Publications
100 results found
Jones B, Buenaventura T, Kanda N, et al., 2018, Targeting GLP-1 receptor trafficking to improve agonist efficacy, Nature Communications, Vol: 9, ISSN: 2041-1723
Glucagon-like peptide-1 receptor (GLP-1R) activation promotes insulin secretion from pancreatic beta cells, causes weight loss, and is an important pharmacological target in type 2 diabetes (T2D). Like other G protein-coupled receptors, the GLP-1R undergoes agonist-mediated endocytosis, but the functional and therapeutic consequences of modulating GLP-1R endocytic trafficking have not been clearly defined. Here, we investigate a novel series of biased GLP-1R agonists with variable propensities for GLP-1R internalization and recycling. Compared to a panel of FDA-approved GLP-1 mimetics, compounds that retain GLP-1R at the plasma membrane produce greater long-term insulin release, which is dependent on a reduction in β-arrestin recruitment and faster agonist dissociation rates. Such molecules elicit glycemic benefits in mice without concomitant increases in signs of nausea, a common side effect of GLP-1 therapies. Our study identifies a set of agents with specific GLP-1R trafficking profiles and the potential for greater efficacy and tolerability as T2D treatments.
Schilperoort M, van Dam AD, Hoeke G, et al., 2018, The GPR120 agonist TUG-891 promotes metabolic health by stimulating mitochondrial respiration in brown fat, EMBO Molecular Medicine, Vol: 10, ISSN: 1757-4676
Brown adipose tissue (BAT) activation stimulates energy expenditure in human adults, which makes it an attractive target to combat obesity and related disorders. Recent studies demonstrated a role for G protein-coupled receptor 120 (GPR120) in BAT thermogenesis. Here, we investigated the therapeutic potential of GPR120 agonism and addressed GPR120-mediated signaling in BAT We found that activation of GPR120 by the selective agonist TUG-891 acutely increases fat oxidation and reduces body weight and fat mass in C57Bl/6J mice. These effects coincided with decreased brown adipocyte lipid content and increased nutrient uptake by BAT, confirming increased BAT activity. Consistent with these observations, GPR120 deficiency reduced expression of genes involved in nutrient handling in BAT Stimulation of brown adipocytes in vitro with TUG-891 acutely induced O2 consumption, through GPR120-dependent and GPR120-independent mechanisms. TUG-891 not only stimulated GPR120 signaling resulting in intracellular calcium release, mitochondrial depolarization, and mitochondrial fission, but also activated UCP1. Collectively, these data suggest that activation of brown adipocytes with the GPR120 agonist TUG-891 is a promising strategy to increase lipid combustion and reduce obesity.
Laughlin WE, Buenaventura T, Oqua AI, et al., 2018, Control of glucagon-like peptide-1 receptor (GLP-1R) palmitoylation, lipid raft partitioning, clustering and signalling by biased agonism, Publisher: WILEY, Pages: 54-55, ISSN: 0742-3071
Gorvin CM, Babinsky VN, Malinauskas T, et al., 2018, A calcium-sensing receptor mutation causing hypocalcemia disrupts a transmembrane salt bridge to activate β-arrestin-biased signaling, Science Signaling, Vol: 11, ISSN: 1937-9145
The calcium-sensing receptor (CaSR) is a G protein-coupled receptor (GPCR) that signals through Gq/11and Gi/oto stimulate cytosolic calcium (Ca2+i) and mitogen-activated protein kinase (MAPK) signaling to control extracellular calcium homeostasis. Studies of loss- and gain-of-functionCASRmutations, which cause familial hypocalciuric hypercalcemia type 1 (FHH1) and autosomal dominant hypocalcemia type 1 (ADH1), respectively, have revealed that the CaSR signals in a biased manner. Thus, some mutations associated with FHH1 lead to signaling predominantly through the MAPK pathway, whereas mutations associated with ADH1 preferentially enhance Ca2+iresponses. We report a previously unidentified ADH1-associated R680G CaSR mutation, which led to the identification of a CaSR structural motif that mediates biased signaling. Expressing CaSRR680Gin HEK 293 cells showed that this mutation increased MAPK signaling without altering Ca2+iresponses. Moreover, this gain of function in MAPK activity occurred independently of Gq/11and Gi/oand was mediated instead by a noncanonical pathway involving β-arrestin proteins. Homology modeling and mutagenesis studies showed that the R680G CaSR mutation selectively enhanced β-arrestin signaling by disrupting a salt bridge formed between Arg680and Glu767, which are located in CaSR transmembrane domain 3 and extracellular loop 2, respectively. Thus, our results demonstrate CaSR signaling through β-arrestin and the importance of the Arg680-Glu767salt bridge in mediating signaling bias.
