Mutations in pericentrin cause Seckel syndrome with defective ATR-dependent DNA damage signaling

Large brain size is one of the defining characteristics of modern humans. Seckel syndrome (MIM 210600), a disorder of markedly reduced brain and body size, is associated with defective ATR-dependent DNA damage signaling. Only a single hypomorphic mutation of ATR has been identified in this genetically heterogeneous condition. We now report that mutations in the gene encoding pericentrin (PCNT)--resulting in the loss of pericentrin from the centrosome, where it has key functions anchoring both structural and regulatory proteins--also cause Seckel syndrome. Furthermore, we find that cells of individuals with Seckel syndrome due to mutations in PCNT (PCNT-Seckel) have defects in ATR-dependent checkpoint signaling, providing the first evidence linking a structural centrosomal protein with DNA damage signaling. These findings also suggest that other known microcephaly genes implicated in either DNA repair responses or centrosomal function may act in common developmental pathways determining human brain and body size

Dynamical R-parity Breaking at the LHC

In a class of extensions of the minimal supersymmetric standard model with (B-L)/left-right symmetry that explains the neutrino masses, breaking R-parity symmetry is an essential and dynamical requirement for successful gauge symmetry breaking. Two consequences of these models are: (i) a new kind of R-parity breaking interaction that protects proton stability but adds new contributions to neutrinoless double beta decay and (ii) an upper bound on the extra gauge and parity symmetry breaking scale which is within the large hadron collider (LHC) energy range. We point out that an important prediction of such theories is a potentially large mixing between the right-handed charged lepton ($e^c$) and the superpartner of the right-handed gauge boson ($\widetilde W_R^+$), which leads to a brand new class of R-parity violating interactions of type $\widetilde{\mu^c}^\dagger\nu_\mu^c e^c$ and \widetilde{d^c}^\dagger\u^c e^c. We analyze the relevant constraints on the sparticle mass spectrum and the LHC signatures for the case with smuon/stau NLSP and gravitino LSP. We note the "smoking gun" signals for such models to be lepton flavor/number violating processes: $pp\to \mu^\pm\mu^\pm e^+e^-jj$ (or $\tau^\pm\tau^\pm e^+e^-jj$) and $pp\to\mu^\pm e^\pm b \bar{b} jj$ (or $\tau^\pm e^\pm b \bar{b} jj$) without significant missing energy. The predicted multi-lepton final states and the flavor structure make the model be distinguishable even in the early running of the LHC.Comment: 30 pages, 13 figures, 6 tables, reference adde

Ownership and control in a competitive industry

We study a differentiated product market in which an investor initially owns a controlling stake in one of two competing firms and may acquire a non-controlling or a controlling stake in a competitor, either directly using her own assets, or indirectly via the controlled firm. While industry profits are maximized within a symmetric two product monopoly, the investor attains this only in exceptional cases. Instead, she sometimes acquires a noncontrolling stake. Or she invests asymmetrically rather than pursuing a full takeover if she acquires a controlling one. Generally, she invests indirectly if she only wants to affect the product market outcome, and directly if acquiring shares is profitable per se. --differentiated products,separation of ownership and control,private benefits of control

Particle creation, classicality and related issues in quantum field theory: II. Examples from field theory

We adopt the general formalism, which was developed in Paper I (arXiv:0708.1233) to analyze the evolution of a quantized time-dependent oscillator, to address several questions in the context of quantum field theory in time dependent external backgrounds. In particular, we study the question of emergence of classicality in terms of the phase space evolution and its relation to particle production, and clarify some conceptual issues. We consider a quantized scalar field evolving in a constant electric field and in FRW spacetimes which illustrate the two extreme cases of late time adiabatic and highly non-adiabatic evolution. Using the time-dependent generalizations of various quantities like particle number density, effective Lagrangian etc. introduced in Paper I, we contrast the evolution in these two limits bringing out key differences between the Schwinger effect and evolution in the de Sitter background. Further, our examples suggest that the notion of classicality is multifaceted and any one single criterion may not have universal applicability. For example, the peaking of the phase space Wigner distribution on the classical trajectory \emph{alone} does not imply transition to classical behavior. An analysis of the behavior of the \emph{classicality parameter}, which was introduced in Paper I, leads to the conclusion that strong particle production is necessary for the quantum state to become highly correlated in phase space at late times.Comment: RevTeX 4; 27 pages; 18 figures; second of a series of two papers, the first being arXiv:0708.1233 [gr-qc]; high resolution figures available from the authors on reques

Particle creation, classicality and related issues in quantum field theory: I. Formalism and toy models

The quantum theory of a harmonic oscillator with a time dependent frequency arises in several important physical problems, especially in the study of quantum field theory in an external background. While the mathematics of this system is straightforward, several conceptual issues arise in such a study. We present a general formalism to address some of the conceptual issues like the emergence of classicality, definition of particle content, back reaction etc. In particular, we parametrize the wave function in terms of a complex number (which we call excitation parameter) and express all physically relevant quantities in terms it. Many of the notions -- like those of particle number density, effective Lagrangian etc., which are usually defined using asymptotic in-out states -- are generalized as time-dependent concepts and we show that these generalized definitions lead to useful and reasonable results. Having developed the general formalism we apply it to several examples. Exact analytic expressions are found for a particular toy model and approximate analytic solutions are obtained in the extreme cases of adiabatic and highly non-adiabatic evolution. We then work out the exact results numerically for a variety of models and compare them with the analytic results and approximations. The formalism is useful in addressing the question of emergence of classicality of the quantum state, its relation to particle production and to clarify several conceptual issues related to this. In Paper II (arXiv:0708.1237), which is a sequel to this, the formalism will be applied to analyze the corresponding issues in the context of quantum field theory in background cosmological models and electric fields.Comment: RevTeX 4; 32 pages; 28 figures; first of a series of two papers, the second being arXiv:0708.1237 [gr-qc]; high resolution figures available from the authors on reques

