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Karalija, N., Papenberg, G., Wåhlin, A., Johansson, J., Andersson, M., Axelsson, J., . . . Nyberg, L. (2019). C957T-mediated Variation in Ligand Affinity Affects the Association between C-11-raclopride Binding Potential and Cognition. Journal of cognitive neuroscience, 31(2), 314-325
Open this publication in new window or tab >>C957T-mediated Variation in Ligand Affinity Affects the Association between C-11-raclopride Binding Potential and Cognition
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2019 (English)In: Journal of cognitive neuroscience, ISSN 0898-929X, E-ISSN 1530-8898, Vol. 31, no 2, p. 314-325Article in journal (Refereed) Published
Abstract [en]

The dopamine (DA) system plays an important role in cognition. Accordingly, normal variation in DA genes has been found to predict individual differences in cognitive performance. However, little is known of the impact of genetic differences on the link between empirical indicators of the DA system and cognition in humans. The present work used PET with C-11-raclopride to assess DA D2-receptor binding potential (BP) and links to episodic memory, working memory, and perceptual speed in 179 healthy adults aged 64-68 years. Previously, the T-allele of a DA D2-receptor single-nucleotide polymorphism, C957T, was associated with increased apparent affinity of C-11-raclopride, giving rise to higher BP values despite similar receptor density values between allelic groups. Consequently, we hypothesized that C-11-raclopride BP measures inflated by affinity rather than D2-receptor density in T-allele carriers would not be predictive of DA integrity and therefore prevent finding an association between C-11-raclopride BP and cognitive performance. In accordance with previous findings, we show that C-11-raclopride BP was increased in T-homozygotes. Importantly, C-11-raclopride BP was only associated with cognitive performance in groups with low or average ligand affinity (C-allele carriers of C957T, n = 124), but not in the high-affinity group (T-homozygotes, n = 55). The strongest C-11-raclopride BP-cognition associations and the highest level of performance were found in C-homozygotes. These findings show that genetic differences modulate the link between BP and cognition and thus have important implications for the interpretation of DA assessments with PET and C-11-raclopride in multiple disciplines ranging from cognitive neuroscience to psychiatry and neurology.

Place, publisher, year, edition, pages
MIT Press, 2019
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-155630 (URN)10.1162/jocn_a_01354 (DOI)000454429400011 ()30407135 (PubMedID)
Funder
Swedish Research CouncilKnut and Alice Wallenberg FoundationRagnar Söderbergs stiftelseTorsten Söderbergs stiftelseThe Swedish Brain FoundationVästerbotten County Council
Available from: 2019-01-28 Created: 2019-01-28 Last updated: 2019-01-28Bibliographically approved
Karalija, N., Wåhlin, A., Ek, J., Rieckmann, A., Papenberg, G., Salami, A., . . . Nyberg, L. (2019). Cardiovascular factors are related to dopamine integrity and cognition in aging. Annals of clinical and translational neurology, 6(11), 2291-2303
Open this publication in new window or tab >>Cardiovascular factors are related to dopamine integrity and cognition in aging
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2019 (English)In: Annals of clinical and translational neurology, E-ISSN 2328-9503, Vol. 6, no 11, p. 2291-2303Article in journal (Refereed) Published
Abstract [en]

Objective: The aging brain undergoes several changes, including reduced vascular, structural, and dopamine (DA) system integrity. Such brain changes have been associated with age‐related cognitive deficits. However, their relative importance, interrelations, and links to risk factors remain elusive.

Methods: The present work used magnetic resonance imaging and positron emission tomography with 11C‐raclopride to jointly examine vascular parameters (white‐matter lesions and perfusion), DA D2‐receptor availability, brain structure, and cognitive performance in healthy older adults (n = 181, age: 64–68 years) from the Cognition, Brain, and Aging (COBRA) study.

