by semiclassical tunneling via a Hawking-Moss instanton. Since the top down view is forced upon us by the quantum nature of the universe, we argue that the approach developed here should still apply when the framework of quantum cosmology will be based on M-Theory.Comment: 21 pages, 1 figur

Parametrization of Born-Infeld Type Phantom Dark Energy Model

Applying the parametrization of dark energy density, we can construct directly independent-model potentials. In Born-Infeld type phantom dark energy model, we consider four special parametrization equation of state parameter. The evolutive behavior of dark energy density with respect to red-shift $z$, potentials with respect to $\phi$ and $z$ are shown mathematically. Moreover, we investigate the effect of parameter $\eta$ upon the evolution of the constructed potential with respect to $z$. These results show that the evolutive behavior of constructed Born-Infeld type dark energy model is quite different from those of the other models.Comment: 5 pages, 4 figures, Accepted for publication in Astrophysics & Space Scienc

Noncommutative Topological Theories of Gravity

The possibility of noncommutative topological gravity arising in the same manner as Yang-Mills theory is explored. We use the Seiberg-Witten map to construct such a theory based on a SL(2,C) complex connection, from which the Euler characteristic and the signature invariant are obtained. This gives us a way towards the description of noncommutative gravitational instantons as well as noncommutative local gravitational anomalies.Comment: 17+1 pages, LaTeX, no figures, some clarifications, comments and references added, style improve

Heat kernel regularization of the effective action for stochastic reaction-diffusion equations

The presence of fluctuations and non-linear interactions can lead to scale dependence in the parameters appearing in stochastic differential equations. Stochastic dynamics can be formulated in terms of functional integrals. In this paper we apply the heat kernel method to study the short distance renormalizability of a stochastic (polynomial) reaction-diffusion equation with real additive noise. We calculate the one-loop {\emph{effective action}} and its ultraviolet scale dependent divergences. We show that for white noise a polynomial reaction-diffusion equation is one-loop {\emph{finite}} in $d=0$ and $d=1$, and is one-loop renormalizable in $d=2$ and $d=3$ space dimensions. We obtain the one-loop renormalization group equations and find they run with scale only in $d=2$.Comment: 21 pages, uses ReV-TeX 3.

Holographic Dark Energy Model and Scalar-Tensor Theories

We study the holographic dark energy model in a generalized scalar tensor theory. In a universe filled with cold dark matter and dark energy, the effect of potential of the scalar field is investigated in the equation of state parameter. We show that for a various types of potentials, the equation of state parameter is negative and transition from deceleration to acceleration expansion of the universe is possible.Comment: 11 pages, no figure. To appear in General Relativity and Gravitatio

A Rigorous Geometric Derivation of the Chiral Anomaly in Curved Backgrounds

We discuss the chiral anomaly for a Weyl field in a curved background and show that a novel index theorem for the Lorentzian Dirac operator can be applied to describe the gravitational chiral anomaly. A formula for the total charge generated by the gravitational and gauge field background is derived directly in Lorentzian signature and in a mathematically rigorous manner. It contains a term identical to the integrand in the Atiyah–Singer index theorem and another term involving the η -invariant of the Cauchy hypersurfaces