Jonas KC, Chen S, Virta M, et al., 2018, Temporal reprogramming of calcium signalling via crosstalk of gonadotrophin receptors that associate as functionally asymmetric heteromers, Scientific Reports, Vol: 8, ISSN: 2045-2322
Signal crosstalk between distinct G protein-coupled receptors (GPCRs) is one mechanism that underlies pleiotropic signalling. Such crosstalk is also pertinent for GPCRs activated by gonadotrophic hormones; follicle-stimulating hormone (FSH) and luteinising hormone (LH), with specific relevance to female reproduction. Here, we demonstrate that gonadotrophin receptor crosstalk alters LH-induced Gαq/11-calcium profiles. LH-induced calcium signals in both heterologous and primary human granulosa cells were prolonged by FSHR coexpression via influx of extracellular calcium in a receptor specific manner. LHR/FSHR crosstalk involves Gαq/11 activation as a Gαq/11 inhibitor abolished calcium responses. Interestingly, the enhanced LH-mediated calcium signalling induced by FSHR co-expression was dependent on intracellular calcium store release and involved Gβγ. Biophysical analysis of receptor and Gαq interactions indicated that ligand-dependent association between LHR and Gαq was rearranged in the presence of FSHR, enabling FSHR to closely associate with Gαq following LHR activation. This suggests that crosstalk may occur via close associations as heteromers. Super-resolution imaging revealed that LHR and FSHR formed constitutive heteromers at the plasma membrane. Intriguingly, the ratio of LHR:FSHR in heterotetramers was specifically altered following LH treatment. We propose that functionally significant FSHR/LHR crosstalk reprograms LH-mediated calcium signalling at the interface of receptor-G protein via formation of asymmetric complexes.
Owens LA, Abbara A, Lerner A, et al., 2018, The direct and indirect effects of kisspeptin-54 on granulosa lutein cell function, Human Reproduction, Vol: 33, Pages: 292-302, ISSN: 1460-2350
STUDY QUESTIONWhat are the in vivo and in vitro actions of kisspeptin-54 on the expression of genes involved in ovarian reproductive function, steroidogenesis and ovarian hyperstimulation syndrome (OHSS) in granulosa lutein (GL) cells when compared with traditional triggers of oocyte maturation?SUMMARY ANSWERThe use of kisspeptin-54 as an oocyte maturation trigger augmented expression of genes involved in ovarian steroidogenesis in human GL cells including, FSH receptor (FSHR), LH/hCG receptor (LHCGR), steroid acute regulatory protein (STAR), aromatase, estrogen receptors alpha and beta (ESR1, ESR2), 3-beta-hydroxysteroid dehydrogenase type 2 (3BHSD2) and inhibin A (INHBA), when compared to traditional maturation triggers, but did not alter markers of OHSS.WHAT IS KNOWN ALREADYhCG is the most widely used trigger of oocyte maturation, but is associated with an increased risk of OHSS. The use of GnRH agonists to trigger oocyte maturation is a safer alternative to hCG. More recently, kisspeptin-54 has emerged as a novel therapeutic option that safely triggers oocyte maturation even in women at high risk of OHSS. Kisspeptin indirectly stimulates gonadotropin secretion by acting on hypothalamic GnRH neurons. Kisspeptin and its receptor are also expressed in the human ovary, but there is limited data on the direct action of kisspeptin on the ovary.STUDY DESIGN SIZE, DURATIONForty-eight women undergoing IVF treatment for infertility consented to kisspeptin-54 triggering and/or granulosa cell collection and were included in the study. Twelve women received hCG, 12 received GnRH agonist and 24 received kisspeptin-54 to trigger oocyte maturation. In the kisspeptin-54 group, 12 received one injection of kisseptin-54 (9.6 nmol/kg) and 12 received two injections of kisspeptin-54 at a 10 h interval (9.6 nmol/kg × 2).PARTICIPANTS/MATERIALS, SETTING, METHODSFollicular fluid was aspirated and pooled from follicles during the retrieval of oocytes for IVF/ICSI. GL cells were iso
