1. |
- Ansell, Brendan R. E., et al.
(författare)
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Divergent Transcriptional Responses to Physiological and Xenobiotic Stress in Giardia duodenalis
- 2016
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Ingår i: Antimicrobial Agents and Chemotherapy. - 0066-4804 .- 1098-6596. ; 60:10, s. 6034-6045
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Tidskriftsartikel (refereegranskat)abstract
- Understanding how parasites respond to stress can help to identify essential biological processes. Giardia duodenalis is a parasitic protist that infects the human gastrointestinal tract and causes 200 to 300 million cases of diarrhea annually. Metronidazole, a major antigiardial drug, is thought to cause oxidative damage within the infective trophozoite form. However, treatment efficacy is suboptimal, due partly to metronidazole-resistant infections. To elucidate conserved and stress-specific responses, we calibrated sublethal metronidazole, hydrogen peroxide, and thermal stresses to exert approximately equal pressure on trophozoite growth and compared transcriptional responses after 24 h of exposure. We identified 252 genes that were differentially transcribed in response to all three stressors, including glycolytic and DNA repair enzymes, a mitogen-activated protein (MAP) kinase, high-cysteine membrane proteins, flavin adenine dinucleotide (FAD) synthetase, and histone modification enzymes. Transcriptional responses appeared to diverge according to physiological or xenobiotic stress. Downregulation of the antioxidant system and alpha-giardins was observed only under metronidazole-induced stress, whereas upregulation of GARP-like transcription factors and their subordinate genes was observed in response to hydrogen peroxide and thermal stressors. Limited evidence was found in support of stress-specific response elements upstream of differentially transcribed genes; however, antisense derepression and differential regulation of RNA interference machinery suggest multiple epigenetic mechanisms of transcriptional control.
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2. |
- Ansell, Brendan R. E., et al.
(författare)
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Drug resistance in Giardia duodenalis
- 2015
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Ingår i: Biotechnology Advances. - : Elsevier BV. - 0734-9750 .- 1873-1899. ; 33:6, s. 888-901
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Forskningsöversikt (refereegranskat)abstract
- Giardia duodenalis is a microaerophilic parasite of the human gastrointestinal tract and a major contributor to diarrheal and post-infectious chronic gastrointestinal disease world-wide. Treatment of G. duodenalis infection currently relies on a small number of drug classes. Nitroheterocyclics, in particular metronidazole, have represented the front line treatment for the last 40 years. Nitroheterocyclic-resistant G. duodenalis have been isolated from patients and created in vitro, prompting considerable research into the biomolecular mechanisms of resistance. These compounds are redox-active and are believed to damage proteins and DNA after being activated by oxidoreductase enzymes in metabolically active cells. In this review, we explore the molecular phenotypes of nitroheterocyclic-resistant G. duodenalis described to date in the context of the protisfs unusual glycolytic and antioxidant systems. We propose that resistance mechanisms are likely to extend well beyond currently described resistance-associated enzymes (i.e., pyruvate ferredoxin oxidoreductases and nitroreductases), to include NAD(P)H- and flavin-generating pathways, and possibly redox-sensitive epigenetic regulation. Mechanisms that allow G. duodenalis to tolerate oxidative stress may lead to resistance against both oxygen and nitroheterocyclics, with implications for clinical control. The present review highlights the potential for systems biology tools and advanced bioinformatics to further investigate the multifaceted mechanisms of nitroheterocyclic resistance in this important pathogen.
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3. |
- Ansell, Brendan R. E., et al.
(författare)
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Time-Dependent Transcriptional Changes in Axenic Giardia duodenalis Trophozoites
- 2015
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Ingår i: PLoS Neglected Tropical Diseases. - : Public Library of Science (PLoS). - 1935-2727 .- 1935-2735. ; 9:12
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Tidskriftsartikel (refereegranskat)abstract
- Giardia duodenalis is the most common gastrointestinal protozoan parasite of humans and a significant contributor to the global burden of both diarrheal disease and post-infectious chronic disorders. Although G. duodenalis can be cultured axenically, significant gaps exist in our understanding of the molecular biology and metabolism of this pathogen. The present study employed RNA sequencing to characterize the mRNA transcriptome of G. duodenalis trophozoites in axenic culture, at log (48 h of growth), stationary (60 h), and declining (96 h) growth phases. Using similar to 400-times coverage of the transcriptome, we identified 754 differentially transcribed genes (DTGs), mainly representing two large DTG groups: 438 that were down-regulated in the declining phase relative to log and stationary phases, and 281 that were up-regulated. Differential transcription of prominent antioxidant and glycolytic enzymes implicated oxygen tension as a key factor influencing the transcriptional program of axenic trophozoites. Systematic bioinformatic characterization of numerous DTGs encoding hypothetical proteins of unknown function was achieved using structural homology searching. This powerful approach greatly informed the differential transcription analysis and revealed putative novel antioxidant-coding genes, and the presence of a nearcomplete two-component-like signaling system that may link cytosolic redox or metabolite sensing to the observed transcriptional changes. Motif searching applied to promoter regions of the two large DTG groups identified different putative transcription factor-binding motifs that may underpin global transcriptional regulation. This study provides new insights into the drivers and potential mediators of transcriptional variation in axenic G. duodenalis and provides context for static transcriptional studies.
