| 1. |
- Niemi, MEK, et al.
(author)
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- 2021
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swepub:Mat__t
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| 2. |
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| 3. |
- Helbig, K. L., et al.
(author)
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De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias
- 2018
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In: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 103:5, s. 666-678
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Journal article (peer-reviewed)abstract
- Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by intractable seizures, abundant epileptiform activity on EEG, and developmental impairment or regression. CACNA1E is highly expressed in the central nervous system and encodes the alpha(1)-subunit of the voltage-gated Ca(V)2.3 channel, which conducts high voltage-activated R-type calcium currents that initiate synaptic transmission. Using next-generation sequencing techniques, we identified de novo CACNA1E variants in 30 individuals with DEE, characterized by refractory infantile-onset seizures, severe hypotonia, and profound developmental impairment, often with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early death. Most of the 14, partially recurring, variants cluster within the cytoplasmic ends of all four S6 segments, which form the presumed Ca(V)2.3 channel activation gate. Functional analysis of several S6 variants revealed consistent gain-of-function effects comprising facilitated voltage-dependent activation and slowed inactivation. Another variant located in the domain II S4-S5 linker results in facilitated activation and increased current density. Five participants achieved seizure freedom on the anti-epileptic drug topiramate, which blocks R-type calcium channels. We establish pathogenic variants in CACNA1E as a cause of DEEs and suggest facilitated R-type calcium currents as a disease mechanism for human epilepsy and developmental disorders.
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| 4. |
- Pinaroli, G., et al.
(author)
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PERCIVAL : Possible applications in X-ray micro-tomography
- 2020
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In: Journal of Instrumentation. - 1748-0221. ; 15:2
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Journal article (peer-reviewed)abstract
- X-ray computed micro-tomography (μCT) is one of the most advanced and common non-destructive techniques in the field of medical imaging and material science. It allows recreating virtual models (3D models), without destroying the original objects, by measuring three-dimensional X-ray attenuation coefficient maps of samples on the (sub) micrometer scale. The quality of the images obtained using μCT is strongly dependent on the performance of the associated X-ray detector i.e. to the acquisition of information of the X-ray beam traversing the patient/sample being precise and accurate. Detectors for μCT have to meet the requirements of the specific tomography procedure in which they are going to be used. In general, the key parameters are high spatial resolution, high dynamic range, uniformity of response, high contrast sensitivity, fast acquisition readout and support of high frame rates. At present the detection devices in commercial μCT scanners are dominated by charge-coupled devices (CCD), photodiode arrays, CMOS acquisition circuits and more recently by hybrid pixel detectors. Monolithic CMOS imaging sensors, which offer reduced pixel sizes and low electronic noise, are certainly excellent candidates for μCT and may be used for the development of novel high-resolution imaging applications. The uses of monolithic CMOS based detectors such as the PERCIVAL detector are being recently explored for synchrotron and FEL applications. PERCIVAL was developed to operate in synchrotron and FEL facilities in the soft X-ray regime from 250 eV to 1 keV and it could offer all the aforementioned technical requirements needed in μCT experiments. In order to adapt the system for a typical tomography application, a scintillator is required, to convert incoming X-ray radiation (∼ tens of KeV) into visible light which may be detected with high efficiency. Such a taper-based scintillator was developed and mounted in front of the sensitive area of the PERCIVAL imager. In this presentation we will report the setup of the detector system and preliminary results of first μCTs of reference objects, which were performed in the TomoLab at ELETTRA.
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| 5. |
- Tomić, I., et al.
(author)
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Shake-table testing of a stone masonry building aggregate : overview of blind prediction study
- 2023
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In: Bulletin of Earthquake Engineering. - : Springer Science and Business Media LLC. - 1570-761X .- 1573-1456.
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Journal article (peer-reviewed)abstract
- City centres of Europe are often composed of unreinforced masonry structural aggregates, whose seismic response is challenging to predict. To advance the state of the art on the seismic response of these aggregates, the Adjacent Interacting Masonry Structures (AIMS) subproject from Horizon 2020 project Seismology and Earthquake Engineering Research Infrastructure Alliance for Europe (SERA) provides shake-table test data of a two-unit, double-leaf stone masonry aggregate subjected to two horizontal components of dynamic excitation. A blind prediction was organized with participants from academia and industry to test modelling approaches and assumptions and to learn about the extent of uncertainty in modelling for such masonry aggregates. The participants were provided with the full set of material and geometrical data, construction details and original seismic input and asked to predict prior to the test the expected seismic response in terms of damage mechanisms, base-shear forces, and roof displacements. The modelling approaches used differ significantly in the level of detail and the modelling assumptions. This paper provides an overview of the adopted modelling approaches and their subsequent predictions. It further discusses the range of assumptions made when modelling masonry walls, floors and connections, and aims at discovering how the common solutions regarding modelling masonry in general, and masonry aggregates in particular, affect the results. The results are evaluated both in terms of damage mechanisms, base shear forces, displacements and interface openings in both directions, and then compared with the experimental results. The modelling approaches featuring Discrete Element Method (DEM) led to the best predictions in terms of displacements, while a submission using rigid block limit analysis led to the best prediction in terms of damage mechanisms. Large coefficients of variation of predicted displacements and general underestimation of displacements in comparison with experimental results, except for DEM models, highlight the need for further consensus building on suitable modelling assumptions for such masonry aggregates.
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| 6. |
- Waszak, S. M., et al.
