Multi-GeV wakefield acceleration in a plasma-modulated plasma accelerator.

We investigate the accelerator stage of a plasma-modulated plasma accelerator (P-MoPA) [Jakobsson et al., Phys. Rev. Lett. 127, 184801 (2021)0031-900710.1103/PhysRevLett.127.184801] using both the paraxial wave equation and particle-in-cell (PIC) simulations. We show that adjusting the laser and plasma parameters of the modulator stage of a P-MoPA allows the temporal profile of pulses within the pulse train to be controlled, which in turn allows the wake amplitude in the accelerator stage to be as much as 72% larger than that generated by a plasma beat-wave accelerator with the same total drive laser energy. Our analysis shows that Rosenbluth-Liu detuning is unimportant in a P-MoPA if the number of pulses in the train is less than ∼30, and that this detuning is also partially counteracted by increased red-shifting, and hence increased pulse spacing, towards the back of the train. An analysis of transverse mode oscillations of the driving pulse train is found to be in good agreement with 2D (Cartesian) PIC simulations. PIC simulations demonstrating energy gains of ∼1.5GeV (∼2.5GeV) for drive pulse energies of 2.4J (5.0J) are presented. Our results suggest that P-MoPAs driven by few-joule, picosecond pulses, such as those provided by high-repetition-rate thin-disk lasers, could accelerate electron bunches to multi-GeV energies at pulse repetition rates in the kilohertz range.

Measurement of the decay of laser-driven linear plasma wakefields.

We present measurements of the temporal decay rate of one-dimensional (1D), linear Langmuir waves excited by an ultrashort laser pulse. Langmuir waves with relative amplitudes of approximately 6% were driven by 1.7J, 50fs laser pulses in hydrogen and deuterium plasmas of density n_{e0}=8.4×10^{17}cm^{-3}. The wakefield lifetimes were measured to be τ_{wf}^{H_{2}}=(9±2) ps and τ_{wf}^{D_{2}}=(16±8) ps, respectively, for hydrogen and deuterium. The experimental results were found to be in good agreement with 2D particle-in-cell simulations. In addition to being of fundamental interest, these results are particularly relevant to the development of laser wakefield accelerators and wakefield acceleration schemes using multiple pulses, such as multipulse laser wakefield accelerators.

Stability of the modulator in a plasma-modulated plasma accelerator.

We explore the regime of operation of the modulator stage of a recently proposed laser-plasma accelerator scheme [Phys. Rev. Lett. 127, 184801 (2021)0031-900710.1103/PhysRevLett.127.184801], dubbed the plasma-modulated plasma accelerator (P-MoPA). The P-MoPA scheme offers a potential route to high-repetition-rate, GeV-scale plasma accelerators driven by picosecond-duration laser pulses from, for example, kilohertz thin-disk lasers. The first stage of the P-MoPA scheme is a plasma modulator in which a long, high-energy "drive" pulse is spectrally modulated by copropagating in a plasma channel with the low-amplitude plasma wave driven by a short, low-energy "seed" pulse. The spectrally modulated drive pulse is converted to a train of short pulses, by introducing dispersion, which can resonantly drive a large wakefield in a subsequent accelerator stage with the same on-axis plasma density as the modulator. In this paper we derive the 3D analytic theory for the evolution of the drive pulse in the plasma modulator and show that the spectral modulation is independent of transverse coordinate, which is ideal for compression into a pulse train. We then identify a transverse mode instability (TMI), similar to the TMI observed in optical fiber lasers, which sets limits on the energy of the drive pulse for a given set of laser-plasma parameters. We compare this analytic theory with particle-in-cell (PIC) simulations and find that even higher energy drive pulses can be modulated than those demonstrated in the original proposal.

Modulational instability in large-amplitude linear laser wakefields.

We investigate the growth of ion density perturbations in large-amplitude linear laser wakefields via two-dimensional particle-in-cell simulations. Growth rates and wave numbers are found to be consistent with a longitudinal strong-field modulational instability. We examine the transverse dependence of the instability for a Gaussian wakefield envelope and show that growth rates and wave numbers can be maximized off axis. On-axis growth rates are found to decrease with increasing ion mass or electron temperature. These results are in close agreement with the dispersion relation of a Langmuir wave with an energy density that is large compared to the plasma thermal energy density. The implications for wakefield accelerators, in particular multipulse schemes, are discussed.

