Astrocytic stress response is induced by exposure to astrocyte-binding antibodies expressed by plasmablasts from pediatric patients with acute transverse myelitis.

BACKGROUND: Pediatric acute transverse myelitis (ATM) accounts for 20-30% of children presenting with a first acquired demyelinating syndrome (ADS) and may be the first clinical presentation of a relapsing ADS such as multiple sclerosis (MS). B cells have been strongly implicated in the pathogenesis of adult MS. However, little is known about B cells in pediatric MS, and even less so in pediatric ATM. Our lab previously showed that plasmablasts (PB), the earliest B cell subtype producing antibody, are expanded in adult ATM, and that these PBs produce self-reactive antibodies that target neurons. The goal of this study was to examine PB frequency and phenotype, immunoglobulin selection, and B cell receptor reactivity in pediatric patients presenting with ATM to gain insight to B cell involvement in disease. METHODS: We compared the PB frequency and phenotype of 5 pediatric ATM patients and 10 pediatric healthy controls (HC) and compared them to previously reported adult ATM patients using cytometric data. We purified bulk IgG from the plasma samples and cloned 20 recombinant human antibodies (rhAbs) from individual PBs isolated from the blood. Plasma-derived IgG and rhAb autoreactivity was measured by mean fluorescence intensity (MFI) in neurons and astrocytes of murine brain or spinal cord and primary human astrocytes. We determined the potential impact of these rhAbs on astrocyte health by measuring stress and apoptotic response. RESULTS: We found that pediatric ATM patients had a reduced frequency of peripheral blood PB. Serum IgG autoreactivity to neurons in EAE spinal cord was similar in the pediatric ATM patients and HC. However, serum IgG autoreactivity to astrocytes in EAE spinal cord was reduced in pediatric ATM patients compared to pediatric HC. Astrocyte-binding strength of rhAbs cloned from PBs was dependent on somatic hypermutation accumulation in the pediatric ATM cohort, but not HC. A similar observation in predilection for astrocyte binding over neuron binding of individual antibodies cloned from PBs was made in EAE brain tissue. Finally, exposure of human primary astrocytes to these astrocyte-binding antibodies increased astrocytic stress but did not lead to apoptosis. CONCLUSIONS: Discordance in humoral immune responses to astrocytes may distinguish pediatric ATM from HC.

KLF2 mutation is the most frequent somatic change in splenic marginal zone lymphoma and identifies a subset with distinct genotype.

To characterise the genetics of splenic marginal zone lymphoma (SMZL), we performed whole exome sequencing of 16 cases and identified novel recurrent inactivating mutations in Kruppel-like factor 2 (KLF2), a gene whose deficiency was previously shown to cause splenic marginal zone hyperplasia in mice. KLF2 mutation was found in 40 (42%) of 96 SMZLs, but rarely in other B-cell lymphomas. The majority of KLF2 mutations were frameshift indels or nonsense changes, with missense mutations clustered in the C-terminal zinc finger domains. Functional assays showed that these mutations inactivated the ability of KLF2 to suppress NF-κB activation by TLR, BCR, BAFFR and TNFR signalling. Further extensive investigations revealed common and distinct genetic changes between SMZL with and without KLF2 mutation. IGHV1-2 rearrangement and 7q deletion were primarily seen in SMZL with KLF2 mutation, while MYD88 and TP53 mutations were nearly exclusively found in those without KLF2 mutation. NOTCH2, TRAF3, TNFAIP3 and CARD11 mutations were observed in SMZL both with and without KLF2 mutation. Taken together, KLF2 mutation is the most common genetic change in SMZL and identifies a subset with a distinct genotype characterised by multi-genetic changes. These different genetic changes may deregulate various signalling pathways and generate cooperative oncogenic properties, thereby contributing to lymphomagenesis.

High-contrast laser acceleration of relativistic electrons in solid cone-wire targets.

The consequences of small scale-length precursor plasmas on high-intensity laser-driven relativistic electrons are studied via experiments and simulations. Longer scale-length plasmas are shown to dramatically increase the efficiency of electron acceleration, yet, if too long, they reduce the coupling of these electrons into the solid target. Evidence for the existence of an optimal plasma scale-length is presented and estimated to be from 1 to 5µm. Experiments on the Trident laser (I=5×10(19)W/cm(2)) diagnosed via Kα emission from Cu wires attached to Au cones are quantitively reproduced using 2D particle-in-cell simulations that capture the full temporal and spatial scale of the nonlinear laser interaction and electron transport. The simulations indicate that 32%±8%(6.5%±2%) of the laser energy is coupled into electrons of all energies (1-3 MeV) reaching the inner cone tip and that, with an optimized scale-length, this could increase to 35% (9%).