(author)
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Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort
- 2018
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In: Lancet Oncology. - : Elsevier BV. - 1470-2045. ; 19:6, s. 785-798
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Journal article (peer-reviewed)abstract
- Background Medulloblastoma is associated with rare hereditary cancer predisposition syndromes; however, consensus medulloblastoma predisposition genes have not been defined and screening guidelines for genetic counselling and testing for paediatric patients are not available. We aimed to assess and define these genes to provide evidence for future screening guidelines. Methods In this international, multicentre study, we analysed patients with medulloblastoma from retrospective cohorts (International Cancer Genome Consortium [ICGC] PedBrain, Medulloblastoma Advanced Genomics International Consortium [MAGIC], and the CEFALO series) and from prospective cohorts from four clinical studies (SJMB03, SJMB12, SJYC07, and I-HIT-MED). Whole-genome sequences and exome sequences from blood and tumour samples were analysed for rare damaging germline mutations in cancer predisposition genes. DNA methylation profiling was done to determine consensus molecular subgroups: WNT (MBWNT), SHH (MBSHH), group 3 (MBGroup3), and group 4 (MBGroup4). Medulloblastoma predisposition genes were predicted on the basis of rare variant burden tests against controls without a cancer diagnosis from the Exome Aggregation Consortium (ExAC). Previously defined somatic mutational signatures were used to further classify medulloblastoma genomes into two groups, a clock-like group (signatures 1 and 5) and a homologous recombination repair deficiency-like group (signatures 3 and 8), and chromothripsis was investigated using previously established criteria. Progression-free survival and overall survival were modelled for patients with a genetic predisposition to medulloblastoma. Findings We included a total of 1022 patients with medulloblastoma from the retrospective cohorts (n=673) and the four prospective studies (n=349), from whom blood samples (n=1022) and tumour samples (n=800) were analysed for germline mutations in 110 cancer predisposition genes. In our rare variant burden analysis, we compared these against 53 105 sequenced controls from ExAC and identified APC, BRCA2, PALB2, PTCH1, SUFU, and TP53 as consensus medulloblastoma predisposition genes according to our rare variant burden analysis and estimated that germline mutations accounted for 6% of medulloblastoma diagnoses in the retrospective cohort. The prevalence of genetic predispositions differed between molecular subgroups in the retrospective cohort and was highest for patients in the MBSHH subgroup (20% in the retrospective cohort). These estimates were replicated in the prospective clinical cohort (germline mutations accounted for 5% of medulloblastoma diagnoses, with the highest prevalence [14%] in the MBSHH subgroup). Patients with germline APC mutations developed MBWNT and accounted for most (five [71%] of seven) cases of MBWNT that had no somatic CTNNB1 exon 3 mutations. Patients with germline mutations in SUFU and PTCH1 mostly developed infant MBSHH. Germline TP53 mutations presented only in childhood patients in the MBSHH subgroup and explained more than half (eight [57%] of 14) of all chromothripsis events in this subgroup. Germline mutations in PALB2 and BRCA2 were observed across the MBSHH, MBGroup3, and MBGroup4 molecular subgroups and were associated with mutational signatures typical of homologous recombination repair deficiency. In patients with a genetic predisposition to medulloblastoma, 5-year progression-free survival was 52% (95% CI 4069) and 5-year overall survival was 65% (95% CI 5281); these survival estimates differed significantly across patients with germline mutations in different medulloblastoma predisposition genes. Interpretation Genetic counselling and testing should be used as a standard-of-care procedure in patients with MBWNT and MBSHH because these patients have the highest prevalence of damaging germline mutations in known cancer predisposition genes. We propose criteria for routine genetic screening for patients with medulloblastoma based on clinical and molecular tumour characteristics. Copyright (c) 2018 The Author(s). Published by Elsevier Ltd.
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| 7. |
- Correa, J., et al.
(author)
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On the Charge Collection Efficiency of the PERCIVAL Detector
- 2016
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In: Journal of Instrumentation. - : IOP. - 1748-0221. ; 11:12
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Journal article (peer-reviewed)abstract
- The PERCIVAL soft X-ray imager is being developed by DESY, RAL, Elettra, DLS, and PAL to address the challenges at high brilliance Light Sources such as new-generation Synchrotrons and Free Electron Lasers. Typical requirements for detector systems at these sources are high frame rates, large dynamic range, single-photon counting capability with low probability of false positives, high quantum efficiency, and (multi)-mega-pixel arrangements. PERCIVAL is a monolithic active pixel sensor, based on CMOS technology. It is designed for the soft X-ray regime and, therefore, it is post-processed in order to achieve high quantum efficiency in its primary energy range (250 eV to 1 keV) . This work will report on the latest experimental results on charge collection efficiency obtained for multiple back-side-illuminated test sensors during two campaigns, at the P04 beam-line at PETRA III, and the CiPo beam-line at Elettra, spanning most of the primary energy range as well as testing the performance for photon-energies below 250 eV . In addition, XPS surface analysis was used to cross-check the obtained results.
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| 8. |
- Correa, J., et al.