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4. |
- Ansell, Brendan R. E., et al.
(författare)
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Transcriptomics Indicates Active and Passive Metronidazole Resistance Mechanisms in Three Seminal Giardia Lines
- 2017
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Ingår i: Frontiers in Microbiology. - : Frontiers Media SA. - 1664-302X. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Giardia duodenalis is an intestinal parasite that causes 200-300 million episodes of diarrhoea annually. Metronidazole (Mtz) is a front-line anti-giardial, but treatment failure is common and clinical resistance has been demonstrated. Mtz is thought to be activated within the parasite by oxidoreductase enzymes, and to kill by causing oxidative damage. In G. duodenalis, Mtz resistance involves active and passive mechanisms. Relatively low activity of iron-sulfur binding proteins, namely pyruvate: ferredoxin oxidoreductase (PFOR), ferredoxins, and nitroreductase-1, enable resistant cells to passively avoid Mtz activation. Additionally, low expression of oxygen-detoxification enzymes can allow passive (non-enzymatic) Mtz detoxification via futile redox cycling. In contrast, active resistance mechanisms include complete enzymatic detoxification of the pro-drug by nitroreductase-2 and enhanced repair of oxidized biomolecules via thioredoxin-dependent antioxidant enzymes. Molecular resistance mechanisms may be largely founded on reversible transcriptional changes, as some resistant lines revert to drug sensitivity during drug-free culture in vitro, or passage through the life cycle. To comprehensively characterize these changes, we undertook strand-specific RNA sequencing of three laboratory-derived Mtz-resistant lines, 106-2ID(10), 713-M3, and WB-M3, and compared transcription relative to their susceptible parents. Common up-regulated genes encoded variant-specific surface proteins (VSPs), a high cysteine membrane protein, calcium and zinc channels, a Mad-2 cell cycle regulator and a putative fatty acid a alpha-oxidase. Down-regulated genes included nitroreductase-1, putative chromate and quinone reductases, and numerous genes that act proximal to PFOR. Transcriptional changes in 106-2ID(10) diverged from those in 713-r and WB-r (r <= 0.2), which were more similar to each other (r = 0.47). In 106-2ID(10), a nonsense mutation in nitroreductase-1 transcripts could enhance passive resistance whereas increased transcription of nitroreductase-2, and a MATE transmembrane pump system, suggest active drug detoxification and efflux, respectively. By contrast, transcriptional changes in 713-M3 and WB-M3 indicated a higher oxidative stress load, attributed to Mtz- and oxygen-derived radicals, respectively. Quantitative comparisons of orthologous gene transcription between Mtz-resistant G. duodenalis and Trichomonas vaginalis, a closely related parasite, revealed changes in transcripts encoding peroxidases, heat shock proteins, and FMN-binding oxidoreductases, as prominent correlates of resistance. This work provides deep insight into Mtz-resistant G. duodenalis, and illuminates resistance-associated features across parasitic species.
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5. |
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6. |
- Emery-Corbin, Samantha J., et al.
