The histone deacetylase inhibitor sodium valproate causes limited transcriptional change in mouse embryonic stem cells but selectively overrides Polycomb-mediated Hoxb silencing.

BACKGROUND: Histone deacetylase inhibitors (HDACi) cause histone hyperacetylation and H3K4 hypermethylation in various cell types. They find clinical application as anti-epileptics and chemotherapeutic agents, but the pathways through which they operate remain unclear. Surprisingly, changes in gene expression caused by HDACi are often limited in extent and can be positive or negative. Here we have explored the ability of the clinically important HDACi valproic acid (VPA) to alter histone modification and gene expression, both globally and at specific genes, in mouse embryonic stem (ES) cells. RESULTS: Microarray expression analysis of ES cells exposed to VPA (1 mM, 8 h), showed that only 2.4% of genes showed a significant, >1.5-fold transcriptional change. Of these, 33% were down-regulated. There was no correlation between gene expression and VPA-induced changes in histone acetylation or H3K4 methylation at gene promoters, which were usually minimal. In contrast, all Hoxb genes showed increased levels of H3K9ac after exposure to VPA, but much less change in other modifications showing bulk increases. VPA-induced changes were lost within 24 h of inhibitor removal. VPA significantly increased the low transcription of Hoxb4 and Hoxb7, but not other Hoxb genes. Expression of Hoxb genes increased in ES cells lacking functional Polycomb silencing complexes PRC1 and PRC2. Surprisingly, VPA caused no further increase in Hoxb transcription in these cells, except for Hoxb1, whose expression increased several fold. Retinoic acid (RA) increased transcription of all Hoxb genes in differentiating ES cells within 24 h, but thereafter transcription remained the same, increased progressively or fell progressively in a locus-specific manner. CONCLUSIONS: Hoxb genes in ES cells are unusual in being sensitive to VPA, with effects on both cluster-wide and locus-specific processes. VPA increases H3K9ac at all Hoxb loci but significantly overrides PRC-mediated silencing only at Hoxb4 and Hoxb7. Hoxb1 is the only Hoxb gene that is further up-regulated by VPA in PRC-deficient cells. Our results demonstrate that VPA can exert both cluster-wide and locus-specific effects on Hoxb regulation.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Building Strong for Tomorrow: Recommendations for the Organizational Design of the NOAA Climate Service

The U.S. Congress asked an expert panel of the National Academy of Public Administration to assist NOAA with a study and analysis of organizational options for a Climate Service within NOAA. Further, NOAA formally asked the Panel to provide an independent assessment of how NOAA should organize its climate capabilities and make recommendations for a Climate Service line office structure that would integrate NOAA's climate science and research with service delivery.Main FindingsThe Panel strongly supports the creation of a Climate Service to be established as a line office within NOAA.The Panel concluded that a NOAA Climate Service, properly configured and implemented, would be uniquely qualified to serve the public and private sectors as a lead federal agency for climate research and services, and to provide an ongoing accessible, authoritative clearinghouse for all federal science and services related to climate.The report also includes the Panel's observations and recommendations regarding the larger federal climate enterprise, key elements of support needed by the NOAA Climate Service and the importance to the new organization of a clear strategic plan and a comprehensive implementation plan. Additionally, the Panel offered observations about institutional change management in the federal sector, identified several management recommendations for implementation and addressed operational priorities and budget challenges

WFPC2 Studies of the Crab Nebula. I. HST and ROSAT Imaging of the Synchrotron Nebula

