keyword
https://read.qxmd.com/read/37158739/susceptibility-of-ugandan-plasmodium-falciparum-isolates-to-the-antimalarial-drug-pipeline
#1
JOURNAL ARTICLE
Oriana Kreutzfeld, Patrick K Tumwebaze, Martin Okitwi, Stephen Orena, Oswald Byaruhanga, Thomas Katairo, Melissa D Conrad, Stephanie A Rasmussen, Jennifer Legac, Ozkan Aydemir, David Giesbrecht, Barbara Forte, Peter Campbell, Alasdair Smith, Hiroki Kano, Samuel L Nsobya, Benjamin Blasco, Maelle Duffey, Jeffrey A Bailey, Roland A Cooper, Philip J Rosenthal
Malaria, especially Plasmodium falciparum infection, remains an enormous problem, and its treatment and control are seriously challenged by drug resistance. New antimalarial drugs are needed. To characterize the Medicines for Malaria Venture pipeline of antimalarials under development, we assessed the ex vivo drug susceptibilities to 19 compounds targeting or potentially impacted by mutations in P. falciparum ABC transporter I family member 1, acetyl-CoA synthetase, cytochrome b , dihydroorotate dehydrogenase, elongation factor 2, lysyl-tRNA synthetase, phenylalanyl-tRNA synthetase, plasmepsin X, prodrug activation and resistance esterase, and V-type H+ ATPase of 998 fresh P...
June 15, 2023: Microbiology Spectrum
https://read.qxmd.com/read/36094216/susceptibilities-of-ugandan-plasmodium-falciparum-isolates-to-proteasome-inhibitors
#2
JOURNAL ARTICLE
Shreeya Garg, Oriana Kreutzfeld, Sevil Chelebieva, Patrick K Tumwebaze, Oswald Byaruhanga, Martin Okitwi, Stephen Orena, Thomas Katairo, Samuel L Nsobya, Melissa D Conrad, Ozkan Aydemir, Jennifer Legac, Alexandra E Gould, Brett R Bayles, Jeffrey A Bailey, Maelle Duffey, Gang Lin, Laura A Kirkman, Roland A Cooper, Philip J Rosenthal
The proteasome is a promising target for antimalarial chemotherapy. We assessed ex vivo susceptibilities of fresh Plasmodium falciparum isolates from eastern Uganda to seven proteasome inhibitors: two asparagine ethylenediamines, two macrocyclic peptides, and three peptide boronates; five had median IC50 values <100 nM. TDI8304, a macrocylic peptide lead compound with drug-like properties, had a median IC50 of 16 nM. Sequencing genes encoding the β2 and β5 catalytic proteasome subunits, the predicted targets of the inhibitors, and five additional proteasome subunits, identified two mutations in β2 (I204T, S214F), three mutations in β5 (V2I, A142S, D150E), and three mutations in other subunits...
September 12, 2022: Antimicrobial Agents and Chemotherapy
https://read.qxmd.com/read/35983950/bcl-x-l-as-prognostic-marker-and-potential-therapeutic-target-in-cholangiocarcinoma
#3
JOURNAL ARTICLE
P Hoffmeister, A Mock, F Nichetti, F Korell, C E Heilig, A-L Scherr, M Günther, T Albrecht, E Kelmendi, K Xu, L Nader, A Kessler, N Schmitt, S Fritzsche, S Weiler, B Sobol, A Stenzinger, S Boeck, C B Westphalen, K Schulze-Osthoff, J Trojan, T Kindler, W Weichert, K Spiekermann, M Bitzer, G Folprecht, A L Illert, M Boerries, F Klauschen, S Ochsenreiter, J Siveke, S Bauer, H Glimm, B Brors, J Hüllein, D Hübschmann, S Uhrig, P Horak, S Kreutzfeld, J M Banales, C Springfeld, D Jäger, P Schirmacher, S Roessler, S Ormanns, B Goeppert, S Fröhling, B C Köhler
Intrahepatic, perihilar and distal cholangiocarcinoma (iCCA, pCCA, dCCA) are highly malignant tumors with increasing mortality rates due to therapy resistances. Among the mechanisms mediating resistance, overexpression of anti-apoptotic Bcl-2 proteins (Bcl-2, Bcl-xL , Mcl-1) is particularly important. In this study, we investigated whether antiapoptotic protein patterns are prognostically relevant and potential therapeutic targets in CCA. Bcl-2 proteins were analyzed in a pan-cancer cohort from the NCT/DKFZ/DKTK MASTER registry trial (n=1140, CCA n=72) via RNA-sequencing and transcriptome-based protein activity interference revealing high ranks of CCA for Bcl-xL and Mcl-1...
