Anxiety Disorders: Hen R

Leonardo ED, Hen R. · Department of Psychiatry, Columbia University, New York, NY, USA. · Neuropsychopharmacology. · Pubmed #17851538 links to  free full text

Abstract: There is increasing recognition that many psychiatric disorders including anxiety disorders are neurodevelopmental in their origins. Here, we review and integrate data from human studies and from animal models that point to a critical period during which neural circuits that mediate anxiety develop. We then postulate that this highly plastic critical period is a time of heightened responsiveness that is particularly susceptible to adverse events. We discuss these concepts in the context the current heightened interest in gene by environment interactions in psychiatric illness emphasizing the importance of the temporal relationship between gene action and environmental milieu.

Leonardo ED, Hen R. · Center for Neurobiology and Behavior, Columbia University, New York, New York 10032, USA. · Annu Rev Psychol. · Pubmed #16318591 No free full text.

Abstract: The study of the genetics of complex behaviors has evolved dramatically from the days of the nature versus nurture debates that dominated much of the past century. Here we discuss advances in our understanding of the genetics of affective and anxiety disorders. In particular, we highlight our growing understanding of specific gene-environment interactions that occur during critical periods in development, setting the stage for later behavioral phenotypes. We review the recent literature in the field, focusing on recent advances in our understanding of the role of the serotonin system in establishing normal anxiety levels during development. We emphasize the importance of understanding the effect of genetic variation at the level of functional circuits and provide examples from the literature of how such an approach has been exploited to study novel genetic endpoints, including genetically based variation in response to medication, a potentially valuable phenotype that has not received much attention to date.

Gross C, Hen R. · European Molecular Biology Laboratory (EMBL), Via Ramarini 32, 00016 Monterotondo (Rome), Italy. · Neurotox Res. · Pubmed #15639782 No free full text.

Abstract: Both genetic and environmental factors influence normal anxiety traits as well as anxiety disorders. In addition it is becoming increasingly clear that these factors interact to produce specific anxiety-related behaviors. For example, in humans and in monkeys mutations in the gene encoding for the serotonin transporter result in increased anxiety in adult life when combined with a stressful environment during development. Another recent example comes from twin studies suggesting that a small hippocampus can be a predisposing condition that renders individuals susceptible to post traumatic stress disorder. Such examples illustrate how specific mutations leading to abnormal brain development may increase vulnerability to environmental insults which may in turn lead to specific anxiety disorders.

Gordon JA, Hen R. · Center for Neurobiology and Behavior, Department of Psychiatry, Columbia University, New York State Psychiatric Institute, New York, NY 10032, USA. · Annu Rev Neurosci. · Pubmed #15217331 No free full text.

Abstract: Anxiety and its disorders have long been known to be familial. Recently, genetic approaches have been used to clarify the role of heredity in the development of anxiety and to probe its neurobiological underpinnings. Twin studies have shown that a significant proportion of the liability to develop any given anxiety disorder is due to genetic factors. Ongoing efforts to map anxiety-related loci in both animals and humans are underway with limited success to date. Animal models have played a large role in furthering our understanding of the genetic basis of anxiety, demonstrating that the genetic factors underlying anxiety are complex and varied. Recent advances in molecular genetic techniques have allowed increasing specificity in the manipulation of gene expression within the central nervous system of the mouse. With this increasing specificity has come the ability to ask and answer precise questions about the mechanisms of anxiety and its treatment.

Gross C, Hen R. · Mouse Biology Programme, European Molecular Biology Laboratory, Via Ramarini 32, 00016 Monterotondo, Rome, Italy. · Nat Rev Neurosci. · Pubmed #15208696 No free full text.

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Gordon JA, Hen R. · Department of Psychiatry, Center for Neurobiology and Behavior, Columbia University, and the New York State Psychiatric Institute, NY, USA. · Neuromolecular Med. · Pubmed #15001810 No free full text.