Results: Covariance was found among several brain indicators, where top predictors of cognitive performance included caudate and hippocampal integrity (D2DR availability and volumes), and cortical blood flow and regional volumes. White‐matter lesion burden was negatively correlated with caudate DA D2‐receptor availability and white‐matter microstructure. Compared to individuals with smaller lesions, individuals with confluent lesions (exceeding 20 mm in diameter) had reductions in cortical and hippocampal perfusion, striatal and hippocampal D2‐receptor availability, white‐matter microstructure, and reduced performance on tests of episodic memory, sequence learning, and processing speed. Higher cardiovascular risk as assessed by treatment for hypertension, systolic blood pressure, overweight, and smoking was associated with lower frontal cortical perfusion, lower putaminal D2DR availability, smaller grey‐matter volumes, a larger number of white‐matter lesions, and lower episodic memory performance.

Interpretation: Taken together, these findings suggest that reduced cardiovascular health is associated with poorer status for brain variables that are central to age‐sensitive cognitive functions, with emphasis on DA integrity.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2019
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-165743 (URN)10.1002/acn3.50927 (DOI)000496520700016 ()31663685 (PubMedID)
Funder
Knut and Alice Wallenberg FoundationTorsten Söderbergs stiftelseRagnar Söderbergs stiftelseThe Swedish Brain FoundationVästerbotten County CouncilMax Planck SocietySwedish Research Council
Available from: 2019-12-10 Created: 2019-12-10 Last updated: 2019-12-10Bibliographically approved
Salami, A., Garrett, D. D., Wåhlin, A., Rieckmann, A., Papenberg, G., Karalija, N., . . . Nyberg, L. (2019). Dopamine D2/3 Binding Potential Modulates Neural Signatures of Working Memory in a Load-Dependent Fashion.. Journal of Neuroscience, 39(3), 537-547
Open this publication in new window or tab >>Dopamine D2/3 Binding Potential Modulates Neural Signatures of Working Memory in a Load-Dependent Fashion.
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2019 (English)In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 39, no 3, p. 537-547Article in journal (Refereed) Published
Abstract [en]

Dopamine (DA) modulates corticostriatal connections. Studies in which imaging of the DA system is integrated with functional imaging during cognitive performance have yielded mixed findings. Some work has shown a link between striatal DA (measured by PET) and fMRI activations, whereas others have failed to observe such a relationship. One possible reason for these discrepant findings is differences in task demands, such that a more demanding task with greater prefrontal activations may yield a stronger association with DA. Moreover, a potential DA–BOLD association may be modulated by task performance. We studied 155 (104 normal-performing and 51 low-performing) healthy older adults (43% females) who underwent fMRI scanning while performing a working memory (WM) n-back task along with DA D2/3 PET assessment using [11C]raclopride. Using multivariate partial-least-squares analysis, we observed a significant pattern revealing positive associations of striatal as well as extrastriatal DA D2/3 receptors to BOLD response in the thalamo–striatal–cortical circuit, which supports WM functioning. Critically, the DA–BOLD association in normal-performing, but not low-performing, individuals was expressed in a load-dependent fashion, with stronger associations during 3-back than 1-/2-back conditions. Moreover, normal-performing adults expressing upregulated BOLD in response to increasing task demands showed a stronger DA–BOLD association during 3-back, whereas low-performing individuals expressed a stronger association during 2-back conditions. This pattern suggests a nonlinear DA–BOLD performance association, with the strongest link at the maximum capacity level. Together, our results suggest that DA may have a stronger impact on functional brain responses during more demanding cognitive tasks.