August 19, 2022: Liver International: Official Journal of the International Association for the Study of the Liver
https://read.qxmd.com/read/34956312/absence-of-pexel-dependent-protein-export-in-plasmodium-liver-stages-cannot-be-restored-by-gain-of-the-hsp101-protein-translocon-atpase
#4
JOURNAL ARTICLE
Oriana Kreutzfeld, Josephine Grützke, Alyssa Ingmundson, Katja Müller, Kai Matuschewski
Host cell remodeling is critical for successful Plasmodium replication inside erythrocytes and achieved by targeted export of parasite-encoded proteins. In contrast, during liver infection the malarial parasite appears to avoid protein export, perhaps to limit exposure of parasite antigens by infected liver cells. HSP101, the force-generating ATPase of the protein translocon of exported proteins (PTEX) is the only component that is switched off during early liver infection. Here, we generated transgenic Plasmodium berghei parasite lines that restore liver stage expression of HSP101...
2021: Frontiers in Genetics
https://read.qxmd.com/read/34460932/decreased-susceptibility-to-dihydrofolate-reductase-inhibitors-associated-with-genetic-polymorphisms-in-ugandan-plasmodium-falciparum-isolates
#5
JOURNAL ARTICLE
Oriana Kreutzfeld, Patrick K Tumwebaze, Oswald Byaruhanga, Thomas Katairo, Martin Okitwi, Stephen Orena, Stephanie A Rasmussen, Jennifer Legac, Melissa D Conrad, Sam L Nsobya, Ozkan Aydemir, Jeffrey A Bailey, Maelle Duffey, Roland A Cooper, Philip J Rosenthal
BACKGROUND: The Plasmodium falciparum dihydrofolate reductase (PfDHFR) inhibitors pyrimethamine and cycloguanil (the active metabolite of proguanil) have important roles in malaria chemoprevention, but drug resistance challenges their efficacies. A new compound, P218, was designed to overcome resistance, but drug susceptibility data for P. falciparum field isolates are limited. METHODS: We studied ex vivo PfDHFR inhibitor susceptibilities of 559 isolates from Tororo and Busia districts, Uganda from 2016-2020, sequenced 383 isolates, and assessed associations between genotypes and drug susceptibility phenotypes...
August 30, 2021: Journal of Infectious Diseases
https://read.qxmd.com/read/34339273/associations-between-varied-susceptibilities-of-pfatp4-inhibitors-and-genotypes-in-ugandan-plasmodium-falciparum-isolates
#6
JOURNAL ARTICLE
Oriana Kreutzfeld, Stephanie A Rasmussen, Aarti A Ramanathan, Patrick K Tumwebaze, Oswald Byaruhanga, Thomas Katairo, Victor Asua, Martin Okitwi, Stephen Orena, Jennifer Legac, Melissa D Conrad, Samuel L Nsobya, Ozkan Aydemir, Jeffrey Bailey, Maelle Duffey, Brett R Bayles, Akhil B Vaidya, Roland A Cooper, Philip J Rosenthal
Among novel compounds under recent investigation as potential new antimalarial drugs are three independently developed inhibitors of the Plasmodium falciparum P-type ATPase (PfATP4): KAE609 (cipargamin), PA92, and SJ733. We assessed ex vivo susceptibilities to these compounds of 374 fresh P. falciparum isolates collected in Tororo and Busia districts, Uganda from 2016-2019. Median IC50 s were 65 nM for SJ733, 9.1 nM for PA92, and 0.5 nM for KAE609. Sequencing of pfatp4 for 218 of these isolates demonstrated many non-synonymous single nucleotide polymorphisms; the most frequent mutations were G1128R (69% of isolates mixed or mutant), Q1081K/R (68%), G223S (25%), N1045K (16%) and D1116G/N/Y (16%)...