Abstract: The wide use of serotonin reuptake inhibitors and serotonin receptor agonists in anxiety disorders has suggested a key role for the modulatory neurotransmitter in anxiety. However, serotonin's specific role is still uncertain. This article reviews the literature concerning how and where serotonergic agents modulate anxiety. Varying and sometimes conflicting data from human and animal studies argue for both anxiolytic and anxiogenic roles for serotonin, depending on the specific disorder, structure, or behavioral task studied. However, recent data from molecular genetic studies in the mouse point toward two important roles for the serotonin 1A receptor. In development, serotonin acts through this receptor to promote development of the circuitry necessary for normal anxiety-like behaviors. In adulthood, serotonin reuptake inhibitors act through the same receptor to stimulate neurogenesis and reduce anxiety-like behaviors. These studies highlight that the complex serotonin system likely plays various roles in the regulation of anxiety both during development and in adulthood.

Santarelli L, Gobbi G, Blier P, Hen R. · Department of Pharmacology, Columbia University, New York, NY 10032, USA. · J Clin Psychiatry. · Pubmed #12562138 No free full text.

Abstract: Depression and anxiety are among the most common diseases in the United States, thus constituting a substantial financial burden for the health care system. Experimental studies of these affective disorders to date have largely focused on the neurotransmitter pathways with well-established pathophysiologic roles, such as serotonergic, noradrenergic, and gamma-aminobutyric acid (GABA)-ergic systems; agents modulating the activity of these pathways are known to be clinically effective. More recently, the neuropeptide substance P (SP) and its receptor (the neurokinin-1 receptor [NK1R]) have been implicated in the pathophysiology of affective disorders, including depression. Earlier preclinical and clinical studies, though, did not provide a clear consensus on the role of SP in the regulation of affective behavior and related pathologic conditions. Recent studies in mice clearly demonstrate that both the genetic disruption and acute pharmacologic blockade of the NK1R result in marked reduction in anxiety-like behavior and stress-related responses. In parallel with these behavioral effects, physiologic changes, such as an increased firing rate of 5-hydroxytryptamine (5-HT) neurons in the dorsal raphe nuclei and a desensitization of presynaptic 5-HT1A inhibitory autoreceptors, were observed. These findings provide further evidence for the regulatory role of the SP-NK1R system in modulation of affective behavior and indicate that its effects are mediated, at least in part, via the serotonergic system. Future studies will attempt to delineate the interaction between the SP-NK1R system and various neurotransmitter pathways in greater detail and to address the specific role(s) of this system in different brain regions.

Sibille E, Hen R. · Center for Neurobiology and Behavior, Columbia University, 722 W. 168th St., PI Annex 731, New York, NY 10032, USA. · Eur Neuropsychopharmacol. · Pubmed #11704418 No free full text.

Abstract: Recent technological advances in genetic manipulations and DNA microarrays are profoundly altering the landscape of biological research, offering opportunities to investigate biological questions that were only dreamed of a few years ago. With this revolution comes the hope of being able to tackle some of the more arduous challenges that the central nervous system has presented to the research community. Specifically, a major goal in the study of neuropsychiatric disorders has been to identify underlying mechanisms of brain dysfunction with the expectation that these insights may allow a better diagnosis, prevention and effective treatments for these disorders. For the most part, treatments of these disorders have relied on serendipitous discovery of pharmacological entities with therapeutic efficacy, while the causes of the disorders have remained unknown. The serotonin system, and the serotonin(1A) (5-HT(1A)) receptor in particular, have been under intense investigation, mostly due to the fact that serotonergic drugs that directly or indirectly affect the 5-HT(1A) receptor, are effective therapeutic agents in treating patients with various neuropsychiatric disorders, including anxiety and depression. Genetic deletion of the receptor in mouse results in increased anxiety, thus supporting an active role for this receptor in mood regulation. However, the analysis of genetic deletion experiments can be confounded by hidden developmental roles of the missing receptor, by adaptive compensatory mechanisms, as well by the fact that the genes or gene products that are responsible for the cellular and molecular aspects of the phenotype may be several steps removed from the genetic intervention. Here, we present a combined methodological approach of tissue specific and conditional genetic manipulations, with large-scale search for altered gene expression, as an experimental framework to investigate the role of genes with complex functions and/or complex expression patterns. The 5-HT(1A) receptor is used as a model of gene product with complex functions and distributions, and as a prototypical system to which these new genetic approaches are currently being applied.

Gingrich JA, Hen R. · Department of Psychiatry and the Division of Developmental Psychobiology, Columbia University, New York, NY 10032, USA. · Psychopharmacology (Berl). · Pubmed #11374326 No free full text.

