Tripled yield in direct-drive laser fusion through statistical modelling.

Focusing laser light onto a very small target can produce the conditions for laboratory-scale nuclear fusion of hydrogen isotopes. The lack of accurate predictive models, which are essential for the design of high-performance laser-fusion experiments, is a major obstacle to achieving thermonuclear ignition. Here we report a statistical approach that was used to design and quantitatively predict the results of implosions of solid deuterium-tritium targets carried out with the 30-kilojoule OMEGA laser system, leading to tripling of the fusion yield to its highest value so far for direct-drive laser fusion. When scaled to the laser energies of the National Ignition Facility (1.9 megajoules), these targets are predicted to produce a fusion energy output of about 500 kilojoules-several times larger than the fusion yields currently achieved at that facility. This approach could guide the exploration of the vast parameter space of thermonuclear ignition conditions and enhance our understanding of laser-fusion physics.

Experimentally Inferred Fusion Yield Dependencies of OMEGA Inertial Confinement Fusion Implosions.

Statistical modeling of experimental and simulation databases has enabled the development of an accurate predictive capability for deuterium-tritium layered cryogenic implosions at the OMEGA laser [V. Gopalaswamy et al.,Nature 565, 581 (2019)10.1038/s41586-019-0877-0]. In this letter, a physics-based statistical mapping framework is described and used to uncover the dependencies of the fusion yield. This model is used to identify and quantify the degradation mechanisms of the fusion yield in direct-drive implosions on OMEGA. The yield is found to be reduced by the ratio of laser beam to target radius, the asymmetry in inferred ion temperatures from the ℓ=1 mode, the time span over which tritium fuel has decayed, and parameters related to the implosion hydrodynamic stability. When adjusted for tritium decay and ℓ=1 mode, the highest yield in OMEGA cryogenic implosions is predicted to exceed 2×10^{14} fusion reactions.

PIN1 is a new therapeutic target of craniosynostosis.

Gain-of-function mutations in fibroblast growth factor receptors (FGFRs) cause congenital skeletal anomalies, including craniosynostosis (CS), which is characterized by the premature closure of craniofacial sutures. Apert syndrome (AS) is one of the severest forms of CS, and the only treatment is surgical expansion of prematurely fused sutures in infants. Previously, we demonstrated that the prolyl isomerase peptidyl-prolyl cis-trans isomerase interacting 1 (PIN1) plays a critical role in mediating FGFR signaling and that Pin1+/- mice exhibit delayed closure of cranial sutures. In this study, using both genetic and pharmacological approaches, we tested whether PIN1 modulation could be used as a therapeutic regimen against AS. In the genetic approach, we crossbred Fgfr2S252W/+, a mouse model of AS, and Pin1+/- mice. Downregulation of Pin1 gene dosage attenuated premature cranial suture closure and other phenotypes of AS in Fgfr2S252W/+ mutant mice. In the pharmacological approach, we intraperitoneally administered juglone, a PIN1 enzyme inhibitor, to pregnant Fgfr2S252W/+ mutant mice and found that this treatment successfully interrupted fetal development of AS phenotypes. Primary cultured osteoblasts from Fgfr2S252W/+ mutant mice expressed high levels of FGFR2 downstream target genes, but this phenotype was attenuated by PIN1 inhibition. Post-translational stabilization and activation of Runt-related transcription factor 2 (RUNX2) in Fgfr2S252W/+ osteoblasts were also attenuated by PIN1 inhibition. Based on these observations, we conclude that PIN1 enzyme activity is important for FGFR2-induced RUNX2 activation and craniofacial suture morphogenesis. Moreover, these findings highlight that juglone or other PIN1 inhibitors represent viable alternatives to surgical intervention for treatment of CS and other hyperostotic diseases.

Navigation programs, are they helpful for perioperative care with thyroid cancer patients?

