A ten-inch manipulator (TIM) based fast-electron spectrometer with multiple viewing angles (OU-ESM).

The measurement of angularly resolved energy distributions of mega-electron-volt electrons is important for gaining a better understanding of the interaction of ultra-intense laser pulses with plasma, especially for fast-ignition laser-fusion research. It is also crucial when evaluating the production of suprathermal (several 10-keV) electrons through laser-plasma instabilities in conventional hot-spot-ignition and shock-ignition research. For these purposes, we developed a 10-in. manipulator-based multichannel electron spectrometer-the Osaka University electron spectrometer (OU-ESM)-that combines angular resolution with high-energy resolution. The OU-ESM consists of five small electron spectrometers set at every 5°, with an energy range from ∼40 keV to ∼40 MeV. A low-magnetic-field option provides a higher spectral resolution for an energy range of up to ∼5 MeV. We successfully obtained angularly resolved electron spectra for various experiments on the OMEGA and OMEGA EP laser systems.

Density and temperature characterization of long-scale length, near-critical density controlled plasma produced from ultra-low density plastic foam.

The ability to produce long-scale length (i.e. millimeter scale-length), homogeneous plasmas is of interest in studying a wide range of fundamental plasma processes. We present here a validated experimental platform to create and diagnose uniform plasmas with a density close or above the critical density. The target consists of a polyimide tube filled with an ultra low-density plastic foam where it was heated by x-rays, produced by a long pulse laser irradiating a copper foil placed at one end of the tube. The density and temperature of the ionized foam was retrieved by using x-ray radiography and proton radiography was used to verify the uniformity of the plasma. Plasma temperatures of 5-10 eV and densities around 10(21) cm(-3) are measured. This well-characterized platform of uniform density and temperature plasma is of interest for experiments using large-scale laser platforms conducting High Energy Density Physics investigations.

Slowdown mechanisms of ultraintense laser propagation in critical density plasma.

We use one- and two-dimensional particle-in-cell simulations to demonstrate that the propagation of an ultraintense laser (I=10(19)W/cm(2)) in critical density plasma can be interfered with by a high density plasma wall region generated at the propagation front. When the electron flow speed of the wall region exceeds a certain relativistic threshold, the region behaves as an overdense plasma due to a decrease of the effective critical density. The region forms then very small overdense plasma islands. The islands impede the propagation intermittently and slow down the propagation speed significantly.

Channeling of multikilojoule high-intensity laser beams in an inhomogeneous plasma.

Channeling experiments were performed that demonstrate the transport of high-intensity (>10(18)W/cm(2)), multikilojoule laser light through a millimeter-sized, inhomogeneous (∼300-µm density scale length) laser-produced plasma up to overcritical density, which is an important step forward for the fast-ignition concept. The background plasma density and the density depression inside the channel were characterized with a novel optical probe system. The channel progression velocity was measured, which agrees well with theoretical predictions based on large scale particle-in-cell simulations, confirming scaling laws for the required channeling laser energy and laser pulse duration, which are important parameters for future integrated fast-ignition channeling experiments.

Measuring the strong electrostatic and magnetic fields with proton radiography for ultra-high intensity laser channeling on fast ignition.

In order to investigate the intense laser propagation and channel formation in dense plasma, we conducted an experiment with proton deflectometry on the OMEGA EP Laser facility. The proton image was analyzed by tracing the trajectory of mono-energetic protons, which provides understanding the electric and magnetic fields that were generated around the channel. The estimated field strengths (E ∼ 10(11) V/m and B ∼ 10(8) G) agree with the predictions from 2D-Particle-in-cell (PIC) simulations, indicating the feasibility of the proton deflectometry technique for over-critical density plasma.

Identification of Toyocamycin, an agent cytotoxic for multiple myeloma cells, as a potent inhibitor of ER stress-induced XBP1 mRNA splicing.