Gorvin CM, Rogers A, Hastoy B, et al., 2018, AP2? Mutations Impair Calcium-Sensing Receptor Trafficking and Signaling, and Show an Endosomal Pathway to Spatially Direct G-Protein Selectivity., Cell Reports, Vol: 22, Pages: 1054-1066, ISSN: 2211-1247
Spatial control of G-protein-coupled receptor (GPCR) signaling, which is used by cells to translate complex information into distinct downstream responses, is achieved by using plasma membrane (PM) and endocytic-derived signaling pathways. The roles of the endomembrane in regulating such pleiotropic signaling via multiple G-protein pathways remain unknown. Here, we investigated the effects of disease-causing mutations of the adaptor protein-2 ? subunit (AP2?) on signaling by the class C GPCR calcium-sensing receptor (CaSR). These AP2? mutations increase CaSR PM expression yet paradoxically reduce CaSR signaling. Hypercalcemia-associated AP2? mutations reduced CaSR signaling via G?q/11 and G?i/o pathways. The mutations also delayed CaSR internalization due to prolonged residency time of CaSR in clathrin structures that impaired or abolished endosomal signaling, which was predominantly mediated by G?q/11. Thus, compartmental bias for CaSR-mediated G?q/11 endomembrane signaling provides a mechanistic basis for multidimensional GPCR signaling.
Sposini S, Jean-Alphonse FG, Ayoub MA, et al., 2017, Integration of GPCR signaling and sorting from very early endosomes via opposing APPL1 mechanisms, Cell Reports, Vol: 21, Pages: 2855-2867, ISSN: 2211-1247
Endocytic trafficking is a critical mechanism for cells to decode complex signaling pathways, including those activated by G-protein-coupled receptors (GPCRs). Heterogeneity in the endosomal network enables GPCR activity to be spatially restricted between early endosomes (EEs) and the recently discovered endosomal compartment, the very early endosome (VEE). However, the molecular machinery driving GPCR activity from the VEE is unknown. Using luteinizing hormone receptor (LHR) as a prototype GPCR for this compartment, along with additional VEE-localized GPCRs, we identify a role for the adaptor protein APPL1 in rapid recycling and endosomal cAMP signaling without impacting the EE-localized β2-adrenergic receptor. LHR recycling is driven by receptor-mediated Gαs/cAMP signaling from the VEE and PKA-dependent phosphorylation of APPL1 at serine 410. Receptor/Gαs endosomal signaling is localized to microdomains of heterogeneous VEE populations and regulated by APPL1 phosphorylation. Our study uncovers a highly integrated inter-endosomal communication system enabling cells to tightly regulate spatially encoded signaling.
Kim SH, Riaposova L, Pohl O, et al., 2017, FP receptor antagonist, OBE002, inhibits both PGF2α- and OT-induced contractions of human pregnant myometrium in vitro, Publisher: OXFORD UNIV PRESS, Pages: 452-452, ISSN: 0268-1161
Riaposova L, Kim SH, Pohl O, et al., 2017, Combination tocolytics on the inhibition of OT-induced contractions of human pregnant myometrium in vitro, 33rd Annual Meeting of the European-Society-of-Human-Reproduction-and-Embryology (ESHRE), Publisher: OXFORD UNIV PRESS, Pages: 54-54, ISSN: 0268-1161