The purpose of this study was to develop and evaluate a navigation program for patients with thyroid cancer. The navigation program was developed following an analysis of the unmet needs of patients who underwent surgery for thyroid cancer. Ninety-nine patients in the control group received usual care, and 95 in the navigation group were managed with a navigation program during the perioperative period. The effectiveness of the navigation program was assessed by administering a questionnaire to both groups. Overall satisfaction scores were significantly higher in the navigation than in the control group (p = .025), as were satisfaction scores on the continuity of information (p < .001), the continuity of management (p = .002), the continuity of relationships with healthcare providers (p<.001), and patient empowerment (p < .001). The newly developed navigation program for patients with thyroid cancer was effective in raising satisfaction levels and in actively managing the disease during the perioperative period.

Clinical outcomes with pemetrexed-based systemic therapies in RET-rearranged lung cancers.

BACKGROUND: RET rearrangements are targetable, oncogenic lung cancer drivers. While previous series have shown durable clinical benefit with pemetrexed-based therapies in ALK- and ROS1-rearranged lung cancers, the benefits of pemetrexed-based treatments in patients with RET-rearranged lung cancers relative to other genomic subsets have not previously been explored. PATIENTS AND METHODS: A retrospective review of patients with pathologically confirmed stage IIIB/IV lung adenocarcinomas and evidence of a RET, ROS1, or ALK rearrangement, or a KRAS mutation was conducted. Patients were eligible if they received treatment with pemetrexed alone or in combination. The primary outcome of progression-free survival (PFS), and secondary outcomes of overall response rate (ORR, RECIST v1.1), time to progression (TTP), and time to treatment discontinuation were compared between RET-rearranged and groups of ROS1-rearranged, ALK-rearranged, and KRAS-mutant lung cancers. RESULTS: We evaluated 104 patients. Patients with RET-rearranged lung cancers (n = 18) had a median PFS of 19 months [95% confidence interval (CI) 12-not reached (NR)] that was comparable with patients with ROS1- (23 months, 95% CI 14-NR, n = 10) and ALK-rearranged (19 months, 95% CI 15-36, n = 36) lung cancers, and significantly improved compared with patients with KRAS-mutant lung cancers (6 months, 95% CI 5-9, P < 0.001, n = 40). ORR (45%), median TTP (20 months, 95% CI 17-NR), and median time to treatment discontinuation (21 months, 95% CI 6-NR) in patients with RET-rearranged lung cancers were not significantly different compared with patients with ALK- and ROS1-rearranged lung cancers, and improved compared with patients with KRAS-mutant lung cancers. CONCLUSION: Durable benefits with pemetrexed-based therapies in RET-rearranged lung cancers are comparable with ALK- and ROS1-rearranged lung cancers. When selecting therapies for patients with RET-rearranged lung cancers, pemetrexed-containing regimens should be considered.

Alpha Heating and Burning Plasmas in Inertial Confinement Fusion.

Estimating the level of alpha heating and determining the onset of the burning plasma regime is essential to finding the path towards thermonuclear ignition. In a burning plasma, the alpha heating exceeds the external input energy to the plasma. Using a simple model of the implosion, it is shown that a general relation can be derived, connecting the burning plasma regime to the yield enhancement due to alpha heating and to experimentally measurable parameters such as the Lawson ignition parameter. A general alpha-heating curve is found, independent of the target and suitable to assess the performance of all laser fusion experiments whether direct or indirect drive. The onset of the burning plasma regime inside the hot spot of current implosions on the National Ignition Facility requires a fusion yield of about 50 kJ.

Three-dimensional hot-spot x-ray emission tomography from cryogenic deuterium-tritium direct-drive implosions on OMEGA.

