The ubiquitin-conjugating DNA repair enzyme is a maternal factor essential for early embryonic development in mice

The Saccharomyces cerevisiae RAD6 protein is required for a surprising diversity of cellular processes, including sporulation and replicational damage bypass of DNA lesions. In mammals, two RAD6-related genes, HR6A and HR6B, encode highly homologous proteins. Here, we describe the phenotype of cells and mice deficient for the mHR6A gene. Just like mHR6B knockout mouse embryonic fibroblasts, mHR6A-deficient cells appear to have normal DNA damage resistance properties, but mHR6A knockout male and female mice display a small decrease in body weight. The necessity for at least one functional mHR6A (X-chromosomal) or mHR6B (autosomal) allele in all somatic cell types is supported by the fact that neither animals lacking both proteins nor females with only one intact mHR6A allele are viable. In striking contrast to mHR6B knockout males, which show a severe spermatogenic defect, mHR6A knockout males are normally fertile. However, mHR6A knockout females fail to produce offspring despite a normal ovarian histology and ovulation. The absence of mHR6A in oocytes prevents development beyond the embryonic two-cell stage but does not result in an aberrant methylation pattern of histone H

String-Unification, Universal One-Loop Corrections and Strongly Coupled Heterotic String Theory

We derive the universal threshold corrections in heterotic string theory including a continuous Wilson line. Unification of gauge and gravitational couplings is shown to be possible even within perturbative string theory. The relative importance of gauge group dependent and independent thresholds on unification is clarified. Equipped with these results we can then attempt an extrapolation to the strongly coupled heterotic string -- M-theory. We argue that such an extrapolation might be meaningful because of the holomorphic structure of the gauge coupling function and the close connection of the threshold corrections to the anomaly cancelation mechanism.Comment: 28 LaTex pages with 2 fig

Non-universal Soft Parameters in Brane World and the Flavor Problem in Supergravity

We consider gravity mediated supersymmetry (SUSY) breaking in 5D spacetime with two 4D branes B1 and B2 separated in the extra dimension. Using an off-shell 5D supergravity (SUGRA) formalism, we argue that the SUSY breaking scales could be non-universal even at the fundamental scale in a brane world setting, since SUSY breaking effects could be effectively localized. As an application, we suggest a model in which the two light chiral MSSM generations reside on B1, while the third generation is located on B2, and the Higgs multiplets as well as gravity and gauge multiplets reside in the bulk. For SUSY breaking of the order of 10--20 TeV caused by a hidden sector localized at B1, the scalars belonging to the first two generations can become sufficiently heavy to overcome the SUSY flavor problem. SUSY breaking on B2 from a different localized hidden sector gives rise to the third generation soft scalar masses of the order of 1 TeV. Gaugino masses are also of the order of 1 TeV if the size of the extra dimension is $\sim 10^{-16}$ ${\rm GeV}^{-1}$. As in 4D effective supersymmetric theory, an adjustment of TeV scale parameters is needed to realize the 100 GeV electroweak symmetry breaking scale.Comment: 1+22 pages, Version to appear in PRD with additional comments and reference

Regularisation Techniques for the Radiative Corrections of Wilson lines and Kaluza-Klein states

Within an effective field theory framework we compute the most general structure of the one-loop corrections to the 4D gauge couplings in one- and two-dimensional orbifold compactifications with non-vanishing constant gauge background (Wilson lines). Although such models are non-renormalisable, we keep the analysis general by considering the one-loop corrections in three regularisation schemes: dimensional regularisation (DR), Zeta-function regularisation (ZR) and proper-time cut-off regularisation (PT). The relations among the results obtained in these schemes are carefully addressed. With minimal re-definitions of the parameters involved, the results obtained for the radiative corrections can be applied to most orbifold compactifications with one or two compact dimensions. The link with string theory is discussed. We mention a possible implication for the gauge couplings unification in such models.Comment: 37 pages, 1 Figure, LaTeX; minor correction

Munc18 and Munc13 regulate early neurite outgrowth

Background information. During development, growth cones of outgrowing neurons express proteins involved in vesicular secretion, such as SNARE (soluble N-ethylmaleimide-sensitive fusion protein-attachment protein receptor) proteins, Munc13 and Munc18. Vesicles are known to fuse in growth cones prior to synapse formation, which may contribute to outgrowth

Coset Space Dimensional Reduction and Wilson Flux Breaking of Ten-Dimensional N=1, E(8) Gauge Theory

