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Wiemerslage, L., Islam, R., van der Kamp, C., Cao, H., Olivo, G., Ence-Eriksson, F., . . . Schiöth, H. B. (2017). A DNA methylation site within the KLF13 gene is associated with orexigenic processes based on neural responses and ghrelin levels. International Journal of Obesity, 41(6), 990-994.
Open this publication in new window or tab >>A DNA methylation site within the KLF13 gene is associated with orexigenic processes based on neural responses and ghrelin levels
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2017 (English)In: International Journal of Obesity, ISSN 0307-0565, E-ISSN 1476-5497, Vol. 41, no 6, 990-994 p.Article in journal (Refereed) Published
Abstract [en]

We investigated five methylation markers recently linked to body-mass index, for their role in the neuropathology of obesity. In neuroimaging experiments, our analysis involving 23 participants showed that methylation levels for the cg07814318 site, which lies within the KLF13 gene, correlated with brain activity in the claustrum, putamen, cingulate gyrus, and frontal gyri, some of which have been previously associated to food signaling, obesity, or reward. Methylation levels at cg07814318 also positively correlated with ghrelin levels. Moreover, expression of KLF13 was augmented in the brains of obese and starved mice. Our results suggest the cg07814318 site could be involved in orexigenic processes, and also implicate KLF13 in obesity. Our findings are the first to associate methylation levels in blood with brain activity in obesity-related regions, and further support previous findings between ghrelin, brain activity, and genetic differences.

National Category
Neurosciences Endocrinology and Diabetes Nutrition and Dietetics
Identifiers
urn:nbn:se:uu:diva-315855 (URN)10.1038/ijo.2017.43 (DOI)000402735900024 ()28194012 (PubMedID)
Funder
Swedish Research CouncilThe Swedish Brain Foundation
Available from: 2017-02-21 Created: 2017-02-21 Last updated: 2018-01-13Bibliographically approved
Ciuculete, D.-M., Bandstein, M., Benedict, C., Waeber, G., Vollenweider, P., Lind, L., . . . Mwinyi, J. (2017). A genetic risk score is significantly associated with statin therapy response in the elderly population. Clinical Genetics, 91(3), 379-385.
Open this publication in new window or tab >>A genetic risk score is significantly associated with statin therapy response in the elderly population
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2017 (English)In: Clinical Genetics, ISSN 0009-9163, E-ISSN 1399-0004, Vol. 91, no 3, 379-385 p.Article in journal (Refereed) Published
Abstract [en]

The ability of statins to strongly reduce low-density lipoprotein cholesterol (LDL-C) varies interindividually and is partially influenced by genetic variants. Based on a comprehensive analysis of 23 single nucleotide polymorphisms (SNPs) known to be associated with pharmacokinetics and dynamics of statins, we developed a genetic risk score to study its impact on the therapy outcome in elderly individuals under at least 5 years statin therapy. The study was performed in a population-based cohort of 1016 elderly individuals, which comprised 168 statin users investigated at age 75 and 80. Using random forest models, the major variants influencing LDL-C levels were summarized in a weighted GRS (wGRS). The wGRS was tested with lipid and glucose outcomes and validated in an independent population-based cohort including 221 statin users. Four SNPs within the APOE cluster (rs7412, rs4420638), ABCC2 (rs2002042) and CELSR/SORT1/PSRC1 (rs646776), displayed a major impact on statin efficacy. The wGRS was significantly associated with lower LDL-C at age 75 and 80. This association was replicated displaying similar results. GRS analysis is a powerful tool to evaluate the additive effects of genetic variants on statin response and to estimate the magnitude of LDL-C reduction to a considerable extent in the older population.