A three-dimensional model of the hot-spot x-ray emission has been developed and applied to the study of low-mode drive asymmetries in direct-drive inertial confinement fusion implosions on OMEGA with cryogenic deuterium-tritium targets. The steady-state model assumes an optically thin plasma and the data from four x-ray diagnostics along quasi-orthogonal lines of sight are used to obtain a tomographic reconstruction of the hot spot. A quantitative analysis of the hot-spot shape is achieved by projecting the x-ray emission into the diagnostic planes and comparing this projection to the measurements. The model was validated with radiation-hydrodynamic simulations assuming a mode-2 laser illumination perturbation resulting in an elliptically shaped hot spot, which was accurately reconstructed by the model using synthetic x-ray images. This technique was applied to experimental data from implosions in polar-direct-drive illumination geometry with a deliberate laser-drive asymmetry, and the hot-spot emission was reconstructed using spherical-harmonic modes of up to ℓ = 3. A 10% stronger drive on the equator relative to that on the poles resulted in a prolate-shaped hot spot at stagnation with a large negative A2,0 coefficient of A2,0 = -0.47 ± 0.03, directly connecting the modal contribution of the hot-spot shape with the modal contribution in laser-drive asymmetry.

Bound on hot-spot mix in high-velocity, high-adiabat direct-drive cryogenic implosions based on comparison of absolute x-ray and neutron yields.

In laser-driven implosions for laboratory fusion, the comparison of hot-spot x-ray yield to neutron production can serve to infer hot-spot mix. For high-performance direct-drive implosions, this ratio depends sensitively on the degree of equilibration between the ion and electron fluids. A scaling for x-ray yield as a function of neutron yield and characteristic ion and electron hot-spot temperatures is developed on the basis of simulations with varying degrees of equilibration. We apply this model to hot-spot x-ray measurements of direct-drive cryogenic implosions typical of the direct-drive designs with best ignition metrics. The comparison of the measured x-ray and neutron yields indicates that hot-spot mix, if present, is below a sensitivity estimated as ∼2% by-atom mix of ablator plastic into the hot spot.

Reconstructing 3D asymmetries in laser-direct-drive implosions on OMEGA.

Three-dimensional reconstruction algorithms have been developed, which determine the hot-spot velocity, hot-spot apparent ion temperature distribution, and fuel areal-density distribution present in laser-direct-drive inertial confinement fusion implosions on the OMEGA laser. These reconstructions rely on multiple independent measurements of the neutron energy spectrum emitted from the fusing plasma. Measurements of the neutron energy spectrum on OMEGA are made using a suite of quasi-orthogonal neutron time-of-flight detectors and a magnetic recoil spectrometer. These spectrometers are positioned strategically around the OMEGA target chamber to provide unique 3D measurements of the conditions of the fusing hot spot and compressed fuel near peak compression. The uncertainties involved in these 3D reconstructions are discussed and are used to identify a new nTOF diagnostic line of sight, which when built will reduce the uncertainty in the hot-spot apparent ion temperature distribution from 700 to <400 eV.

Achieving cellular resolution for in vivo retinal images of transgenic GFAP-GFP mice via image processing.

In vivo retinal images of transgenic mice, expressing GFP under the control of the GFAP (glial fibrillary acidic protein) promoter, have very poor signal-to-noise ratio (SNR) and cellular resolution such that the analysis of GFAP-GFP expressing retinal cells from these images can be a very challenging task. We report an image averaging method based on a pixel rank matching criterion which significantly enhances both these image attributes. We also show that it compares favorably against direct image averaging and a commercial averaging routine available from the Heidelberg Retinal Angiograph 2 software.

Diagnostic Accuracy of T1-Weighted Dynamic Contrast-Enhanced-MRI and DWI-ADC for Differentiation of Glioblastoma and Primary CNS Lymphoma.