Investigation of fast-electron-induced Kα x rays in laser-produced blow-off plasma.

Refluxing of fast electrons generated by high-intensity, short-pulse lasers was investigated by measuring electron-induced Kα x rays from a buried tracer layer. Using planar foils of Au/Cu/CH, the 150-J, 0.7-ps TITAN short-pulse laser was focused on the gold foil to generate fast electrons and the 3-ns, 300-J long pulse beam irradiated on the CH side to create expanding plasma as a conducting medium. By delaying the short-pulse beam timing from the long pulse laser irradiation, the plasma size was varied to change electron refluxing in the target rear. The total yields and two-dimensional images of 8.05-keV Cu-Kα x ray were recorded with an x-ray spectrometer and two monochromatic crystal imagers. The measurements show that the integrated yields decrease by a factor of 10 from refluxing to the nonrefluxing limit. Similar radial profiles of the Kα images in the rear were observed at all delays. Hybrid-particle-in-cell simulations using plasma profiles calculated by a radiation-hydrodynamic code HYDRA agree well with the measured Kα yields. The simulations suggest that conducting plasma with the size of ∼300 µm in the laser direction and ∼600 µm in the lateral direction at the density of 2 × 1020 1/cm3 is sufficiently large to prevent electrons from refluxing in the target. The parameters found in this study can be useful in designing experiments utilizing a Kα x-ray source in refluxing regime or a tracer layer in nonrefluxing regime.

Performance of high-convergence, layered DT implosions with extended-duration pulses at the National Ignition Facility.

Radiation-driven, low-adiabat, cryogenic DT layered plastic capsule implosions were carried out on the National Ignition Facility (NIF) to study the sensitivity of performance to peak power and drive duration. An implosion with extended drive and at reduced peak power of 350 TW achieved the highest compression with fuel areal density of ~1.3±0.1 g/cm2, representing a significant step from previously measured ~1.0 g/cm2 toward a goal of 1.5 g/cm2. Future experiments will focus on understanding and mitigating hydrodynamic instabilities and mix, and improving symmetry required to reach the threshold for thermonuclear ignition on NIF.

Onset of hydrodynamic mix in high-velocity, highly compressed inertial confinement fusion implosions.

Deuterium-tritium inertial confinement fusion implosion experiments on the National Ignition Facility have demonstrated yields ranging from 0.8 to 7×10(14), and record fuel areal densities of 0.7 to 1.3 g/cm2. These implosions use hohlraums irradiated with shaped laser pulses of 1.5-1.9 MJ energy. The laser peak power and duration at peak power were varied, as were the capsule ablator dopant concentrations and shell thicknesses. We quantify the level of hydrodynamic instability mix of the ablator into the hot spot from the measured elevated absolute x-ray emission of the hot spot. We observe that DT neutron yield and ion temperature decrease abruptly as the hot spot mix mass increases above several hundred ng. The comparison with radiation-hydrodynamic modeling indicates that low mode asymmetries and increased ablator surface perturbations may be responsible for the current performance.

Dynamics of high-energy proton beam acceleration and focusing from hemisphere-cone targets by high-intensity lasers.

Acceleration and focusing of high-energy proton beams from fast-ignition (FI) -related hemisphere-cone assembled targets have been numerically studied by hybrid particle-in-cell simulations and compared with those from planar-foil and open-hemisphere targets. The whole physical process including the laser-plasma interaction has been self-consistently modeled for 15 ps, at which time the protons reach asymptotic motion. It is found that the achievable focus of proton beams is limited by the thermal pressure gradients in the co-moving hot electrons, which induce a transverse defocusing electric field that bends proton trajectories near the axis. For the advanced hemisphere-cone target, the flow of hot electrons along the cone wall induces a local transverse focusing sheath field, resulting in a clear enhancement in proton focusing; however, it leads to a significant loss of longitudinal sheath potential, reducing the total conversion efficiency from laser to protons.

Dynamics of relativistic laser-plasma interaction on solid targets.

A novel time-resolved diagnostic is used to record the critical surface motion during picosecond-scale relativistic laser interaction with a solid target. Single-shot measurements of the specular light show a redshift decreasing with time during the interaction, corresponding to a slowing-down of the hole boring process into overdense plasma. On-shot full characterization of the laser pulse enables simulations of the experiment without any free parameters. Two-dimensional particle-in-cell simulations yield redshifts that agree with the data, and support a simple explanation of the slowing-down of the critical surface based on momentum conservation between ions and reflected laser light.

Hot electron temperature and coupling efficiency scaling with prepulse for cone-guided fast ignition.

