Fabrication of nested elliptical KB mirrors using profile coating for synchrotron radiation X-ray focusing
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Due to be launched in late 2021, the Imaging X-ray Polarimetry Explorer (IXPE) is a NASA Small Explorer mission designed to perform polarization measurements in the 2–8 keV band, complemented with imaging, spectroscopy and timing capabilities. At the heart of the focal plane is a set of three polarization-sensitive Gas Pixel Detectors (GPD), each based on a custom ASIC acting as a charge-collecting anode. In this paper we shall review the design, manufacturing, and test of the IXPE focal-plane detectors, with particular emphasis on the connection between the science drivers, the performance metrics and the operational aspects. We shall present a thorough characterization of the GPDs in terms of effective noise, trigger efficiency, dead time, uniformity of response, and spectral and polarimetric performance. In addition, we shall discuss in detail a number of instrumental effects that are relevant for high-level science analysis—particularly as far as the response to unpolarized radiation and the stability in time are concerned.
Highlights: •The three ERM proteins are expressed in vascular smooth muscle cell. •ERM depletion inhibited PDGF-evoked migration redundantly. •ERM depletion increased cell adhesion redundantly. •ERM depletion did not affect PDGF-evoked Ca signal, Rac1 activation, proliferation. •ERM proteins control PDGF-induced migration by regulating adhesion. -- Abstract: Ezrin, radixin, and moesin possess a very similar structure with a C-terminal actin-binding domain and a N-terminal FERM interacting domain. They are known to be involved in cytoskeleton organization in several cell types but their function in vascular smooth muscle cells (VSMC) is still unknown. The aim of this study was to investigate the role of ERM proteins in cell migration induced by PDGF, a growth factor involved in pathophysiological processes like angiogenesis or atherosclerosis. We used primary cultured VSMC obtained from rat aorta, which express the three ERM proteins. Simultaneous depletion of the three ERM proteins with specific siRNAs abolished the effects of PDGF on cell architecture and migration and markedly increased cell adhesion and focal adhesion size, while these parameters were only slightly affected by depletion of ezrin, radixin or moesin alone. Rac1 activation, cell proliferation, and Ca{sup 2+} signal in response to PDGF were unaffected by ERM depletion. These results indicate that ERM proteins exert a redundant control on PDGF-induced VSMC migration by regulating focal adhesion turn-over and cell adhesion to substrate.
Background: Atherosclerosis is a common and serious vascular disease predisposing individuals to myocardial infarction and stroke. Intravascular plaques, the pathologic lesions of atherosclerosis, are largely composed of cholesterol-laden luminal macrophage-rich infiltrates within a fibrous cap. The ability to detect those macrophages non-invasively within the aorta, carotid artery and other vessels would allow physicians to determine plaque burden, aiding management of patients with atherosclerosis. Methods and results: We previously developed a low-molecular-weight imaging agent, [{sup 125}I]iodo-DPA-713 (iodoDPA), which selectively targets macrophages. Here we use it to detect both intravascular macrophages and macrophage infiltrates within the myocardium in the ApoE -/- mouse model of atherosclerosis using single photon emission computed tomography (SPECT). SPECT data were confirmed by echocardiography, near-infrared fluorescence imaging and histology. SPECT images showed focal uptake of radiotracer at the aortic root in all ApoE -/- mice, while the age-matched controls were nearly devoid of radiotracer uptake. Focal radiotracer uptake along the descending aorta and within the myocardium was also observed in affected animals. Conclusions: IodoDPA is a promising new imaging agent for atherosclerosis, with specificity for the macrophage component of the lesions involved. - Highlights: • [{sup 125}I]iodoDPA SPECT detects atherosclerotic plaques in ApoE -/- mice with high contrast. • Plaques are detected in ApoE -/- mice regardless of diet with iodoDPA. • iodoDPA has very low uptake in healthy tissue including healthy TSPO + tissues at 24 h.