(författare)
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Eukaryote-Conserved Methylarginine Is Absent in Diplomonads and Functionally Compensated in Giardia
- 2020
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Ingår i: Molecular biology and evolution. - : OXFORD UNIV PRESS. - 0737-4038 .- 1537-1719. ; 37:12, s. 3525-3549
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Tidskriftsartikel (refereegranskat)abstract
- Methylation is a common posttranslational modification of arginine and lysine in eukaryotic proteins. Methylproteomes are best characterized for higher eukaryotes, where they are functionally expanded and evolved complex regulation. However, this is not the case for protist species evolved from the earliest eukaryotic lineages. Here, we integrated bioinformatic, proteomic, and drug-screening data sets to comprehensively explore the methylproteome of Giardia duodenalis-a deeply branching parasitic protist. We demonstrate that Giardia and related diplomonads lack arginine-methyltransferases and have remodeled conserved RGG/RG motifs targeted by these enzymes. We also provide experimental evidence for methylarginine absence in proteomes of Giardia but readily detect methyllysine. We bioinformatically infer 11 lysine-methyltransferases in Giardia, including highly diverged Su(var)3-9, Enhancer-of-zeste and Trithorax proteins with reduced domain architectures, and novel annotations demonstrating conserved methyllysine regulation of eukaryotic elongation factor 1 alpha. Using mass spectrometry, we identifymore than 200methyllysine sites in Giardia, including in species-specific gene families involved in cytoskeletal regulation, enriched in coiled-coil features. Finally, we use known methylation inhibitors to show that methylation plays key roles in replication and cyst formation in this parasite. This study highlights reduced methylation enzymes, sites, and functions early in eukaryote evolution, including absent methylarginine networks in the Diplomonadida. These results challenge the view that arginine methylation is eukaryote conserved and demonstrate that functional compensation of methylarginine was possible preceding expansion and diversification of these key networks in higher eukaryotes.
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7. |
- Freitas, Áureo, et al.
(författare)
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CONTROL SYSTEM SUITE FOR BEAM POSITION MONITORS AT MAX IV
- 2022
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Ingår i: 2022 International Beam Instrumentation Conference, IBIC 2022 - Proceedings. - 2673-5350. - 9783954502417 ; , s. 496-499
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Konferensbidrag (refereegranskat)abstract
- MAX IV is a fourth generation synchrotron facility at Lund, Sweden. It is composed of a full energy linear accelerator and two storage rings with 1.5 GeV and 3 GeV, which requires hundreds of beam position monitors. In this context, Libera Single Pass E and Libera Brilliance+ are employed as BPM instruments. This paper will present an overview of the control system suite used in the facility, including the communication, data acquisition and storage pipelines, monitoring, configuration and software maintainability.
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8. |
- Lorek, Eleonora, et al.
(författare)
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Size and shape dependent few-cycle near-field dynamics of bowtie nanoantennas
- 2015
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Ingår i: Optics Express. - 1094-4087. ; 23:24, s. 31460-31471
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Tidskriftsartikel (refereegranskat)abstract
- Metal nanostructures can transfer electromagnetic energy from femtosecond laser pulses to the near-field down to spatial scales well below the optical diffraction limit. By combining few-femtosecond laser pulses with photoemission electron microscopy, we study the dynamics of the induced few-cycle near-field in individual bowtie nanoantennas. We investigate how the dynamics depend on antenna size and exact bowtie shape resulting from fabrication. Different dynamics are, as expected, measured for antennas of different sizes. However, we also detect comparable dynamics differences between individual antennas of similar size. With Finite-difference time-domain simulations we show that these dynamics differences between similarly sized antennas can be due to small lateral shape variations generally induced during the fabrication.
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9. |
- Mansten, Erik, et al.
(författare)
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Cancellation of klystron-induced energy and arrival-time variations in linear accelerators with arc-type bunch compressors
- 2024
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Ingår i: Physical Review Accelerators and Beams. - 2469-9888. ; 27:4
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Tidskriftsartikel (refereegranskat)abstract
- We explain how the accelerating field amplitude and phase vary with modulator voltage in pulsed radio frequency high-power amplifiers based on klystron tubes. Changes in modulator voltage give rise to correlated changes of amplitude and phase, affecting the properties of the accelerated beam, in particular energy, arrival time, and bunch duration. We show, both theoretically and experimentally, that there exists a postcrest acceleration phase (the magic angle) where the changes of beam energy due to phase and amplitude shifts caused by modulator-voltage variations cancel out. When accelerating at the magic angle, the klystron modulator voltage jitter no longer contributes to energy and arrival-time jitter in the accelerator. Off-crest operation at the magic angle can be implemented for bunch compression schemes in accelerators with arc-type bunch compressors, which have positive momentum compaction. The experimental results, obtained at the MAX IV laboratory, show the benefit of operating close to the magic angle in arc-type bunch compressors. In a direct measurement of normalized electron-energy jitter, the energy jitter was reduced by a factor of 1.8 down to 8.2×10-5 when operating at the magic angle.
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10. |
- Matko, Drago, et al.
(författare)
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Validation of Astrodynamic Formation Flying Models Against SPACE-SI Experiments with Prisma Satellites
- 2012
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Ingår i: 26th Annual AIAA/USU Conference on Small Satellites, Logan, Utah, USA.