The effect of increasing prepulse energy levels on the energy spectrum and coupling into forward-going electrons is evaluated in a cone-guided fast-ignition relevant geometry using cone-wire targets irradiated with a high intensity (10(20) W/cm(2)) laser pulse. Hot electron temperature and flux are inferred from Kα images and yields using hybrid particle-in-cell simulations. A two-temperature distribution of hot electrons was required to fit the full profile, with the ratio of energy in a higher energy (MeV) component increasing with a larger prepulse. As prepulse energies were increased from 8 mJ to 1 J, overall coupling from laser to all hot electrons entering the wire was found to fall from 8.4% to 2.5% while coupling into only the 1-3 MeV electrons dropped from 0.57% to 0.03%.

Focusing of relativistic electrons in dense plasma using a resistivity-gradient-generated magnetic switchyard.

A method for producing a self-generated magnetic focussing structure for a beam of laser-generated relativistic electrons using a complex array of resistivity gradients is proposed and demonstrated using numerical simulations. The array of resistivity gradients is created by using a target consisting of alternating layers of different Z material. This new scheme is capable of effectively focussing the fast electrons even when the source is highly divergent. The application of this technique to cone-guided fast ignition inertial confinement fusion is considered, and it is shown that it may be possible to deposit over 25% of the fast electron energy into a hot spot even when the fast electron divergence angle is very large (e.g., 70° half-angle).

A novel zirconium Kα imager for high energy density physics research.

We report on the development and characterization of a zirconium Kα imager for high energy density physics research. The imager consists of a spherically bent quartz crystal operating at 15.7 keV photon energy. We compare the performance of the imager in terms of integrated reflectivity (R(int)) and temperature dependent collection efficiency (η(Te)) to that of the widely used Cu Kα imager. Our collisional-radiative simulations show that the new imager can be reliably used up to 250 eV plasma temperature. Monte Carlo simulations show that for a 25 µm thick tracer layer of zirconium, the contribution to Kα production from photo-pumping is only 2%. We present, for the first time, 2D spatially resolved images of zirconium plasmas generated by a high intensity short pulse laser interacting with Zr solid targets.

Limitation on prepulse level for cone-guided fast-ignition inertial confinement fusion.

The viability of fast-ignition (FI) inertial confinement fusion hinges on the efficient transfer of laser energy to the compressed fuel via multi-MeV electrons. Preformed plasma due to the laser prepulse strongly influences ultraintense laser plasma interactions and hot electron generation in the hollow cone of an FI target. We induced a prepulse and consequent preplasma in copper cone targets and measured the energy deposition zone of the main pulse by imaging the emitted K_{alpha} radiation. Simulation of the radiation hydrodynamics of the preplasma and particle in cell modeling of the main pulse interaction agree well with the measured deposition zones and provide an insight into the energy deposition mechanism and electron distribution. It was demonstrated that a under these conditions a 100 mJ prepulse eliminates the forward going component of approximately 2-4 MeV electrons.

Rare white-flowered morphs increase the reproductive success of common purple morphs in a food-deceptive orchid.

How floral colour polymorphism can be maintained in evolutionary time is still debated. In rewardless orchids, it is unknown whether rare white-flowered morphs differ in scent chemistry from pigmented morphs, and whether such intraspecific variation in floral signals may have an impact on reproductive success. We compared the chemical composition of floral volatiles emitted by white- and purple-flowered morphs of Orchis mascula, and recorded the fruit set of both colour morphs. We also used white ping-pong balls to mimic white-flowered morphs in field bioassays. We found that colour polymorphism was not associated with floral odour polymorphism. Surprisingly, when populations of purple-flowered plants included a few white-flowered individuals, the fruit set of the purple morph increased significantly (from 6 to 27%), while that of the white morph remained low. We obtained the same fourfold increase in fruit set when using ping-pong balls as visual lures, demonstrating the association between colour variation and fruit set, and the key role of visual signals in pollinator attraction. Our results are incompatible with negative frequency-dependent selection, a hypothesis invoked to explain colour polymorphism in other rewardless orchids. We propose several hypotheses to explain the maintenance of white morphs in O. mascula.

Effect of reentrant cone geometry on energy transport in intense laser-plasma interactions.

The energy transport in cone-guided low- Z targets has been studied for laser intensities on target of 2.5x10(20) W cm(-2). Extreme ultraviolet (XUV) imaging and transverse optical shadowgraphy of the rear surfaces of slab and cone-slab targets show that the cone geometry strongly influences the observed transport patterns. The XUV intensity showed an average spot size of 65+/-10 microm for slab targets. The cone slabs showed a reduced spot size of 44+/-10 microm. The shadowgraphy for the aforementioned shots demonstrate the same behavior. The transverse size of the expansion pattern was 357+/-32 microm for the slabs and reduced to 210+/-30 microm. A transport model was constructed which showed that the change in transport pattern is due to suppression of refluxing electrons in the material surrounding the cone.

