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  1. Article ; Online: Methylation of the Glucocorticoid Receptor Gene (NR3C1) in Adolescents with a History of Childhood Adversity Engaging in Non-Suicidal Self-Injury.

    Hammann, Nicole / Kaess, Michael / Rujescu, Dan / Brunner, Romuald / Hartmann, Annette M / Reichl, Corinna

    Psychopathology

    2023  Volume 57, Issue 2, Page(s) 81–90

    Abstract: Introduction: Non-suicidal self-injury (NSSI) is a large phenomenon among adolescents, and adverse childhood experiences (ACEs) are a major risk factor in its development. Malfunctioning of the hypothalamus-pituitary-adrenal (HPA) axis has been ... ...

    Abstract Introduction: Non-suicidal self-injury (NSSI) is a large phenomenon among adolescents, and adverse childhood experiences (ACEs) are a major risk factor in its development. Malfunctioning of the hypothalamus-pituitary-adrenal (HPA) axis has been repeatedly reported for ACE as well as for NSSI. The glucocorticoid receptor (GR) is essential for the correct functioning of the HPA axis, thus alterations in the expression of the GR through altered methylation of the GR gene (NR3C1) (and more specifically exon 1F) might contribute to the development of NSSI in individuals with a history of ACEs, as has been reported for different other mental disorders.
    Methods: In this case-control study, we compared the methylation levels of exon 1F of the GR gene (NR3C1-1F) in adolescents with engagement in NSSI (n = 67) and a healthy control group (HC; n = 47). We preserved buccal swabs and used a mass spectrometry-based method called EpiTYPER for analyzing mean methylation of NR3C1-1F.
    Results: Adolescents in the NSSI group reported significantly more ACEs. The mean methylation level was about 3% in both groups with no significant group differences. Furthermore, no significant relation was found between ACE and methylation of NR3C1-1F, neither in the overall sample nor in the NSSI or HC group.
    Conclusion: Our results are contradictory to previous research showing an increased methylation in individuals with ACE. Regarding relations between methylation of NR3C1-1F and mental disorders, previous studies reported inconsistent findings. Our study points to NSSI being either unrelated to methylation of NR3C1-1F or to yet not identified moderators on relations between methylation of NR3C1-1F and engagement in NSSI during adolescence.
    MeSH term(s) Humans ; Adolescent ; Glucocorticoids/metabolism ; Receptors, Glucocorticoid/genetics ; Receptors, Glucocorticoid/metabolism ; DNA Methylation/genetics ; Hypothalamo-Hypophyseal System ; Adverse Childhood Experiences ; Case-Control Studies ; Pituitary-Adrenal System/metabolism
    Chemical Substances Glucocorticoids ; Receptors, Glucocorticoid ; NR3C1 protein, human
    Language English
    Publishing date 2023-08-02
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 605604-0
    ISSN 1423-033X ; 0254-4962
    ISSN (online) 1423-033X
    ISSN 0254-4962
    DOI 10.1159/000531253
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: RFC1 repeat expansions in downbeat nystagmus syndromes: frequency and phenotypic profile.

    Pellerin, David / Heindl, Felix / Traschütz, Andreas / Rujescu, Dan / Hartmann, Annette M / Brais, Bernard / Houlden, Henry / Dufke, Claudia / Riess, Olaf / Haack, Tobias / Strupp, Michael / Synofzik, Matthis

    Journal of neurology

    2024  Volume 271, Issue 5, Page(s) 2886–2892

    Abstract: Objectives: The cause of downbeat nystagmus (DBN) remains unknown in a substantial number of patients ("idiopathic"), although intronic GAA expansions in FGF14 have recently been shown to account for almost 50% of yet idiopathic cases. Here, we ... ...