Keywords
PET, aging, dopamine, fMRI, working memory
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-155492 (URN)10.1523/JNEUROSCI.1493-18.2018 (DOI)000455849400013 ()30478031 (PubMedID)
Funder
Swedish Research CouncilKnut and Alice Wallenberg FoundationTorsten Söderbergs stiftelseRagnar Söderbergs stiftelseThe Swedish Brain FoundationVästerbotten County Council
Available from: 2019-01-18 Created: 2019-01-18 Last updated: 2019-02-08Bibliographically approved
de Boer, L., Axelsson, J., Chowdhury, R., Riklund, K., Dolan, R. J., Nyberg, L., . . . Guitart-Masip, M. (2019). Dorsal striatal dopamine D1 receptor availability predicts an instrumental bias in action learning. Proceedings of the National Academy of Sciences of the United States of America, 116(1), 261-270
Open this publication in new window or tab >>Dorsal striatal dopamine D1 receptor availability predicts an instrumental bias in action learning
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2019 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 116, no 1, p. 261-270Article in journal (Refereed) Published
Abstract [en]

Learning to act to obtain reward and inhibit to avoid punishment is easier compared with learning the opposite contingencies. This coupling of action and valence is often thought of as a Pavlovian bias, although recent research has shown it may also emerge through instrumental mechanisms. We measured this learning bias with a rewarded go/no-go task in 60 adults of different ages. Using computational modeling, we characterized the bias as being instrumental. To assess the role of endogenous dopamine (DA) in the expression of this bias, we quantified DA D1 receptor availability using positron emission tomography (PET) with the radioligand [11C]SCH23390. Using principal-component analysis on the binding potentials in a number of cortical and striatal regions of interest, we demonstrated that cortical, dorsal striatal, and ventral striatal areas provide independent sources of variance in DA D1 receptor availability. Interindividual variation in the dorsal striatal component was related to the strength of the instrumental bias during learning. These data suggest at least three anatomical sources of variance in DA D1 receptor availability separable using PET in humans, and we provide evidence that human dorsal striatal DA D1 receptors are involved in the modulation of instrumental learning biases.

Place, publisher, year, edition, pages
National Academy of Sciences, 2019
Keywords
decision making, dopamine, Pavlovian bias, instrumental learning, positron emission tomography
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-155637 (URN)10.1073/pnas.1816704116 (DOI)000454707700042 ()30563856 (PubMedID)
Funder
Swedish Research Council, VR521-2013-2589
Available from: 2019-01-25 Created: 2019-01-25 Last updated: 2019-01-25Bibliographically approved
Jonasson, L. S., Nyberg, L., Axelsson, J., Kramer, A. F., Riklund, K. & Boraxbekk, C.-J. (2019). Higher striatal D2-receptor availability in aerobically fit older adults but non-selective intervention effects after aerobic versus resistance training. NeuroImage, 202, Article ID 116044.
Open this publication in new window or tab >>Higher striatal D2-receptor availability in aerobically fit older adults but non-selective intervention effects after aerobic versus resistance training
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2019 (English)In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 202, article id 116044Article in journal (Refereed) Published
Abstract [en]

There is much evidence that dopamine is vital for cognitive functioning in aging. Here we tested the hypothesis that aerobic exercise and fitness influence dopaminergic neurotransmission in the striatum, and in turn performance on offline working-memory updating tasks. Dopaminergic neurotransmission was measured by positron emission tomography (PET) and the non-displacable binding potential (BPND) of [11C]raclopride, i.e. dopamine (DA) D2-receptor (D2R) availability. Fifty-four sedentary older adults underwent a six-months exercise intervention, performing either aerobic exercise or stretching, toning, and resistance active control training. At baseline, higher aerobic fitness levels (VO2peak) were associated with higher BPND in the striatum, providing evidence of a link between an objective measure of aerobic fitness and D2R in older adults. BPND decreased substantially over the intervention in both groups but the intervention effects were non-selective with respect to exercise group. The decrease was several times larger than any previously estimated annual decline in D2R, potentially due to increased endogenous DA. Working-memory was unrelated to D2R both at baseline and following the intervention. To conclude, we provide partial evidence for a link between physical exercise and DA. Utilizing a PET protocol able to disentangle both D2R and DA levels could shed further light on whether, and how, aerobic exercise impacts the dopaminergic system in older adults.