Macrophage infiltration in adipose tissue is a well-established cause of obesity-linked insulin resistance. AMP-activated protein kinase (AMPK) activation in peripheral tissues such as adipose tissue has beneficial effects on the protection against obesity-induced insulin resistance, which is mainly mediated by prevention of adipose tissue macrophage infiltration and inflammation. In examining the role of AMPK on adipose tissue inflammation, we unexpectedly found that compound C (CC), despite its inhibition of AMPK, robustly inhibited macrophage chemotaxis in RAW 264.7 cells when adipocyte conditioned medium (CM) was used as a chemoattractant. Here, we report that CC inhibition of macrophage migration occurred independently of AMPK. Mechanistically, this inhibitory effect of cell migration by CC was mediated by inhibition of the focal adhesion kinase, AKT, nuclear factor κB pathways. Moreover, the expression of chemokine monocyte chemoattractant protein-1 and pro-inflammatory genes such as tumor necrosis factor α and inducible nitric oxide synthase were prevented by CC treatment in RAW 264.7 cells stimulated with either adipocyte CM or lipopolysaccharide. Lastly, in accord with the findings of the anti-inflammatory effect of CC, we demonstrated that CC functioned as a repressor of macrophage CM-mediated insulin resistance in adipocytes. Taken together, our results suggest that CC serves as a useful inhibitory molecule against macrophage chemotaxis into adipose tissue and thus might have therapeutic potential for the treatment of obesity-linked adipose inflammation. - Highlights: • Compound C (CC) inhibits macrophage chemotaxis regardless of AMPK suppression. • CC enhances insulin sensitivity in adipocytes. • CC inhibits focal adhesion kinase, AKT, and NF-κB signaling in RAW 264.7 cells.
Highlights: • Image-based 3D simulation model for intercellular and intracellular Ca{sup 2+} waves. • Metabolic reactions were divided into membrane and cytoplasm domains. • Ca{sup 2+} and IP{sub 3} diffused across the cell and gap junctions. • Ca{sup 2+} waves are propagated from focal stimulated point in numerical simulation. • Ca{sup 2+} wave speed was in agreement with those from cell culture experiments. Intracellular and intercellular Ca{sup 2+} waves play key roles in cellular functions, and focal stimulation triggers Ca{sup 2+} wave propagation from stimulation points to neighboring cells, involving localized metabolism reactions and specific diffusion processes. Among these, inositol 1,4,5-trisphosphate (IP{sub 3}) is produced at membranes and diffuses into the cytoplasm to release Ca{sup 2+} from endoplasmic reticulum (ER). In this study, we developed a three-dimensional (3D) simulation model for intercellular and intracellular Ca{sup 2+} waves in endothelial cells (ECs). 3D model of 2 cells was reconstructed from confocal microscopic images and was connected via gap junctions. Cells have membrane and cytoplasm domains, and metabolic reactions were divided into each domain. Finally, the intracellular and intercellular Ca{sup 2+} wave propagations were induced using microscopic stimulation and were compared between numerical simulations and experiments. The experiments showed that initial sharp increases in intracellular Ca{sup 2+} occurred approximately 0.3 s after application of stimuli. In addition, Ca{sup 2+} wave speeds remained constant in cells, with intracellular and intercellular speeds of approximately 35 and 15 μm/s, respectively. Simulations indicated initial increases in Ca{sup 2+} concentrations at points of stimulation, and these were then propagated across stimulated and neighboring cells. In particular, initial rapid increases in intracellular Ca{sup 2+} were delayed and subsequent intracellular and intercellular Ca{sup 2+} wave speeds were approximately 25 and 12 μm/s, respectively. Simulation results were in agreement with those from cell culture experiments, indicating the utility of our 3D model for investigations of intracellular and intercellular messaging in ECs.