    Abstract Objectives: The cause of downbeat nystagmus (DBN) remains unknown in a substantial number of patients ("idiopathic"), although intronic GAA expansions in FGF14 have recently been shown to account for almost 50% of yet idiopathic cases. Here, we hypothesized that biallelic RFC1 expansions may also represent a recurrent cause of DBN syndrome.
    Methods: We genotyped the RFC1 repeat and performed in-depth phenotyping in 203 patients with DBN, including 65 patients with idiopathic DBN, 102 patients carrying an FGF14 GAA expansion, and 36 patients with presumed secondary DBN.
    Results: Biallelic RFC1 AAGGG expansions were identified in 15/65 patients with idiopathic DBN (23%). None of the 102 GAA-FGF14-positive patients, but 2/36 (6%) of patients with presumed secondary DBN carried biallelic RFC1 expansions. The DBN syndrome in RFC1-positive patients was characterized by additional cerebellar impairment in 100% (15/15), bilateral vestibulopathy (BVP) in 100% (15/15), and polyneuropathy in 80% (12/15) of cases. Compared to GAA-FGF14-positive and genetically unexplained patients, RFC1-positive patients had significantly more frequent neuropathic features on examination and BVP. Furthermore, vestibular function, as measured by the video head impulse test, was significantly more impaired in RFC1-positive patients.
    Discussion: Biallelic RFC1 expansions are a common monogenic cause of DBN syndrome.
    MeSH term(s) Humans ; Replication Protein C/genetics ; Male ; Female ; Middle Aged ; Phenotype ; Adult ; Nystagmus, Pathologic/genetics ; Aged ; DNA Repeat Expansion/genetics ; Fibroblast Growth Factors/genetics ; Young Adult ; Bilateral Vestibulopathy/genetics ; Bilateral Vestibulopathy/physiopathology
    Chemical Substances Replication Protein C (EC 3.6.4.-) ; RFC1 protein, human ; fibroblast growth factor 14 ; Fibroblast Growth Factors (62031-54-3)
    Language English
    Publishing date 2024-02-21
    Publishing country Germany
    Document type Journal Article ; Letter
    ZDB-ID 187050-6
    ISSN 1432-1459 ; 0340-5354 ; 0012-1037 ; 0939-1517 ; 1619-800X
    ISSN (online) 1432-1459
    ISSN 0340-5354 ; 0012-1037 ; 0939-1517 ; 1619-800X
    DOI 10.1007/s00415-024-12229-z
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: GAA-FGF14 disease: defining its frequency, molecular basis, and 4-aminopyridine response in a large downbeat nystagmus cohort.

    Pellerin, David / Heindl, Felix / Wilke, Carlo / Danzi, Matt C / Traschütz, Andreas / Ashton, Catherine / Dicaire, Marie-Josée / Cuillerier, Alexanne / Del Gobbo, Giulia / Boycott, Kym M / Claassen, Jens / Rujescu, Dan / Hartmann, Annette M / Zuchner, Stephan / Brais, Bernard / Strupp, Michael / Synofzik, Matthis

    EBioMedicine

    2024  Volume 102, Page(s) 105076

    Abstract: Background: GAA-FGF14 disease/spinocerebellar ataxia 27B is a recently described neurodegenerative disease caused by (GAA): Methods: Retrospective cohort study of 170 patients with idiopathic DBN, comprising in-depth phenotyping and assessment of 4- ... ...