Place, publisher, year, edition, pages
Elsevier, 2019
Keywords
Aerobic exercise, Fitness, Dopamine, D2, Working memory, Raclopride
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-162742 (URN)10.1016/j.neuroimage.2019.116044 (DOI)000491861000044 ()31352122 (PubMedID)2-s2.0-85069908673 (Scopus ID)
Available from: 2019-08-27 Created: 2019-08-27 Last updated: 2019-11-20Bibliographically approved
Papenberg, G., Jonasson, L. S., Karalija, N., Johansson, J., Koehncke, Y., Salami, A., . . . Backman, L. (2019). Mapping the landscape of human dopamine D2/3 receptors with [11C]raclopride. Brain Structure and Function, 224(8), 2871-2882
Open this publication in new window or tab >>Mapping the landscape of human dopamine D2/3 receptors with [11C]raclopride
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2019 (English)In: Brain Structure and Function, ISSN 1863-2653, E-ISSN 1863-2661, Vol. 224, no 8, p. 2871-2882Article in journal (Refereed) Published
Abstract [en]

The dopamine D2/3 system is fundamental for sensory, motor, emotional, and cognitive aspects of behavior. Small-scale human histopathological and animal studies show high density of D2/3 dopamine receptors (D2/3DR) in striatum, but also demonstrate the existence of such receptors across cortical and limbic regions. Assessment of D2/3DR BPND in the extrastriatal regions with [C-11]raclopride has long been considered unreliable due to the relatively low density of D2/3DR outside the striatum. We describe the distribution and interregional links of D2/3DR availability measured with PET and [C-11]raclopride across the human brain in a large sample (N = 176; age range 64-68 years). Structural equation modeling revealed that D2/3DR availability can be organized according to anatomical (nigrostriatal, mesolimbic, mesocortical) and functional (limbic, associative, sensorimotor) dopamine pathways. D2/3DR availability in corticolimbic functional subdivisions showed differential associations to corresponding striatal subdivisions, extending animal and pharmacological work. Our findings provide evidence on the dimensionality and organization of [C-11]raclopride D2/3DR availability in the living human brain that conforms to known dopaminergic pathways.

Keywords
[C-11]raclopride, Dopamine D2, 3 receptors, Inter-individual differences, Structural-equation deling, COBRA study
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-165669 (URN)10.1007/s00429-019-01938-1 (DOI)000489147300018 ()31444615 (PubMedID)
Available from: 2019-12-06 Created: 2019-12-06 Last updated: 2019-12-06Bibliographically approved
Rutegård, M., Båtsman, M., Axelsson, J., Brynolfsson, P., Brännström, F., Rutegård, J., . . . Riklund, K. (2019). PET/MRI and PET/CT hybrid imaging of rectal cancer - description and initial observations from the RECTOPET (REctal Cancer trial on PET/MRI/CT) study. Cancer Imaging, 19, Article ID 52.
Open this publication in new window or tab >>PET/MRI and PET/CT hybrid imaging of rectal cancer - description and initial observations from the RECTOPET (REctal Cancer trial on PET/MRI/CT) study
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2019 (English)In: Cancer Imaging, ISSN 1740-5025, E-ISSN 1470-7330, Vol. 19, article id 52Article in journal (Refereed) Published
Abstract [en]