(author)
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The PERCIVAL soft X-ray Detector
- 2018
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In: 2018 IEEE Nuclear Science Symposium and Medical Imaging Conference, NSS/MIC 2018 - Proceedings. - : Institute of Electrical and Electronics Engineers (IEEE). - 9781538684948
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Conference paper (peer-reviewed)abstract
- The PERCIVAL collaboration to develop a soft X-ray imager able to address the challenges of high brilliance light sources, such as new-generation synchrotrons and Free Electron Lasers, has reached one of its major milestones: a full 2-MegaPixel (P2M) system (uninterrupted 4 × 4 cm2 active area) has already seen its first light.Smaller prototypes of the device, a monolithic active pixel sensor based on CMOS technology, have already been fully characterised, and have demonstrated high frame rate, large dynamic range, and relatively high quantum efficiency.The PERCIVAL modular layout allows for clover-leaf like arrangement of up to four P2M systems. Moreover, it will be post-processed in order to achieve a high quantum efficiency in its primary energy range (250 eV to 1 keV).We will present the P2M system, its status and newest results, bring these in context with achieved prototype performance, and outline future steps.
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| 9. |
- Galosi, Serena, et al.
(author)
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De novo DHDDS variants cause a neurodevelopmental and neurodegenerative disorder with myoclonus
- 2022
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In: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 145:1, s. 208-223
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Journal article (peer-reviewed)abstract
- Subcellular membrane systems are highly enriched in dolichol, whose role in organelle homeostasis and endosomal-lysosomal pathway remains largely unclear besides being involved in protein glycosylation. DHDDS encodes for the catalytic subunit (DHDDS) of the enzyme cis-prenyltransferase (cis-PTase), involved in dolichol biosynthesis and dolichol-dependent protein glycosylation in the endoplasmic reticulum. An autosomal recessive form of retinitis pigmentosa (retinitis pigmentosa 59) has been associated with a recurrent DHDDS variant. Moreover, two recurring de novo substitutions were detected in a few cases presenting with neurodevelopmental disorder, epilepsy, and movement disorder. We evaluated a large cohort of patients (n=25) with de novo pathogenic variants in DHDDS and provided the first systematic description of the clinical features and long-term outcome of this new neurodevelopmental and neurodegenerative disorder. The functional impact of the identified variants was explored by yeast complementation system and enzymatic assay. Patients presented during infancy or childhood with a variable association of neurodevelopmental disorder, generalized epilepsy, action myoclonus/cortical tremor, and ataxia. Later in the disease course they experienced a slow neurological decline with the emergence of hyperkinetic and/or hypokinetic movement disorder, cognitive deterioration, and psychiatric disturbances. Storage of lipidic material and altered lysosomes were detected in myelinated fibers and fibroblasts, suggesting a dysfunction of the lysosomal enzymatic scavenger machinery. Serum glycoprotein hypoglycosylation was not detected and, in contrast to retinitis pigmentosa and other congenital disorders of glycosylation involving dolichol metabolism, the urinary dolichol D18/D19 ratio was normal. Mapping the disease-causing variants into the protein structure revealed that most of them clustered around the active site of the DHDDS subunit. Functional studies using yeast complementation assay and in vitro activity measurements confirmed that these changes affected the catalytic activity of the cis-PTase and showed growth defect in yeast complementation system as compared with the wild-type enzyme and retinitis pigmentosa-associated protein. In conclusion, we characterized a distinctive neurodegenerative disorder due to de novo DHDDS variants, which clinically belongs to the spectrum of genetic progressive encephalopathies with myoclonus. Clinical and biochemical data from this cohort depicted a condition at the intersection of congenital disorders of glycosylation and inherited storage diseases with several features akin to of progressive myoclonus epilepsy such as neuronal ceroid lipofuscinosis and other lysosomal disorders.
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| 10. |
- Guerrini, Niccolo, et al.
(author)
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Charging Mechanism of Li2MnO3
- 2020
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In: Chemistry of Materials. - : AMER CHEMICAL SOC. - 0897-4756 .- 1520-5002. ; 32:9, s. 3733-3740
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Journal article (peer-reviewed)abstract
- Operando mass spectroscopy demonstrates quantitatively that lithium extraction from Li2MnO3 is charge compensated by oxygen loss (O-loss) not oxidation of oxide ions that are retained within the structural framework (O-redox). This fact is confirmed by X-ray absorption and emission spectroscopy. Li NMR shows that the two-phase core-shell structure, which forms on charging, is composed of an intact Li2MnO3 core and a highly disordered shell containing no Li, with a composition close to MnO2. Discharge involves Li insertion into the disordered shell. CO2 and O-2 are detected on charging at 15 mA g(-1), whereas charging by galvanostatic intermittent titration technique (GITT) forms only CO2; an observation in agreement with the previously described model of oxygen evolution from high-voltage cathodes producing singlet O-2 that reacts with the electrolyte forming CO2. The dominance of oxygen evolution over O-redox is in accordance with the model of O-loss occurring when the oxide ions are undercoordinated; O in the shell devoid of Li is coordinated by only 2 Mn.
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| 11. |
- Khromova, A., et al.
(author)
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Report on recent results of the PERCIVAL soft X-ray imager
- 2016
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In: Journal of Instrumentation. - : IOP. - 1748-0221. ; 11:November
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Journal article (peer-reviewed)abstract
- The PERCIVAL (Pixelated Energy Resolving CMOS Imager, Versatile And Large) soft X-ray 2D imaging detector is based on stitched, wafer-scale sensors possessing a thick epi-layer, which together with back-thinning and back-side illumination yields elevated quantum efficiency in the photon energy range of 125–1000 eV. Main application fields of PERCIVAL are foreseen in photon science with FELs and synchrotron radiation. This requires high dynamic range up to 105 ph @ 250 eV paired with single photon sensitivity with high confidence at moderate frame rates in the range of 10–120 Hz. These figures imply the availability of dynamic gain switching on a pixel-by-pixel basis and a highly parallel, low noise analog and digital readout, which has been realized in the PERCIVAL sensor layout. Different aspects of the detector performance have been assessed using prototype sensors with different pixel and ADC types. This work will report on the recent test results performed on the newest chip prototypes with the improved pixel and ADC architecture. For the target frame rates in the 10–120 Hz range an average noise floor of 14e− has been determined, indicating the ability of detecting single photons with energies above 250 eV. Owing to the successfully implemented adaptive 3-stage multiple-gain switching, the integrated charge level exceeds 4 centerdot 106 e− or 57000 X-ray photons at 250 eV per frame at 120 Hz. For all gains the noise level remains below the Poisson limit also in high-flux conditions. Additionally, a short overview over the updates on an oncoming 2 Mpixel (P2M) detector system (expected at the end of 2016) will be reported.