    Abstract Background: GAA-FGF14 disease/spinocerebellar ataxia 27B is a recently described neurodegenerative disease caused by (GAA)
    Methods: Retrospective cohort study of 170 patients with idiopathic DBN, comprising in-depth phenotyping and assessment of 4-aminopyridine treatment response, including re-analysis of placebo-controlled video-oculography treatment response data from a previous randomised double-blind 4-aminopyridine trial.
    Findings: Frequency of FGF14 (GAA)
    Interpretation: This study confirms that FGF14 GAA expansions are a frequent cause of DBN syndromes. It provides preliminary evidence that (GAA)
    Funding: This work was supported by the Clinician Scientist program "PRECISE.net" funded by the Else Kröner-Fresenius-Stiftung (to CW, AT, and MSy), the grant 779257 "Solve-RD" from the European's Union Horizon 2020 research and innovation program (to MSy), and the grant 01EO 1401 by the German Federal Ministry of Education and Research (BMBF) (to MSt). This work was also supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) N° 441409627, as part of the PROSPAX consortium under the frame of EJP RD, the European Joint Programme on Rare Diseases, under the EJP RD COFUND-EJP N° 825575 (to MSy, BB and-as associated partner-SZ), the NIH National Institute of Neurological Disorders and Stroke (grant 2R01NS072248-11A1 to SZ), the Fondation Groupe Monaco (to BB), and the Montreal General Hospital Foundation (grant PT79418 to BB). The Care4Rare Canada Consortium is funded in part by Genome Canada and the Ontario Genomics Institute (OGI-147 to KMB), the Canadian Institutes of Health Research (CIHR GP1-155867 to KMB), Ontario Research Foundation, Genome Quebec, and the Children's Hospital of Eastern Ontario Foundation. The funders had no role in the conduct of this study.
    MeSH term(s) Child ; Humans ; 4-Aminopyridine/therapeutic use ; Fibroblast Growth Factors ; Neurodegenerative Diseases/drug therapy ; Nystagmus, Pathologic/chemically induced ; Nystagmus, Pathologic/drug therapy ; Ontario ; Retrospective Studies
    Chemical Substances 4-Aminopyridine (BH3B64OKL9) ; fibroblast growth factor 14 ; Fibroblast Growth Factors (62031-54-3)
    Language English
    Publishing date 2024-03-19
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 2851331-9
    ISSN 2352-3964
    ISSN (online) 2352-3964
    DOI 10.1016/j.ebiom.2024.105076
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Neurobiological origins of individual differences in mathematical ability.

    Skeide, Michael A / Wehrmann, Katharina / Emami, Zahra / Kirsten, Holger / Hartmann, Annette M / Rujescu, Dan

    PLoS biology

    2020  Volume 18, Issue 10, Page(s) e3000871

    Abstract: Mathematical ability is heritable and related to several genes expressing proteins in the brain. It is unknown, however, which intermediate neural phenotypes could explain how these genes relate to mathematical ability. Here, we examined genetic effects ... ...

    Abstract Mathematical ability is heritable and related to several genes expressing proteins in the brain. It is unknown, however, which intermediate neural phenotypes could explain how these genes relate to mathematical ability. Here, we examined genetic effects on cerebral cortical volume of 3-6-year-old children without mathematical training to predict mathematical ability in school at 7-9 years of age. To this end, we followed an exploration sample (n = 101) and an independent replication sample (n = 77). We found that ROBO1, a gene known to regulate prenatal growth of cerebral cortical layers, is associated with the volume of the right parietal cortex, a key region for quantity representation. Individual volume differences in this region predicted up to a fifth of the behavioral variance in mathematical ability. Our findings indicate that a fundamental genetic component of the quantity processing system is rooted in the early development of the parietal cortex.
    MeSH term(s) Behavior ; Brain/physiology ; Child ; Child, Preschool ; Female ; Genetic Association Studies ; Genotype ; Gray Matter/anatomy & histology ; Growth Cones/physiology ; Humans ; Individuality ; Male ; Mathematics ; Nerve Tissue Proteins/genetics ; Organ Size ; Parietal Lobe/anatomy & histology ; Receptors, Immunologic/genetics ; Roundabout Proteins
    Chemical Substances Nerve Tissue Proteins ; Receptors, Immunologic
    Language English
    Publishing date 2020-10-22
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2126776-5
    ISSN 1545-7885 ; 1544-9173
    ISSN (online) 1545-7885
    ISSN 1544-9173
    DOI 10.1371/journal.pbio.3000871
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  5. Article ; Online: Impact of genetic variants within serotonin turnover enzymes on human cerebral monoamine oxidase A in vivo.