BACKGROUND AND PURPOSE: Glioblastoma and primary CNS lymphoma dictate different neurosurgical strategies; it is critical to distinguish them preoperatively. However, current imaging modalities do not effectively differentiate them. We aimed to examine the use of DWI and T1-weighted dynamic contrast-enhanced-MR imaging as potential discriminative tools. MATERIALS AND METHODS: We retrospectively reviewed 18 patients with primary CNS lymphoma and 36 matched patients with glioblastoma with pretreatment DWI and dynamic contrast-enhanced-MR imaging. VOIs were drawn around the tumor on contrast-enhanced T1WI and FLAIR images; these images were transferred onto coregistered ADC maps to obtain the ADC and onto dynamic contrast-enhanced perfusion maps to obtain the plasma volume and permeability transfer constant. Histogram analysis was performed to determine the mean and relative ADCmean and relative 90th percentile values for plasma volume and the permeability transfer constant. Nonparametric tests were used to assess differences, and receiver operating characteristic analysis was performed for optimal threshold calculations. RESULTS: The enhancing component of primary CNS lymphoma was found to have significantly lower ADCmean (1.1 × 10-3 versus 1.4 × 10-3; P < .001) and relative ADCmean (1.5 versus 1.9; P < .001) and relative 90th percentile values for plasma volume (3.7 versus 5.0; P < .05) than the enhancing component of glioblastoma, but not significantly different relative 90th percentile values for the permeability transfer constant (5.4 versus 4.4; P = .83). The nonenhancing portions of glioblastoma and primary CNS lymphoma did not differ in these parameters. On the basis of receiver operating characteristic analysis, mean ADC provided the best threshold (area under the curve = 0.83) to distinguish primary CNS lymphoma from glioblastoma, which was not improved with normalized ADC or the addition of perfusion parameters. CONCLUSIONS: ADC was superior to dynamic contrast-enhanced-MR imaging perfusion, alone or in combination, in differentiating primary CNS lymphoma from glioblastoma.

Genomic Alterations and Outcomes with VEGF-Targeted Therapy in Patients with Clear Cell Renal Cell Carcinoma.

Background: Mutations in VHL, PBRM1, SETD2, BAP1, and KDM5C are common in clear cell renal cell carcinoma (ccRCC), and presence of certain mutations has been associated with outcomes in patients with non-metastatic disease. Limited information is available regarding the correlation between genomic alterations and outcomes in patients with metastatic disease, including response to VEGF-targeted therapy. Objective: To explore correlations between mutational profiles and cancer-specific outcomes, including response to standard VEGF-targeted agents, in patients with metastatic cc RCC. Methods: A retrospective review of 105 patients with metastatic ccRCC who had received systemic therapy and had targeted next-generation sequencing of tumors was conducted. Genomic alterations were correlated to outcomes, including overall survival and time to treatment failure to VEGF-targeted therapy. Results: The most frequent mutations were detected in VHL (83%), PBRM1 (51%), SETD2 (35%), BAP1 (24%), KDM5C (16%), and TERT (14%). Time to treatment failure with VEGF-targeted therapy differed significantly by PBRM1 mutation status (p = 0.01, median 12.0 months for MT versus 6.9 months for WT) and BAP1 mutation status (p = 0.01, median 6.4 months for MT versus 11.0 months for WT). Shorter overall survival was associated with TERT mutations (p = 0.03, median 29.6 months for MT versus 52.6 months for WT) or BAP1 mutations (p = 0.02, median 28.7 months for MT versus not reached for WT). Conclusions: Genomic alterations in ccRCC tumors have prognostic implications in patients with metastatic disease. BAP1 and TERT promoter mutations may be present in higher frequency than previously thought, and based on this data, deserve further study for their association with poor prognosis.

Core conditions for alpha heating attained in direct-drive inertial confinement fusion.

It is shown that direct-drive implosions on the OMEGA laser have achieved core conditions that would lead to significant alpha heating at incident energies available on the National Ignition Facility (NIF) scale. The extrapolation of the experimental results from OMEGA to NIF energy assumes only that the implosion hydrodynamic efficiency is unchanged at higher energies. This approach is independent of the uncertainties in the physical mechanism that degrade implosions on OMEGA, and relies solely on a volumetric scaling of the experimentally observed core conditions. It is estimated that the current best-performing OMEGA implosion [Regan et al., Phys. Rev. Lett. 117, 025001 (2016)10.1103/PhysRevLett.117.025001] extrapolated to a 1.9 MJ laser driver with the same illumination configuration and laser-target coupling would produce 125 kJ of fusion energy with similar levels of alpha heating observed in current highest performing indirect-drive NIF implosions.