Highlights: • ADCK4 is located on human chromosome 19q13.2 and encodes the ADCK4 protein, which interacts with members of the CoQ10 biosynthesis pathway. • Mutations in the ADCK4 gene can cause CoQ10 deficiency and mitochondrial nephropathy (ADCK4-associated glomerulopathy, ADCK4-GN). • ADCK4-GN mainly manifests as steroid resistant nephrotic syndrome clinically and focal segmental glomerulosclerosis pathologically. • The C-terminal portion in ADCK4 is important and indispensable. The upstream nonsense/frameshift mutations should be considered deleterious. • CoQ10 treatment may reduce proteinuria and postpone ADCK4-GN progression. AarF domain-containing kinase 4 (ADCK4)-associated glomerulopathy (ADCK4-GN) is an inherited mitochondrial nephropathy caused by mutations in the ADCK4 gene. Herein, we report a case of ADCK4-GN. The patient, a 14-year-old Chinese male, presented with asymptomatic proteinuria and steroid resistance. A renal biopsy showed focal segmental glomerulosclerosis (FSGS) and dysmorphic mitochondria in podocytes. Coenzyme Q10 treatment was partially effective. No adverse events were observed. Next generation and Sanger sequencing analyses revealed compound heterozygous mutations (c.625C > G, p.D209H and c.918G > T, p.C306X). Both inherited mutations are located in the highly conserved ABC1 domain. The unreported nonsense mutation causes a loss of 197 amino acids from the C-terminal portion of ADCK4, suggesting a deleterious effect of the truncating mutation by abolishing ADCK4 function. In conclusion, we identified a novel ABC1 domain-localized pathogenic mutation responsible for ADCK4-GN, further supporting the importance of the C-terminal portion of ADCK4. Next generation sequencing facilitated the early diagnosis. CoQ{sub 10} treatment may reduce proteinuria and postpone ADCK4-GN progression.
The effects of indoor environmental conditions on human health, satisfaction, and performance have been the focal point of research for decades. This paper reviews and summarizes the impact of lighting environment on task performance, specifically for the built environment audience. Existing studies included a variety of performance tests on cognitive performance and perception, visual acuity and reaction, memory, reasoning, and labor productivity. Illuminance, luminance ratio and correlated color temperature were found to affect performance in different ways, reflecting the impact of experimental techniques, conditions, performance evaluation methods used and data analysis methods. These were reviewed and categorized, with discussion on limitations related to sample size, modeling approach, carryover effects and other factors affecting individual differences in performance, with recommendations for future improvement. Although no universal conclusions can be made, in general, task performance seems to improve with higher illuminances, contrast ratios in the range of 7–11:1 (while always making sure that glare will not occur in the space) and higher correlated color temperature, while spectral tuning in the red or blue wavelengths has also shown positive effects. To obtain more generic evidence, future studies should be more consistent in terms of experimental procedures and overall light conditions, and also consider the effects of vertical illuminance, daylight provision/control, and outside views on task performance. Finally, studying performance with multi-factorial designs in a human-centered optimized manner (such as deploying variable lighting scenarios optimized for various tasks) can lead to deeper understanding of lighting effects on task performance, and ultimately to improved lighting design and operation in buildings overall.
The electron cyclotron emission imaging (ECEI) diagnostic is a powerful tool to study the MHD and turbulent transport in magnetically confined fusion plasmas. In this work, the optical system including the local oscillator (LO) coupling and radio frequency (RF) receiving optics, has been designed and analyzed for the HL-2M ECEI diagnostic. The LO optics can illuminate the antenna array and drive the mixer diode to work efficiently, with more than 36% of the beam intensity for the channels which probe the plasma edge relative to those of channels which probe the plasma core. The RF optics aims at guiding the plasma emission signal to the antenna array. To meet different physical requirements, three types of field of view have been achieved for the plasma imaging, with zoom factors of around 1, 1.5 and 2, respectively. The focal surfaces are almost flat, with a maximum off-mapping (defined as the radial distance between the beam waists of the lower-/uppermost antennas and electron cyclotron emission layer) less than 2.5 cm, which can match the electron cyclotron emission layer quite well and suppress the image distortion in the plasma edge region. Furthermore, the impact of possible vibrations and installation error on the focal plane has been evaluated. In addition, the predefined MHD and turbulence perturbations are well reproduced by combining the optical simulation results and synthetic ECEI modeling, which further verifies the good performance of the RF optics.