    Spies, Marie / Murgaš, Matej / Vraka, Chrysoula / Philippe, Cecile / Gryglewski, Gregor / Nics, Lukas / Balber, Theresa / Baldinger-Melich, Pia / Hartmann, Annette M / Rujescu, Dan / Hacker, Marcus / Winkler-Pjrek, Edda / Winkler, Dietmar / Lanzenberger, Rupert

    Translational psychiatry

    2023  Volume 13, Issue 1, Page(s) 208

    Abstract: Variants within the monoamine oxidase A (MAO-A, MAOA) and tryptophan hydroxylase 2 (TPH2) genes, the main enzymes in cerebral serotonin (5-HT) turnover, affect risk for depression. Depressed cohorts show increased cerebral MAO-A in positron emission ... ...

    Abstract Variants within the monoamine oxidase A (MAO-A, MAOA) and tryptophan hydroxylase 2 (TPH2) genes, the main enzymes in cerebral serotonin (5-HT) turnover, affect risk for depression. Depressed cohorts show increased cerebral MAO-A in positron emission tomography (PET) studies. TPH2 polymorphisms might also influence brain MAO-A because availability of substrates (i.e. monoamine concentrations) were shown to affect MAO-A levels. We assessed the effect of MAOA (rs1137070, rs2064070, rs6323) and TPH2 (rs1386494, rs4570625) variants associated with risk for depression and related clinical phenomena on global MAO-A distribution volume (V
    MeSH term(s) Humans ; Brain/diagnostic imaging ; Brain/metabolism ; Harmine/metabolism ; Monoamine Oxidase/genetics ; Monoamine Oxidase/metabolism ; Seasonal Affective Disorder/metabolism ; Serotonin/metabolism
    Chemical Substances Harmine (4FHH5G48T7) ; Monoamine Oxidase (EC 1.4.3.4) ; Serotonin (333DO1RDJY) ; monoamine oxidase A, human (EC 1.4.3.4.)
    Language English
    Publishing date 2023-06-15
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2609311-X
    ISSN 2158-3188 ; 2158-3188
    ISSN (online) 2158-3188
    ISSN 2158-3188
    DOI 10.1038/s41398-023-02506-2
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  6. Article ; Online: Frequency and Phenotype of

    Traschütz, Andreas / Heindl, Felix / Bilal, Muhammad / Hartmann, Annette M / Dufke, Claudia / Riess, Olaf / Zwergal, Andreas / Rujescu, Dan / Haack, Tobias / Synofzik, Matthis / Strupp, Michael

    Neurology

    2023  Volume 101, Issue 10, Page(s) e1001–e1013

    Abstract: Background and objectives: Bilateral vestibulopathy (BVP) is a chronic debilitating neurologic disorder with no monogenic cause established so far despite familiar presentations. We hypothesized that replication factor complex subunit 1 (RFC1) repeat ... ...

