Online charge measurement for petawatt laser-driven ion acceleration.

Laser-driven ion beams have gained considerable attention for their potential use in multidisciplinary research and technology. Preclinical studies into their radiobiological effectiveness have established the prospect of using laser-driven ion beams for radiotherapy. In particular, research into the beneficial effects of ultrahigh instantaneous dose rates is enabled by the high ion bunch charge and uniquely short bunch lengths present for laser-driven ion beams. Such studies require reliable, online dosimetry methods to monitor the bunch charge for every laser shot to ensure that the prescribed dose is accurately applied to the biological sample. In this paper, we present the first successful use of an Integrating Current Transformer (ICT) for laser-driven ion accelerators. This is a noninvasive diagnostic to measure the charge of the accelerated ion bunch. It enables online estimates of the applied dose in radiobiological experiments and facilitates ion beam tuning, in particular, optimization of the laser ion source, and alignment of the proton transport beamline. We present the ICT implementation and the correlation with other diagnostics, such as radiochromic films, a Thomson parabola spectrometer, and a scintillator.

Demonstration of non-destructive and isotope-sensitive material analysis using a short-pulsed laser-driven epi-thermal neutron source.

Neutrons are a valuable tool for non-destructive material investigation as their interaction cross sections with matter are isotope sensitive and can be used complementary to x-rays. So far, most neutron applications have been limited to large-scale facilities such as nuclear research reactors, spallation sources, and accelerator-driven neutron sources. Here we show the design and optimization of a laser-driven neutron source in the epi-thermal and thermal energy range, which is used for non-invasive material analysis. Neutron resonance spectroscopy, neutron radiography, and neutron resonance imaging with moderated neutrons are demonstrated for investigating samples in terms of isotope composition and thickness. The experimental results encourage applications in non-destructive and isotope-sensitive material analysis and pave the way for compact laser-driven neutron sources with high application potential.

Assessment of TP53 lesions for p53 system functionality and drug resistance in multiple myeloma using an isogenic cell line model.

Recent advances in molecular diagnostics have shown that lesions affecting both copies of the gene for tumor suppressor protein 53 (TP53) count among the most powerful predictors for high-risk disease in multiple myeloma (MM). However, the functional relevance and potential therapeutic implications of single hits to TP53 remain less well understood. Here, we have for the first time approximated the different constellations of mono- and bi-allelic TP53 lesions observed in MM patients within the frame of a single MM cell line model and assessed their potential to disrupt p53 system functionality and to impart drug resistance. Both types of common first hit: point mutation with expression of mutant p53 protein or complete loss of contribution from one of two wildtype alleles strongly impaired p53 system functionality and increased resistance to melphalan. Second hits abolished remaining p53 activity and increased resistance to genotoxic drugs even further. These results fit well with the clinical drive to TP53 single- and double-hit disease in MM patients, provide a rationale for the most commonly observed double-hit constellation (del17p+ TP53 point mutation), and underscore the potential increases in MM cell malignancy associated with any type of initial TP53 lesion.

Experimental verification of high energy laser-generated impulse for remote laser control of space debris.

Walking along a beach one may notice debris being washed ashore from the vast oceans. Then, turning your head up at night you even might noticed a shooting star or a bright spot passing by. Chances are, that you witnessed space debris, endangering future space flight in lower earth orbit. If it was possible to turn cm-sized debris into shooting stars the problem might be averted. Unfortunately, these fragments counting in the 100 thousands are not controllable. To possibly regain control we demonstrate how to exert forces on a free falling debris object from a distance by ablating material with a high energy ns-laser-system. Thrust effects did scale as expected from simulations and led to speed gains above 0.3 m/s per laser pulse in an evacuated micro-gravity environment.

GONG p-Mode Parameters Through Two Solar Cycles.