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| 12. |
- Marras, A., et al.
(author)
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Percival P2M-FSI detector : First test at a Synchrotron Ring beamline with tender x-ray photons
- 2019
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In: 2019 IEEE Nuclear Science Symposium and Medical Imaging Conference, NSS/MIC 2019. - : IEEE. - 9781728141640
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Conference paper (peer-reviewed)abstract
- In this paper, we are presenting the results of the first test of the Percival P2M-FSI detector with tender x-rays photons at a synchrotron beamline. Percival is a monolithic CMOS Imager for detection of x-rays in Synchrotron Rings and Free Electron Lasers: the Front-Side-Illuminated (FSI) version of the detector has been proven able to successfully distinguish tender (2keV) x-ray single photons.
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| 13. |
- Naylor, Andrew J., et al.
(author)
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Depth-dependent oxygen redox activity in lithium-rich layered oxide cathodes
- 2019
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In: Journal of Materials Chemistry A. - : Royal Society of Chemistry. - 2050-7488. ; 7:44, s. 25355-25368
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Journal article (peer-reviewed)abstract
- Lithium-rich materials, such as Li1.2Ni0.2Mn0.6O2, exhibit capacities not limited by transition metal redox, through the reversible oxidation of oxide anions. Here we offer detailed insight into the degree of oxygen redox as a function of depth within the material as it is charged and cycled. Energy-tuned photoelectron spectroscopy is used as a powerful, yet highly sensitive technique to probe electronic states of oxygen and transition metals from the top few nanometers at the near-surface through to the bulk of the particles. Two discrete oxygen species are identified, On− and O2−, where n < 2, confirming our previous model that oxidation generates localised hole states on O upon charging. This is in contrast to the oxygen redox inactive high voltage spinel LiNi0.5Mn1.5O4, for which no On− species is detected. The depth profile results demonstrate a concentration gradient exists for On− from the surface through to the bulk, indicating a preferential surface oxidation of the layered oxide particles. This is highly consistent with the already well-established core–shell model for such materials. Ab initio calculations reaffirm the electronic structure differences observed experimentally between the surface and bulk, while modelling of delithiated structures shows good agreement between experimental and calculated binding energies for On−.
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| 14. |
- Sedgwick, I., et al.
(author)
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P2M : First Optical Characterisation Results of a 2MPixel CMOS Image Sensor for Soft X-Ray Detection
- 2019
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In: 2019 IEEE NUCLEAR SCIENCE SYMPOSIUM AND MEDICAL IMAGING CONFERENCE (NSS/MIC). - : IEEE. - 9781728141640
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Conference paper (peer-reviewed)abstract
- High brilliance synchrotrons and FELs require high performing detector systems to realise their full potential. High dynamic range, low noise and high frame rate are all of great importance. In this paper we present first optical characterization results of the P2M CMOS sensor, designed for soft X-ray detection at such facilities. Previous work is summarised and an overview of the sensor is presented. Test results for the sensor's column-parallel ADC and readout chain are presented, and first test results for the pixel acquired using the Photon Transfer Curve (PTC) method are shown. Finally, an outline of future work is provided.
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| 15. |
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| 16. |
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| 17. |
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| 18. |
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| 19. |
- Wunderer, C. B., et al.
(author)
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Detector developments at DESY
- 2016
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In: Journal of Synchrotron Radiation. - 0909-0495 .- 1600-5775. ; 23, s. 111-117
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Journal article (peer-reviewed)abstract
- With the increased brilliance of state-of-the-art synchrotron radiation sources and the advent of free-electron lasers (FELs) enabling revolutionary science with EUV to X-ray photons comes an urgent need for suitable photon imaging detectors. Requirements include high frame rates, very large dynamic range, single-photon sensitivity with low probability of false positives and (multi)-megapixels. At DESY, one ongoing development project-in collaboration with RAL/STFC, Elettra Sincrotrone Trieste, Diamond, and Pohang Accelerator Laboratory-is the CMOS-based soft X-ray imager PERCIVAL. PERCIVAL is a monolithic active-pixel sensor back-thinned to access its primary energy range of 250 eV to 1 keV with target efficiencies above 90%. According to preliminary specifications, the roughly 10 cm × 10 cm, 3.5k × 3.7k monolithic sensor will operate at frame rates up to 120 Hz (commensurate with most FELs) and use multiple gains within 27 μm pixels to measure 1 to ∼ 100000 (500 eV) simultaneously arriving photons. DESY is also leading the development of the AGIPD, a high-speed detector based on hybrid pixel technology intended for use at the European XFEL. This system is being developed in collaboration with PSI, University of Hamburg, and University of Bonn. The AGIPD allows singlepulse imaging at 4.5 MHz frame rate into a 352-frame buffer, with a dynamic range allowing single-photon detection and detection of more than 10000 photons at 12.4 keV in the same image. Modules of 65k pixels each are configured to make up (multi)megapixel cameras. This review describes the AGIPD and the PERCIVAL concepts and systems, including some recent results and a summary of their current status. It also gives a short overview over other FEL-relevant developments where the Photon Science Detector Group at DESY is involved. © 2016 International Union of Crystallography.
