Absolute Timing of the Crab Pulsar with RXTE

We have monitored the phase of the main X-ray pulse of the Crab pulsar with the Rossi X-ray Timing Explorer (RXTE) for almost eight years, since the start of the mission in January 1996. The absolute time of RXTE's clock is sufficiently accurate to allow this phase to be compared directly with the radio profile. Our monitoring observations of the pulsar took place bi-weekly (during the periods when it was at least 30 degrees from the Sun) and we correlated the data with radio timing ephemerides derived from observations made at Jodrell Bank. We have determined the phase of the X-ray main pulse for each observation with a typical error in the individual data points of 50 us. The total ensemble is consistent with a phase that is constant over the monitoring period, with the X-ray pulse leading the radio pulse by 0.0102+/-0.0012 period in phase, or 344+/-40 us in time. The error estimate is dominated by a systematic error of 40 us in the radio data, arising from uncertainties in the variable amount of pulse delay due to interstellar scattering and instrumental calibration. The statistical error is 0.00015 period, or 5 us. The separation of the main pulse and interpulse appears to be unchanging at time scales of a year or less, with an average value of 0.4001+/-0.0002 period. There is no apparent variation in these values with energy over the 2-30 keV range. The lag between the radio and X-ray pulses may be constant in phase (rotational) or constant in time (linear pathlength). We are not (yet) able to distinguish between these two interpretations.Comment: 11 pages, 2 figure

C1− Continuous crack propagation for mixed-mode fracture problems

In this work a C1− continuous crack propagation algorithm is proposed to improve the numerical simulation of localized deformation patterns, using higher order elements. The algorithm is applied for a standard smeared crack model and is validated by a mixed-mode fracture problem. From the results a reduction of mesh-induced directional bias is observed

Epigenetic Editing:On the Verge of Reprogramming Gene Expression at Will

Genome targeting has quickly developed as one of the most promising fields in science. By using programmable DNA-binding platforms and nucleases, scientists are now able to accurately edit the genome. These DNA-binding tools have recently also been applied to engineer the epigenome for gene expression modulation. Such epigenetic editing constructs have firmly demonstrated the causal role of epigenetics in instructing gene expression. Another focus of epigenome engineering is to understand the order of events of chromatin remodeling in gene expression regulation. Groundbreaking approaches in this field are beginning to yield novel insights into the function of individual chromatin marks in the context of maintaining cellular phenotype and regulating transient gene expression changes. This review focuses on recent advances in the field of epigenetic editing and highlights its promise for sustained gene expression reprogramming

Advances of epigenetic editing

Epigenetic editing refers to the locus-specific targeting of epigenetic enzymes to rewrite the local epigenetic landscape of an endogenous genomic site, often with the aim of transcriptional reprogramming. Implementing clustered regularly interspaced short palindromic repeat-dCas9 greatly accelerated the advancement of epigenetic editing, yielding preclinical therapeutic successes using a variety of epigenetic enzymes. ,CRISPR/dCas9 Here, were review the current applications of these epigenetic editing tools in mammalians and shed light on biochemical improvements that facilitate versatile applications

Exploiting epigenetics for the treatment of inborn errors of metabolism

Gene therapy is currently considered as the optimal treatment for inborn errors of metabolism (IEMs), as it aims to permanently compensate for the primary genetic defect. However, emerging gene editing approaches such as CRISPR-Cas9, in which the DNA of the host organism is edited at a precise location, may have outperforming therapeutic potential. Gene editing strategies aim to correct the actual genetic mutation, while circumventing issues associated with conventional compensation gene therapy. Such strategies can also be repurposed to normalize gene expression changes that occur secondary to the genetic defect. Moreover, besides the genetic causes of IEMs, it is increasingly recognized that their clinical phenotypes are associated with epigenetic changes. Because epigenetic alterations are principally reversible, this may offer new opportunities for treatment of IEM patients. Here, we present an overview of the promises of epigenetics in eventually treating IEMs. We discuss the concepts of gene and epigenetic editing, and the advantages and disadvantages of current and upcoming gene-based therapies for treatment of IEMs.</p

The Endothelium as a Target for Anti-Atherogenic Therapy:A Focus on the Epigenetic Enzymes EZH2 and SIRT1

Endothelial cell inflammatory activation and dysfunction are key events in the pathophysiology of atherosclerosis, and are associated with an elevated risk of cardiovascular events. Yet, therapies specifically targeting the endothelium and atherosclerosis are lacking. Here, we review how endothelial behaviour affects atherogenesis and pose that the endothelium may be an efficacious cellular target for antiatherogenic therapies. We discuss the contribution of endothelial inflammatory activation and dysfunction to atherogenesis and postulate that the dysregulation of specific epigenetic enzymes, EZH2 and SIRT1, aggravate endothelial dysfunction in a pleiotropic fashion. Moreover, we propose that commercially available drugs are available to clinically explore this postulation

Critical analysis on the use of the shove test for investigating the shear-sliding behavior of brick masonry

The shove test (ASTM Standard C1531) is an experimental technique aimed at studying the shear-sliding behavior of brick masonry. It can be executed according to various testing methods that differ in the way the vertical compression load is applied and in the way bricks and/or joints are locally removed for inserting jacks. One of the most critical aspects is the correct evaluation of the compressive stress state on the sliding brick. The objective of the present paper is to investigate the capability of the shove test in determining the shear strength parameters of brick masonries and to highlight the main advantages and disadvantages of the various testing methods. To this aim, nonlinear numerical simulations of the shove test were performed by adopting a brick-to-brick modeling strategy. The 2D numerical model was calibrated and validated through comparisons with experimental results of triplet tests and shove tests. The numerical analyses allowed to understand the influence the different testing methods and the masonry mechanical properties, such as dilatancy, may have on the test results. Based on the numerical outcomes, correction factors were calibrated for the proper evaluation of the compressive stress state on the sliding brick. Improvements with regards to the experimental procedures, i.e. additional test phases and measurements, were also proposed to enhance the results interpretation

SN1993J VLBI (I): The Center of the Explosion and a Limit on Anisotropic Expansion

Phase-referenced VLBI observations of supernova 1993J at 24 epochs, from 50 days after shock breakout to the present, allowed us to determine the coordinates of the explosion center relative to the quasi-stationary core of the host galaxy M81 with an accuracy of 45 micro-arcsec, and to determine the nominal proper motion of the geometric center of the radio shell with an accuracy of 9micro-arcsec/yr. The uncertainties correspond to 160 AU for the position and 160 km/s for the proper motion at the distance of the source of 3.63 Mpc. After correcting for the expected galactic proper motion of the supernova around the core of M81 using HI rotation curves, we obtain a peculiar proper motion of the radio shell center of only 320 +/- 160 km/s to the south, which limits any possible one-sided expansion of the shell. We also find that the shell is highly circular, the outer contours in fact being circular to within 3%. Combining our proper motion values with the degree of circular symmetry, we find that the expansion of the shockfront from the explosion center is isotropic to within 5.5% in the plane of the sky. This is a more fundamental result on isotropic expansion than can be derived from the circularity of the images alone. The brightness of the radio shell, however, varies along the ridge and systematically changes with time. The degree of isotropy in the expansion of the shockfront contrasts with the asymmetries and polarization found in optical spectral lines. Asymmetric density distributions in the ejecta or more likely in the circumstellar medium, are favored to reconcile the radio and optical results. We see no sign of any disk-like density distribution of the circumstellar material, with the average axis ratio of the radio shell of SN1993J being less than 1.04.Comment: 21 pages, LaTex + 5 Figures (encapulsated PostScript), Accepted for Publication in the Astrophysical Journa