PurposeThe role of hybrid imaging using F-18-fluoro-2-deoxy-D-glucose positron-emission tomography (FDG-PET), computed tomography (CT) and magnetic resonance imaging (MRI) to improve preoperative evaluation of rectal cancer is largely unknown. To investigate this, the RECTOPET (REctal Cancer Trial on PET/MRI/CT) study has been launched with the aim to assess staging and restaging of primary rectal cancer. This report presents the study workflow and the initial experiences of the impact of PET/CT on staging and management of the first patients included in the RECTOPET study.MethodsThis prospective cohort study, initiated in September 2016, is actively recruiting patients from Region Vasterbotten in Sweden. This pilot study includes patients recruited and followed up until December 2017. All patients had a biopsy-verified rectal adenocarcinoma and underwent a minimum of one preoperative FDG-PET/CT and FDG-PET/MRI examination. These patients were referred to the colorectal cancer multidisciplinary team meeting at Umea University Hospital. All available data were evaluated when making management recommendations. The clinical course was noted and changes consequent to PET imaging were described; surgical specimens underwent dedicated MRI for anatomical matching between imaging and histopathology.ResultsTwenty-four patients have so far been included in the study. Four patients were deemed unresectable, while 19 patients underwent or were scheduled for surgery; one patient was enrolled in a watch-and-wait programme after restaging. Consequent to taking part in the study, two patients were upstaged to M1 disease: one patient was diagnosed with a solitary hepatic metastasis detected using PET/CT and underwent metastasectomy prior to rectal cancer surgery, while one patient with a small, but metabolically active, lung nodulus experienced no change of management. PET/MRI did not contribute to any recorded change in patient management.ConclusionsThe RECTOPET study investigating the role of PET/CT and PET/MRI for preoperative staging of primary rectal cancer patients will provide novel data that clarify the value of adding hybrid to conventional imaging, and the role of PET/CT versus PET/MRI.Trial registrationNCT03846882.

Place, publisher, year, edition, pages
BMC, 2019
Keywords
Rectal neoplasm, Rectal tumour, Staging, Lymph nodes, Tumour deposits, PET, CT, FDG-PET, CT, PET
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-161991 (URN)10.1186/s40644-019-0237-1 (DOI)000477054900002 ()31337428 (PubMedID)
Available from: 2019-08-13 Created: 2019-08-13 Last updated: 2019-08-13Bibliographically approved
Sandgren, K., Johansson, L., Axelsson, J., Jonsson, J., Ögren, M., Ögren, M., . . . Widmark, A. (2019). Radiation dosimetry of [Ga-68]PSMA-11 in low-risk prostate cancer patients. EJNMMI Physics, 6, Article ID 2.
Open this publication in new window or tab >>Radiation dosimetry of [Ga-68]PSMA-11 in low-risk prostate cancer patients
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2019 (English)In: EJNMMI Physics, ISSN 2197-7364, E-ISSN 2191-219X, Vol. 6, article id 2Article in journal (Refereed) Published
Abstract [en]

Background: 68Ga-labeled Glu-NH-CO-NH-Lys(Ahx)-HBED-CC ([68Ga]PSMA-11) has been increasingly used to image prostate cancer using positron emission tomography (PET)/computed tomography (CT) both during diagnosis and treatment planning. It has been shown to be of clinical value for patients both in the primary and secondary stages of prostate cancer. The aim of this study was to determine the effective dose and organ doses from injection of [68Ga]PSMA-11 in a cohort of low-risk prostate cancer patients.

Methods: Six low-risk prostate cancer patients were injected with 133–178 MBq [68Ga]PSMA-11 and examined with four PET/CT acquisitions from injection to 255 min post-injection. Urine was collected up to 4 h post-injection, and venous blood samples were drawn at 45 min, 85 min, 175 min, and 245 min post-injection. Kidneys, liver, lungs, spleen, salivary and lacrimal glands, and total body where delineated, and cumulated activities and absorbed organ doses calculated. The software IDAC-Dose 2.1 was used to calculate absorbed organ doses according to the International Commission on Radiological Protection (ICRP) publication 107 using specific absorbed fractions published in ICRP 133 and effective dose according to ICRP Publication 103. We also estimated the absorbed dose to the eye lenses using Monte Carlo methods.

Results: [68Ga]PSMA-11 was rapidly cleared from the blood and accumulated preferentially in the kidneys and the liver. The substance has a biological half-life in blood of 6.5 min (91%) and 4.4 h (9%). The effective dose was calculated to 0.022 mSv/MBq. The kidneys received approximately 40 mGy after an injection with 160 MBq [68Ga]PSMA-11 while the lacrimal glands obtained an absorbed dose of 0.12 mGy per administered MBq. Regarding the eye lenses, the absorbed dose was low (0.0051 mGy/MBq).

