HoxA9 binds and represses the Cebpa +8 kb enhancer

C/EBPα plays a key role in specifying myeloid lineage development. HoxA9 is expressed in myeloid progenitors, with its level diminishing during myeloid maturation, and HOXA9 is over-expressed in a majority of acute myeloid leukemia cases, including those expressing NUP98-HOXD13. The objective of this study was to determine whether HoxA9 directly represses Cebpa gene expression. We find 4-fold increased HoxA9 and 5-fold reduced Cebpa in marrow common myeloid and LSK progenitors from Vav-NUP98-HOXD13 transgenic mice. Conversely, HoxA9 decreases 5-fold while Cebpa increases during granulocytic differentiation of 32Dcl3 myeloid cells. Activation of exogenous HoxA9-ER in 32Dcl3 cells reduces Cebpa mRNA even in the presence of cycloheximide, suggesting direct repression. Cebpa transcription in murine myeloid cells is regulated by a hematopoietic-specific +37 kb enhancer and by a more widely active +8 kb enhancer. ChIP-Seq analysis of primary myeloid progenitor cells expressing exogenous HoxA9 or HoxA9-ER demonstrates that HoxA9 localizes to both the +8 kb and +37 kb Cebpa enhancers. Gel shift analysis demonstrates HoxA9 binding to three consensus sites in the +8 kb enhancer, but no affinity for the single near-consensus site present in the +37 kb enhancer. Activity of a Cebpa +8 kb enhancer/promoter-luciferase reporter in 32Dcl3 or MOLM14 myeloid cells is increased ~2-fold by mutation of its three HOXA9-binding sites, suggesting that endogenous HoxA9 represses +8 kb Cebpa enhancer activity. In contrast, mutation of five C/EBPα-binding sites in the +8 kb enhancer reduces activity 3-fold. Finally, expression of a +37 kb enhancer/promoter-hCD4 transgene reporter is reduced ~2-fold in marrow common myeloid progenitors when the Vav-NUP98-HOXD13 transgene is introduced. Overall, these data support the conclusion that HoxA9 represses Cebpa expression, at least in part via inhibition of its +8 kb enhancer, potentially allowing normal myeloid progenitors to maintain immaturity and contributing to the pathogenesis of acute myeloid leukemia associated with increased HOXA9

Voltage-gated calcium channel and antisense oligonucleotides thereto

An antisense oligonucleotide of 10 to 35 nucleotides in length that can hybridize with a region of the .alpha..sub.1 subunit of the SA-Cat channel gene DNA or mRNA is provided, together with pharmaceutical compositions containing and methods utilizing such antisense oligonucleotide

Short-Pulse, Compressed Ion Beams at the Neutralized Drift Compression Experiment

We have commenced experiments with intense short pulses of ion beams on the Neutralized Drift Compression Experiment (NDCX-II) at Lawrence Berkeley National Laboratory, with 1-mm beam spot size within 2.5 ns full-width at half maximum. The ion kinetic energy is 1.2 MeV. To enable the short pulse duration and mm-scale focal spot radius, the beam is neutralized in a 1.5-meter-long drift compression section following the last accelerator cell. A short-focal-length solenoid focuses the beam in the presence of the volumetric plasma that is near the target. In the accelerator, the line-charge density increases due to the velocity ramp imparted on the beam bunch. The scientific topics to be explored are warm dense matter, the dynamics of radiation damage in materials, and intense beam and beam-plasma physics including select topics of relevance to the development of heavy-ion drivers for inertial fusion energy. Below the transition to melting, the short beam pulses offer an opportunity to study the multi-scale dynamics of radiation-induced damage in materials with pump-probe experiments, and to stabilize novel metastable phases of materials when short-pulse heating is followed by rapid quenching. First experiments used a lithium ion source; a new plasma-based helium ion source shows much greater charge delivered to the target.Comment: 4 pages, 2 figures, 1 table. Submitted to the proceedings for the Ninth International Conference on Inertial Fusion Sciences and Applications, IFSA 201

The Detection of Ionizing Radiation by Plasma Panel Sensors: Cosmic Muons, Ion Beams and Cancer Therapy

The plasma panel sensor is an ionizing photon and particle radiation detector derived from PDP technology with high gain and nanosecond response. Experimental results in detecting cosmic ray muons and beta particles from radioactive sources are described along with applications including high energy and nuclear physics, homeland security and cancer therapeuticsComment: Presented at SID Symposium, June 201

Plasma Panel Sensors for Particle and Beam Detection

The plasma panel sensor (PPS) is an inherently digital, high gain, novel variant of micropattern gas detectors inspired by many operational and fabrication principles common to plasma display panels (PDPs). The PPS is comprised of a dense array of small, plasma discharge, gas cells within a hermetically-sealed glass panel, and is assembled from non-reactive, intrinsically radiation-hard materials such as glass substrates, metal electrodes and mostly inert gas mixtures. We are developing the technology to fabricate these devices with very low mass and small thickness, using gas gaps of at least a few hundred micrometers. Our tests with these devices demonstrate a spatial resolution of about 1 mm. We intend to make PPS devices with much smaller cells and the potential for much finer position resolutions. Our PPS tests also show response times of several nanoseconds. We report here our results in detecting betas, cosmic-ray muons, and our first proton beam tests.Comment: 2012 IEEE NS

Development of a plasma panel radiation detector: recent progress and key issues

A radiation detector based on plasma display panel technology, which is the principal component of plasma television displays is presented. Plasma Panel Sensor (PPS) technology is a variant of micropattern gas radiation detectors. The PPS is conceived as an array of sealed plasma discharge gas cells which can be used for fast response (O(5ns) per pixel), high spatial resolution detection (pixel pitch can be less than 100 micrometer) of ionizing and minimum ionizing particles. The PPS is assembled from non-reactive, intrinsically radiation-hard materials: glass substrates, metal electrodes and inert gas mixtures. We report on the PPS development program, including simulations and design and the first laboratory studies which demonstrate the usage of plasma display panels in measurements of cosmic ray muons, as well as the expansion of experimental results on the detection of betas from radioactive sources.Comment: presented at IEEE NSS 2011 (Barcelona