All-Optical GeV Electron Bunch Generation in a Laser-Plasma Accelerator via Truncated-Channel Injection.

We describe a simple scheme, truncated-channel injection, to inject electrons directly into the wakefield driven by a high-intensity laser pulse guided in an all-optical plasma channel. We use this approach to generate dark-current-free 1.2 GeV, 4.5% relative energy spread electron bunches with 120 TW laser pulses guided in a 110 mm-long hydrodynamic optical-field-ionized plasma channel. Our experiments and particle-in-cell simulations show that high-quality electron bunches were only obtained when the drive pulse was closely aligned with the channel axis, and was focused close to the density down ramp formed at the channel entrance. Start-to-end simulations of the channel formation, and electron injection and acceleration show that increasing the channel length to 410 mm would yield 3.65 GeV bunches, with a slice energy spread ∼5×10^{-4}.

Fluorine-18 fluorodeoxyglucose positron emission tomography-computed tomography for staging of canine insulinoma: 3 cases (2019-2020).

OBJECTIVES: Canine insulinomas are uncommon malignant functional pancreatic neuroendocrine tumours with a high metastatic rate. Diagnostic imaging aids with staging and surgical planning of these tumours; however, identification is unpredictable across modalities. High-grade human pancreatic neuroendocrine tumours display increased avidity on 18 F-fluorodeoxyglucose positron emission tomography-CT. MATERIALS AND METHODS: Dogs with clinicopathologic findings consistent with pancreatic insulinoma were prospectively enrolled. Patients underwent 18 F-fluorodeoxyglucose positron emission tomography-CT and CT angiography, followed by exploratory laparotomy. RESULTS: Three patients met the inclusion criteria and had histologically confirmed insulinomas. Both metastatic lesions in patient 1 were mildly avid (SUVmax 2.79 and 3.01). In patient 2, the primary pancreatic insulinoma was minimally avid (SUVmax 2.16). The primary pancreatic lesion in patient 3 had similar avidity to normal pancreatic parenchyma (SUVmax 1.54) and was undetected on 18 F-fluorodeoxyglucose positron emission tomography-CT. Insulinomas demonstrated variable attenuation and contrast enhancement patterns on CT angiography and certain lesions were more conspicuous than on 18 F-fluorodeoxyglucose positron emission tomography-CT. Two metastatic lesions not visible on either imaging modality were discovered in patient 2 at surgery. CLINICAL SIGNIFICANCE: Canine insulinomas were inconsistently avid on 18 F-fluorodeoxyglucose positron emission tomography-CT. This finding is likely attributable to the confounding clinicopathological features and multifaceted transformation of these tumours, in addition to the influence of variable tumour size, composition and vascularity. Unpredictable tumoural avidity limits the value of 18 F-fluorodeoxyglucose positron emission tomography-CT for staging canine insulinomas.

Gev-Scale Accelerators Driven by Plasma-Modulated Pulses from Kilohertz Lasers.

We describe a new approach for driving GeV-scale plasma accelerators with long laser pulses. We show that the temporal phase of a long, high-energy driving laser pulse can be modulated periodically by copropagating it with a low-amplitude plasma wave driven by a short, low-energy seed pulse. Compression of the modulated driver by a dispersive optic generates a train of short pulses suitable for resonantly driving a plasma accelerator. Modulation of the driver occurs via well-controlled linear processes, as confirmed by good agreement between particle-in-cell (PIC) simulations and an analytic model. PIC simulations demonstrate that a 1.7 J, 1 ps driver, and a 140 mJ, 40 fs seed pulse can accelerate electrons to energies of 0.65 GeV in a plasma channel with an axial density of 2.5×10^{17} cm^{-3}. This work opens a route to high repetition-rate, GeV-scale plasma accelerators driven by thin-disk lasers, which can provide joule-scale, picosecond-duration laser pulses at multikilohertz repetition rates and high wall-plug efficiencies.

Meter-scale conditioned hydrodynamic optical-field-ionized plasma channels.