Heptameric ring structure of the heat-shock protein ClpB, a protein-activated ATPase in Escherichia coli.

The heat-shock protein ClpB is a protein-activated ATPase that is essential for survival of Escherichia coli at high temperatures. ClpB has also recently been suggested to function as a chaperone in reactivation of aggregated proteins. In addition, the clpB gene has been shown to contain two translational initiation sites and therefore encode two polypeptides of different size. To determine the structural organization of ClpB, the ClpB proteins were subjected to chemical cross-linking analysis and electron microscopy. The average images of the ClpB proteins with end-on orientation revealed a seven-membered, ring-shaped structure with a central cavity. Their side-on view showed a two-layered structure with an equal distribution of mass across the equatorial plane of the complex. Since the ClpB subunit has two large regions containing consensus sequences for nucleotide binding, each layer of the ClpB heptamer appears to represent the side projection of one of the major domains arranged on a ring. In the absence of salt and ATP, the ClpB proteins showed a high tendency to form a heptamer. However, they dissociated into various species of oligomers with smaller sizes, depending on salt concentration. Above 0.2 M NaCl, the ClpB proteins behaved most likely as a monomer in the absence of ATP, but assembled into a heptamer in its presence. Furthermore, mutations of the first ATP-binding site, but not the second site, prevented the ATP-dependent oligomerization of the ClpB proteins in the presence of 0.3 M NaCl. These results indicate that ClpB has a heptameric ring-shaped structure with a central cavity and this structural organization requires ATP binding to the first nucleotide-binding site localized to the N-terminal half of the ATPase.

The phosphatidylinositol 3-kinase, p38, and extracellular signal-regulated kinase pathways are involved in osteoclast differentiation.

Phosphatidylinositol 3-kinase (PI 3-kinase) and mitogen-activated protein kinases (MAPKs) have been implicated in diverse cellular functions, including proliferation, migration, and survival. In this study, we examined the involvement of these kinases in osteoclast differentiation by employing specific inhibitors of the kinases. The osteoclast differentiation was assessed in three different culture systems: a coculture of mouse bone marrow cells with mouse calvarial osteoblasts, a mouse bone marrow cell culture in the presence of receptor activator of NF-kappaB ligand (RANKL) and macrophage-colony stimulating factor (M-CSF), and a culture of bone-resident osteoclast precursor cells driven by RANKL and M-CSF. LY294002, a specific inhibitor of PI 3-kinase, potently inhibited osteoclast differentiation in all culture systems when assessed by both tartrate-resistant acid phosphatase (TRAP) staining and dentine resorption assays. Inhibition of p38 MAPK by SB202190 resulted in a strong suppression in the exogenous RANKL dependent mouse bone marrow and bone resident precursor cell cultures. Another MAPK pathway inhibitor (PD98059), which blocks the activation of extracellular signal-regulated kinase (ERK) by inhibiting the upstream kinase MAPK-ERK kinase (MEK) 1, exerted an inhibitory effect on osteoclast differentiation only at the highest concentration tested (30 micromol/L) in many cases. Whether the signaling pathways involving these kinases are activated by RANKL was also examined. The RANKL-stimulated phosphorylation of Akt, a downstream target of PI 3-kinase, and that of ERK were observed. RANKL also stimulated the activity of p38. These results suggest that PI 3 kinase, p38, and ERK play roles in osteoclast differentiation, at least in part, by participating in RANKL signaling.

Conversion of normal human oral keratinocytes to tumorigenic cells is associated with the acquisition of resistance to TGF-beta.