Experiments were performed at the LLNL Titan laser to measure the propagation direction of the energetic electrons that were generated during the interaction of the polarized laser beam with solid targets in the case of normal incidence. The energetic electrons propagated through vacuum to spectator metal wires in the polarization direction and in the perpendicular direction, and the K shell spectra from the different wire materials were recorded as functions of the distance from the laser focal spot. It was found that the fluence of the energetic electrons driven into the spectator wires in the polarization direction compared to the perpendicular direction was larger and increased with the distance from the focal spot. Finally, this indicates that energetic electrons are preferentially driven in the direction of the intense oscillating electric field of the incident laser beam in agreement with the multiphoton inverse Bremsstrahlung absorption process.
Purpose: To review the factors that influence outcome and patterns of relapse in patients with cutaneous squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) with perineural infiltration (PNI) without clinical or radiologic features, treated with surgery and radiotherapy. Methods and Materials: Between 1991 and 2004, 222 patients with SCC or BCC with PNI on pathologic examination but without clinical or radiologic PNI features were identified. Charts were reviewed retrospectively and relevant data collected. All patients were treated with curative intent; all had radiotherapy, and most had surgery. The primary endpoint was 5-year relapse-free survival from the time of diagnosis. Results: Patients with SCC did significantly worse than those with BCC (5-year relapse-free survival, 78% vs. 91%; p < 0.01). Squamous cell carcinoma with PNI at recurrence did significantly worse than de novo in terms of 5-year local failure (40% vs. 19%; p < 0.01) and regional relapse (29% vs. 5%; p < 0.01). Depth of invasion was also a significant factor. Of the PNI-specific factors for SCC, focal PNI did significantly better than more-extensive PNI, but involved nerve diameter or presence of PNI at the periphery of the tumor were not significant factors. Conclusions: Radiotherapy in conjunction with surgery offers an acceptable outcome for cutaneous SCC and BCC with PNI. This study suggests that focal PNI is not an adverse feature.
Purpose: To determine the feasibility of and acute toxicity associated with hypofractionated whole breast radiation (HypoRT) after breast-conserving surgery in patients excluded from or underrepresented in randomized trials comparing HypoRT with conventional fractionation schedules. Methods and Materials: A review was conducted of all patients consecutively treated with HypoRT at University of Chicago. All patients were treated to 42.56 Gy in 2.66 Gy daily fractions in either the prone or supine position. Planning was performed in most cases using wedges and large segments or a 'field-in-field' technique. Breast volume was estimated using volumetric measurements of the planning target volume (PTV). Dosimetric parameters of heterogeneity (V105, V107, V110, and maximum dose) were recorded for each treatment plan. Acute toxicity was scored for each treated breast. Results: Between 2006 and 2010, 78 patients were treated to 80 breasts using HypoRT. Most women were overweight or obese (78.7%), with a median body mass index of 29.2 kg/m{sup 2}. Median breast volume was 1,351 mL. Of the 80 treated breasts, the maximum acute skin toxicity was mild erythema or hyperpigmentation in 70.0% (56/80), dry desquamation in 21.25% (17/80), and focal moist desquamation in 8.75% (7/80). Maximum acute toxicity occurred after the completion of radiation in 31.9% of patients. Separation >25 cm was not associated with increased toxicity. Breast volume was the only patient factor significantly associated with moist desquamation on multivariable analysis (p = 0.01). Patients with breast volume >2,500 mL experienced focal moist desquamation in 27.2% of cases compared with 6.34% in patients with breast volume <2,500 mL (p = 0.03). Conclusions: HypoRT is feasible and safe in patients with separation >25 cm and in patients with large breast volume when employing modern planning and positioning techniques. We recommend counseling regarding expected increases in skin toxicity in women with a PTV volume >2,500 mL.