Conclusion: The effective dose for [68Ga]PSMA-11 is 0.022 mSv/MBq, where the kidneys and lacrimal glands receiving the highest organ dose.

Place, publisher, year, edition, pages
Springer, 2019
Keywords
Radiation dosimetry, [Ga-68]PSMA-11, PSMA, PET-tracer, Prostate cancer, Absorbed dose and effective dose, Glu-NH-CO-NH-Lys(Ahx)-HBED-CC
National Category
Cancer and Oncology Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:umu:diva-155760 (URN)10.1186/s40658-018-0239-2 (DOI)000455503100001 ()30631980 (PubMedID)
Available from: 2019-01-28 Created: 2019-01-28 Last updated: 2019-01-28Bibliographically approved
Leffler, K., Axelsson, J., Larsson, A., Häggström, I. & Yu, J. (2019). Sharper Positron Emission Tomography: Intelligent Data Sampling to Promote Accelerated Medical Imaging. In: : . Paper presented at Winter Conference in Statistics 2019 - Machine Learning, March 10-14, 2019, Hemavan, Sweden.
Open this publication in new window or tab >>Sharper Positron Emission Tomography: Intelligent Data Sampling to Promote Accelerated Medical Imaging
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2019 (English)Conference paper, Poster (with or without abstract) (Other academic)
National Category
Probability Theory and Statistics Medical Image Processing
Research subject
Mathematical Statistics
Identifiers
urn:nbn:se:umu:diva-157665 (URN)
Conference
Winter Conference in Statistics 2019 - Machine Learning, March 10-14, 2019, Hemavan, Sweden
Projects
Statistical modelling and intelligent data sampling in MRI and PET measurements for cancer therapy assessment
Funder
Swedish Research Council, 340-2013-534
Available from: 2019-03-28 Created: 2019-03-28 Last updated: 2019-04-12Bibliographically approved
Papenberg, G., Karalija, N., Salami, A., Andersson, M., Axelsson, J., Riklund, K., . . . Bäckman, L. (2019). The Influence of Hippocampal Dopamine D2 Receptors on Episodic Memory Is Modulated by BDNF and KIBRA Polymorphisms. Journal of cognitive neuroscience, 31(9), 1422-1429
Open this publication in new window or tab >>The Influence of Hippocampal Dopamine D2 Receptors on Episodic Memory Is Modulated by BDNF and KIBRA Polymorphisms
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2019 (English)In: Journal of cognitive neuroscience, ISSN 0898-929X, E-ISSN 1530-8898, Vol. 31, no 9, p. 1422-1429Article in journal (Refereed) Published
Abstract [en]

Episodic memory is a polygenic trait influenced by different molecular mechanisms. We used PET and a candidate gene approach to investigate how individual differences at the molecular level translate into between-person differences in episodic memory performance of elderly persons. Specifically, we examined the interactive effects between hippocampal dopamine D2 receptor (D2DR) availability and candidate genes relevant for hippocampus-related memory functioning. We show that the positive effects of high D2DR availability in the hippocampus on episodic memory are confined to carriers of advantageous genotypes of the brain-derived neurotrophic factor (BDNF, rs6265) and the kidney and brain expressed protein (KIBRA, rs17070145) polymorphisms. By contrast, these polymorphisms did not modulate the positive relationship between caudate D2DR availability and episodic memory.

Place, publisher, year, edition, pages
MIT Press, 2019
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-162391 (URN)10.1162/jocn_a_01429 (DOI)000477974100012 ()31112471 (PubMedID)2-s2.0-85070257740 (Scopus ID)
Available from: 2019-08-20 Created: 2019-08-20 Last updated: 2019-08-20Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-3731-3612

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