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

QFT, String Temperature and the String Phase of De Sitter Space-time

The density of mass levels \rho(m) and the critical temperature for strings in de Sitter space-time are found. QFT and string theory in de Sitter space are compared. A `Dual'-transform is introduced which relates classical to quantum string lengths, and more generally, QFT and string domains. Interestingly, the string temperature in De Sitter space turns out to be the Dual transform of the QFT-Hawking-Gibbons temperature. The back reaction problem for strings in de Sitter space is addressed selfconsistently in the framework of the `string analogue' model (or thermodynamical approach), which is well suited to combine QFT and string study.We find de Sitter space-time is a self-consistent solution of the semiclassical Einstein equations in this framework. Two branches for the scalar curvature R(\pm) show up: a classical, low curvature solution (-), and a quantum high curvature solution (+), enterely sustained by the strings. There is a maximal value for the curvature R_{\max} due to the string back reaction. Interestingly, our Dual relation manifests itself in the back reaction solutions: the (-) branch is a classical phase for the geometry with intrinsic temperature given by the QFT-Hawking-Gibbons temperature.The (+) is a stringy phase for the geometry with temperature given by the intrinsic string de Sitter temperature. 2 + 1 dimensions are considered, but conclusions hold generically in D dimensions.Comment: LaTex, 24 pages, no figure

Finite-temperature scalar fields and the cosmological constant in an Einstein universe

We study the back reaction effect of massless minimally coupled scalar field at finite temperatures in the background of Einstein universe. Substituting for the vacuum expectation value of the components of the energy-momentum tensor on the RHS of the Einstein equation, we deduce a relationship between the radius of the universe and its temperature. This relationship exhibit a maximum temperature, below the Planck scale, at which the system changes its behaviour drastically. The results are compared with the case of a conformally coupled field. An investigation into the values of the cosmological constant exhibit a remarkable difference between the conformally coupled case and the minimally coupled one.Comment: 7 pages, 2 figure

Supersymmetry and Stationary Solutions in Dilaton-Axion Gravity

New stationary solutions of $4$-dimensional dilaton-axion gravity are presented, which correspond to the charged Taub-NUT and Israel-Wilson-Perjes (IWP) solutions of Einstein-Maxwell theory. The charged axion-dilaton Taub-NUT solutions are shown to have a number of interesting properties: i) manifest $SL(2,R)$ symmetry, ii) an infinite throat in an extremal limit, iii) the throat limit coincides with an exact CFT construction. The IWP solutions are shown to admit supersymmetric Killing spinors, when embedded in $d=4,N=4$ supergravity. This poses a problem for the interpretation of supersymmetric rotating solutions as physical ground states. In the context of $10$-dimensional geometry, we show that dimensionally lifted versions of the IWP solutions are dual to certain gravitational waves in string theory.Comment: 23 pages (latex), SU-ITP-94-12, UMHEP-407, QMW-PH-94-1

On "Non-Geometric" Contribution To The Entropy Of Black Hole Due To Quantum Corrections

The quantum corrections to the entropy of charged black holes are calculated. The Reissner-Nordstrem and dilaton black holes are considered. The appearance of logarithmically divergent terms not proportional to the horizon area is demonstrated. It is shown that the complete entropy which is sum of classical Bekenstein-Hawking entropy and the quantum correction is proportional to the area of quantum-corrected horizon.Comment: Latex, 9 page

One-loop Quantum Corrections to the Entropy for an Extremal Reissner-Nordstr\"om Black Hole

The first quantum corrections to the entropy for an eternal 4-dimensional extremal Reissner-Nordstr\"om black hole is investigated at one-loop level, in the large mass limit of the black hole, making use of the conformal techniques related to the optical metric. A leading cubic horizon divergence is found and other divergences appear due to the singular nature of the optical manifold. The area law is shown to be violated.Comment: 10 pages, LaTe

Thermal partition function of photons and gravitons in a Rindler wedge

The thermal partition function of photons in any covariant gauge and gravitons in the harmonic gauge, propagating in a Rindler wedge, are computed using a local $\zeta$-function regularization approach. The correct Planckian leading order temperature dependence $T^4$ is obtained in both cases. For the photons, the existence of a surface term giving a negative contribution to the entropy is confirmed, as earlier obtained by Kabat, but this term is shown to be gauge dependent in the four-dimensional case and, therefore is discarded. It is argued that similar terms could appear dealing with any integer spin $s\geq 1$ in the massless case and in more general manifolds. Our conjecture is checked in the case of a graviton in the harmonic gauge, where different surface terms also appear, and physically consistent results arise dropping these terms. The results are discussed in relation to the quantum corrections to the black hole entropy.Comment: 29 pages, RevTeX, no figures. Minor errors corrected and a few comments changed since first submission. To be published on Phys.Rev.

A toy model for quantum mechanics

The toy model used by Spekkens [R. Spekkens, Phys. Rev. A 75, 032110 (2007)] to argue in favor of an epistemic view of quantum mechanics is extended by generalizing his definition of pure states (i.e. states of maximal knowledge) and by associating measurements with all pure states. The new toy model does not allow signaling but, in contrast to the Spekkens model, does violate Bell-CHSH inequalities. Negative probabilities are found to arise naturally within the model, and can be used to explain the Bell-CHSH inequality violations.Comment: in which the author breaks his vow to never use the words "ontic" and "epistemic" in publi

Cosmological Surrealism: More than ``Eternal Reality" is Needed

Inflationary Cosmology makes the universe ``eternal" and provides for recurrent universe creation, ad infinitum -- making it also plausible to assume that ``our" Big Bang was also preceeded by others, etc.. However, GR tells us that in the ``parent" universe's reference frame, the newborn universe's expansion will never start. Our picture of ``reality" in spacetime has to be enlarged.Comment: 7 pages, TAUP N23