Over the past decade, there has been an increasing use of radiotherapy (RT) for the treatment of liver metastases. Most often, ablative doses are delivered to focal liver metastases with the goal of local control and ultimately improving survival. In contrast, low-dose whole-liver RT may be used for the palliation of symptomatic diffuse metastases. This review examines the available clinical data for both approaches. The review found that RT is effective both for local ablation of focal liver metastases and for palliation of patients with symptomatic liver metastases. However, there is a lack of a high level of evidence from randomized clinical trials.
Purpose: For focal boost strategies in the prostate, the robustness of magnetic resonance imaging-based tumor delineations needs to be improved. To this end we developed a statistical model that predicts tumor presence on a voxel level (2.5 Multiplication-Sign 2.5 Multiplication-Sign 2.5 mm3) inside the peripheral zone. Furthermore, we show how this model can be used to derive a valuable input for radiotherapy treatment planning. Methods and Materials: The model was created on 87 radiotherapy patients. For the validation of the voxelwise performance of the model, an independent group of 12 prostatectomy patients was used. After model validation, the model was stratified to create three different risk levels for tumor presence: gross tumor volume (GTV), high-risk clinical target volume (CTV), and low-risk CTV. Results: The model gave an area under the receiver operating characteristic curve of 0.70 for the prediction of tumor presence in the prostatectomy group. When the registration error between magnetic resonance images and pathologic delineation was taken into account, the area under the curve further improved to 0.89. We propose that model outcome values with a high positive predictive value can be used to define the GTV. Model outcome values with a high negative predictive value can be used to define low-risk CTV regions. The intermediate outcome values can be used to define a high-risk CTV. Conclusions: We developed a logistic regression with a high diagnostic performance for voxelwise prediction of tumor presence. The model output can be used to define different risk levels for tumor presence, which in turn could serve as an input for dose planning. In this way the robustness of tumor delineations for focal boost therapy can be greatly improved.
Purpose: Defining prostate cancer (PCa) lesion clinical target volumes (CTVs) for multiparametric magnetic resonance imaging (mpMRI) could support focal boosting or treatment to improve outcomes or lower morbidity, necessitating appropriate CTV margins for mpMRI-defined gross tumor volumes (GTVs). This study aimed to identify CTV margins yielding 95% coverage of PCa tumors for prospective cases with high likelihood. Methods and Materials: Twenty-five men with biopsy-confirmed clinical stage T1 or T2 PCa underwent pre-prostatectomy mpMRI, yielding T2-weighted, dynamic contrast-enhanced, and apparent diffusion coefficient images. Digitized whole-mount histology was contoured and registered to mpMRI scans (error ≤2 mm). Four observers contoured lesion GTVs on each mpMRI scan. CTVs were defined by isotropic and anisotropic expansion from these GTVs and from multiparametric (unioned) GTVs from 2 to 3 scans. Histologic coverage (proportions of tumor area on co-registered histology inside the CTV, measured for Gleason scores [GSs] ≥6 and ≥7) and prostate sparing (proportions of prostate volume outside the CTV) were measured. Nonparametric histologic-coverage prediction intervals defined minimal margins yielding 95% coverage for prospective cases with 78% to 92% likelihood. Results: On analysis of 72 true-positive tumor detections, 95% coverage margins were 9 to 11 mm (GS ≥ 6) and 8 to 10 mm (GS ≥ 7) for single-sequence GTVs and were 8 mm (GS ≥ 6) and 6 mm (GS ≥ 7) for 3-sequence GTVs, yielding CTVs that spared 47% to 81% of prostate tissue for the majority of tumors. Inclusion of T2-weighted contours increased sparing for multiparametric CTVs with 95% coverage margins for GS ≥6, and inclusion of dynamic contrast-enhanced contours increased sparing for GS ≥7. Anisotropic 95% coverage margins increased the sparing proportions to 71% to 86%. Conclusions: Multiparametric magnetic resonance imaging–defined GTVs expanded by appropriate margins may support focal boosting or treatment of PCa; however, these margins, accounting for interobserver and intertumoral variability, may preclude highly conformal CTVs. Multiparametric GTVs and anisotropic margins may reduce the required margins and improve prostate sparing.