Keyword
pharmacogenetics, polygenetic risk score, random forest analysis, single nucleotide polymorphism, statins
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-318494 (URN)10.1111/cge.12890 (DOI)000395007600004 ()27943270 (PubMedID)
Funder
Swedish Society for Medical Research (SSMF)Swedish Research CouncilGlaxoSmithKline (GSK)
Available from: 2017-03-24 Created: 2017-03-24 Last updated: 2018-01-13Bibliographically approved
Xu, J., Boström, A., Saeed, M., Dubey, R. K., Waeber, G., Vollenweider, P., . . . Schiöth, H. B. (2017). A genetic variant in the catechol-O-methyl transferase (COMT) gene is related to age-dependent differences in the therapeutic effect of calcium-channel blockers. Medicine (Baltimore, Md.), 96(30), Article ID e7029.
Open this publication in new window or tab >>A genetic variant in the catechol-O-methyl transferase (COMT) gene is related to age-dependent differences in the therapeutic effect of calcium-channel blockers
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2017 (English)In: Medicine (Baltimore, Md.), ISSN 0025-7974, E-ISSN 1536-5964, Vol. 96, no 30, e7029Article in journal (Refereed) Published
Abstract [en]

Hypertension is the leading risk factor for cardiovascular disease and one of the major health concerns worldwide. Genetic factors impact both the risk for hypertension and the therapeutic effect of antihypertensive drugs. Sex- and age-specific variances in the prevalence of hypertension are partly induced by estrogen. We investigated 6 single nucleotide polymorphisms in genes encoding enzymes involved in estrogen metabolism in relation to sex- and age-specific differences in the systolic and diastolic blood pressure (SBP and DBP) outcome under the treatment of diuretics, calcium-channel blockers (CCBs), angiotensin-converting-enzyme inhibitors, and angiotensin-receptor blockers (ARBs). We included 5064 subjects (age: 40-82) from the population-based CoLaus cohort. Participants were genotyped for the catechol-O-methyltransferase gene (COMT) variants rs4680, rs737865, and rs165599; the uridine-diphospho-glucuronosyltransferase 1A gene family (UGT1A) variants rs2070959 and rs887829; and the aromatase gene (CYP19A1) variant rs10046. Binomial and linear regression analyses were performed correcting for age, sex, body mass index, smoking, diabetes, and antihypertensive therapy to test whether the variants in focus are significantly associated with BP. All investigated COMT variants were strongly associated with the effect of diuretics, CCBs, and ARBs on SBP or DBP (P<.05), showing an additive effect when occurring in combination. After Bonferroni correction the polymorphism rs4680 (Val(158)Met) in COMT was significantly associated with lower SBP in participants treated with CCBs (P=.009) with an especially strong impact in elderly individuals (age >= 70) alone (Delta=-14.08 mm Hg, P=.0005). These results underline the important role of estrogens and catecholamines in hypertension and the importance of genotype dependent, age-related adjustments of calcium-channel blocker treatment.

Place, publisher, year, edition, pages
LIPPINCOTT WILLIAMS & WILKINS, 2017
Keyword
age- and sex-related effect, calcium-channel blockers, catechol-O-methyltransferase, estrogen, hypertension, pharmacogenetics, single nucleotide polymorphism
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-333404 (URN)10.1097/MD.0000000000007029 (DOI)000406480500003 ()28746172 (PubMedID)
Funder
Swedish Society for Medical Research (SSMF)Swedish Research CouncilGlaxoSmithKline (GSK)
Available from: 2017-11-14 Created: 2017-11-14 Last updated: 2017-11-14Bibliographically approved
Ciuculete, D.-M., Boström, A. E., Voisin, S., Philipps, H., Titova, O. E., Bandstein, M., . . . Schiöth, H. B. (2017). A methylome-wide mQTL analysis reveals associations of methylation sites with GAD1 and HDAC3 SNPs and a general psychiatric risk score. Translational Psychiatry, 7, Article ID e1002.
Open this publication in new window or tab >>A methylome-wide mQTL analysis reveals associations of methylation sites with GAD1 and HDAC3 SNPs and a general psychiatric risk score
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2017 (English)In: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 7, e1002Article in journal (Refereed) Published
Abstract [en]