Khanjani S, West C, Lavery S, et al., 2017, Reprogramming of the hCG signalling profile in human endometrial stromal cells from recurrent miscarriage patients, 33rd Annual Meeting of the European-Society-of-Human-Reproduction-and-Embryology (ESHRE), Publisher: OXFORD UNIV PRESS, Pages: 353-354, ISSN: 0268-1161
Hanyaloglu AC, Grammatopoulos DK, 2017, Pleiotropic GPCR signaling in health and disease, Molecular and Cellular Endocrinology, Vol: 449, Pages: 1-2, ISSN: 0303-7207
Sposini S, Hanyaloglu AC, 2017, Spatial encryption of G protein-coupled receptor signaling in endosomes; mechanisms and applications, Biochemical Pharmacology, Vol: 143, Pages: 1-9, ISSN: 1873-2968
Within any cellular signaling system membrane trafficking is a critical mechanism for cells to translate complex networks into specific downstream responses, including the signal pathways activated by the superfamily of G protein-coupled receptors (GPCRs). Classically, membrane trafficking is viewed as a mechanism to regulate ligand sensitivity of a target tissue by controlling the level of surface receptors. Recent studies, however, have not only highlighted that GPCR trafficking is a tightly regulated process critical for spatio-temporal control of signaling, but that heterotrimeric G protein signaling can also be reactivated or continue to signal from distinct endocytic compartments, and even endosomal microdomains. The significance of spatio-temporal control will be discussed, not only with respect to how these novel molecular pathways impact our basic understanding of cellular regulation, but also our view of how aberrant signaling can result in disease. Furthermore, these mechanisms offer the potential application for novel therapeutic strategies to identify GPCR compounds with high specificity in their actions
Kim SH, Ahmed H, Riaposova L, et al., 2017, Both OTR Antagonists, Atosiban and Nolasiban, Inhibits PGE(2)/PGF(2 alpha)-Induced Contractions of Human Pregnant Myometrium In Vitro., 64th Annual Scientific Meeting of the Society-for-Reproductive-Investigation (SRI), Publisher: SAGE PUBLICATIONS INC, Pages: 245A-245A, ISSN: 1933-7191
West C, Kim SH, Khanjani S, et al., 2017, Oxytocin Activates Pro-Inflammatory Pathways in Decidualised Human Endometrial Stromal Cells., 64th Annual Scientific Meeting of the Society-for-Reproductive-Investigation (SRI), Publisher: SAGE PUBLICATIONS INC, Pages: 162A-162A, ISSN: 1933-7191
Khanjani S, West C, Brosens JJ, et al., 2017, Reprogramming of the hCG Signaling Profile in Human Endometrial Stromal Cells from Recurrent Miscarriage Patients, 64th Annual Scientific Meeting of the Society-for-Reproductive-Investigation (SRI), Publisher: SAGE PUBLICATIONS INC, Pages: 227A-228A, ISSN: 1933-7191
Jonas KC, Hanyaloglu AC, 2017, Impact of G protein-coupled receptor heteromers in endocrine systems, Molecular and Cellular Endocrinology, Vol: 449, Pages: 21-27, ISSN: 0303-7207
The fine-tuning of endocrine homeostasis is regulated by dynamic receptor mediated processes. Thesuperfamily of G protein-coupled receptors (GPCRs) have diverse roles in the modulation of all endocrineaxes, thus understanding the mechanisms underpinning their functionality is paramount for treatmentof endocrinopathies. Evidence over the last 20 years has highlighted homo and heteromerization as a keymode of mediating GPCR functional diversity. This review will discuss the concept of GPCR heteromerizationand its relevance to endocrine function, detailing in vitro and in vivo evidence, and exploringcurrent and potential pharmacological strategies for specific targeting of GPCR heteromers in endocrineheath and disease.