    Abstract Background and objectives: Bilateral vestibulopathy (BVP) is a chronic debilitating neurologic disorder with no monogenic cause established so far despite familiar presentations. We hypothesized that replication factor complex subunit 1 (RFC1) repeat expansions might present a recurrent monogenic cause of BVP.
    Methods: The study involved RFC1 screening and in-depth neurologic, vestibulo-oculomotor, and disease evolution phenotyping of 168 consecutive patients with idiopathic at least "probable BVP" from a tertiary referral center for balance disorders, with127 of them meeting current diagnostic criteria of BVP (Bárány Society Classification).
    Results: Biallelic AAGGG repeat expansions in RFC1 were identified in 10/127 patients (8%) with BVP and 1/41 with probable BVP. Heterozygous expansions in 10/127 patients were enriched compared with those in reference populations. RFC1-related BVP manifested at a median age of 60 years (range 34-72 years) and co-occurred predominantly with mild polyneuropathy (10/11). Additional cerebellar involvement (7/11) was subtle and limited to oculomotor signs in early stages, below recognition of classic cerebellar ataxia, neuropathy, and vestibular areflexia syndrome. Clear dysarthria, appendicular ataxia, or cerebellar atrophy developed 6-8 years after onset. Dysarthria, absent patellar reflexes, and downbeat nystagmus best discriminated RFC1-positive BVP from RFC1-negative BVP, but neither sensory symptoms nor fine motor problems. Video head impulse gains of patients with RFC1-positive BVP were lower relative to those of patients with RFC1-negative BVP and decreased until 10 years disease duration, indicating a potential progression and outcome marker for RFC1-disease.
    Discussion: This study identifies RFC1 as the first-and frequent-monogenic cause of BVP. It characterizes RFC1-related BVP as part of the multisystemic evolution of
    Classification of evidence: This study provides Class II evidence that RFC1 repeat expansions cause BVP.
    MeSH term(s) Humans ; Ataxia ; Bilateral Vestibulopathy/genetics ; Bilateral Vestibulopathy/diagnosis ; Cerebellar Ataxia/diagnosis ; Dysarthria ; Phenotype ; Reflex, Abnormal ; Vestibular Diseases/genetics
    Chemical Substances RFC1 protein, human
    Language English
    Publishing date 2023-07-17
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 207147-2
    ISSN 1526-632X ; 0028-3878
    ISSN (online) 1526-632X
    ISSN 0028-3878
    DOI 10.1212/WNL.0000000000207553
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  7. Article: Intronic

    Pellerin, David / Heindl, Felix / Wilke, Carlo / Danzi, Matt C / Traschütz, Andreas / Ashton, Catherine / Dicaire, Marie-Josée / Cuillerier, Alexanne / Del Gobbo, Giulia / Boycott, Kym M / Claassen, Jens / Rujescu, Dan / Hartmann, Annette M / Zuchner, Stephan / Brais, Bernard / Strupp, Michael / Synofzik, Matthis

    medRxiv : the preprint server for health sciences

    2023  

    Abstract: The cause of downbeat nystagmus (DBN) remains unknown in approximately 30% of patients (idiopathic DBN). Here, we hypothesized that: (i) ...

    Abstract The cause of downbeat nystagmus (DBN) remains unknown in approximately 30% of patients (idiopathic DBN). Here, we hypothesized that: (i)
    Language English
    Publishing date 2023-08-05
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.07.30.23293380
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Effect of MAOA DNA Methylation on Human in Vivo Protein Expression Measured by [11C]harmine Positron Emission Tomography.

    Handschuh, Patricia A / Murgaš, Matej / Vraka, Chrysoula / Nics, Lukas / Hartmann, Annette M / Winkler-Pjrek, Edda / Baldinger-Melich, Pia / Wadsak, Wolfgang / Winkler, Dietmar / Hacker, Marcus / Rujescu, Dan / Domschke, Katharina / Lanzenberger, Rupert / Spies, Marie

    The international journal of neuropsychopharmacology

    2022  Volume 26, Issue 2, Page(s) 116–124

    Abstract: Background: Epigenetic modifications like DNA methylation are understood as an intermediary between environmental factors and neurobiology. Cerebral monoamine oxidase A (MAO-A) levels are altered in depression, as are DNA methylation levels within the ... ...