We demonstrate through experiments and numerical simulations that low-density, low-loss, meter-scale plasma channels can be generated by employing a conditioning laser pulse to ionize the neutral gas collar surrounding a hydrodynamic optical-field-ionized (HOFI) plasma channel. We use particle-in-cell simulations to show that the leading edge of the conditioning pulse ionizes the neutral gas collar to generate a deep, low-loss plasma channel which guides the bulk of the conditioning pulse itself as well as any subsequently injected pulses. In proof-of-principle experiments, we generate conditioned HOFI (CHOFI) waveguides with axial electron densities of n_{e0}≈1×10^{17}cm^{-3} and a matched spot size of 26µm. The power attenuation length of these CHOFI channels was calculated to be L_{att}=(21±3)m, more than two orders of magnitude longer than achieved by HOFI channels. Hydrodynamic and particle-in-cell simulations demonstrate that meter-scale CHOFI waveguides with attenuation lengths exceeding 1 m could be generated with a total laser pulse energy of only 1.2 J per meter of channel. The properties of CHOFI channels are ideally suited to many applications in high-intensity light-matter interactions, including multi-GeV plasma accelerator stages operating at high pulse repetition rates.

Hydrodynamic optical-field-ionized plasma channels.

We present experiments and numerical simulations which demonstrate that fully ionized, low-density plasma channels could be formed by hydrodynamic expansion of plasma columns produced by optical field ionization. Simulations of the hydrodynamic expansion of plasma columns formed in hydrogen by an axicon lens show the generation of 200 mm long plasma channels with axial densities of order n_{e}(0)=1×10^{17}cm^{-3} and lowest-order modes of spot size W_{M}≈40µm. These simulations show that the laser energy required to generate the channels is modest: of order 1 mJ per centimeter of channel. The simulations are confirmed by experiments with a spherical lens which show the formation of short plasma channels with 1.5×10^{17}cm^{-3}≲n_{e}(0)≲1×10^{18}cm^{-3} and 61µm≳W_{M}≳33µm. Low-density plasma channels of this type would appear to be well suited as multi-GeV laser-plasma accelerator stages capable of long-term operation at high pulse repetition rates.

47Sc production development by cyclotron irradiation of 48Ca.

The therapeutic radionuclide 47Sc was produced through the 48Ca(p,2n) channel on a proton beam accelerator. The obtained results show that the optimum proton energies are in the range of 24-17 MeV, giving the possibility to produce 47Sc radionuclide containing 7.4% of 48Sc. After activation, the powdery CaCO3 target material was dissolved in HCl and scandium isotopes were isolated from the targets. The performed separation experiments indicate that, due to the simplicity of the operations and the chemical purity of the obtained 47Sc the best separation process is when scandium radioisotopes are separated on the 0.2 µm filter.

Excitation and Control of Plasma Wakefields by Multiple Laser Pulses.

We demonstrate experimentally the resonant excitation of plasma waves by trains of laser pulses. We also take an important first step to achieving an energy recovery plasma accelerator by showing that a plasma wave can be damped by an out-of-resonance trailing laser pulse. The measured laser wakefields are found to be in excellent agreement with analytical and numerical models of wakefield excitation in the linear regime. Our results indicate a promising direction for achieving highly controlled, GeV-scale laser-plasma accelerators operating at multikilohertz repetition rates.

Assessing the safety of del Nido cardioplegia solution in adult congenital cases.

PURPOSE: del Nido cardioplegia solution (CPS) has been successfully used for myocardial protection in the pediatric population. We propose this solution can be used safely in adult congenital patients. The proposed benefit of this solution is the avoidance of the need for repetitive interruption of the operation to administer multiple doses of standard cardioplegia. METHODS: As part of a quality improvement initiative, 47 consecutive adult patients (mean age 40.9 years, range 18-71) undergoing congenital heart surgery were given del Nido CPS. Cardiac function was assessed pre- and post-operatively by echocardiography (ECHO). Inotrope use, troponin levels and restoration of cardiac rhythm were also evaluated. RESULTS: The average duration of the longest ischemic time was 52.5 minutes ± 15.57 minutes. In patients receiving a single dose (40%, n=19) of CPS, the average ischemic time was 49.8 minutes ± 18.8 minutes. No patients demonstrated any ventricular electrical activity while the aorta was cross-clamped. Post-operative ECHO showed that 94% (n=44) had no change in ejection fraction from the pre-operative ECHO. Patients requiring inotropic support at the time of leaving the operating room (OR) was 43% (n=20). The percentage of patients requiring inotropic support twenty-four hours post-operatively was 17% (n=8). Spontaneous restoration of cardiac rhythm (without the need for defibrillation) after cross-clamp removal occurred in 91% (n=43) of patients. The average troponin T level post-op was 1.86 ± 2.9 µg/L. CONCLUSIONS: del Nido CPS can be used for myocardial protection during adult congenital cardiac surgery without any apparent adverse effects. In addition, we were able to change our re-dosing protocol to 45 minutes with del Nido CPS compared to 20 minutes with our adult 4:1 blood CPS.