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| 20. |
- Wunderer, C. B., et al.
(author)
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The Percival 2-Megapixel monolithic active pixel imager
- 2019
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In: Journal of Instrumentation. - 1748-0221. ; 14:1
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Journal article (peer-reviewed)abstract
- The peak brilliance reached by today's Free-Electron Laser and Synchrotron light sources requires photon detectors matching their output intensity and other characteristics in order to fully realize the sources' potential. The Pixellated Energy Resolving CMOS Imager, Versatile And Large (Percival) is a dedicated soft X-ray imager (0.25-1 keV) developed for this purpose by a collaboration of DESY, Rutherford Appleton Laboratory/STFC, Elettra Sincrotrone Trieste, Diamond Light Source, and Pohang Accelerator Laboratory. Following several generations of prototypes, the Percival "P2M" 2-Megapixel imager - a 4.5x5 cm monolithic, stitched sensor with an uninterrupted imaging area of 4x4 cm(2) (1408x1484 pixels of 27x27 mu m - was produced and has demonstrated basic functionality with a first-light image using visible light. It is currently being brought to full operation in a front-illuminated configuration. The readout system being commissioned in parallel has been developed specifically for this imager which will produce - at full 300 Hz frame rate - data at 20 Gbit/s. A first wafer with eight Percival P2M chips has undergone backthinning to enable soft X-ray detection. It has been diced and chips are currently being wirebonded. We summarize here the P2M system, the project status, and show the P2M sensor's first response to visible light.
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| 21. |
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| 22. |
- Baumgartner, T., et al.
(author)
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A survey of the European Reference Network EpiCARE on clinical practice for selected rare epilepsies
- 2021
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In: Epilepsia Open. - : Wiley. - 2470-9239. ; 6:1, s. 160-170
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Journal article (peer-reviewed)abstract
- Objective: Clinical care of rare and complex epilepsies is challenging, because evidence-based treatment guidelines are scarce, the experience of many physicians is limited, and interdisciplinary treatment of comorbidities is required. The pathomechanisms of rare epilepsies are, however, increasingly understood, which potentially fosters novel targeted therapies. The objectives of our survey were to obtain an overview of the clinical practice in European tertiary epilepsy centers treating patients with 5 arbitrarily selected rare epilepsies and to get an estimate of potentially available patients for future studies. Methods: Members of the European Reference Network for rare and complex epilepsies (EpiCARE) were invited to participate in a web-based survey on clinical practice of patients with Dravet syndrome, tuberous sclerosis complex (TSC), autoimmune encephalitis, and progressive myoclonic epilepsies including Unverricht Lundborg and Unverricht-like diseases. A consensus-based questionnaire was generated for each disease. Results: Twenty-six of 30 invited epilepsy centers participated. Cohorts were present in most responding centers for TSC (87%), Dravet syndrome (85%), and autoimmune encephalitis (71%). Patients with TSC and Dravet syndrome represented the largest cohorts in these centers. The antiseizure drug treatments were rather consistent across the centers especially with regard to Dravet syndrome, infantile spasms in TSC, and Unverricht Lundborg / Unverricht-like disease. Available, widely used targeted therapies included everolimus in TSC and immunosuppressive therapies in autoimmune encephalitis. Screening for comorbidities was routinely done, but specific treatment protocols were lacking in most centers. Significance: The survey summarizes the current clinical practice for selected rare epilepsies in tertiary European epilepsy centers and demonstrates consistency as well as heterogeneity in the treatment, underscoring the need for controlled trials and recommendations. The survey also provides estimates for potential participants of clinical trials recruited via EpiCARE, emphasizing the great potential of Reference Networks for future studies to evaluate new targeted therapies and to identify novel biomarkers. © 2020 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy
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| 23. |
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| 24. |
- Bianchini, F, et al.
(author)
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Human neutralizing antibodies to cold linear epitopes and subdomain 1 of the SARS-CoV-2 spike glycoprotein
- 2023
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In: Science immunology. - : American Association for the Advancement of Science (AAAS). - 2470-9468. ; 8:81, s. eade0958-
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Journal article (peer-reviewed)abstract
- Emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants diminishes the efficacy of vaccines and antiviral monoclonal antibodies. Continued development of immunotherapies and vaccine immunogens resilient to viral evolution is therefore necessary. Using coldspot-guided antibody discovery, a screening approach that focuses on portions of the virus spike glycoprotein that are both functionally relevant and averse to change, we identified human neutralizing antibodies to highly conserved viral epitopes. Antibody fp.006 binds the fusion peptide and cross-reacts against coronaviruses of the four genera, including the nine human coronaviruses, through recognition of a conserved motif that includes the S2′ site of proteolytic cleavage. Antibody hr2.016 targets the stem helix and neutralizes SARS-CoV-2 variants. Antibody sd1.040 binds to subdomain 1, synergizes with antibody rbd.042 for neutralization, and, similar to fp.006 and hr2.016, protects mice expressing human angiotensin-converting enzyme 2 against infection when present as a bispecific antibody. Thus, coldspot-guided antibody discovery reveals donor-derived neutralizing antibodies that are cross-reactive with Orthocoronavirinae, including SARS-CoV-2 variants.