    Abstract Background: Epigenetic modifications like DNA methylation are understood as an intermediary between environmental factors and neurobiology. Cerebral monoamine oxidase A (MAO-A) levels are altered in depression, as are DNA methylation levels within the MAOA gene, particularly in the promoter/exon I/intron I region. An effect of MAOA methylation on peripheral protein expression was shown, but the extent to which methylation affects brain MAO-A levels is not fully understood.
    Methods: Here, the influence of MAOA promoter/exon I/intron I region DNA methylation on global MAO-A distribution volume (VT), an index of MAO-A density, was assessed via [11C]harmine positron emission tomography in 22 patients (14 females) suffering from seasonal affective disorder and 30 healthy controls (17 females).
    Results: No significant influence of MAOA DNA methylation on global MAO-A VT was found, despite correction for health status, sex, season, and MAOA variable number of tandem repeat genotype. However, season affected average methylation in women, with higher levels in spring and summer (Puncorr = .03). We thus did not find evidence for an effect of MAOA DNA methylation on brain MAO-A VT.
    Conclusions: In contrast to a previous study demonstrating an effect of methylation of a MAOA promoter region located further 5' on brain MAO-A, MAOA methylation of the region assessed here appears to affect brain protein levels to a limited extent at most. The observed effect of season on methylation levels is in accordance with extensive evidence for seasonal effects within the serotonergic system.
    Clinicaltrials.gov identifier: NCT02582398 (https://clinicaltrials.gov/ct2/show/NCT02582398).
    MeSH term(s) Humans ; Female ; Harmine ; DNA Methylation ; Monoamine Oxidase/genetics ; Monoamine Oxidase/metabolism ; Carbon Radioisotopes ; Positron-Emission Tomography/methods
    Chemical Substances Harmine (4FHH5G48T7) ; Monoamine Oxidase (EC 1.4.3.4) ; Carbon-11 ; Carbon Radioisotopes
    Language English
    Publishing date 2022-12-21
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1440129-0
    ISSN 1469-5111 ; 1461-1457
    ISSN (online) 1469-5111
    ISSN 1461-1457
    DOI 10.1093/ijnp/pyac085
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  9. Article: High-risk Allele for Herpes Labialis Severity at the IFNL3/4 Locus is Associated With Vestibular Neuritis.

    Rujescu, Dan / Herrling, Marko / Hartmann, Annette M / Maul, Stephan / Giegling, Ina / Konte, Bettina / Strupp, Michael

    Frontiers in neurology

    2020  Volume 11, Page(s) 570638

    Abstract: Objective: ...

    Abstract Objective:
    Language English
    Publishing date 2020-10-08
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2564214-5
    ISSN 1664-2295
    ISSN 1664-2295
    DOI 10.3389/fneur.2020.570638
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  10. Article ; Online: A Variation in FGF14 Is Associated with Downbeat Nystagmus in a Genome-Wide Association Study.

    Strupp, Michael / Maul, Stephan / Konte, Bettina / Hartmann, Annette M / Giegling, Ina / Wollenteit, Sophia / Feil, Katharina / Rujescu, Dan

    Cerebellum (London, England)

    2020  Volume 19, Issue 3, Page(s) 348–357

    Abstract: Downbeat nystagmus (DBN) is a frequent form of acquired persisting central fixation nystagmus, often associated with other cerebellar ocular signs, such as saccadic smooth pursuit or gaze-holding deficits. Despite its distinct clinical features, the ... ...

    Abstract Downbeat nystagmus (DBN) is a frequent form of acquired persisting central fixation nystagmus, often associated with other cerebellar ocular signs, such as saccadic smooth pursuit or gaze-holding deficits. Despite its distinct clinical features, the underlying etiology of DBN often remains unclear. Therefore, a genome-wide association study (GWAS) was conducted in 106 patients and 2609 healthy controls of European ancestry to identify genetic variants associated with DBN. A genome-wide significant association (p < 5 × 10
    MeSH term(s) Aged ; Aged, 80 and over ; Female ; Fibroblast Growth Factors/genetics ; Genetic Variation/genetics ; Genome-Wide Association Study/methods ; Germany/epidemiology ; Humans ; Male ; Middle Aged ; Nystagmus, Pathologic/diagnosis ; Nystagmus, Pathologic/epidemiology ; Nystagmus, Pathologic/genetics
    Chemical Substances fibroblast growth factor 14 ; Fibroblast Growth Factors (62031-54-3)
    Language English
    Publishing date 2020-03-10
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2112586-7
    ISSN 1473-4230 ; 1473-4222
    ISSN (online) 1473-4230
    ISSN 1473-4222
    DOI 10.1007/s12311-020-01113-x
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