Carboxyhemoglobinemia in a pediatric cardiopulmonary bypass patient derived from a contaminated unit of allogenic blood.

A 4.3 kg, three-month-old patient, diagnosed with a perimembranous ventricular septal defect, presented for cardiac surgery. Upon initiation of cardiopulmonary bypass (CPB), the patient developed carboxyhemoglobinemia (11.1%). Potential sources for the unexpected acquired carboxyhemoglobinemia were sought quickly. Testing of residual blood from the unit of packed red blood cells (PRBCs) used to prime the CPB circuit revealed a carboxyhemoglobin (COHb) of 15.1 %. A decrease in cerebral oximetry (rSO(2)) on CPB was initially felt to be a result of the elevated COHb levels. When ventilation of the oxygenator with 100% oxygen (O(2)) failed to decrease COHb levels, a partial exchange transfusion was performed with reduction in COHb to 7.1%. The operation was completed successfully and the patient's COHb levels returned to normal within 75 minutes. Post case analysis of events and data collected during the case revealed a broader differential for explaining the compromised patient's O(2) delivery than the transient acquired carboxyhemoglobinemia. A partial obstruction of the superior vena cava could have triggered the drop in rSO(2) on CPB. Follow-up of the donor blood confirmed the donor had previously undiagnosed carboxyhemoglobinemia as a result of chronic carbon monoxide exposure from a faulty vehicle exhaust system.

A clinical evaluation of the Dideco Kids D100 neonatal oxygenator.

In August 2006, Duke University Perfusion Services had the opportunity to be the first institution in the United States to clinically evaluate the Dideco D100 Neonatal Oxygenator. The device was used on six pediatric patients to facilitate correction or palliation of their cardiac defects, which included two arterial switch operations, two truncus arteriosus repairs, one stage 1 Norwood and one repair of total anomalous pulmonary venous return. The average patient weight was 3.1 kg. The average cardiopulmonary bypass (CPB) time was 135 minutes and the average cross-clamp time was 61 minutes. Arterial and venous blood gasses were drawn and used to calculate oxygen transfer. The average oxygen transfer was 14.8 +/- 10.3 ml/O2/min. The Dideco D100 Oxygenator is the first oxygenation device designed specifically for neonates. The Dideco D100 is a microporous hollow-fiber device. It has a static priming volume of 31 ml and a maximum rated flow of 700 ml/min. The integral hard-shell venous reservoir has a minimum operating level of 10 ml and a reservoir capacity of 500 ml. For this evaluation, the Dideco Kids D100 Neonatal Oxygenator performed adequately on patients weighing up to 5 kg. This device provides an excellent first step towards offering very small children appropriate circuitry without having to sacrifice safety or performance.

Autoregulation of the human liver X receptor alpha promoter.

Previous work has implicated the nuclear receptors liver X receptor alpha (LXR alpha) and LXR beta in the regulation of macrophage gene expression in response to oxidized lipids. Macrophage lipid loading leads to ligand activation of LXRs and to induction of a pathway for cholesterol efflux involving the LXR target genes ABCA1 and apoE. We demonstrate here that autoregulation of the LXR alpha gene is an important component of this lipid-inducible efflux pathway in human macrophages. Oxidized low-density lipoprotein, oxysterols, and synthetic LXR ligands induce expression of LXR alpha mRNA in human monocyte-derived macrophages and human macrophage cell lines but not in murine peritoneal macrophages or cell lines. This is in contrast to peroxisome proliferator-activated receptor gamma (PPAR gamma)-specific ligands, which stimulate LXR alpha expression in both human and murine macrophages. We further demonstrate that LXR and PPAR gamma ligands cooperate to induce LXR alpha expression in human but not murine macrophages. Analysis of the human LXR alpha promoter led to the identification of multiple LXR response elements. Interestingly, the previously identified PPAR response element (PPRE) in the murine LXR alpha gene is not conserved in humans; however, a different PPRE is present in the human LXR 5'-flanking region. These results have implications for cholesterol metabolism in human macrophages and its potential to be regulated by synthetic LXR and/or PPAR gamma ligands. The ability of LXR alpha to regulate its own promoter is likely to be an integral part of the macrophage physiologic response to lipid loading.