A dual-channel, curved-crystal spectrograph for petawatt laser, x-ray backlighter source studies.

A dual-channel, curved-crystal spectrograph was designed to measure time-integrated x-ray spectra in the approximately 1.5 to 2 keV range (6.2-8.2 A wavelength) from small-mass, thin-foil targets irradiated by the VULCAN petawatt laser focused up to 4x10(20) W/cm(2). The spectrograph consists of two cylindrically curved potassium-acid-phthalate crystals bent in the meridional plane to increase the spectral range by a factor of approximately 10 compared to a flat crystal. The device acquires single-shot x-ray spectra with good signal-to-background ratios in the hard x-ray background environment of petawatt laser-plasma interactions. The peak spectral energies of the aluminum He(alpha) and Ly(alpha) resonance lines were approximately 1.8 and approximately 1.0 mJ/eV sr (approximately 0.4 and 0.25 J/A sr), respectively, for 220 J, 10 ps laser irradiation.

Determination of electron-heated temperatures of petawatt laser-irradiated foil targets with 256 and 68 eV extreme ultraviolet imaging.

Measurements of plasma temperature at the rear surface of foil targets due to heating by hot electrons, which were produced in short pulse high intensity laser matter interactions using the 150 J, 0.5 ps Titan laser, are reported. Extreme ultraviolet (XUV) imaging at 256 and 68 eV energies is used to determine spatially resolved target rear surface temperature patterns by comparing absolute intensities to radiation hydrodynamic modeling. XUV mirrors at these two energies were absolutely calibrated at the Advanced Light Source at the Lawrence Berkeley Laboratory. Temperatures deduced from both imagers are validated against each other within the range of 75-225 eV.

A Bremsstrahlung spectrometer using k-edge and differential filters with image plate dosimeters.

A Bremsstrahlung spectrometer using k-edge and differential filtering has been used with image plate dosimeters to measure the x-ray fluence from short-pulse laser/target interactions. An electron spectrometer in front of the Bremsstrahlung spectrometer deflects electrons from the x-ray line of sight and simultaneously measures the electron spectrum. The response functions were modeled with the Monte Carlo code INTEGRATED TIGER SERIES 3.0 and the dosimeters calibrated with radioactive sources. An electron distribution with a slope temperature of 1.3 MeV is inferred from the Bremsstrahlung spectra.

Electron heated target temperature measurements in petawatt laser experiments based on extreme ultraviolet imaging and spectroscopy.

Three independent methods (extreme ultraviolet spectroscopy, imaging at 68 and 256 eV) have been used to measure planar target rear surface plasma temperature due to heating by hot electrons. The hot electrons are produced by ultraintense laser-plasma interactions using the 150 J, 0.5 ps Titan laser. Soft x-ray spectroscopy in the 50-400 eV region and imaging at the 68 and 256 eV photon energies give a planar deuterated carbon target rear surface pre-expansion temperature in the 125-150 eV range, with the rear plasma plume averaging a temperature approximately 74 eV.

Diagnostics for fast ignition science (invited).

The ignition concept for electron fast ignition inertial confinement fusion requires sufficient energy be transferred from an approximately 20 ps laser pulse to the compressed fuel via approximately MeV electrons. We have assembled a suite of diagnostics to characterize such transfer, simultaneously fielding absolutely calibrated extreme ultraviolet multilayer imagers at 68 and 256 eV; spherically bent crystal imagers at 4.5 and 8 keV; multi-keV crystal spectrometers; MeV x-ray bremmstrahlung, electron and proton spectrometers (along the same line of sight), and a picosecond optical probe interferometer. These diagnostics allow careful measurement of energy transport and deposition during and following the laser-plasma interactions at extremely high intensities in both planar and conical targets. Together with accurate on-shot laser focal spot and prepulse characterization, these measurements are yielding new insights into energy coupling and are providing critical data for validating numerical particle-in-cell (PIC) and hybrid PIC simulation codes in an area crucial for fast ignition and other applications. Novel aspects of these diagnostics and how they are combined to extract quantitative data on ultrahigh intensity laser-plasma interactions are discussed.

Plasma jets driven by ultraintense-laser interaction with thin foils.

Experimental evidence of plasma jets ejected from the rear side of thin solid targets irradiated by ultraintense (>10(19) W cm(-2)) laser pulses is presented. The jets, detected by transverse interferometric measurements with high spatial and temporal resolutions, show collimated expansion lasting for several hundreds of picoseconds and have substantially steep density gradients at their periphery. The role played by radiation pressure of the laser in the jet formation process is highlighted analytically and by extensive two-dimensional particle-in-cell simulations.