Magma and related hydrothermal fluid movement, and their interaction with solid rock, in active volcanic regions, generate a wide variety of seismic waves whose characterization can mitigate the risk of a potential eruption. Located in the western region of the Trans-Mexican Volcanic Belt, Ceboruco Volcano, whose last eruptive period was 1870–1875, is considered to be one of the most hazardous volcanoes in Mexico. We have conducted a detailed study of the seismicity in the surroundings of Ceboruco's volcanic edifice to assess the current state of this volcano. A dense temporary seismic network with 25 seismic stations in an area of 16 km × 16 km was deployed between November 2016 and July 2017, as part of the P-24 project of the CeMIEGeo consortium; this effort has allowed the detection of 81 earthquakes concentrated beneath the crater with depths between 4 and 8 km. In this study, we observe that the recorded seismicity occurs in swarms, and we specifically identify four sequences that we characterize in detail via the first focal mechanisms available for this volcano. Our results suggest a change in the local seismicity distribution compared to earlier observations, which reported seismic activity near the volcano edifice associated with fluid migration along zones of weakness related to the extensional stresses of the Tepic-Zacoalco rift. The changes in seismic patterns and obtained focal mechanisms are consistent with observed fluid effects at many geothermal sites worldwide, but also could suggest resumption of activity at this currently dormant volcano.
Dose or treatment planning management is necessary for the re-irradiation of intracranial relapses after focal irradiation, radiosurgery, or stereotactic radiotherapy. The current clinical guidelines for metastatic brain tumors are the use of focal irradiation if the patient presents with 4 lesions or less. Salvage treatments with the use of whole brain radiation therapy (WBRT) can then be used to limit disease progression if there is an intracranial relapse. However, salvage WBRT poses a number of challenges in dose planning to limit disease progression and preserve neurocognitive function. This work presents the dose planning management that addresses a method of delineating previously treated volumes, dose level matching, and the dose delivery techniques for WBRT.
CyberKnife is an image-guided stereotactical dose delivery system designed for both focal irradiation and radiation therapy (SRT). Focal irradiation refers the use of many small beams to deliver highly focus dose to a small target region in a few fractions. The system consists of a 6-MV linac mounted to a robotic arm, coupled with a digital x-ray imaging system. The radiation dose is delivered using many beams oriented at a number of defined or nodal positions around the patients. The CyberKnife can be used for both intracranial and extracranial treaments unlike the Gamma Knife which is limited to intracranial cases. Multiplan (Accuray Inc., Sunnyvale, CA) is the treatment planning system developed to cooperate with this accurate and versatile SRS and SRT system, and exploit the full function of Cyberknife in high-precision radiosurgery and therapy. Optimized inverse treatment plan can be achieved by fine-tuning contours and planning parameters. Precision is the newest version of Cyberknife treatment planning system (TPS) and an upgrade to Multiplan. It offers several new features such as Monte Carlo for multileaf collimator (MLC) and retreatment for other modalities that added more support for the Cyberknife system. The Cybeknife TPS is an easy-to-use and versatile inverse planning platform, suitable for stereotactic radiosurgery and radiation therapy. The knowledge and experience of the planner in this TPS is essential to improve the quality of patient care.