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Konferensbidrag (refereegranskat)abstract
- In this paper several astrodynamical formation flying models are assessed against the experimental results derived from the SPACE-SI formation flying experiments performed in September 2011 with the OHB Sweden developed Prisma satellites Mango and Tango. In these formation flying experiments critical manoeuvres for three types of missions were investigated with respect to in-orbit performances. The experiments included parallel flying with in track displacement demonstrating high-resolution optical dual satellite imaging and radar interferometric constellation, circumvolution as well as encircling of the target demonstrating debris observation and parallel flying with the radial displacement demonstrating fractionated spacecraft and accurate pointing of the formation. The astrodynamic data of the experiment are used to verify several formation flying models including a nonlinear model, a linear Hill-Clohessy-Wiltshire model, STK models with four propagators (Earth mass point, J2, default HPOP and HPOP with all disturbances) and the hereby originally proposed extension to the Hill-Clohessy-Wiltshire model, a linear model for orbits with small eccentricities.
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11. |
- Meirose, Bernhard, et al.
(författare)
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Real-time accelerator diagnostic tools for the max iv storage rings
- 2020
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Ingår i: Instruments. - : MDPI AG. - 2410-390X. ; 4:3
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Tidskriftsartikel (refereegranskat)abstract
- In this paper, beam diagnostic and monitoring tools developed by the MAX IV Operations Group are discussed. In particular, beam position monitoring and accelerator tunes visualization software tools, as well as tools that directly influence the beam quality and stability, are introduced. An availability and downtime monitoring application is also presented.
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12. |
- Mårsell, Erik, et al.
(författare)
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Direct subwavelength imaging and control of near-field localization in individual silver nanocubes
- 2015
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Ingår i: Applied Physics Letters. - : AIP Publishing. - 0003-6951 .- 1077-3118. ; 107:20
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Tidskriftsartikel (refereegranskat)abstract
- We demonstrate the control of near-field localization within individual silver nanocubes through photoemission electron microscopy combined with broadband, few-cycle laser pulses. We find that the near-field is concentrated at the corners of the cubes, and that it can be efficiently localized to different individual corners depending on the polarization of the incoming light. The experimental results are confirmed by finite-difference time-domain simulations, which also provide an intuitive picture of polarization dependent near-field localization in nanocubes. (C) 2015 AIP Publishing LLC.
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13. |
- Mårsell, Erik, et al.
(författare)
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Nanoscale imaging of local few-femtosecond near-field dynamics within a single plasmonic nanoantenna.
- 2015
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Ingår i: Nano Letters. - : American Chemical Society (ACS). - 1530-6992 .- 1530-6984. ; 15:10, s. 6601-6608
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Tidskriftsartikel (refereegranskat)abstract
- The local enhancement of few-cycle laser pulses by plasmonic nanostructures opens up for spatiotemporal control of optical interactions on a nanometer and few-femtosecond scale. However, spatially resolved characterization of few-cycle plasmon dynamics poses a major challenge due to the extreme length and time scales involved. In this letter, we experimentally demonstrate local variations in the dynamics during the few strongest cycles of plasmon-enhanced fields within individual rice-shaped silver nanoparticles. This was done using 5.5 fs laser pulses in an interferometric time-resolved photoemission electron microscopy setup. The experiments are supported by finite-difference time-domain simulations of similar silver structures. The observed differences in the field dynamics across a single particle do not reflect differences in plasmon resonance frequency or dephasing time. They instead arise from a combination of retardation effects and the coherent superposition between multiple plasmon modes of the particle, inherent to a few-cycle pulse excitation. The ability to detect and predict local variations in the few-femtosecond time evolution of multi-mode coherent plasmon excitations in rationally synthesized nanoparticles can be used in the tailoring of nanostructures for ultrafast and nonlinear plasmonics.
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14. |
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15. |
- Svärd, Daniel, et al.