Normal human epithelial cells cannot proliferate and undergo apoptosis in the presence of transforming growth factor-beta (TGF-beta) in vitro, but many human epidermoid cancer cells are resistant to TGF-beta. Resistance to TGF-beta may thus, in part, be responsible for uncontrolled proliferation of cancer cells. Though detailed mechanisms for the resistance of cancer cells to TGF-beta remain unknown, resistance may be due to decreased expression of TGF-beta receptors from cancer cells. To investigate this possibility, we determined the expression of TGF-beta and type II TGF-beta receptor in primary normal human oral keratinocytes (NHOK), human papillomavirus-immortalized human oral keratinocytes (HOK-16B) and two tumor cell lines derived from HOK-16B (CTHOK-16B-BaP and CTHOK-16B-DMBA). Our results show that (1) the cellular and secretory TGF-beta levels in immortalized and tumor cells were notably lower than in NHOK and (2) the level of type II TGF-beta receptor of the tested cells was similar to each other. Taken together, the conversion of NHOK to tumorigenic cells may, in part, be due to the acquisition of NHOK resistance to TGF-beta through underexpression of this cytokine.

Nickel (II)-induced apoptosis and G2/M enrichment.

Treatment with certain DNA-damaging agents induce a complex cellular response comprising pertubation of cell cycle progression and/or apoptosis on proliferating mammalian cells. Our studies were focused on the cellular effects of nickel (II) acetate, DNA-damaging agent, on Chinese hamster ovary (CHO) cells. Fragmented DNAs were examined by agarose gel electrophoresis and cell cycle was determined by DNA flow cytometry using propidium iodide fluorescence. Apparent DNA laddering was observed in cells treated with 240 microM nickel (II) and increased with a concentration-dependent manner. Treatment of nickel (II) acetate resulted in apoptosis which was accompanied by G2/M cell accumulation. Proportion of CHO cells in G2/M phase was also significantly increased in cells exposed to at least 480 microM nickel (II) from 57.7% of cells in the G0/G1 phase, 34.7% in the S phase, and 7.6% in the G2/M1 phase for 0 microM nickel (II), to 58.6%, 14.5%, and 26.9% for 640 microM nickel (II). These findings suggest that nickel (II) can modulate cellular response through some common effectors involving in both apoptotic and cell cycle regulatory pathways.

Purification and characterization of a poly-L-lysine-activated serine endoprotease from Lumbricus rubellus.

An endoprotease in earthworm (Lumbricus rubellus) is purified to apparent homogeneity using 125I-lactalbumin as a substrate. The protease has a molecular mass of 27 kDa and is markedly activated by poly-L-lysine or poly-L-arginine. It is a chymotrypsin-like serine protease. Its activity is distributed to coelomic fluid but relatively little to coelomocytes.

Korean population data on the PCR-based loci LDLR, GYPA, HBGG, D7S8, Gc, HLA-DQA1, and D1S80.

Korean population data was generated for the loci LDLR, GYPA, HBGG, D7S8, Gc, HLA-DQA1, and D1S80. The genotype frequency distributions for the loci do not deviate from Hardy Weinberg expectations. Furthermore, there was no evidence for departures from expectations of independence between the loci. Using a test for homogeneity all the loci, except for D1S80, were similar between the Korean population sample and a Chinese population sample.

Suberoylanilide hydroxamic acid enhances odontoblast differentiation.

Previous studies have shown that histone deacetylase (HDAC) inhibitors stimulate osteoblast differentiation in vitro and bone formation in vivo. However, the effects of HDAC inhibitors on odontoblasts have not been elucidated. Therefore, in this study, we examined the effect of suberoylanilide hydroxamic acid (SAHA), an HDAC inhibitor, on odontoblast differentiation using an MDPC23 odontoblast-like cell line. SAHA significantly enhanced matrix mineralization and the expression levels of odontoblast marker genes. SAHA increased the expression levels of nuclear factor I/C (Nfic) and dentin sialophosphoprotein (Dspp). Nfic bound directly to the Dspp promoter and stimulated Dspp transcription. SAHA increased both basal and Nfic-induced Dspp promoter activity. SAHA-induced Dspp promoter activity disappeared when mutations were introduced within the Nfic binding element of the Dspp promoter. Nfic knockdown by siRNA blocked SAHA stimulation of Dspp expression. These results indicate that SAHA enhances odontoblast differentiation and that SAHA increases Dspp expression, at least in part, by increasing the expression level of Nfic.