We investigate the parameters of global solar p-mode oscillations, namely damping width Γ , amplitude A , mean squared velocity 〈 v 2 〉 , energy E , and energy supply rate d E / d t , derived from two solar cycles' worth (1996 - 2018) of Global Oscillation Network Group (GONG) time series for harmonic degrees l = 0 - 150 . We correct for the effect of fill factor, apparent solar radius, and spurious jumps in the mode amplitudes. We find that the amplitude of the activity-related changes of Γ and A depends on both frequency and harmonic degree of the modes, with the largest variations of Γ for modes with 2400 µ Hz ≤ ν ≤ 3300 µ Hz and 31 ≤ l ≤ 60 with a minimum-to-maximum variation of 26.6 ± 0.3 % and of A for modes with 2400 µ Hz ≤ ν ≤ 3300 µ Hz and 61 ≤ l ≤ 100 with a minimum-to-maximum variation of 27.4 ± 0.4 % . The level of correlation between the solar radio flux F 10.7 and mode parameters also depends on mode frequency and harmonic degree. As a function of mode frequency, the mode amplitudes are found to follow an asymmetric Voigt profile with ν max = 3073.59 ± 0.18 µ Hz . From the mode parameters, we calculate physical mode quantities and average them over specific mode frequency ranges. In this way, we find that the mean squared velocities 〈 v 2 〉 and energies E of p modes are anticorrelated with the level of activity, varying by 14.7 ± 0.3 % and 18.4 ± 0.3 % , respectively, and that the mode energy supply rates show no significant correlation with activity. With this study we expand previously published results on the temporal variation of solar p-mode parameters. Our results will be helpful to future studies of the excitation and damping of p modes, i.e., the interplay between convection, magnetic field, and resonant acoustic oscillations.

Creation and characterization of free-standing cryogenic targets for laser-driven ion acceleration.

A technique for the creation of free-standing cryogenic targets for laser-driven ion acceleration is presented, which allows us to create solid state targets consisting of initially gaseous materials. In particular, the use of deuterium and the methods for its preparation as a target material for laser-driven ion acceleration are discussed. Moving in the phase diagram through the liquid phase leads to the substance covering an aperture on a cooled copper frame where it is solidified through further cooling. An account of characterization techniques for target thickness is given, with a focus on deducing thickness values from distance values delivered by chromatic confocal sensors.

Laser-plasmas in the relativistic-transparency regime: Science and applications.

Laser-plasma interactions in the novel regime of relativistically induced transparency (RIT) have been harnessed to generate intense ion beams efficiently with average energies exceeding 10 MeV/nucleon (>100 MeV for protons) at "table-top" scales in experiments at the LANL Trident Laser. By further optimization of the laser and target, the RIT regime has been extended into a self-organized plasma mode. This mode yields an ion beam with much narrower energy spread while maintaining high ion energy and conversion efficiency. This mode involves self-generation of persistent high magnetic fields (∼104 T, according to particle-in-cell simulations of the experiments) at the rear-side of the plasma. These magnetic fields trap the laser-heated multi-MeV electrons, which generate a high localized electrostatic field (∼0.1 T V/m). After the laser exits the plasma, this electric field acts on a highly structured ion-beam distribution in phase space to reduce the energy spread, thus separating acceleration and energy-spread reduction. Thus, ion beams with narrow energy peaks at up to 18 MeV/nucleon are generated reproducibly with high efficiency (≈5%). The experimental demonstration has been done with 0.12 PW, high-contrast, 0.6 ps Gaussian 1.053 µm laser pulses irradiating planar foils up to 250 nm thick at 2-8 × 1020 W/cm2. These ion beams with co-propagating electrons have been used on Trident for uniform volumetric isochoric heating to generate and study warm-dense matter at high densities. These beam plasmas have been directed also at a thick Ta disk to generate a directed, intense point-like Bremsstrahlung source of photons peaked at ∼2 MeV and used it for point projection radiography of thick high density objects. In addition, prior work on the intense neutron beam driven by an intense deuterium beam generated in the RIT regime has been extended. Neutron spectral control by means of a flexible converter-disk design has been demonstrated, and the neutron beam has been used for point-projection imaging of thick objects. The plans and prospects for further improvements and applications are also discussed.

Hydrothermal Oxidation of Fecal Sludge: Experimental Investigations and Kinetic Modeling.