August 2, 2021: Antimicrobial Agents and Chemotherapy
https://read.qxmd.com/read/33112933/rapid-deployment-of-sars-cov-2-testing-the-cliahub
#7
JOURNAL ARTICLE
Emily D Crawford, Irene Acosta, Vida Ahyong, Erika C Anderson, Shaun Arevalo, Daniel Asarnow, Shannon Axelrod, Patrick Ayscue, Camillia S Azimi, Caleigh M Azumaya, Stefanie Bachl, Iris Bachmutsky, Aparna Bhaduri, Jeremy Bancroft Brown, Joshua Batson, Astrid Behnert, Ryan M Boileau, Saumya R Bollam, Alain R Bonny, David Booth, Michael Jerico B Borja, David Brown, Bryan Buie, Cassandra E Burnett, Lauren E Byrnes, Katelyn A Cabral, Joana P Cabrera, Saharai Caldera, Gabriela Canales, Gloria R Castañeda, Agnes Protacio Chan, Christopher R Chang, Arthur Charles-Orszag, Carly Cheung, Unseng Chio, Eric D Chow, Y Rose Citron, Allison Cohen, Lillian B Cohn, Charles Chiu, Mitchel A Cole, Daniel N Conrad, Angela Constantino, Andrew Cote, Tre'Jon Crayton-Hall, Spyros Darmanis, Angela M Detweiler, Rebekah L Dial, Shen Dong, Elias M Duarte, David Dynerman, Rebecca Egger, Alison Fanton, Stacey M Frumm, Becky Xu Hua Fu, Valentina E Garcia, Julie Garcia, Christina Gladkova, Miriam Goldman, Rafael Gomez-Sjoberg, M Grace Gordon, James C R Grove, Shweta Gupta, Alexis Haddjeri-Hopkins, Pierce Hadley, John Haliburton, Samantha L Hao, George Hartoularos, Nadia Herrera, Melissa Hilberg, Kit Ying E Ho, Nicholas Hoppe, Shayan Hosseinzadeh, Conor J Howard, Jeffrey A Hussmann, Elizabeth Hwang, Danielle Ingebrigtsen, Julia R Jackson, Ziad M Jowhar, Danielle Kain, James Y S Kim, Amy Kistler, Oriana Kreutzfeld, Jessie Kulsuptrakul, Andrew F Kung, Charles Langelier, Matthew T Laurie, Lena Lee, Kun Leng, Kristoffer E Leon, Manuel D Leonetti, Sophia R Levan, Sam Li, Aileen W Li, Jamin Liu, Heidi S Lubin, Amy Lyden, Jennifer Mann, Sabrina Mann, Gorica Margulis, Diana M Marquez, Bryan P Marsh, Calla Martyn, Elizabeth E McCarthy, Aaron McGeever, Alexander F Merriman, Lauren K Meyer, Steve Miller, Megan K Moore, Cody T Mowery, Tanzila Mukhtar, Lusajo L Mwakibete, Noelle Narez, Norma F Neff, Lindsay A Osso, Diter Oviedo, Suping Peng, Maira Phelps, Kiet Phong, Peter Picard, Lindsey M Pieper, Neha Pincha, Angela Oliveira Pisco, Angela Pogson, Sergei Pourmal, Robert R Puccinelli, Andreas S Puschnik, Elze Rackaityte, Preethi Raghavan, Madhura Raghavan, James Reese, Joseph M Replogle, Hanna Retallack, Helen Reyes, Donald Rose, Marci F Rosenberg, Estella Sanchez-Guerrero, Sydney M Sattler, Laura Savy, Stephanie K See, Kristin K Sellers, Paula Hayakawa Serpa, Maureen Sheehy, Jonathan Sheu, Sukrit Silas, Jessica A Streithorst, Jack Strickland, Doug Stryke, Sara Sunshine, Peter Suslow, Renaldo Sutanto, Serena Tamura, Michelle Tan, Jiongyi Tan, Alice Tang, Cristina M Tato, Jack C Taylor, Iliana Tenvooren, Erin M Thompson, Edward C Thornborrow, Eric Tse, Tony Tung, Marc L Turner, Victoria S Turner, Rigney E Turnham, Mary J Turocy, Trisha V Vaidyanathan, Ilia D Vainchtein, Manu Vanaerschot, Sara E Vazquez, Anica M Wandler, Anne Wapniarski, James T Webber, Zara Y Weinberg, Alexandra Westbrook, Allison W Wong, Emily Wong, Gajus Worthington, Fang Xie, Albert Xu, Terrina Yamamoto, Ying Yang, Fauna Yarza, Yefim Zaltsman, Tina Zheng, Joseph L DeRisi
No abstract text is available yet for this article.