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| 25. |
- Bianchini, F, et al.
(author)
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Human neutralizing antibodies to cold linear epitopes and subdomain 1 of the SARS-CoV-2 spike glycoprotein
- 2023
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In: Science immunology. - : American Association for the Advancement of Science (AAAS). - 2470-9468. ; 8:81, s. eade0958-
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Journal article (peer-reviewed)abstract
- Emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants diminishes the efficacy of vaccines and antiviral monoclonal antibodies. Continued development of immunotherapies and vaccine immunogens resilient to viral evolution is therefore necessary. Using coldspot-guided antibody discovery, a screening approach that focuses on portions of the virus spike glycoprotein that are both functionally relevant and averse to change, we identified human neutralizing antibodies to highly conserved viral epitopes. Antibody fp.006 binds the fusion peptide and cross-reacts against coronaviruses of the four genera, including the nine human coronaviruses, through recognition of a conserved motif that includes the S2′ site of proteolytic cleavage. Antibody hr2.016 targets the stem helix and neutralizes SARS-CoV-2 variants. Antibody sd1.040 binds to subdomain 1, synergizes with antibody rbd.042 for neutralization, and, similar to fp.006 and hr2.016, protects mice expressing human angiotensin-converting enzyme 2 against infection when present as a bispecific antibody. Thus, coldspot-guided antibody discovery reveals donor-derived neutralizing antibodies that are cross-reactive with Orthocoronavirinae, including SARS-CoV-2 variants.
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| 26. |
- Bianchini, F, et al.
(author)
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Human neutralizing antibodies to cold linear epitopes and to subdomain 1 of SARS-CoV-2
- 2022
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In: bioRxiv : the preprint server for biology. - : Cold Spring Harbor Laboratory.
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Journal article (other academic/artistic)abstract
- Emergence of SARS-CoV-2 variants diminishes the efficacy of vaccines and antiviral monoclonal antibodies. Continued development of immunotherapies and vaccine immunogens resilient to viral evolution is therefore necessary. Using coldspot-guided antibody discovery, a screening approach that focuses on portions of the virus spike that are both functionally relevant and averse to change, we identified human neutralizing antibodies to highly conserved viral epitopes. Antibody fp.006 binds the fusion peptide and cross-reacts against coronaviruses of the fourgenera, including the nine human coronaviruses, through recognition of a conserved motif that includes the S2’ site of proteolytic cleavage. Antibody hr2.016 targets the stem helix and neutralizes SARS-CoV-2 variants. Antibody sd1.040 binds to subdomain 1, synergizes with antibody rbd.042 for neutralization and, like fp.006 and hr2.016, protects mice when present as bispecific antibody. Thus, coldspot-guided antibody discovery reveals donor-derived neutralizing antibodies that are cross-reactive withOrthocoronavirinae, including SARS-CoV-2 variants.Broadly cross-reactive antibodies that protect from SARS-CoV-2 variants are revealed by virus coldspot-driven discovery.
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| 27. |
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| 28. |
- Correa, J., et al.
(author)
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The PERCIVAL detector : first user experiments
- 2023
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In: Journal of Synchrotron Radiation. - 0909-0495 .- 1600-5775. ; 30, s. 242-250
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Journal article (peer-reviewed)abstract
- The PERCIVAL detector is a CMOS imager designed for the soft X-ray regime at photon sources. Although still in its final development phase, it has recently seen its first user experiments: ptychography at a free-electron laser, holographic imaging at a storage ring and preliminary tests on X-ray photon correlation spectroscopy. The detector performed remarkably well in terms of spatial resolution achievable in the sample plane, owing to its small pixel size, large active area and very large dynamic range; but also in terms of its frame rate, which is significantly faster than traditional CCDs. In particular, it is the combination of these features which makes PERCIVAL an attractive option for soft X-ray science.
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| 29. |
- Ferrari, A., et al.
(author)
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Attenuation of diet-induced obesity and induction of white fat browning with a chemical inhibitor of histone deacetylases
- 2017
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In: International Journal of Obesity. - : NATURE PUBLISHING GROUP. - 0307-0565 .- 1476-5497. ; 41:2, s. 289-298
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Journal article (peer-reviewed)abstract
- BACKGROUND/OBJECTIVES: In the last decade, a strict link between epigenetics and metabolism has been demonstrated. Histone deacetylases (HDACs) have emerged as key epigenetic regulators involved in metabolic homeostasis in normal and pathologic conditions. Here we investigated the effect of the class I HDAC inhibitor MS-275 in a model of obesity induced by a high-fat diet (HFD). METHODS: C57BL6/J male mice were fed HFD for 17 weeks and then randomized in two groups, treated intraperitoneally with vehicle dimethylsulfoxide (DMSO) or with the class I selective HDAC inhibitor MS-275 every other day for 22 days. Glucose tolerance test and measurement of body temperature during cold exposure were performed. Adipose tissues and liver were phenotypically characterized through histological analysis. Gene and protein expression analysis of brown and white adipose tissues (WATs) were performed. RESULTS: MS-275 treated mice showed 10% reduction of body weight, lower adipocyte size and improved glucose tolerance. Inhibition of class I HDAC determined reduction of adipocyte size and of fat mass, paralleled by higher expression of adipose functionality markers and by increased rate of lipolysis and fatty acid beta-oxidation. MS-275 also promoted thermogenic capacity, related to `browning' of visceral and subcutaneous WAT, showing increased expression of uncoupling protein 1. In brown adipose tissue, we observed limited effects on gene expression and only reduction of brown adipocyte size. CONCLUSIONS: This study provides evidence that class I HDAC inhibition stimulated functionality and oxidative potential of adipose tissue, improving glucose tolerance and ameliorating the metabolic profile in diet-induced obese mice.