Hydrothermal oxidation (HTO) provides an efficient technique to completely destroy wet organic wastes. In this study, HTO was applied to treat fecal sludge at well-defined experimental conditions. Four different kinetic models were adjusted to the obtained data. Among others, a distributed activation energy model (DAEM) was applied. A total of 33 experiments were carried out in an unstirred batch reactor with pressurized air as the oxidant at temperatures of <470 °C, oxygen-to-fuel equivalence ratios between 0 and 1.9, feed concentrations between 3.9 and 9.8 molTOC L-1 (TOC = total organic carbon), and reaction times between 86 and 1572 s. Decomposition of the fecal sludge was monitored by means of the conversion of TOC to CO2 and CO. In the presence of oxygen, ignition of the reaction was observed around 300 °C, followed by further rapid decomposition of the organic material. The TOC was completely decomposed to CO2 within 25 min at 470 °C and an oxygen-to-fuel equivalence ratio of 1.2. CO was formed as an intermediate product, and no other combustible products were found in the gas. At certain reaction conditions, the formation of unwanted coke and tarlike products occurred. The reaction temperature and oxygen-to-fuel equivalence ratio showed a significant influence on TOC conversion, while the initial TOC concentration did not. Conversion of TOC to CO2 could be well described with a first-order rate law and an activation energy of 39 kJ mol-1.

Towards highest peak intensities for ultra-short MeV-range ion bunches.

A laser-driven, multi-MeV-range ion beamline has been installed at the GSI Helmholtz center for heavy ion research. The high-power laser PHELIX drives the very short (picosecond) ion acceleration on µm scale, with energies ranging up to 28.4 MeV for protons in a continuous spectrum. The necessary beam shaping behind the source is accomplished by applying magnetic ion lenses like solenoids and quadrupoles and a radiofrequency cavity. Based on the unique beam properties from the laser-driven source, high-current single bunches could be produced and characterized in a recent experiment: At a central energy of 7.8 MeV, up to 5 × 10(8) protons could be re-focused in time to a FWHM bunch length of τ = (462 ± 40) ps via phase focusing. The bunches show a moderate energy spread between 10% and 15% (ΔE/E0 at FWHM) and are available at 6 m distance to the source und thus separated from the harsh laser-matter interaction environment. These successful experiments represent the basis for developing novel laser-driven ion beamlines and accessing highest peak intensities for ultra-short MeV-range ion bunches.

Diagnostics for studies of novel laser ion acceleration mechanisms.

Diagnostic for investigating and distinguishing different laser ion acceleration mechanisms has been developed and successfully tested. An ion separation wide angle spectrometer can simultaneously investigate three important aspects of the laser plasma interaction: (1) acquire angularly resolved energy spectra for two ion species, (2) obtain ion energy spectra for multiple species, separated according to their charge to mass ratio, along selected axes, and (3) collect laser radiation reflected from and transmitted through the target and propagating in the same direction as the ion beam. Thus, the presented diagnostic constitutes a highly adaptable tool for accurately studying novel acceleration mechanisms in terms of their angular energy distribution, conversion efficiency, and plasma density evolution.

Impact of S-adenosylmethionine decarboxylase 1 on pulmonary vascular remodeling.

BACKGROUND: Pulmonary hypertension (PH) is a life-threatening disease characterized by vascular remodeling and increased pulmonary vascular resistance. Chronic alveolar hypoxia in animals is often used to decipher pathways being regulated in PH. Here, we aimed to investigate whether chronic hypoxia-induced PH in mice can be reversed by reoxygenation and whether possible regression can be used to identify pathways activated during the reversal and development of PH by genome-wide screening. METHODS AND RESULTS: Mice exposed to chronic hypoxia (21 days, 10% O2) were reoxygenated for up to 42 days. Full reversal of PH during reoxygenation was evident by normalized right ventricular pressure, right heart hypertrophy, and muscularization of small pulmonary vessels. Microarray analysis from these mice revealed s-adenosylmethionine decarboxylase 1 (AMD-1) as one of the most downregulated genes. In situ hybridization localized AMD-1 in pulmonary vessels. AMD-1 silencing decreased the proliferation of pulmonary arterial smooth muscle cells and diminished phospholipase Cγ1 phosphorylation. Compared with the respective controls, AMD-1 depletion by heterozygous in vivo knockout or pharmacological inhibition attenuated PH during chronic hypoxia. A detailed molecular approach including promoter analysis showed that AMD-1 could be regulated by early growth response 1, transcription factor, as a consequence of epidermal growth factor stimulation. Key findings from the animal model were confirmed in human idiopathic pulmonary arterial hypertension. CONCLUSIONS: Our study indicates that genome-wide screening in mice from a PH model in which full reversal of PH occurs can be useful to identify potential key candidates for the reversal and development of PH. Targeting AMD-1 may represent a promising strategy for PH therapy.