October 2020: PLoS Pathogens
https://read.qxmd.com/read/28620583/engineering-of-genetically-arrested-parasites-gaps-for-a-precision-malaria-vaccine
#8
REVIEW
Oriana Kreutzfeld, Katja Müller, Kai Matuschewski
Continuous stage conversion and swift changes in the antigenic repertoire in response to acquired immunity are hallmarks of complex eukaryotic pathogens, including Plasmodium species, the causative agents of malaria. Efficient elimination of Plasmodium liver stages prior to blood infection is one of the most promising malaria vaccine strategies. Here, we describe different genetically arrested parasites (GAPs) that have been engineered in Plasmodium berghei, P. yoelii and P. falciparum and compare their vaccine potential...
2017: Frontiers in Cellular and Infection Microbiology
https://read.qxmd.com/read/19115204/decreased-expression-of-angiogenesis-antagonist-efemp1-in-sporadic-breast-cancer-is-caused-by-aberrant-promoter-methylation-and-points-to-an-impact-of-efemp1-as-molecular-biomarker
#9
JOURNAL ARTICLE
Ariane Sadr-Nabavi, Juliane Ramser, Juliane Volkmann, Joerg Naehrig, Frank Wiesmann, Beate Betz, Heide Hellebrand, Stefanie Engert, Susanne Seitz, Rene Kreutzfeld, Takako Sasaki, Norbert Arnold, Rita Schmutzler, Marion Kiechle, Dieter Niederacher, Nadia Harbeck, Edgar Dahl, Alfons Meindl
EGF-containing fibulin-like extracellular matrix protein 1 (EFEMP1) was recently described as an antagonist of angiogenesis. Motivated by a strong dependence of tumor growth and metastasis on angiogenesis, we investigated the role of EFEMP1 in human breast cancer. We applied RNA microarray expression analysis and quantitative real-time PCR (QRT) in a total of 45 sporadic breast cancer tissues and found EFEMP1 down-regulation in 59% and 61% of the analyzed tissues, respectively. This down-regulation was confirmed on protein level...
April 1, 2009: International Journal of Cancer. Journal International du Cancer
https://read.qxmd.com/read/15586368/systematic-identification-and-molecular-characterization-of-genes-differentially-expressed-in-breast-and-ovarian-cancer
#10
MULTICENTER STUDY
Edgar Dahl, Ariane Sadr-Nabavi, Eva Klopocki, Beate Betz, Susanne Grube, Rene Kreutzfeld, Marina Himmelfarb, Han-Xiang An, Stephen Gelling, Irina Klaman, Bernd Hinzmann, Glen Kristiansen, Robert Grützmann, Ruprecht Kuner, Beate Petschke, Kerstin Rhiem, Kai Wiechen, Christine Sers, Otmar Wiestler, Achim Schneider, Heinz Höfler, Jörg Nährig, Manfred Dietel, Reinhold Schäfer, André Rosenthal, Rita Schmutzler, Matthias Dürst, Alfons Meindl, Dieter Niederacher
The identification of novel disease-associated genes in gynaecological tumours has important implications for understanding the process of tumourigenesis and the development of novel treatment regimens. cDNA libraries from disease tissues may represent a valuable source to identify such genes. Recently, a bio-informatic procedure based on an 'electronic Northern' approach was established to screen expressed sequence tag (EST) libraries for genes differentially expressed in tumour and normal tissues, and identified 450 candidate genes differentially expressed in breast and ovarian cancer...
January 2005: Journal of Pathology
https://read.qxmd.com/read/14518235/-modification-of-immune-response-after-polytrauma-and-cardiopulmonary-bypass-by-hematopoietic-growth-factors
#11
JOURNAL ARTICLE
S Flohé, J Börgermann, E Kreutzfelder, L Lim, R Flach, M Majetschak, U Obertacke, F U Schade
Cardiac surgery and polytrauma result in an impaired immune response as it can be demonstrated by a reduced endotoxin-stimulated TNF alpha production of whole blood cultures ex vivo. The immune-stimulating hematopoetic growth factor GM-CSF is in vitro capable to antagonize the suppressed immune function after trauma and cardiac surgery and, therefore, GM-CSF represents a potential therapeutic for immune suppressed states.