Genome-wide association studies have identified a number of single-nucleotide polymorphisms (SNPs) that are associated with psychiatric diseases. Increasing body of evidence suggests a complex connection of SNPs and the transcriptional and epigenetic regulation of gene expression, which is poorly understood. In the current study, we investigated the interplay between genetic risk variants, shifts in methylation and mRNA levels in whole blood from 223 adolescents distinguished by a risk for developing psychiatric disorders. We analyzed 37 SNPs previously associated with psychiatric diseases in relation to genome-wide DNA methylation levels using linear models, with Bonferroni correction and adjusting for cell-type composition. Associations between DNA methylation, mRNA levels and psychiatric disease risk evaluated by the Development and Well-Being Assessment (DAWBA) score were identified by robust linear models, Pearson's correlations and binary regression models. We detected five SNPs (in HCRTR1, GAD1, HADC3 and FKBP5) that were associated with eight CpG sites, validating five of these SNP-CpG pairs. Three of these CpG sites, that is, cg01089319 (GAD1), cg01089249 (GAD1) and cg24137543 (DIAPH1), manifest in significant gene expression changes and overlap with active regulatory regions in chromatin states of brain tissues. Importantly, methylation levels at cg01089319 were associated with the DAWBA score in the discovery group. These results show how distinct SNPs linked with psychiatric diseases are associated with epigenetic shifts with relevance for gene expression. Our findings give a novel insight on how genetic variants may modulate risks for the development of psychiatric diseases.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2017
National Category
Psychiatry Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-319660 (URN)10.1038/tp.2016.275 (DOI)000396451500002 ()28094813 (PubMedID)
Funder
Swedish Research CouncilNovo NordiskThe Swedish Brain Foundation
Available from: 2017-04-07 Created: 2017-04-07 Last updated: 2018-01-13Bibliographically approved
Boström, A., Ciuculete, D.-M., Attwood, M. M., Krattinger, R., Nikontovic, L., Titova, O. E., . . . Schiöth, H. B. (2017). A MIR4646 associated methylation locus is hypomethylated in adolescent depression. Journal of Affective Disorders, 220, 117-128.
Open this publication in new window or tab >>A MIR4646 associated methylation locus is hypomethylated in adolescent depression
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2017 (English)In: Journal of Affective Disorders, ISSN 0165-0327, E-ISSN 1573-2517, Vol. 220, 117-128 p.Article in journal (Refereed) Published
Abstract [en]

Background: Studies of epigenetics and transcriptional activity in adolescents may provide knowledge about possible preventive strategies of depression. Methods: We present a methylome-wide association study (MWAS) and cohort validation analysis of depression in adolescents, in two separate cohorts: discovery (n = 93) and validation data set 1 (n = 78). The genome-wide methylation pattern was measured from whole blood using the Illumina 450K array. A second validation cohort, validation data set 2, consists of post-mortem brain biopsies from depressed adults (n = 58). We performed a MWAS by robust multiple linear regressions of methylation to a modified risk-score assessment of depression. Methylation levels of candidate CpG sites were correlated with expression levels of the associated gene in an independent cohort of 11 healthy volunteers. Results: The methylation state of two CpG sites reliably predicted ratings of depression in adolescents (cg13227623 and cg04102384) (p < 10E-06). Cohort validation analysis confirmed cg04102384 - located in the promoter region of microRNA 4646 (MIR4646) - to be hypomethylated in both validation data set 1 and validation data set 2 (p < 0.05). Cg04102384 was inversely correlated to expression levels of MIR4646-3p in healthy controls (p < 0.05). Limitations: MIR4646 was not differentially expressed in a subset of samples with adolescent depression measured by qRT-PCR measurements. Conclusion: We identify a specific MIR4646 associated epigenetic risk site to be associated with depression in adolescents. Cg04102384 putatively regulates gene expression of MIR4646-3p. Target gene prediction and gene set overrepresentation analysis revealed involvement of this miRNA in fatty acid elongation, a process related to omega-3 fatty acids, previously associated with depression.