RG flows from Spin(7), CY 4-fold and HK manifolds to AdS, Penrose limits and pp waves

We obtain explicit realizations of holographic renormalization group (RG) flows from M-theory, from E^{2,1} \times Spin(7) at UV to AdS_4 \times \tilde{S^7} (squashed S^7) at IR, from E^{2,1} \times CY4 at UV to AdS_4 \times Q^{1,1,1} at IR, and from E^{2,1} \times HK (hyperKahler) at UV to AdS_4 \times N^{0,1,0} at IR. The dual type IIA string theory configurations correspond to D2-D6 brane systems where D6 branes wrap supersymmetric four-cycles. We also study the Penrose limits and obtain the pp-wave backgrounds for the above configurations. Besides, we study some examples of non-supersymmetric and supersymmetric flows in five-dimensional gauge theories.Comment: 42 pages, 6 eps figures, typos and misprints correcte

Reconstructing genome evolution in historic samples of the Irish potato famine pathogen

Responsible for the Irish potato famine of 1845–49, the oomycete pathogen Phytophthora infestans caused persistent, devastating outbreaks of potato late blight across Europe in the 19th century. Despite continued interest in the history and spread of the pathogen, the genome of the famine-era strain remains entirely unknown. Here we characterize temporal genomic changes in introduced P. infestans. We shotgun sequence five 19th-century European strains from archival herbarium samples—including the oldest known European specimen, collected in 1845 from the first reported source of introduction. We then compare their genomes to those of extant isolates. We report multiple distinct genotypes in historical Europe and a suite of infection-related genes different from modern strains. At virulence-related loci, several now-ubiquitous genotypes were absent from the historical gene pool. At least one of these genotypes encodes a virulent phenotype in modern strains, which helps explain the 20th century’s episodic replacements of European P. infestans lineages

Serous cystic neoplasm of the pancreas: A multinational study of 2622 patients under the auspices of the International Association of Pancreatology and European Pancreatic Club (European Study Group on Cystic Tumors of the Pancreas)

OBJECTIVES: Serous cystic neoplasm (SCN) is a cystic neoplasm of the pancreas whose natural history is poorly known. The purpose of the study was to attempt to describe the natural history of SCN, including the specific mortality. DESIGN: Retrospective multinational study including SCN diagnosed between 1990 and 2014. RESULTS: 2622 patients were included. Seventy-four per cent were women, and median age at diagnosis was 58\u2005years (16-99). Patients presented with non-specific abdominal pain (27%), pancreaticobiliary symptoms (9%), diabetes mellitus (5%), other symptoms (4%) and/or were asymptomatic (61%). Fifty-two per cent of patients were operated on during the first year after diagnosis (median size: 40\u2005mm (2-200)), 9% had resection beyond 1\u2005year of follow-up (3\u2005years (1-20), size at diagnosis: 25\u2005mm (4-140)) and 39% had no surgery (3.6\u2005years (1-23), 25.5\u2005mm (1-200)). Surgical indications were (not exclusive) uncertain diagnosis (60%), symptoms (23%), size increase (12%), large size (6%) and adjacent organ compression (5%). In patients followed beyond 1\u2005year (n=1271), size increased in 37% (growth rate: 4\u2005mm/year), was stable in 57% and decreased in 6%. Three serous cystadenocarcinomas were recorded. Postoperative mortality was 0.6% (n=10), and SCN's related mortality was 0.1% (n=1). CONCLUSIONS: After a 3-year follow-up, clinical relevant symptoms occurred in a very small proportion of patients and size slowly increased in less than half. Surgical treatment should be proposed only for diagnosis remaining uncertain after complete workup, significant and related symptoms or exceptionally when exists concern with malignancy. This study supports an initial conservative management in the majority of patients with SCN

Stochastic Theory of Relativistic Particles Moving in a Quantum Field: II. Scalar Abraham-Lorentz-Dirac-Langevin Equation, Radiation Reaction and Vacuum Fluctuations

We apply the open systems concept and the influence functional formalism introduced in Paper I to establish a stochastic theory of relativistic moving spinless particles in a quantum scalar field. The stochastic regime resting between the quantum and semi-classical captures the statistical mechanical attributes of the full theory. Applying the particle-centric world-line quantization formulation to the quantum field theory of scalar QED we derive a time-dependent (scalar) Abraham-Lorentz-Dirac (ALD) equation and show that it is the correct semiclassical limit for nonlinear particle-field systems without the need of making the dipole or non-relativistic approximations. Progressing to the stochastic regime, we derive multiparticle ALD-Langevin equations for nonlinearly coupled particle-field systems. With these equations we show how to address time-dependent dissipation/noise/renormalization in the semiclassical and stochastic limits of QED. We clarify the the relation of radiation reaction, quantum dissipation and vacuum fluctuations and the role that initial conditions may play in producing non-Lorentz invariant noise. We emphasize the fundamental role of decoherence in reaching the semiclassical limit, which also suggests the correct way to think about the issues of runaway solutions and preacceleration from the presence of third derivative terms in the ALD equation. We show that the semiclassical self-consistent solutions obtained in this way are ``paradox'' and pathology free both technically and conceptually. This self-consistent treatment serves as a new platform for investigations into problems related to relativistic moving charges.Comment: RevTex; 20 pages, 3 figures, Replaced version has corrected typos, slightly modified derivation, improved discussion including new section with comparisons to related work, and expanded reference