Pre-plasma formation in experiments using petawatt lasers.

We used time-resolved shadowgraphy to characterize the pre-plasma formation in solid-target interaction experiments with micrometer-scale accuracy. We performed quantitative measurements of the plasma density for amplified spontaneous emission (ASE) levels ranging from 2 · 10(-7) to 10(-10) backed with 2-dimensional hydrodynamic simulations. We find that ASE levels above 10(-9) are able to create a significant pre-plasma plume that features a plasma canal driving a self-focusing of the laser beam. For ASE levels of 10(-10), no ASE pre-plasma could be detected.

A spectrometer on chemical vapour deposition-diamond basis for the measurement of the charge-state distribution of heavy ions in a laser-generated plasma.

This article reports on the development and the first applications of a new spectrometer which enables the precise and time-resolved measurement of both the energy loss and the charge-state distribution of ion beams with 10 < Z < 30 at energies of 4-8 MeV/u after their interaction with a laser-generated plasma. The spectrometer is based on five 20 × 7 mm(2) large and 20 µm thick polycrystalline diamond samples produced via the Chemical Vapour Deposition (CVD) process and was designed with the help of ion-optical simulations. First experiments with the spectrometer were successfully carried out at GSI using (48)Ca ions at an energy of 4.8 MeV/u interacting with a carbon plasma generated by the laser irradiation of a thin foil target. Owing to the high rate capability and the short response time of the spectrometer, pulsed ion beams with 10(3)-10(4) ions per bunch at a bunch frequency of 108 MHz could be detected. The temporal evolution of the five main charge states of the calcium ion beams as well as the corresponding energy loss values could be measured simultaneously. Due to the outstanding properties of diamond as a particle detector, a beam energy resolution ΔEE ≈ 0.1% could be reached using the presented experimental method, while a precision of 10% in the energy loss and charge-state distribution data was obtained.

Function of NADPH oxidase 1 in pulmonary arterial smooth muscle cells after monocrotaline-induced pulmonary vascular remodeling.

AIMS: Chronic hypoxia induces pulmonary hypertension (PH) that is concomitant with pulmonary vascular remodeling. Reactive oxygen species (ROS) are thought to play a major role in this. Recent findings suggest that ROS production by NADPH oxidase 4 (Nox4) is important in this remodeling. We investigated whether ROS production by Nox is also important in an inflammatory model of monocrotaline (MCT)-induced PH. We examined ROS production, their possible sources, and their impact on the function of pulmonary arterial smooth muscle cells (PASMC) isolated from MCT-treated and healthy rats. RESULTS: MCT-PASMC showed increased intracellular superoxide production, migration, and proliferation compared with healthy controls due to increased Nox1 expression. A comparison of PASMC from MCT- and nontreated rats revealed an up-regulation of Sod2, Nrf2, cyclin D1, and matrix metalloproteinase-9 (MMP-9) as well as an increased phosphorylation of cofilin and extracellular signal-regulated kinases (Erk). Expression of Sod2, Nrf2, and cyclin D1 and phosphorylation of cofilin and Erk were Nox1 dependent. INNOVATION: The role of ROS in PH is not fully understood. Mitochondria and Nox have been suggested as sources of altered ROS generation in PH, yet it remains unclear whether increased or decreased ROS contributes to the development of PH. Our studies provide evidence that for different triggers of PH, different Nox isoforms regulate proliferation and migration of PASMC. CONCLUSION: In contrast to hypoxia-induced PH, Nox1 but not Nox4 is responsible for pathophysiological proliferation and migration of PASMC in an inflammatory model of MCT-induced PH via increased superoxide production. Thus, different Nox isoforms may be targeted in different forms of PH.