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| 30. |
- Graafsma, Heinz, et al.
(author)
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PERCIVAL soft X-ray imager
- 2013
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In: IEEE Nuclear Science Symposium Conference Record. - : IEEE conference proceedings. - 9781479905348 ; , s. Art. no. 6829506-
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Conference paper (peer-reviewed)abstract
- Our goal is to provide the scientific community with a large (10cm × 10cm) pixellated detector featuring a large dynamic range (1-105 photons), good spatial resolution (27μm), good Quantum Efficiency (QE) in the low energy range (250eV-1keV), variable readout speed (up to 120 frames/s), i.e. with characteristics compatible with user needs at today's of low-energy Free Electron Lasers (FEL) and synchrotron sources. © 2013 IEEE.
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| 31. |
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| 32. |
- Luo, Kun, et al.
(author)
-
Anion Redox Chemistry in the Cobalt Free 3d Transition Metal Oxide Intercalation Electrode Li[Li0.2Ni0.2Mn0.6]O-2
- 2016
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In: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 138:35, s. 11211-11218
-
Journal article (peer-reviewed)abstract
- Conventional intercalation cathodes for lithium batteries store charge in redox reactions associated with the transition metal cations, e.g., Mn3+/4+ in LiMn2O4, and this limits the energy storage of Li-ion batteries. Compounds such as Li[Li0.2Ni0.2Mn0.6]O-2 exhibit a capacity to store charge in excess of the transition metal redox reactions. The additional capacity occurs at and above 4.5 V versus Li+/Li. The capacity at 4.5 V is dominated by oxidation of the O-2(-) anions accounting for similar to 0.43 e(-)/formula unit, with an additional 0.06 e(-)/formula unit being associated with O loss from the lattice. In contrast, the capacity above 4.5 V is mainly O loss, similar to 0.08 e(-)/formula. The O redox reaction involves the formation of localized hole states on O during charge, which are located on O coordinated by (Mn4+/Li+). The results have been obtained by combining operando electrochemical mass spec on 180 labeled Li[Li0.2Ni0.2Mn0.6]O-2 with XANES, soft X-ray spectroscopy, resonant inelastic X-ray spectroscopy, and Raman spectroscopy. Finally the general features of O redox are described with discussion about the role of comparatively ionic (less covalent) 3d metal oxygen interaction on anion redox in lithium rich cathode materials.
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| 33. |
- Luo, Kun, et al.
(author)
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Charge-compensation in 3d-transition-metal-oxide intercalation cathodes through the generation of localized electron holes on oxygen
- 2016
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In: Nature Chemistry. - 1755-4330 .- 1755-4349. ; 8:7, s. 684-691
-
Journal article (peer-reviewed)abstract
- During the charging and discharging of lithium-ion-battery cathodes through the de-and reintercalation of lithium ions, electroneutrality is maintained by transition-metal redox chemistry, which limits the charge that can be stored. However, for some transition-metal oxides this limit can be broken and oxygen loss and/or oxygen redox reactions have been proposed to explain the phenomenon. We present operando mass spectrometry of O-18-labelled Li-1.2[Ni0.132+Co0.133+Mn0.544+]O-2, which demonstrates that oxygen is extracted from the lattice on charging a Li-1.2[Ni0.132+Co0.133+Mn0.544+]O-2 cathode, although we detected no O-2 evolution. Combined soft X-ray absorption spectroscopy, resonant inelastic X-ray scattering spectroscopy, X-ray absorption near edge structure spectroscopy and Raman spectroscopy demonstrates that, in addition to oxygen loss, Li+ removal is charge compensated by the formation of localized electron holes on O atoms coordinated by Mn4+ and Li+ ions, which serve to promote the localization, and not the formation, of true O-2(2-)( peroxide, O-O similar to 1.45 angstrom) species. The quantity of charge compensated by oxygen removal and by the formation of electron holes on the O atoms is estimated, and for the case described here the latter dominates.
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| 34. |
- Marras, A., et al.
(author)
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Experimental characterization of the PERCIVAL soft X-ray detector
- 2016
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In: 2015 IEEE Nuclear Science Symposium and Medical Imaging Conference, NSS/MIC 2015. - : Institute of Electrical and Electronics Engineers (IEEE). - 9781467398626
-
Conference paper (other academic/artistic)abstract
- Considerable interest has been manifested for the use of high-brilliance X-ray synchrotron sources and X-ray Free-Electron Lasers for the investigation of samples.
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| 35. |
- Opheim, G., et al.