Abstract: RATIONALE: The serotonin system has an important role in the modulation of several processes relevant to psychiatry such as anxiety, affect, aggression, and drug abuse. This review summarizes the recent progress in elucidating the function of the serotonergic system using knockout mice. This review while not exhaustive, highlights recent findings of relevance to psychopharmacology. OBJECTIVES: To familiarize the reader with the technique and the findings from serotonergic knockout mice. METHODS: Information included in this review was drawn from our own experience in this field and relevant publications from other investigators. RESULTS: We have focused on three main themes that have emerged from studies with mice bearing single-gene mutations of serotonergic genes: anxiety, aggression, and drug abuse. Mice lacking the 5-HT1A have been found to be more anxious in several behavioral paradigms. Elevated levels of aggression have been reported in mice lacking the monoamine oxidase A and the 5-HT1B receptor genes. The mice lacking the 5-HT1B receptor have also been reported to exhibit an increased vulnerability to cocaine. The molecular basis of this enhanced vulnerability has been linked to compensatory changes in the nucleus accumbens. These results and their correlation with pharmacological studies will be discussed. CONCLUSION: Mice lacking key components of the serotonin system have provided us with important animal models of genetic vulnerability to conditions such as anxiety disorders, aggression, and drug abuse. Ongoing research with these mice may help elucidate the mechanistic functioning of this complex system.

Zhuang X, Gross C, Santarelli L, Compan V, Trillat AC, Hen R. · Center for Neurobiology and Behavior, Columbia University, New York, NY 10032, USA. · Neuropsychopharmacology. · Pubmed #10432489 links to  free full text

Abstract: Dysfunctions of the serotonergic system have been implicated in a number of psychiatric disorders including depression, anxiety and disorders of impulse control. To model these disorders we have generated mice with altered serotonergic systems. Specifically, we have created mice that lack or express reduced levels of two serotonin receptors: 5-HT1A and 5-HT1B receptors. These receptors are localized both on serotonergic neurons where they act as autoreceptors and on non-serotonergic neurons. As a result, the 5-HT1A and 5-HT1B receptors control the tone of the serotonergic system and mediate some of the postsynaptic effects of serotonin. Agonists of these receptors are currently used in the treatment of migraine and anxiety disorders. Mice lacking these receptors develop, feed, and breed normally and do not display any obvious abnormalities. However, when analyzed in a number of behavioral paradigms, the 5-HT1A and 5-HT1B knockout mice display a number of contrasting phenotypes. While the 5-HT1B knockout mice are more aggressive, more reactive, and less anxious than the wild-types, the 5-HT1A knockouts are less reactive, more anxious, and possibly less aggressive than the wild-types. We are currently investigating with tissue-specific knockout mice which neural circuits are responsible for these phenotypes.

David DJ, Samuels BA, Rainer Q, Wang JW, Marsteller D, Mendez I, Drew M, Craig DA, Guiard BP, Guilloux JP, Artymyshyn RP, Gardier AM, Gerald C, Antonijevic IA, Leonardo ED, Hen R. · Université Paris-Sud EA 3544, Faculté de Pharmacie, Châtenay-Malabry Cedex F-92296, France. · Neuron. · Pubmed #19477151 No free full text.

Abstract: Understanding the physiopathology of affective disorders and their treatment relies on the availability of experimental models that accurately mimic aspects of the disease. Here we describe a mouse model of an anxiety/depressive-like state induced by chronic corticosterone treatment. Furthermore, chronic antidepressant treatment reversed the behavioral dysfunctions and the inhibition of hippocampal neurogenesis induced by corticosterone treatment. In corticosterone-treated mice where hippocampal neurogenesis is abolished by X-irradiation, the efficacy of fluoxetine is blocked in some, but not all, behavioral paradigms, suggesting both neurogenesis-dependent and -independent mechanisms of antidepressant action. Finally, we identified a number of candidate genes, the expression of which is decreased by chronic corticosterone and normalized by chronic fluoxetine treatment selectively in the hypothalamus. Importantly, mice deficient in one of these genes, beta-arrestin 2, displayed a reduced response to fluoxetine in multiple tasks, suggesting that beta-arrestin signaling is necessary for the antidepressant effects of fluoxetine.