1998: Langenbecks Archiv Für Chirurgie. Supplement. Kongressband
https://read.qxmd.com/read/12794759/chromosomal-region-15q21-1-is-a-frequent-target-of-allelic-imbalance-in-advanced-breast-carcinomas
#12
JOURNAL ARTICLE
Kerstin Rhiem, Annette Klein, Miriam Münch, Rene Kreutzfeld, Juliane Ramser, Eva Wardelmann, Gabriele Schackert, Andreas Von Deimling, Otmar D Wiestler, Rita K Schmutzler
Allelic imbalance constitutes a major mechanism of genetic aberrations in breast cancer and strongly indicates the involvement of tumor associated genes in the affected chromosomal regions. Preliminary results from our study indicated the existence of a tumor suppressor gene located on chromosomal arm 15q which may be involved in breast cancer progression.1 In the present study, 210 primary breast carcinomas, 30 metastases and 26 local recurrences from primary breast carcinomas have been analyzed with a panel of 18 highly polymorphic microsatellite markers spanning the chromosomal region 15q11-21...
August 10, 2003: International Journal of Cancer. Journal International du Cancer
https://read.qxmd.com/read/11004663/tumor-derived-p53-mutant-c174y-is-a-gain-of-function-mutant-which-activates-the-fos-promoter-and-enhances-colony-formation
#13
JOURNAL ARTICLE
U Preuss, R Kreutzfeld, K H Scheidtmann
SV40 large T antigen-induced primitive neuroectodermal tumors of the rat provide a model system to study induction and progression of primitive neuroectodermal tumors at the molecular level. A cell line derived from such a tumor reproducibly gave rise to malignant derivatives that ceased large T-antigen expression but harbored a mutant p53 allele with a common mutation at Cys(174) to Tyr (C174Y). To determine whether this p53 mutation contributes to tumor progression, we analyzed mutant C174Y functionally. Co-transfection experiments in Saos-2 cells with mutant or wild-type p53 and reporter genes linked to various p53-responsive promoters revealed that mutant C174Y failed to transcriptionally transactivate the Mdm2, Waf1, Cyclin G and Bax promoters...
October 15, 2000: International Journal of Cancer. Journal International du Cancer
https://read.qxmd.com/read/9072870/-incidence-of-juvenile-onset-diabetes-in-denmark-a-prospective-registration-in-the-counties-of-fyn-ribe-s%C3%A3-nderjylland-and-vejle
#14
JOURNAL ARTICLE
A J Svendsen, J C Kreutzfeld, E B Lund, K O Kyvik, A Green
To provide contemporary figures of the incidence of childhood onset diabetes mellitus in Denmark, a prospective routine registration system has been established. The present study covered the population of children aged 0-14 years in four Danish counties, observed during the calendar years 1989 through 1993 concerning new cases of the disease. A total of 201 cases (113 boys and 88 girls) were registered, corresponding with a sex- and age-adjusted incidence rate of 17.4 per 100,000 person-years. Based on a validation analysis the study material is considered virtually complete...
February 24, 1997: Ugeskrift for Laeger
https://read.qxmd.com/read/6395598/-diagnosis-and-course-of-creutzfeldt-jakob-disease-clinico-pathologoanatomic-parallels
#15
JOURNAL ARTICLE
E G Orlova, L V Salimova
Long-term observations of five patients aged 40 to 70 years made it possible to diagnose Creutzfeld-Jacob's disease (CJD) in their life time. In three cases, the diagnosis of CJD was confirmed at autopsy; one patient died at home. The works of I. Kreutzfeld and A. Jacob and the authors' observations confirm that the disease lasts 4-5 years or more. Marked manifestations of the disease were observed for two years. Some differential diagnostic criteria are presented permitting the differentiation of CJD from other atrophic processes described by Alzheimer, Pick and others...