The course of dynamic cerebral autoregulation during cervical internal carotid artery occlusion.

OBJECTIVES: The selection of patients with cervical internal carotid artery occlusion (ICAO) for extracranial-intracranial bypass surgery is based on exhausted cerebrovascular reactivity to vasodilatory stimuli. However, a spontaneous increase in this reactivity can occur with time, questioning the ideal time for bypass surgery. In contrast, the natural course of dynamic cerebral autoregulation is not known in these patients. METHODS: Patients with cervical ICAO were examined at baseline and after a mean interval of 15 months. Dynamic autoregulation was determined by transcranial Doppler sonography in both middle cerebral arteries via respiratory-induced 0.1-Hz oscillations (phase, available for n=47 patients) and correlation analysis between diastolic blood pressure and Doppler signal (index Dx, n=55 patients). Pre-defined cut-off values and repeatability measures of healthy controls were used to define significant individual changes in autoregulation. RESULTS: Group mean comparisons between studies were not significant for any autoregulation parameter. The intraclass correlation coefficient between studies was high for phase (ipsilateral: 0.83; contralateral: 0.74), and moderate for Dx (ipsilateral: 0.63; contralateral: 0.35). There was no clear trend for an improvement across cut-off values. A significant individual improvement/deterioration in autoregulation occurred in 6%/6% for phase and 13%/9% for Dx. DISCUSSION: Dynamic autoregulation only rarely improves during the course of ICAO. This finding should be considered when deciding for or against a policy of delaying extracranial-intracranial bypass surgery for reasons of a potentially improving hemodynamic status.

Inducible NOS inhibition reverses tobacco-smoke-induced emphysema and pulmonary hypertension in mice.

Chronic obstructive pulmonary disease (COPD) is one of the most common causes of death worldwide. We report in an emphysema model of mice chronically exposed to tobacco smoke that pulmonary vascular dysfunction, vascular remodeling, and pulmonary hypertension (PH) precede development of alveolar destruction. We provide evidence for a causative role of inducible nitric oxide synthase (iNOS) and peroxynitrite in this context. Mice lacking iNOS were protected against emphysema and PH. Treatment of wild-type mice with the iNOS inhibitor N(6)-(1-iminoethyl)-L-lysine (L-NIL) prevented structural and functional alterations of both the lung vasculature and alveoli and also reversed established disease. In chimeric mice lacking iNOS in bone marrow (BM)-derived cells, PH was dependent on iNOS from BM-derived cells, whereas emphysema development was dependent on iNOS from non-BM-derived cells. Similar regulatory and structural alterations as seen in mouse lungs were found in lung tissue from humans with end-stage COPD.

Heme oxygenase-2 and large-conductance Ca2+-activated K+ channels: lung vascular effects of hypoxia.

RATIONALE: Hypoxic pulmonary vasoconstriction (HPV) is an important mechanism by which pulmonary gas exchange is optimized by the adaptation of blood flow to alveolar ventilation. In chronic hypoxia, in addition to HPV a vascular remodeling process leads to pulmonary hypertension. A complex of heme oxygenase-2 (HO-2) and the BK channel has been suggested as a universal oxygen sensor system. OBJECTIVES: We investigated whether this complex serves as an oxygen sensor for the vascular effects of alveolar hypoxia in the lung. METHODS: The investigations were performed in chronically hypoxic mice, in isolated perfused and ventilated lungs, and on the cellular level, including HO-2- and BK-channel deficient mice. MEASUREMENTS AND MAIN RESULTS: Immunohistochemical analysis of mouse lungs identified HO-2 mainly in pulmonary arteries, the bronchial epithelium, and alveolar epithelial cells. BK channel alpha-subunit (BKalpha) immunoreactivity was found primarily in the bronchial and vascular smooth muscle layer. Immunofluorescence staining and coimmunoprecipitation suggested only a weak complexation of HO-2 and BKalpha in pulmonary arterial smooth muscle cells. The strength of acute and sustained HPV, determined in isolated perfused and ventilated lungs, was not different among wild-type, HO-2-deficient, and BKalpha-deficient mice. Exposure of mice to 3 weeks of chronic hypoxia resulted in a slight down-regulation of HO-2 and no alteration in BKalpha expression. The degree of pulmonary hypertension that developed, quantified on the basis of right ventricular pressure, right-heart hypertrophy, and the degree of muscularization of precapillary pulmonary arteries, was not different among wild-type, HO-2-deficient, and BKalpha-deficient mice. CONCLUSIONS: It is demonstrated that neither deletion of HO-2 nor BK channels affect acute, sustained, and chronic vascular responses to alveolar hypoxia in the lung.