Keyword
MIR4646, Methylome-wide association study, Adolescent depression, Omega-3, MicroRNA
National Category
Neurology Psychiatry
Identifiers
urn:nbn:se:uu:diva-333057 (URN)10.1016/j.jad.2017.05.017 (DOI)000406463700017 ()28618313 (PubMedID)
Funder
Swedish Research CouncilThe Swedish Brain Foundation
Available from: 2017-11-10 Created: 2017-11-10 Last updated: 2017-11-10Bibliographically approved
Wiemerslage, L., Zhou, W., Olivo, G., Stark, J., Hogenkamp, P. S., Larsson, E.-M., . . . Schiöth, H. B. (2017). A resting-state fMRI study of obese females between pre- and postprandial states before and after bariatric surgery.. European Journal of Neuroscience, 45(3), 333-341.
Open this publication in new window or tab >>A resting-state fMRI study of obese females between pre- and postprandial states before and after bariatric surgery.
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2017 (English)In: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 45, no 3, 333-341 p.Article in journal (Refereed) Published
Abstract [en]

Past studies utilizing resting-state functional MRI (rsfMRI), have shown that obese humans exhibit altered activity in brain areas related to reward compared to normal-weight controls. However, to what extent bariatric surgery-induced weight loss alters resting-state brain activity in obese humans is less well-studied. Thus, we measured the fractional amplitude of low-frequency fluctuations (fALFF) from eyes-closed, rsfMRI in obese females (n = 11, mean age = 42 years, mean BMI = 41 kg/m(2) ) in both a pre- and post-prandial state at two time points: four weeks before, and four weeks after bariatric surgery. Several brain areas showed altered resting-state activity following bariatric surgery, including the putamen, insula, cingulate, thalamus, and frontal regions. Activity augmented by surgery was also dependent on prandial state. For example, in the fasted state, activity in the middle frontal, and pre- and postcentral gyri was found to be decreased after surgery. In the sated state, activity within the insula was increased before, but not after surgery. Collectively, our results suggest that resting-state neural functions are rapidly affected following bariatric surgery and the associated weight loss and change in diet. 

National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-305755 (URN)10.1111/ejn.13428 (DOI)000393180900002 ()27718507 (PubMedID)
Funder
Swedish Research CouncilThe Swedish Brain FoundationSwedish Society for Medical Research (SSMF)
Note

De två första författarna delar förstaförfattarskapet.

Available from: 2016-10-21 Created: 2016-10-21 Last updated: 2018-01-14Bibliographically approved
Solstrand Dahlberg, L., Wiemerslage, L., Swenne, I., Larsen, A., Stark, J., Rask-Andersen, M., . . . Brooks, S. J. (2017). Adolescents newly diagnosed with eating disorders have structural differences in brain regions linked with eating disorder symptoms. Nordic Journal of Psychiatry, 71(3), 188-196.
Open this publication in new window or tab >>Adolescents newly diagnosed with eating disorders have structural differences in brain regions linked with eating disorder symptoms
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2017 (English)In: Nordic Journal of Psychiatry, ISSN 0803-9488, E-ISSN 1502-4725, Vol. 71, no 3, 188-196 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Adults with eating disorders (ED) show brain volume reductions in the frontal, insular, cingulate, and parietal cortices, as well as differences in subcortical regions associated with reward processing. However, little is known about the structural differences in adolescents with behavioural indications of early stage ED.

AIM: This is the first study to investigate structural brain changes in adolescents newly diagnosed with ED compared to healthy controls (HC), and to study whether ED cognitions correlate with structural changes in adolescents with ED of short duration.

METHODS: Fifteen adolescent females recently diagnosed with ED, and 28 age-matched HC individuals, were scanned with structural magnetic resonance imaging (MRI). Whole-brain and region-of-interest analyses were conducted using voxel-based morphometry (VBM). ED cognitions were measured with self-report questionnaires and working memory performance was measured with a neuropsychological computerized test.