Hanyaloglu AC, Fanelli F, Jonas KC, 2017, Class A GPCR: Di/Oligomerization of Glycoprotein Hormone Receptors, G-PROTEIN-COUPLED RECEPTOR DIMERS, Editors: Herrick-Davis, Milligan, DiGiovanni, Publisher: HUMANA PRESS INC, Pages: 207-231, ISBN: 978-3-319-60172-4
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Owens L, Lerner A, Sposini S, et al., 2016, Insight into the molecular mechanisms underlying enhanced gonadotropin hormone receptor activity in polycystic ovarian syndrome, Publisher: SPRINGER LONDON LTD, Pages: 370-370, ISSN: 0021-1265
Babinsky VN, Hannan FM, Gorvin CM, et al., 2016, Allosteric modulation of the calcium-sensing receptor rectifies signaling abnormalities associated with G-protein Alpha-11 mutations causing hypercalcemic and hypocalcemic disorders, Journal of Biological Chemistry, Vol: 291, Pages: 10876-10885, ISSN: 1083-351X
Germline loss- and gain-of-function mutations of G-protein alpha-11 (Gα11), which couples the calcium-sensing receptor (CaSR) to intracellular calcium (Ca2+i) signaling, lead to familial hypocalciuric hypercalcemia type 2 (FHH2) and autosomal dominant hypocalcemia type 2 (ADH2), respectively, whereas somatic Gα11 mutations mediate uveal melanoma development by constitutively upregulating MAPK signaling. Cinacalcet and NPS-2143 are allosteric CaSR activators and inactivators, respectively, that ameliorate signaling disturbances associated with CaSR mutations, but their potential to modulate abnormalities of the downstream Gα11 protein is unknown. This study investigated whether cinacalcet and NPS-2143 may rectify Ca2+i alterations associated with FHH2- and ADH2-causing Gα11 mutations, and evaluated the influence of germline gain-of-function Gα11 mutations on MAPK signaling by measuring ERK phosphorylation, and assessed the effect of NPS-2143 on a uveal melanoma Gα11 mutant. WT and mutant Gα11 proteins causing FHH2, ADH2 or uveal melanoma were transfected in CaSR-expressing HEK293 cells, and Ca2+i and ERK1/2 phosphorylation responses measured by flow-cytometry and Alphascreen immunoassay following exposure to extracellular Ca2+ (Ca2+o) and allosteric modulators. Cinacalcet and NPS-2143 rectified the Ca2+i responses of FHH2- and ADH2-associated Gα11 loss- and gain-of-function mutations, respectively. ADH2-causing Gα11 mutations were demonstrated not to be constitutively activating and induced ERK phosphorylation following Ca2+o stimulation only. The increased ERK phosphorylation associated with ADH2 and uveal melanoma mutants was rectified by NPS-2143. These findings demonstrate that CaSR-targeted compounds can rectify signaling disturbances caused by germline and somatic Gα11 mutations, which respectively lead to calcium disorders and tumorigenesis; and that ADH2-causing Gα11 mutations induce non-consti
Khanjani S, Larsen C, Stavrinidis C, et al., 2016, Programming Prostanoid EP2 Receptor Function in Human Labour via GPCR Crosstalk with Oxytocin Receptor., 63rd Annual Scientific Meeting of the Society-for-Reproductive-Investigation, Publisher: SAGE PUBLICATIONS INC, Pages: 61A-61A, ISSN: 1933-7191
Jonas KC, Huhtaniemi I, Hanyaloglu AC, 2016, Single-molecule resolution of G protein-coupled receptor (GPCR) complexes, G PROTEIN-COUPLED RECEPTORS: SIGNALING, TRAFFICKING AND REGULATION, Editors: Shukla, Publisher: ELSEVIER ACADEMIC PRESS INC, Pages: 55-72, ISBN: 978-0-12-803595-5
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- Citations: 29
Kim SH, MacIntyre DA, Hanyaloglu AC, et al., 2015, The oxytocin receptor antagonist, Atosiban, activates pro-inflammatory pathways in human amnion via G(alpha i) signalling, Molecular and Cellular Endocrinology, Vol: 420, Pages: 11-23, ISSN: 1872-8057
West C, Hanyaloglu AC, 2015, Minireview: Spatial Programming of G Protein-Coupled Receptor Activity: Decoding Signaling in Health and Disease., Molecular Endocrinology, Vol: 29, Pages: 1095-1106, ISSN: 1944-9917
Probing the multiplicity of hormone signaling via G protein-coupled receptors (GPCRs) has demonstrated the complex signal pathways that underlie the multiple functions these receptors play in vivo. This is highly pertinent for the GPCRs key in reproduction and pregnancy that are exposed to cyclical and dynamic changes in their extracellular milieu. How such functional pleiotropy in GPCR signaling is translated to specific downstream cellular responses, however, is largely unknown. Emerging data strongly support mechanisms for a central role of receptor location in signal regulation via membrane trafficking. In this review, we discuss current progress in our understanding of the role membrane trafficking plays in location control of GPCR signaling, from organized plasma membrane signaling microdomains, potentially provided by both distinct endocytic and exocytic pathways, to more recent evidence for spatial control within the endomembrane system. Application of these emerging mechanisms in their relevance to GPCR activity in physiological and pathophysiological conditions will also be discussed, and in improving therapeutic strategies that exploits these mechanisms in order to program highly regulated and distinct signaling profiles.