Surget A, Saxe M, Leman S, Ibarguen-Vargas Y, Chalon S, Griebel G, Hen R, Belzung C. · U930, INSERM, Université François Rabelais de Tours, Tours, France. · Biol Psychiatry. · Pubmed #18406399 No free full text.

Abstract: BACKGROUND: Depression and anxiety disorders have been linked to dysfunction of the hypothalamo-pituitary-adrenal (HPA) axis and structural changes within the hippocampus. Unpredictable chronic mild stress (UCMS) can recapitulate these effects in a mouse model, and UCMS-induced changes, including downregulation of hippocampal neurogenesis, can be reversed by antidepressant (AD) treatment. We investigated causality between changes in hippocampal neurogenesis and the effects of both chronic stress and chronic ADs. METHODS: Mice were treated with either a sham procedure or focal hippocampal irradiation to disrupt cell proliferation before being confronted with 5 weeks of UCMS. From the third week onward, we administered monoaminergic ADs (imipramine, fluoxetine), the corticotropin-releasing factor 1 (CRF(1)) antagonist SSR125543, or the vasopressin 1b (V(1b)) antagonist SSR149415 daily. The effects of UCMS regimen, AD treatments, and irradiation were assessed by physical measures (coat state, weight), behavioral testing (Splash test, Novelty-Suppressed feeding test, locomotor activity), and hippocampal BrdU labeling. RESULTS: Our results show that elimination of hippocampal neurogenesis has no effect on animals' sensitivity to UCMS in several behavioral assays, suggesting that reduced neurogenesis is not a cause of stress-related behavioral deficits. Second, we present evidence for both neurogenesis-dependent and -independent mechanisms for the reversal of stress-induced behaviors by AD drugs. Specifically, loss of neurogenesis completely blocked the effects of monoaminergic ADs (imipramine, fluoxetine) but did not prevent most effects of the CRF(1) and the V(1b) antagonists. CONCLUSIONS: Hippocampal neurogenesis might thus be used by the monoaminergic ADs to counteract the effects of stress, whereas similar effects could be achieved by directly targeting the HPA axis and related neuropeptides.

Meshi D, Drew MR, Saxe M, Ansorge MS, David D, Santarelli L, Malapani C, Moore H, Hen R. · Department of Biological Sciences, Columbia University, New York, New York 10027, USA. · Nat Neurosci. · Pubmed #16648847 No free full text.

Abstract: Environmental enrichment increases adult hippocampal neurogenesis and alters hippocampal-dependent behavior in rodents. To investigate a causal link between these two observations, we analyzed the effect of enrichment on spatial learning and anxiety-like behavior while blocking adult hippocampal neurogenesis. We report that environmental enrichment alters behavior in mice regardless of their hippocampal neurogenic capability, providing evidence that the newborn cells do not mediate these effects of enrichment.

Gordon JA, Lacefield CO, Kentros CG, Hen R. · Center for Neurobiology and Behavior, Department of Psychiatry, Columbia University, New York, New York 10032, USA. · J Neurosci. · Pubmed #16014712 links to  free full text

Abstract: Mice lacking the serotonin 1A receptor (5-HT(1A)R) show increased levels of anxiety-related behavior across multiple tests and background strains. Tissue-specific rescue experiments, lesion studies, and neurophysiological findings all point toward the hippocampus as a potential mediator of the phenotype. Serotonin, acting through 5-HT(1A)Rs, can suppress hippocampal theta-frequency oscillations, suggesting that theta oscillations might be increased in the knock-outs. To test this hypothesis, local field potential recordings were obtained from the hippocampus of awake, behaving knock-outs and wild-type littermates. The magnitude of theta oscillations was increased in the knock-outs, specifically in the anxiety-provoking elevated plus maze and not in a familiar environment or during rapid eye movement sleep. Theta power correlated with the fraction of time spent in the open arms, an anxiety-related behavioral variable. These results suggest a possible role for the hippocampus, and theta oscillations in particular, in the expression of anxiety in 5-HT(1A)R-deficient mice.