The IRE1α-XBP1 pathway, a key component of the endoplasmic reticulum (ER) stress response, is considered to be a critical regulator for survival of multiple myeloma (MM) cells. Therefore, the availability of small-molecule inhibitors targeting this pathway would offer a new chemotherapeutic strategy for MM. Here, we screened small-molecule inhibitors of ER stress-induced XBP1 activation, and identified toyocamycin from a culture broth of an Actinomycete strain. Toyocamycin was shown to suppress thapsigargin-, tunicamycin- and 2-deoxyglucose-induced XBP1 mRNA splicing in HeLa cells without affecting activating transcription factor 6 (ATF6) and PKR-like ER kinase (PERK) activation. Furthermore, although toyocamycin was unable to inhibit IRE1α phosphorylation, it prevented IRE1α-induced XBP1 mRNA cleavage in vitro. Thus, toyocamycin is an inhibitor of IRE1α-induced XBP1 mRNA cleavage. Toyocamycin inhibited not only ER stress-induced but also constitutive activation of XBP1 expression in MM lines as well as primary samples from patients. It showed synergistic effects with bortezomib, and induced apoptosis of MM cells including bortezomib-resistant cells at nanomolar levels in a dose-dependent manner. It also inhibited growth of xenografts in an in vivo model of human MM. Taken together, our results suggest toyocamycin as a lead compound for developing anti-MM therapy and XBP1 as an appropriate molecular target for anti-MM therapy.

Development of multi-channel electron spectrometer.

In order to obtain the angular dependent electron energy distributions, we developed a multichannel electron spectrometer (MCESM) with high energy and angular resolutions. The MCESM consists of seven small electron spectrometers set in every 5° on the basement, each of which detection range is up to 25 MeV. In the experiment, we successfully obtained electron spectra from imploded cone-shell target as well as gold plane target irradiated by ultraintense (300 J/5 ps) laser beam.

Diphtheria toxin receptor-mediated conditional and targeted cell ablation in transgenic mice.

Specific cell ablation is a useful method for analyzing the in vivo function of cells. We have developed a simple and sensitive method for conditional cell ablation in transgenic mice, called "toxin receptor-mediated cell knockout." We expressed the diphtheria toxin (DT) receptor in transgenic mice using a hepatocyte-specific promoter and found that injection of DT caused fulminant hepatitis. Three independently established transgenic lines demonstrated a good correlation between the sensitivity of hepatocytes to DT and the expression level of the DT receptors. Moreover, the degree of hepatocyte damage was easily controlled over a wide range of doses of injected DT without any obvious abnormalities in other cells or tissues. This system is useful for generating mouse models of disease and for studying the recovery or regeneration of tissues from cell damage or loss. As DT is a potent inhibitor of protein synthesis in both growing and non-growing cells, the method is applicable to a wide range of cells and tissues in mice or in other DT-insensitive animals.

Translational control by the ER transmembrane kinase/ribonuclease IRE1 under ER stress.

Under conditions of endoplasmic reticulum (ER) stress, mammalian cells induce both translational repression and the unfolded protein response that transcriptionally activates genes encoding ER-resident molecular chaperones. To date, the only known pathway for translational repression in response to ER stress has been the phosphorylation of eIF-2alpha by the double-stranded RNA-activated protein kinase (PKR) or the transmembrane PKR-like ER kinase (PERK). Here we report another pathway in which the ER transmembrane kinase/ribonuclease IRE1beta induces translational repression through 28S ribosomal RNA cleavage in response to ER stress. The evidence suggests that both pathways are important for efficient translational repression during the ER stress response.

Identification of a potential nurr1 response element that activates the tyrosine hydroxylase gene promoter in cultured cells.

Expression of the gene encoding tyrosine hydroxylase (TH), the initial and rate-limiting enzyme of catecholamine biosynthesis, is regulated at the transcriptional level during neuronal development and in response to a variety of environmental stimuli. Nur-related factor 1 (Nurr1), a member of the orphan nuclear receptor superfamily, is required for development of dopamine-producing neurons in the ventral midbrain and for expression of TH in these neurons. In the present study, we found a direct activation of the rat TH gene promoter by Nurr1 in cultured cell lines. This activation appeared to be dependent on multiple regulatory elements conferring Nurr1 responsiveness to the promoter. We identified a Nurr1 response element (TH-NBRE1) in the proximal region of the TH promoter that mediates a moderate activation of the promoter. The sequence of TH-NBRE1 was highly homologous to that of the typical NGFI-B response element. Our findings suggest that Nurr1 may be implicated in the transcriptional control of TH gene expression during development or in response to altered physiological states.

Phyllodes tumor in a patient with a preexistent fibrocystic disease.

A phyllodes tumor appeared at the site of a resected fibrocystic disease focus. Administration of danazol resulted in temporary regression, but the tumor resumed growth. Relative hyperestrogenism also continued to increase in spite of continued long-term administration of danazol. After 12 months a simple mastectomy was performed. Most of the resected mass consisted of the phyllodes tumor, but it also contained fibrocystic disease.