Jonas KC, Fanelli F, Huhtaniemi IT, et al., 2015, Single molecule analysis of functionally asymmetric G protein-coupled receptor (GPCR) oligomers reveals diverse spatial and structural assemblies, Journal of Biological Chemistry, Vol: 290, Pages: 3875-3892, ISSN: 1083-351X
Background: GPCRs form complex oligomers whose role in signaling is poorly understood.Results: Super-resolution imaging of functionally asymmetric oligomers reveals diverse functional and structural organizationsand the ability to alter signal responses.Conclusion: GPCR oligomers may fine-tune receptor signaling by altering the functional role of individual protomers.Significance: Distinct oligomers could be exploited pharmacologically to improve efficacy, selectivity, and/or specificity.
Hanyaloglu A, Jonas K, 2015, Advancing applications of super-resolution imaging: 10 November 2014, Charles Darwin House, London, UK, Biochemist, Vol: 37, Pages: 52-52, ISSN: 0954-982X
Sposini S, Caltabiano G, Hanyaloglu AC, et al., 2014, Identification of transmembrane domains that regulate spatial arrangements and activity of prokineticin receptor 2 dimers, Molecular and Cellular Endocrinology, Vol: 399, Pages: 362-372, ISSN: 1872-8057
The chemokine prokineticin 2 (PK2) activates its cognate G protein-coupled receptor (GPCR) PKR2 to elicit various downstream signaling pathways involved in diverse biological processes. Many GPCRs undergo dimerization that can modulate a number of functions including membrane delivery and signal transduction. The aim of this study was to elucidate the interface of PKR2 protomers within dimers by analyzing the ability of PKR2 transmembrane (TM) deletion mutants to associate with wild type (WT) PKR2 in yeast using co-immunoprecipitation and mammalian cells using bioluminescence resonance energy transfer. Deletion of TMs 5-7 resulted in a lack of detectable association with WT PKR2, but could associate with a truncated mutant lacking TMs 6-7 (TM1-5). Interestingly, TM1-5 modulated the distance, or organization, between protomers and positively regulated Gαs signaling and surface expression of WT PKR2. We propose that PKR2 protomers form type II dimers involving TMs 4 and 5, with a role for TM5 in modulation of PKR2 function.
Nikolopoulou E, Papacleovoulou G, Jean-Alphonse F, et al., 2014, Arachidonic acid-dependent gene regulation during preadipocyte differentiation controls adipocyte potential, Journal of Lipid Research, Vol: 55, Pages: 2479-2490, ISSN: 0022-2275
Arachidonic acid (AA) is a major PUFA that has been implicated in the regulation of adipogenesis. We examined the effect of a short exposure to AA at different stages of 3T3-L1 adipocyte differentiation. AA caused the upregulation of fatty acid binding protein 4 (FABP4/aP2) following 24 h of differentiation. This was mediated by the prostaglandin F2α (PGF2α), as inhibition of cyclooxygenases or PGF2α receptor signaling counteracted the AA-mediated aP2 induction. In addition, calcium, protein kinase C, and ERK are all key elements of the pathway through which AA induces the expression of aP2. We also show that treatment with AA during the first 24 h of differentiation upregulates the expression of the transcription factor Fos-related antigen 1 (Fra-1) via the same pathway. Finally, treatment with AA for 24 h at the beginning of the adipocyte differentiation is sufficient to inhibit the late stages of adipogenesis through a Fra-1-dependent pathway, as Fra-1 knockdown rescued adipogenesis. Our data show that AA is able to program the differentiation potential of preadipocytes by regulating gene expression at the early stages of adipogenesis.
Psichas A, Sleeth ML, Murphy KG, et al., 2014, The short chain fatty acid propionate stimulates GLP-1 and PYY secretion via free fatty acid receptor 2 in rodents, International Journal of Obesity, Vol: 39, Pages: 424-429, ISSN: 1476-5497
Khanjani S, Kandola MK, Lee YS, et al., 2014, EP2 Receptor Activates Dual G Protein Signalling Pathways That Mediate Contrasting Pro- and Anti-Labor Responses in Term Pregnant Human Myometrium, REPRODUCTIVE SCIENCES, Vol: 21, Pages: 124A-124A, ISSN: 1933-7191
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