(författare)
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Cognitive interference processing in adult survivors of childhood acute lymphoblastic leukemia using functional magnetic resonance imaging
- 2022
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Ingår i: Acta Oncologica. - 1651-226X. ; 61:3, s. 333-340
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Tidskriftsartikel (refereegranskat)abstract
- Background: Childhood acute lymphoblastic leukemia (ALL) is associated with cognitive impairment in adulthood. Cognitive interference processing and its correlated functional magnetic resonance imaging (fMRI) activity in the brain have not yet been studied in this patient group.Material: Twenty-six adult childhood ALL survivors (median [interquartile range {IQR}] age, 40.0 [37.0-42.3] years) were investigated at median age (IQR), 35.0 (32.0-37.0) years after treatment with intrathecal and intravenous chemotherapy as well as cranial radiotherapy (24 Gy) and compared with 26 matched controls (median [IQR] age, 37.5 [33.0-41.5] years).Methods: Cognitive interference processing was investigated in terms of behavioral performance (response times [ms] and accuracy performance [%]) and fMRI activity in the cingulo-fronto-parietal (CFP) attention network as well as other parts of the brain using the multisource interference task (MSIT).Results: ALL survivors had longer response times and reduced accuracy performance during cognitive interference processing (median [IQR] interference effect, 371.9 [314.7-453.3] ms and 6.7 [4.2-14.7]%, respectively) comparedwith controls (303.7 [275.0-376.7] ms and 2.3 [1.6-4.3]%, respectively), but did not exhibit altered fMRI activity in the CFP attention network or elsewhere in the brain.Conclusion: Adult childhood ALL survivors demonstrated impaired behavioral performance but no altered fMRI activity when performing cognitive interference processing when compared with controls. The results can be used to better characterize this patient group and to optimize follow-up care and support for these individuals.
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16. |
- Svärd, Daniel, et al.
(författare)
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Cognitive interference processing in adults with childhood craniopharyngioma using functional magnetic resonance imaging
- 2021
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Ingår i: Endocrine. - : Springer Science and Business Media LLC. - 1355-008X .- 1559-0100. ; 74:3, s. 714-722
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To assess cognitive interference processing in adults with childhood craniopharyngioma (CP), with and without hypothalamic injury, respectively, in terms of behavioral performance and functional magnetic resonance imaging (fMRI) activity, using the multi-source interference task (MSIT).METHODS: Twenty-eight CP patients (median age 34.5 [29.0-39.5] years) were investigated at median 20.5 (16.3-28.8) years after treatment with surgical resection and in some cases additional radiotherapy (n = 10) and compared to 29 matched controls (median age 37.0 [32.5-42.0] years). The subjects performed the MSIT during fMRI acquisition and behavioral performance in terms of response times (ms) and accuracy performance (%) were recorded.RESULTS: The MSIT activated the cingulo-fronto-parietal (CFP) attention network in both CP patients and controls. No differences were found in behavioral performance nor fMRI activity between CP patients (interference effect 333.9 [287.3-367.1] ms and 3.1 [1.6-5.6]%, respectively) and controls (309.1 [276.4-361.0] ms and 2.6 [1.6-4.9]%). No differences were found in behavioral performance nor fMRI activity between the two subgroups with (332.0 [283.6-353.4] ms and 4.2 [2.3-5.7]%, respectively) and without hypothalamic injury (355.7 [293.7-388.7] ms and 2.1 [1.0-5.2]%, respectively), respectively, and controls.CONCLUSION: Adults with childhood CP performed cognitive interference processing equally well as controls and demonstrated no compensatory fMRI activity in the CFP attention network compared to controls. This was also true for the two subgroups with and without hypothalamic injury. The results can be useful to better characterize this condition, and to optimize treatment and support for these individuals.
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17. |
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18. |
- Thorin, Sara, et al.
(författare)
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Experience and initial measurements of magnetic linearisation in the MAX IV linac bunch compressors
- 2017
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Ingår i: Proceedings of FEL2017, Santa Fe, NM, USA. - 9783954501793 ; , s. 273-275
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- The MAX IV Linac is now in routine operation for injection into two storage rings, and as a high-brightness driver for a Short Pulse Facility (SPF). In short-pulse mode the electron bunch is created in a photo cathode gun and compressed in two double achromat bunch compressors that also linearise longitudinal phase space with the second order transfer matrix element T566. T566 in the compressors canbe tweaked with weak sextupoles located at high dispersion. In this paper we present the current experience from operating the bunch compressors at MAX IV and results from initial measurements of longitudinal phase space using our version of the the zero-crossing method.
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19. |
- Thorin, Sara, et al.
(författare)
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Status of MAX IV linac beam commissioning and performance
- 2017
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Ingår i: IPAC 2017 - Proceedings of the 8th International Particle Accelerator Conference. - 9783954501823 ; , s. 1547-1549
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Konferensbidrag (refereegranskat)abstract
- The MAX IV linac is used both for injection into a 3 GeV storage ring, and as a high brightness driver for a Short Pulse Facility (SPF). It has also been deigned to handle the high demands of an FEL injector. The linac is now routinely injecting into the two storagerings, and commissioning work is focused towards delivering high brightness pulses to the SPF. In this paper we present results from characterisation of the linac in ring injection mode, as well as results from measurements of key parameters for the SPF such as bunch length and emittance.
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