RESULTS AND CONCLUSIONS: The left superior temporal gyrus had a smaller volume in adolescents with ED than in HC, which correlated with ED cognitions (concerns about eating, weight, and shape). Working memory reaction time correlated positively with insula volumes in ED participants, but not HC. In ED, measurements of restraint and obsession was negatively correlated with temporal gyrus volumes, and positively correlated with cerebellar and striatal volumes. Thus, adolescents with a recent diagnosis of ED had volumetric variations in brain areas linked to ED cognitions, obsessions, and working memory. The findings emphasize the importance of early identification of illness, before potential long-term effects on structure and behaviour occur.

Keyword
Eating disorders, adolescents, MRI, eating disorders not otherwise specified, anorexia nervosa
National Category
Psychiatry
Identifiers
urn:nbn:se:uu:diva-311299 (URN)10.1080/08039488.2016.1250948 (DOI)000399501200004 ()27844498 (PubMedID)
Funder
The Swedish Brain FoundationSwedish Research Council Formas
Available from: 2016-12-22 Created: 2016-12-22 Last updated: 2017-05-30Bibliographically approved
Mwinyi, J., Pisanu, C., Castelao, E., Stringhini, S., Preisig, M. & Schiöth, H. B. (2017). Anxiety Disorders are Associated with Low Socioeconomic Status in Women but Not in Men. Women's health issues, 27(3), 302-307.
Open this publication in new window or tab >>Anxiety Disorders are Associated with Low Socioeconomic Status in Women but Not in Men
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2017 (English)In: Women's health issues, ISSN 1049-3867, E-ISSN 1878-4321, Vol. 27, no 3, 302-307 p.Article in journal (Refereed) Published
Abstract [en]

Objectives: We investigated to what extent the lifetime prevalence of anxiety disorders relates to negative economic changes, taking important lifestyle factors and unexpected life events into consideration. Methods: We included 3,695 participants recruited in the city of Lausanne (Switzerland), from the population-based CoLaus/PsyCoLaus study. The association between anxiety disorders, lifestyle factors, and life events related to income was investigated using binary logistic regression analyses correcting for demographic and clinical confounders. Results: Compared with men, women with anxiety disorders showed a significantly lower socioeconomic status (Mann-Whitney U = 56,318; p < .001) and reported a higher negative impact of substantial reduction of income (Mann-Whitney U = 68,531; p = .024). When performing adjusted analyses, low socioeconomic status (odd ratio, 0.87; p = .001) and negative impact of reduction of income (odd ratio, 1.01; p = .004) were associated significantly with anxiety disorders in women but not in men. Conclusion: Our results suggest that anxiety disorders aggravate already existing gender differences in economic conditions, and that women with anxiety need additional support to attain socioeconomic security similar to that of men.

National Category
Public Health, Global Health, Social Medicine and Epidemiology Occupational Health and Environmental Health
Identifiers
urn:nbn:se:uu:diva-329124 (URN)10.1016/j.whi.2017.01.001 (DOI)000403781300008 ()28215982 (PubMedID)
Funder
Swedish Society for Medical Research (SSMF)Swedish Research CouncilThe Swedish Brain Foundation
Available from: 2017-10-12 Created: 2017-10-12 Last updated: 2018-01-13Bibliographically approved
Cedernaes, J., Osorio, R. S., Varga, A. W., Kam, K., Schiöth, H. B. & Benedict, C. (2017). Candidate mechanisms underlying the association between sleep-wake disruptions and Alzheimer's disease.. Sleep Medicine Reviews, 31, 102-111, Article ID S1087-0792(16)00018-6.
Open this publication in new window or tab >>Candidate mechanisms underlying the association between sleep-wake disruptions and Alzheimer's disease.
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2017 (English)In: Sleep Medicine Reviews, ISSN 1087-0792, E-ISSN 1532-2955, Vol. 31, 102-111 p., S1087-0792(16)00018-6Article, review/survey (Refereed) Published
Abstract [en]