We consider a N=1 supersymmetric E(8) gauge theory, defined in ten dimensions and we determine all four-dimensional gauge theories resulting from the generalized dimensional reduction a la Forgacs-Manton over coset spaces, followed by a subsequent application of the Wilson flux spontaneous symmetry breaking mechanism. Our investigation is constrained only by the requirements that (i) the dimensional reduction leads to the potentially phenomenologically interesting, anomaly free, four-dimensional E(6), SO(10) and SU(5) GUTs and (ii) the Wilson flux mechanism makes use only of the freely acting discrete symmetries of all possible six-dimensional coset spaces.Comment: 45 pages, 2 figures, 10 tables, uses xy.sty, longtable.sty, ltxtable.sty, (a shorter version will be published in Eur. Phys. J. C

Differences in Trial and Real-world Populations in the Dutch Castration-resistant Prostate Cancer Registry

__Background:__ Trials in castration-resistant prostate cancer (CRPC) treatment have shown improved outcomes, including survival. However, as trial populations are selected, results may not be representative for the real-world population. The aim of this study was to assess the differences between patients treated in a clinical trial versus standard care during the course of CRPC in a real-world CRPC population. __Design, setting, and participants:__ Castration-resistant Prostate Cancer Registry is a population-based, observational, retrospective registry. CRPC patients from 20 hospitals in the Netherlands have been included from 2010 to 2013. __Outcome measurements and statistical analysis:__ Baseline characteristics, systemic treatment, and overall survival were the main outcomes. Descriptive statistics, multivariate Cox regression, and multiple imputations with the Monte Carlo Markov Chain method were used. __Results and limitations:__ In total, 1524 patients were enrolled of which 203 patients had participated in trials at any time. The median follow-up period was 23 mo. Patients in the trial group were significantly younger and had less comorbidities. Docetaxel treatment was more freque

Solar parameters for modeling interplanetary background

The goal of the Fully Online Datacenter of Ultraviolet Emissions (FONDUE) Working Team of the International Space Science Institute in Bern, Switzerland, was to establish a common calibration of various UV and EUV heliospheric observations, both spectroscopic and photometric. Realization of this goal required an up-to-date model of spatial distribution of neutral interstellar hydrogen in the heliosphere, and to that end, a credible model of the radiation pressure and ionization processes was needed. This chapter describes the solar factors shaping the distribution of neutral interstellar H in the heliosphere. Presented are the solar Lyman-alpha flux and the solar Lyman-alpha resonant radiation pressure force acting on neutral H atoms in the heliosphere, solar EUV radiation and the photoionization of heliospheric hydrogen, and their evolution in time and the still hypothetical variation with heliolatitude. Further, solar wind and its evolution with solar activity is presented in the context of the charge exchange ionization of heliospheric hydrogen, and in the context of dynamic pressure variations. Also the electron ionization and its variation with time, heliolatitude, and solar distance is presented. After a review of all of those topics, we present an interim model of solar wind and the other solar factors based on up-to-date in situ and remote sensing observations of solar wind. Results of this effort will further be utilised to improve on the model of solar wind evolution, which will be an invaluable asset in all heliospheric measurements, including, among others, the observations of Energetic Neutral Atoms by the Interstellar Boundary Explorer (IBEX).Comment: Chapter 2 in the planned "Cross-Calibration of Past and Present Far UV Spectra of Solar System Objects and the Heliosphere", ISSI Scientific Report No 12, ed. R.M. Bonnet, E. Quemerais, M. Snow, Springe

Personality, dangerous driving, and involvement in accidents: Testing a contextual mediated model

The present study tested the role of various personality traits in explaining dangerous driving and involvement in accidents, using a contextual mediated model (N = 311). We initially found direct effects of personality traits on dangerous driving indicators (Big-5, Dark Triad, sensation seeking, aggression, and impulsivity). Subsequently, personality variables with predictive power were tested in the mediation model. Indirect effects of anger, psychopathy and sensation seeking on the history of involvement in traffic accidents were found, which was predicted directly by risky driving. The results are discussed based on the characteristics of each trait. Overall, our research replicates and extends previous findings and highlights the importance of psychological evaluations (e.g., personality test) when prospective drivers are applying for a driver license

Clusters in a chain of coupled oscillators behave like a single oscillator:Relevance to spontaneous otoacoustic emissions from human ears

Spontaneous otoacoustic emissions (SOAEs) provide startling evidence that there is an active process at the core of the mammalian cochlea, but the mechanism involved is unclear. Models involving single, active Van der Pol oscillators have found favor, but here we extend the system to a chain of coupled, active nonlinear oscillators. It is found that the inherent clustering of oscillators in the chain produces an effect in which each cluster, or frequency plateau, behaves just like a single oscillator, most clearly in terms of phase lock to external tones and phase slip in the presence of noise