Cerebral autoregulation dynamics in acute ischemic stroke after rtPA thrombolysis.

BACKGROUND: To investigate whether there is: (1) a specific temporal course of cerebral dysautoregulation in acute ischemic stroke, and (2) a separate detrimental effect of recombinant tissue plasminogen activator (rtPA) on autoregulation dynamics in this situation. METHODS: We studied 16 patients with acute middle cerebral artery (MCA) occlusion and rtPA thrombolysis (intra-arterial or intravenous application, or both). Controls were 71 healthy adults and 11 patients with minor stroke not receiving rtPA. Dynamic autoregulation was recorded from spontaneous fluctuations of blood pressure and MCA flow velocity (transcranial Doppler) using two well-described approaches (index Mx, phase shift). Three measurements were performed (study 1: 20 +/- 9 h of ictus; study 2: 64 +/- 10 h; study 3: 112 +/- 7 h). RESULTS: Two groups of clinical outcome were identified: good (modified Rankin scale 2, n = 7, MCA infarct volume = 62 +/- 21%). In the good outcome group, no relevant changes in Mx and phase were observed on both MCA sides compared with controls. In the poor outcome group, the index Mx deteriorated over studies 1-3 on affected sides, with worse values compared to the controls (p < 0.05). Phase was already impaired on affected sides of poor outcome patients in study 1 (p < 0.01 vs. controls) and tended to decrease further until study 3. Phase also decreased moderately on contralateral sides in poor outcome patients from studies 1 to 3 (p < 0.05, nonsignificant compared with controls). CONCLUSIONS: Cerebral autoregulation is increasingly impaired, mainly on the affected side, over the first 5 days of major ischemic stroke after unsuccessful rtPA thrombolysis. It is bilaterally preserved in minor stroke after successful rtPA thrombolysis, indicating no separate detrimental effect of rtPA on the cerebral autoregulatory mechanism.

Cerebral dysautoregulation and the risk of ischemic events in occlusive carotid artery disease.

Dynamic cerebral autoregulation assessed from blood pressure transients can be considerably impaired in severe internal carotid artery (ICA) obstruction. It is unknown whether impaired autoregulation indicates an increased risk of subsequent ischemic events in this situation. 165 patients with ICA stenosis (> 70 %) or occlusion were prospectively followed until anterior circulation stroke, transient ischemic attack, carotid recanalization without prior event, death or study end. Transcranial Doppler sonography was used to determine autoregulation in both middle cerebral arteries from spontaneous blood pressure fluctuations (correlation coefficient indices Dx and Mx) and respiratory- induced 0.1 Hz oscillations (phase). Standard CO(2) reactivity (CO(2)R) was additionally assessed. All indices were classified as impaired vs. preserved according to reference values from 79 agematched controls. During median follow-up of 24.5 months, there were 16 ischemic events over ipsilateral sides. Competing risk analysis revealed a significant predictive effect on ipsilateral ischemic events for impaired Dx (rate ratio 8.2 [95 % confidence interval 1.7-39], p = 0.0079), phase (5.0 [2-13], p = 0.0007) and CO(2)R (9.4 [2.2-40], p = 0.0025). Restricting analysis to severe stenosis alone (n = 103), only impaired phase (rate ratio 8.6 [1.6-45], p = 0.01) remained as a significant predictor. In a continuous statistical model, only Dx and Mx were significant predictors of ischemic events (p = 0.012 and p = 0.016). In conclusion, impaired dynamic cerebral autoregulation indicates an increased risk of subsequent ischemic events in severe obstructive ICA disease. Its clinical application might thus be of help in identifying higher risk patients.