Klemenhagen KC, Gordon JA, David DJ, Hen R, Gross CT. · Center for Neurobiology and Behavior, Columbia University, New York, NY 10032-2695, USA. · Neuropsychopharmacology. · Pubmed #15920501 links to  free full text

Abstract: Serotonin 1A receptor knockout (5-HT1AR KO) mice exhibit increased behavioral inhibition in conflict tests. To gain further insight into their anxiety-related phenotype, we subjected these mice to additional behavioral tests. First, we considered whether behavioral inhibition in these knockout mice is a consequence of reduced exploratory motivation. The knockout mice engage in normal exploration during a light-dark test and normal exploration of a novel object in a familiar environment, suggesting that the anxiety-related phenotype is not due to reduced exploratory drive. Second, we tested whether these mice exhibit increased behavioral inhibition in response to any aversive cues, or whether this response depends on cue modality. Knockout mice respond normally to discrete aversive cues in the Vogel lick-suppression test, arguing that their phenotype is restricted to conflict tests based on complex or spatial aversive cues. Third, to probe the processing of spatial aversive cues, we assessed fear conditioning to contextual cues. After contextual fear conditioning, knockout and wild-type (WT) mice express freezing responses when exposed to the training environment. However, when placed in an ambiguous environment containing both conditioned and novel cues, the freezing response of knockout mice does not significantly decrease as it does in WT mice, suggesting that the knockout fear response is biased toward threatening cues. We hypothesize that this inappropriate generalization of fearful behavior to a context containing both fearful and neutral stimuli, a phenomenon that occurs in a subset of human anxiety disorders such as panic disorder and post-traumatic stress disorder, underlies the anxiety phenotype of 5-HT1AR KO mice.

Ansorge MS, Zhou M, Lira A, Hen R, Gingrich JA. · Sackler Institute for Developmental Psychobiology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA. · Science. · Pubmed #15514160 links to  free full text

Abstract: Reduced serotonin transporter (5-HTT) expression is associated with abnormal affective and anxiety-like symptoms in humans and rodents, but the mechanism of this effect is unknown. Transient inhibition of 5-HTT during early development with fluoxetine, a commonly used serotonin selective reuptake inhibitor, produced abnormal emotional behaviors in adult mice. This effect mimicked the behavioral phenotype of mice genetically deficient in 5-HTT expression. These findings indicate a critical role of serotonin in the maturation of brain systems that modulate emotional function in the adult and suggest a developmental mechanism to explain how low-expressing 5-HTT promoter alleles increase vulnerability to psychiatric disorders.

Dulawa SC, Holick KA, Gundersen B, Hen R. · Center for Neurobiology and Behavior, Columbia University, New York, NY 10032, USA. · Neuropsychopharmacology. · Pubmed #15085085 links to  free full text

Abstract: The onset of the therapeutic response to antidepressant treatment exhibits a characteristic delay. Animal models sensitive to chronic, but not acute, antidepressant treatment are greatly needed for studying antidepressant mechanisms. We initially assessed four inbred mouse strains for their behavioral response to chronic treatment with the selective-serotonin reuptake inhibitor fluoxetine (0, 5, 10 mg/kg/day in drinking water), which is used for the treatment of mood and anxiety disorders. Only the highly anxious BALB/c strain exhibited sensitivity to fluoxetine in the forced swim test. Additionally, fluoxetine reduced locomotion in C57BL/6 and 129SvEv, but not BALB/c and DBA/2, strains. We then evaluated the effects of subchronic (approximately 4 days) and chronic (approximately 24 days) fluoxetine treatment (0, 10, 18, 25 mg/kg/day) on measures of anxiety and depression in BALB/c mice. Anxiety measures were obtained using the open field and novelty-induced hypophagia tests. Antidepressant effects were evaluated using the forced swim test. We found 18 mg/kg/day of chronic fluoxetine to be active in all three paradigms; subchronic treatment had no effect. Anxiety-related measures were reduced by 18 mg/kg/day. In the forced swim test, 10 and 18 mg/kg/day increased swimming and reduced immobility. Here we present several novel effects of chronic, but not subchronic, antidepressant treatment.

Sibille E, Hen R. · Center for Neurobiology and Behavior, Columbia University, NYSPI Kolb Research Annex, 1051 Riverside Drive, New York, NY 10032, USA. · Behav Pharmacol. · Pubmed #11742136 No free full text.