During wakefulness, extracellular levels of metabolites in the brain increase. These include amyloid beta (Aβ), which contributes to the pathogenesis of Alzheimer's disease (AD). Counterbalancing their accumulation in the brain, sleep facilitates the removal of these metabolites from the extracellular space by convective flow of the interstitial fluid from the para-arterial to the para-venous space. However, when the sleep-wake cycle is disrupted (characterized by increased brain levels of the wake-promoting neuropeptide orexin and increased neural activity), the central nervous system (CNS) clearance of extracellular metabolites is diminished. Disruptions to the sleep-wake cycle have furthermore been linked to increased neuronal oxidative stress and impaired blood-brain barrier function - conditions that have also been proposed to play a role in the development and progression of AD. Notably, recent human and transgenic animal studies have demonstrated that AD-related pathophysiological processes that occur long before the clinical onset of AD, such as Aβ deposition in the brain, disrupt sleep and circadian rhythms. Collectively, as proposed in this review, these findings suggest the existence of a mechanistic interplay between AD pathogenesis and disrupted sleep-wake cycles, which is able to accelerate the development and progression of this disease.

Keyword
Aging, Amyloid beta, Blood brain barrier, Circadian misalignment, Neurodegeneration, Orexin, Oxidative stress, Sleep disruption, Slow-wave sleep, Tau
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-318575 (URN)10.1016/j.smrv.2016.02.002 (DOI)26996255 (PubMedID)
Available from: 2017-03-26 Created: 2017-03-26 Last updated: 2018-01-13
Chicca, A., Nicolussi, S., Bartholomäus, R., Blunder, M., Rey, A. A., Petrucci, V., . . . Gertsch, J. (2017). Chemical probes to potently and selectively inhibit endocannabinoid cellular reuptake. Proceedings of the National Academy of Sciences of the United States of America, 114(25), E5006-E5015.
Open this publication in new window or tab >>Chemical probes to potently and selectively inhibit endocannabinoid cellular reuptake
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2017 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, no 25, E5006-E5015 p.Article in journal (Refereed) Published
Abstract [en]

The extracellular effects of the endocannabinoids anandamide and 2-arachidonoyl glycerol are terminated by enzymatic hydrolysis after crossing cellular membranes by facilitated diffusion. The lack of potent and selective inhibitors for endocannabinoid transport has prevented the molecular characterization of this process, thus hindering its biochemical investigation and pharmacological exploitation. Here, we report the design, chemical synthesis, and biological profiling of natural product-derived N-substituted 2,4-dodecadienamides as a selective endocannabinoid uptake inhibitor. The highly potent (IC50 = 10 nM) inhibitor N-(3,4-dimethoxyphenyl) ethyl amide (WOBE437) exerted pronounced cannabinoid receptor-dependent anxiolytic, antiinflammatory, and analgesic effects in mice by increasing endocannabinoid levels. A tailored WOBE437-derived diazirine-containing photoaffinity probe (RX-055) irreversibly blocked membrane transport of both endocannabinoids, providing mechanistic insights into this complex process. Moreover, RX-055 exerted site-specific anxiolytic effects on in situ photoactivation in the brain. This study describes suitable inhibitors to target endocannabinoid membrane trafficking and uncovers an alternative endocannabinoid pharmacology.

Place, publisher, year, edition, pages
NATL ACAD SCIENCES, 2017
Keyword
endocannabinoid reuptake, 2-AG, inhibitor, endocannabinoid system, lipid transport
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-329659 (URN)10.1073/pnas.1704065114 (DOI)000403687300016 ()28584105 (PubMedID)
Funder
Lars Hierta Memorial Foundation
Available from: 2017-09-20 Created: 2017-09-20 Last updated: 2018-01-13Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-7112-0921

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