1984: Zhurnal Nevropatologii i Psikhiatrii Imeni S.S. Korsakova
https://read.qxmd.com/read/3974412/dexamethasone-and-zinc-in-combination-inhibit-the-anchorage-independent-growth-of-s-91-cloudman-murine-melanoma
#16
JOURNAL ARTICLE
K L Kreutzfeld, K Y Lei, M D Bregman, F L Meyskens
Zinc inhibited the colony formation of Cloudman S-91 murine melanoma cells in a dose dependent manner with an ID50 of 3.4 ug/ml. Total inhibition of the melanoma colony-forming units occurred at a zinc concentration of 4.42 ug/ml. In the presence of dexamethasone the ID50 for zinc inhibition was reduced by 49% and total inhibition of anchorage-independent growth occurred at the achievable in vivo zinc concentration of 3.0 ug/ml. Dexamethasone and zinc in combination effected a greater than additive inhibition of the murine melanoma colony-forming units...
March 4, 1985: Life Sciences
https://read.qxmd.com/read/3926559/stimulation-of-s91-melanoma-tyrosinase-activity-by-superpotent-alpha-melanotropins
#17
COMPARATIVE STUDY
M M Marwan, Z A Abdel Malek, K L Kreutzfeld, M E Hadley, B C Wilkes, V J Hruby, A M Castrucci
alpha-Melanocyte-stimulating hormone (alpha-MSH, alpha-melanotropin), [Nle4,D-Phe7]-alpha-MSH and related fragment analogues, Ac-[Nle4,D-Phe7]-alpha-MSH4-11-NH2 and Ac-[Nle4,D-Phe7]-alpha-MSH4-10-NH2, were studied for their ability to stimulate tyrosinase activity in Cloudman S91 mouse melanoma cells in tissue culture. All of the melanotropins stimulated tyrosinase activity in a dose-dependent manner. [Nle4,D-Phe7]-alpha-MSH was about 100 times more active than alpha-MSH as determined from the minimal effective dose (MED) required to activate the enzyme above control (basal) levels...
July 1985: Molecular and Cellular Endocrinology
https://read.qxmd.com/read/3266330/presence-of-pteridine-pigments-in-isolated-iridophores
#18
JOURNAL ARTICLE
J T Bagnara, K L Kreutzfeld, P J Fernandez, A C Cohen
No abstract text is available yet for this article.
1988: Pigment Cell Research
https://read.qxmd.com/read/3089218/potent-and-prolonged-melanotropic-activities-of-the-alpha-msh-fragment-analog-ac-nle4-d-phe7-alpha-msh4-9-nh2
#19
JOURNAL ARTICLE
D G Klemes, K L Kreutzfeld, M E Hadley, W L Cody, V J Hruby
Ac-[Nle4, D-Phe7]-alpha-MSH4-9-NH2 and Ac-[Nle4]-alpha-MSH4-9-NH2, fragment analogs of the tridecapeptide, alpha-melanocyte stimulating hormone (alpha-MSH, alpha-melanotropin), were synthesized. The potency and prolonged activity of the analogs were compared to alpha-MSH in several melanotropin bioassays. The D-Phe-containing hexapeptide was 10 times more active than alpha-MSH in stimulating melanoma tyrosinase activity. This analog was also 10-fold more potent than alpha-MSH in the lizard skin bioassay and about 10-fold less active in the frog skin bioassay...
June 13, 1986: Biochemical and Biophysical Research Communications
https://read.qxmd.com/read/3081484/long-term-and-residual-melanotropin-stimulated-tyrosinase-activity-in-s91-melanoma-cells-is-density-dependent
#20
JOURNAL ARTICLE
Z A Abdel Malek, K L Kreutzfeld, M E Hadley, M D Bregman, V J Hruby, F L Meyskens
Cell density is a factor that affects the capacity of Cloudman S91 melanoma cells to respond to melanotropins in monolayer culture. Continuous exposure of melanoma cells to alpha-melanotropin or its potent analog [Nle4, D-Phe7]-alpha-MSH, resulted in maximal stimulation of tyrosinase after 2 d of treatment, but the magnitude of stimulation decreased thereafter despite the continued presence of the melanotropins. However, when melanoma cells continually exposed to melanotropins were subcultured to an initial low cell density and maintained in contact with alpha-MSH or [Nle4, D-Phe7]-alpha-MSH (long-term culture), tyrosinase activity was rapidly restored and greatly enhanced...
February 1986: In Vitro Cellular & Developmental Biology: Journal of the Tissue Culture Association
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