Abstract: The serotonin1A (5-HT1A) receptor has been under intense investigation, mostly due to its putative role in both the etiology and therapeutic treatments of depression and anxiety-related behaviors. However, the exact contribution of this receptor to normal brain physiology and disease processes remains poorly understood, due to a complex expression pattern and multiple functions. Recent development in genetic and genomic approaches allows not only for more refined functional dissection, but also for probing large gene databases for unknown gene product interactions. Here, we describe an experimental approach that is based on a combination of regional and temporal genetic manipulations of the 5-HT1A receptor with large-scale gene expression profiling to attempt to untangle the distinct roles for this receptor in particular brain regions, as well as to identify molecular partners that mediate its function. In turn, new leads for understanding mechanisms of anxiety, depression and their pharmacological treatments may be generated.

Santarelli L, Gobbi G, Debs PC, Sibille ET, Blier P, Hen R, Heath MJ. · Center for Neurobiology and Behavior, Columbia University, New York, NY 10032, USA. · Proc Natl Acad Sci U S A. · Pubmed #11172050 links to  free full text

Abstract: Alterations in serotonin (5-hydroxytriptamine, 5-HT), norepinephrine, and gamma-aminobutyric acid have been linked to the pathophysiology of anxiety and depression, and medications that modulate these neurotransmitters are widely used to treat mood disorders. Recently, the neuropeptide substance P (SP) and its receptor, the neurokinin 1 receptor (NK1R), have been proposed as possible targets for new antidepressant and anxiolytic therapies. However, animal and human studies have so far failed to provide a clear consensus on the role of SP in the modulation of emotional states. Here we show that both genetic disruption and acute pharmacological blockade of the NK1R in mice result in a marked reduction of anxiety and stress-related responses. These behavioral changes are paralleled by an increase in the firing rate of 5-HT neurons in the dorsal raphe nucleus, a major source of serotonergic input to the forebrain. NK1R disruption also results in a selective desensitization of 5-HT1A inhibitory autoreceptors, which resembles the effect of sustained antidepressant treatment. Together these results indicate that the SP system powerfully modulates anxiety and suggest that this effect is at least in part mediated by changes in the 5-HT system.

Weissman MM, Fyer AJ, Haghighi F, Heiman G, Deng Z, Hen R, Hodge SE, Knowles JA. · Department of Psychiatry, College of Physicians and Surgeons at Columbia University, New York, New York, USA. · Am J Med Genet. · Pubmed #10686548 No free full text.

Abstract: This paper reports evidence for a possible "chromosome 13 syndrome," which includes panic disorder, kidney or bladder problems, serious headaches, thyroid problems (usually hypothyroid), and/or mitral valve prolapse (MVP). In the course of a genetic linkage study of panic disorder, we noted these medical conditions in individual family members. (We were blind to family relationships and marker data.) We hypothesized that there may exist a subgroup of panic families with these medical conditions, which for simplicity we called it the "syndrome." Subsequently we reclassified the families as with or without the "syndrome" and extended the phenotype for analysis to include the above medical conditions. All these classifications were also done before the analysis and blind to marker data. We then examined our linkage results, looking for significant differences between families with and without the "syndrome" (using several definitions of the "syndrome")-i.e., testing for genetic heterogeneity. When the families with and without bladder/kidney problems were separated from each other, one marker-D13S779 (ATA26D07)-yielded a lod score of over 3 in the families with bladder/kidney problems. This lod score went up to 4.2 in these families when we diagnosed any individual with any one of the "syndrome" conditions as affected. These results were statistically significant even after applying an extremely overconservative Bonferroni correction for multiple tests. We present these results in order to alert other investigators working on panic disorder, for replication. If replicated, one may hypothesize that a candidate gene for the syndrome should be expressed in CNS, kidney, gut, thyroid, etc. We also noted that two independent studies report recent linkage findings between schizophrenia and the same region on chromosome 13. No connection between schizophrenia and panic disorder has ever been reported. Finally, we suggest that genetic studies of psychiatric disorders might prove more fruitful if phenotypes were expanded to include possible manifestations of the disorder in medical (non-mental) symptoms. Am. J. Med. Genet.(Neuropsychiatr. Genet.) 96:24-35, 2000.

Keller MB, Krystal JH, Hen R, Neumeister A, Simon NM. · No affiliation provided · J Clin Psychiatry. · Pubmed #16420087 No free full text.

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