(author)
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7T Epilepsy Task Force Consensus Recommendations on the Use of 7T MRI in Clinical Practice
- 2021
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In: Neurology. - : Ovid Technologies (Wolters Kluwer Health). - 0028-3878 .- 1526-632X. ; 96:7, s. 327-341
-
Journal article (peer-reviewed)abstract
- Identifying a structural brain lesion on MRI has important implications in epilepsy and is the most important factor that correlates with seizure freedom after surgery in patients with drug-resistant focal onset epilepsy. However, at conventional magnetic field strengths (1.5 and 3T), only approximately 60%-85% of MRI examinations reveal such lesions. Over the last decade, studies have demonstrated the added value of 7T MRI in patients with and without known epileptogenic lesions from 1.5 and/or 3T. However, translation of 7T MRI to clinical practice is still challenging, particularly in centers new to 7T, and there is a need for practical recommendations on targeted use of 7T MRI in the clinical management of patients with epilepsy. The 7T Epilepsy Task Force-an international group representing 21 7T MRI centers with experience from scanning over 2,000 patients with epilepsy-would hereby like to share its experience with the neurology community regarding the appropriate clinical indications, patient selection and preparation, acquisition protocols and setup, technical challenges, and radiologic guidelines for 7T MRI in patients with epilepsy. This article mainly addresses structural imaging; in addition, it presents multiple nonstructural MRI techniques that benefit from 7T and hold promise as future directions in epilepsy. Answering to the increased availability of 7T MRI as an approved tool for diagnostic purposes, this article aims to provide guidance on clinical 7T MRI epilepsy management by giving recommendations on referral, suitable 7T MRI protocols, and image interpretation.
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| 36. |
- Viti, M., et al.
(author)
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Spatial resolution studies for the PERCIVAL sensor
- 2015
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In: Journal of Instrumentation. - 1748-0221. ; 10
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Journal article (peer-reviewed)abstract
- The PERCIVAL ("Pixelated Energy Resolving CMOS Imager, Versatile and Large") is a collaboration of DESY, RAL/STFC, ELETTRA, and DLS to develop a monolithic active pixel sensor (MAPS) to provide a suitable detector for photon science for the photon energy regime between 250 eV and 1 keV. An important performance parameter is the spatial resolution which can be inferred from the Modulation Transfer Function (MTF). The MTF measures in optical systems the relative contrast of a pattern in function of the spatial frequency. With a back-thinned and back- illuminated PERCIVAL prototype chip, dedicated MTF evaluation data were taken at Elettra's TwinMic Beamline in March 2014 at a photon energy of 535 eV. We will present our MTF derivation approaches together with MTF results for 3 pixel types of the irradiated test sensor.
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| 37. |
- Wunderer, C. B., et al.
(author)
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The PERCIVAL soft X-ray imager
- 2015
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In: Journal of Instrumentation. - 1748-0221. ; 10:2
-
Journal article (peer-reviewed)abstract
- With the increased brilliance of state-of-the-art Synchrotron radiation sources and the advent of Free Electron Lasers enabling revolutionary science on atomic length and time scales with EUV to X-ray photons comes an urgent need for suitable photon imaging detectors. Requirements include high frame rates, very large dynamic range, single-photon counting capability with low probability of false positives, and (multi)-megapixels. PERCIVAL ("Pixelated Energy Resolving CMOS Imager, Versatile And Large") is currently being developed by a collaboration of DESY, RAL, Elettra, DLS and Pohang to address this need for the soft X-ray regime. PERCIVAL is a monolithic active pixel sensor (MAPS), i.e. based on CMOS technology. It will be back-thinned to access its primary energy range of 250 eV to 1 keV with target efficiencies above 90%. According to its preliminary specifications, the roughly 10 × 10 cm2, 3.5k × 3.7k monolithic "PERCIVAL13M" sensor will operate at frame rates up to 120 Hz (commensurate with most FELs) and use multiple gains within its 27 μm pixels to measure 1 to ∼ 105 (500 eV) simultaneously-arriving photons. A smaller "PERCIVAL2M" with ∼ 1.4k × 1.5k pixels is also planned. Currently, small-scale back-illuminated prototype systems (160 × 210 pixels of 25 μm pitch) are undergoing detailed testing with X-rays and optical photons. In March 2014, a prototype sensor was tested at 350 eV-2 keV at Elettra's TwinMic beamline. The data recorded include diffraction patterns at 350 eV and 400 eV, knife edge and sub-pixel pinhole illuminations, and comparisons of different pixel types. Another prototype chip will be submitted in fall 2014, first larger sensors could be in hand in late 2015.
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| 38. |
- Wunderer, C. B., et al.
(author)
-
The PERCIVAL soft X-ray imager
- 2014
-
In: Journal of Instrumentation. - 1748-0221. ; 9:3
-
Journal article (peer-reviewed)abstract
- With the increased brilliance of state-of-the-art Synchrotron radiation sources and the advent of Free Electron Lasers enabling revolutionary science with EUV to X-ray photons comes an urgent need for suitable photon imaging detectors. Requirements include high frame rates, very large dynamic range, single-photon counting capability with low probability of false positives, and (multi)-megapixels. PERCIVAL (''Pixelated Energy Resolving CMOS Imager, Versatile and Large'') is currently being developed by a collaboration of DESY, RAL, Elettra and DLS to address this need for the soft X-ray regime. PERCIVAL is a monolithic active pixel sensor (MAPS), i.e. based on CMOS technology. It will be back-thinned to access its primary energy range of 250 eV to 1 keV with target efficiencies above 90%. According to its preliminary specifications, the roughly 10 × 10 cm2, 3520 × 3710 pixel monolithic sensor will operate at frame rates up to 120 Hz (commensurate with most FELs) and use multiple gains within its 27 μm pixels to measure (e.g. at 500 eV) 1 to ∼ 105 simultaneously-arriving photons. Currently, small-scale front-illuminated prototype systems (160 × 210 pixels) are undergoing detailed testing with visible-light as well as X-ray photons. © 2014 IOP Publishing Ltd and Sissa Medialab srl.
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| 39. |
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