Bioconversion of the anthracycline analogue desacetyladriamycin by recombinant DoxA, a P450-monooxygenase from Streptomyces sp. strain C5.

[reaction: see text] A recombinant P450-monooxygenase, DoxA, obtained from Streptomyces sp. strain C5, the producer of the anticancer compound daunorubicin, was expressed in S. lividans TK24 and therein used to catalyze the conversion of the anthracycline analogue desacetyladriamycin into the new anthracycline, 10-hydroxydesacetyladriamycin. This work establishes a new function for DoxA and demonstrates the use of a recombinant enzyme to prepare a new anthracycline analogue.

Structural analysis of new local features in SECIS RNA hairpins.

Decoding of the UGA selenocysteine codon for selenoprotein translation requires the SECIS element, a stem-loop motif in the 3'-UTR of the mRNA carrying short or large apical loops. In previous structural studies, we derived a secondary structure model for SECIS RNAs with short apical loops. Work from others proposed that intra-apical loop base pairing can occur in those SECIS that possess large apical loops, yielding form 2 SECIS versus the form 1 with short loops. In this work, SECIS elements arising from eight different selenoprotein mRNAs were assayed by enzymatic and/or chemical probing showing that seven can adopt form 2. Further, database searches led to the discovery in drosophila and zebrafish of SECIS elements in the selenophosphate synthetase 2, type 1 deiodinase and SelW mRNAs. Alignment of SECIS sequences not only highlighted the predominance of form 2 but also made it possible to classify the SECIS elements according to the type of selenoprotein mRNA they belong to. Interestingly, the alignment revealed that an unpaired adenine, previously thought to be invariant, is replaced by a guanine in four SECIS elements. Tested in vivo, neither the A to G nor the A to U changes at this position greatly affected the activity while the most detrimental effect was provided by a C. The putative contribution of the various SECIS motifs to function and ligand binding is discussed.

Nonactin biosynthesis: the potential nonactin biosynthesis gene cluster contains type II polyketide synthase-like genes.

Nonactin is the parent compound of a group of highly atypical polyketide metabolites produced by Streptomyces griseus subsp. griseus ETH A7796. In this paper we describe the isolation, sequencing, and analysis of 15¿ omitted¿559 bp of chromosomal DNA, containing the potential nonactin biosynthesis gene cluster, from S. griseus subsp. griseus ETH A7796. Fourteen open reading frames were observed in the DNA sequence. Significantly, type II polyketide synthase (PKS) homologues were discovered in an apparent operon structure, which also contained the nonactate synthase gene (nonS), clustered with the tetranactin resistance gene. The deduced products of two of the genes (nonK and nonJ) are quite unusual ketoacyl synthase (KAS) alpha and KASbeta homologues. We speculate that nonactic acid, the polyketide precursor of nonactin, is synthesized by a type II PKS system.

Purification, properties, and characterization of recombinant Streptomyces sp. strain C5 DoxA, a cytochrome P-450 catalyzing multiple steps in doxorubicin biosynthesis.

DoxA is a cytochrome P-450 monooxygenase involved in the late stages of daunorubicin and doxorubicin biosynthesis that has a broad substrate specificity for anthracycline glycone substrates. Recombinant DoxA was purified to homogeneity from Streptomyces lividans transformed with a plasmid containing the Streptomyces sp. strain C5 doxA gene under the control of the strong SnpR-activated snpA promoter. The purified enzyme was a monomeric, soluble protein with an apparent Mr of 47,000. Purified DoxA catalyzed the 13-hydroxylation of 13-deoxydaunorubicin, the 13-oxidation of 13-dihydrocarminomycin and 13-dihydrodaunorubicin, and the 14-hydroxylation of daunorubicin. The pH optimum for heme activation was pH 7.5, and the temperature optimum was 30 degreesC. The kcat/Km values for the oxidation of anthracycline substrates by purified DoxA, incubated with appropriate electron-donating components, were as follows: for 13-deoxydaunorubicin, 22,000 M-1 x s-1; for 13-dihydrodaunorubicin, 14,000 M-1 x s-1; for 13-dihydrocarminomycin, 280 M-1 x s-1; and for daunorubicin, 130 M-1 x s-1. Our results indicate that the conversion of daunorubicin to doxorubicin by this enzyme is not a favored reaction and that the main anthracycline flux through the late steps of the daunorubicin biosynthetic pathway catalyzed by DoxA is likely directed through the 4-O-methyl series of anthracyclines.