We present images of the Crab synchrotron nebula obtained with the Wide Field and Planetary Camera 2 (WFPC2) on board the Hubble Space Telescope. These data are compared with ROSAT HRI images, and with 0':5 resolution Canada-France-Hawaii Telescope (CFHT) images previously published by van den Bergh & Pritchet (1989). These data strengthen the emerging picture of the Crab as a cylindrically symmetrical object with an axis running southeast to northwest, and inclined by ~20°-30° with respect to the plane of the sky. Identification of structure very near to the pulsar which shares this symmetry helps to better establish the link between the symmetry axis of the nebula and the spin axis of the pulsar. We report the discovery of a bright knot of visible emission located 0º.65 to the southeast of the pulsar, along the axis of the system. This knot and a second knot 3".8 from the pulsar appear to be present but not well resolved in the 1988 CFHT image, indicating that they are persistent structures. The inner knot is interpreted as a shock in the pulsar wind ~ 1500 AU above the pole of the pulsar. No corresponding knots are seen to the northwest of the pulsar, which may indicate that the characteristics of the wind from the two poles are not symmetrical. The closest of the "wisps" to the northwest of the pulsar appear to close into a ringlike "halo" encircling the axis of the nebula. The wisps are resolved, with widths of ~ 0".2. This allows· calculation of their volumes and volume emissivities, and in turn their equipartition fields and pressures. Equipartition pressures calculated for the knots and wisps are typically 10 to as much as 80 times the equipartition pressure calculated for the nebula as a whole. The wisps show significant substructure which changed considerably between 1988 and 1994. Previous reports of relativistic motions of the wisps were probably due to changes in the unresolved substructure of these features. Comparison of the CFHT and WFPC2 images show remarkable changes in the inner nebula, but inferences about physical conditions based on this comparison are limited by the resolution of the CFHT data and the long 5 year baseline between the images. The structure of the nebula in 1994 may be inconsistent with the recent model by Gallant & Arons (1994). Very fine fibrous texture visible in the WFPC2 image follows the structure of the X-ray torus. A puzzling anticorrelation is seen between the X-ray and visible surface brightness through part of the torus. Long contiguous low contrast features with widths of ~ 1"-2" are seen to run throughout the volume of the nebula. These features are seen to move outward through the nebula at velocities in excess of homologous expansion. These features trace the magnetic structure of the nebula; they are probably due to differences in emissivity accompanying varying degrees of departure from equipartition at roughly constant total pressure. Visible fibers "drape over" and appear to expand away from an X-ray counterjet to the northwest of the pulsar, supporting the interpretation of the counterjet as a directed flow of energy along the symmetry axis of the nebula. Other associations are also seen between X-ray and visible structures, including X-ray emission surrounding the east and west bays. An association is proposed between the observed structure of the nebula and different latitude zones found in models of winds from partially oblique rotators. We concur with previous suggestions that the X-ray torus and the sharp visible fibers associated with it mark a shock at r_s ~ 1.2 x 10^(18) cm in an equatorial striped magnetic wind. The halo and anvil arise at a distance of ~ 1.4 x 10^(17) cm from the pulsar in a helically polarized wind at latitudes greater than about 35°. Well collimated polar jets may be responsible for the knots to the southeast of the pulsar and for the jet and counterjet seen at X-ray and visible wavelengths

Automating the packing heuristic design process with genetic programming

The literature shows that one-, two-, and three-dimensional bin packing and knapsack packing are difficult problems in operational research. Many techniques, including exact, heuristic, and metaheuristic approaches, have been investigated to solve these problems and it is often not clear which method to use when presented with a new instance. This paper presents an approach which is motivated by the goal of building computer systems which can design heuristic methods. The overall aim is to explore the possibilities for automating the heuristic design process. We present a genetic programming system to automatically generate a good quality heuristic for each instance. It is not necessary to change the methodology depending on the problem type (one-, two-, or three-dimensional knapsack and bin packing problems), and it therefore has a level of generality unmatched by other systems in the literature. We carry out an extensive suite of experiments and compare with the best human designed heuristics in the literature. Note that our heuristic design methodology uses the same parameters for all the experiments. The contribution of this paper is to present a more general packing methodology than those currently available, and to show that, by using this methodology, it is possible for a computer system to design heuristics which are competitive with the human designed heuristics from the literature. This represents the first packing algorithm in the literature able to claim human competitive results in such a wide variety of packing domains