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Lopez-Otin and Daley retract Nature Cell Biology paper

The 2015 Nature Cell Biology paper by the Spanish cancer researcher Carlos Lopez-Otin and his US partner George Q Daley, stem cell titan and dean of Harvard Medical School, is being retracted. First author and Lopez-Otin's student Clara Soria-Valles caused Daley even more trouble: her next groundbreaking paper was meant to be already published, but it is not even submitted and might never be.

Boom, the 2015 Nature Cell Biology paper by the famous, award-winning and now fugitive Spanish cancer and ageing researcher Carlos Lopez-Otin and his US partner George Q Daley, stem cell titan and dean of Harvard Medical School, is retracted. That happens because correct original data was unavailable, prompted by a prolonged debate on PubPeer (which in turn followed my reporting on Lopez-Otin’s data integrity practices), which established that the figures do not match what the authors deposited as supplement.

The paper Soria-Valles et al 2015 established the role of the transcription factor protein NF-kB in cellular senescence and cell reprogramming, while offering a potential cure to child patients suffering from the deadly premature ageing syndrome, such as Néstor–Guillermo or Hutchinson–Gilford progeria. Under this premise, the impactful Nature-themed paper earned Lopez-Otin in 2017 an ERC grant of €2.5 million, for a project named “Deconstructing Ageing: from molecular mechanisms to intervention strategies“. Earlier this year however, Lopez-Otin abandoned his ERC funded lab at University of Oviedo and escaped to Paris, to stay with his Photoshop expert friend Guido Kroemer. If past behaviour is anything to go by, ERC will now probably again play three monkeys and pretend that Lopez-Otin is still in Spain and his grant-deciding Nature Cell Biology paper was never retracted.

Another Soria-Valles et al paper from Daley lab, which proposed a way to produce haematopoietic stem cells via iPS technology and save people with leukaemia, was meant to be already published, but it is not even submitted and might never be. This and the retracted study’s first author Clara Soria-Valles was a former PhD student of Lopez-Otin, funded by EMBO postdoctoral fellowship and delegated to the Harvard labs of Daley and his junior partner Thorsten Schlaeger, to learn cellular reprogramming technique. Daley and Schlaeger are reported to be all but ready to apply the blood cell making technique in the clinic, at Boston Children’s Hospital, but now nobody knows if Soria-Valles’ preclinical data is anywhere near reproducible.

It is indeed difficult to find out what results still might be reliable. Soria-Valles disappeared already in April 2018 on a medical leave, though Daley still pays her (neither Daley nor Harvard normally pays any medical leaves for other sick lab members). Nobody else on that manuscript is available, because the Schlaeger lab people involved also left since. Money to try and reproduce it is not an issue though: the research project was funded from Daley’s biggest grant, the NHLBI Progenitor Cell Translational Consortium (NIH U01), which is worth almost $50 million.

Screenshot_2018-12-05 Blood stem cell breakthrough 'tantalizingly close'
Breakthrough manuscript as yet not even submitted to a journal. Screenshot: UBS

As I was informed, that Soria-Valles paper on haematopoietic reprogramming was meant to be originally submitted to the elite Cell family journal Cell Stem Cell (this is how the circulated draft was labelled in April 2018). Later on, roughly in August 2018, when my article appeared, the chosen target journal was Stem Cell Reports (published by International Society for Stem Cell Research, ISSCR). For someone like Daley this is a huge status reduction of journal venue. The results were presented earlier by Soria-Valles at the ISSCR annual meeting in 2017:

INTEGRATION-FREE SYSTEM FOR GENERATION OF HEMATOPOIETIC STEM AND PROGENITOR CELLS FROM HUMAN PLURIPOTENT STEM CELLS
Soria-Valles, Clara 1 , Sugimura, Ryohichi 1 , Kumar Jha, Deepak 1 , Lummertz da Rocha, Edroaldo 1 and Daley, George 2
1 Boston Children’s Hospital, Boston, MA, USA, 2 Stem Cell Program, Boston Children´s Hospital, Boston, MA, USA
The generation of hematopoietic stem cells (HSCs) from human pluripotent stem cells (PSCs) constitutes a valuable tool with promising applications for research and therapy. However, derivation of HSCs with in vivo long-term engraftment and multi-lineage potential remains elusive. We have described a combinatorial approach, based on the directed differentiation of hemogenic endothelium (HE) and transduction with five transcription factors (TF) (RUNX1, ERG, LCOR, HOXA5 and HOXA9) expressed in lentiviral vectors that allowed the conversion of human PSCs into hematopoietic stem
and progenitor cells (HSPCs). The resulted cells exhibited long-term and multi-lineage hematopoietic capabilities when injected into irradiated immune-deficient mice.
Despite this proof of principle, the engineered cells have a limited self-renewal capacity due to the integration of the transgenes and are still molecularly distinct from bona fide HSCs. Thus, in an attempt to achieve bona fide HSCs and make them safer for future therapeutic interventions, we have established integration-free systems that have shown comparable efficiency to the previously developed lentiviral strategy through in vitro and in vivo experiments. Therefore, this new method may overcome some limitations of the lentiviral approach and hold the key for future regenerative medicine advances in blood diseases.

Soria-Valles however was not present at the 2018 ISSCR meeting (a conference which I incidentally wrote about here, in a story about another dishonest stem cell researcher, who was set to be ISSCR 2018 keynote speaker). Nobody knows how much of Soria-Valles’ claim to make haematopoietic stem cells via iPS technology is still valid. Sources were quoted with estimates of too low a yield or even not sure of producing any haematopoietic stem cells at all. Yet just this September 2018, Daley spoke at a lecture at Dana-Farber-Institute of his future Stem Cell Reports paper and even of his plans to apply the method to treat paediatric patients with congenital bone marrow deficiencies, in particular Shwachman Diamond Syndrome and Diamond Blackfan Anemia.

Screenshot_2018-12-05 University of Oviedo - nueva terapia logra reprogramar envejecimiento celular - News
Press release by University of Oviedo. Photo shows Soria-Valles with her fiancée and co-author Fernando Garcia Osorio

But now back to the main subject, the Nature Cell Biology retraction. The journal warned readers on 4 October 2018 with an editorial note that “that the reliability of data presented in this manuscript has been the subject of criticisms“. 4 December 2018 was the deadline imposed by the publisher to submit signatures from co-authors for a retraction. Lopez-Otin’s Oviedo colleague Jose Maria Perez Freije collected the signatures of all authors, including the elusive Soria-Valles, and submitted them to the publisher Nature.

This is the retraction notice:

“We, the authors, are retracting this Article due to issues that have come to our attention regarding data availability, data description and figure assembly. Specifically, original numerical data are not available for the majority of the graphs presented in the paper. Although original data were available for most EMSA and immunoblot experiments, those corresponding to the published EMSA data of Supplementary Fig. 8a, the independent replicate immunoblots of Fig. 8b and Supplementary Fig. 1e, and the independent replicate EMSA data of Supplementary Figs 6e, 8b, 8c and 8d, are unavailable. Mistakes were detected in the presentation of Figs 3c, 4i and Supplementary Figs 6a, 8a, 8d, 9, and in some cases the β-actin immunoblots were erroneously described in the figure legends as loading controls, rather than as sample processing controls that were run on separate gels. Although we, the authors, believe that the key findings of the paper are still valid, given the issues with data availability we have concluded that the most appropriate course of action is to retract the Article. We deeply regret these errors and apologize to the scientific community for any confusion this publication may have caused. All authors agree with the retraction.”

This slide show illustrates the data issues mentioned in the retraction notice. 

This slideshow requires JavaScript.

And this slide show illustrates the issues the retraction notice chose not to address at all. 

This slideshow requires JavaScript.

In Daley’s lab, more things do not work as expected. His most famous Nature paper, Park et al 2008 , meant to compete with Shinya Yamanaka for induced pluripotency (iPS) fame and the Nobel Prize, is being plucked apart on PubPeer, accused of not having delivered any pluripotency as such. The exogenously delivered reprogramming transgenes remained namely active, while they were supposed to become silenced as cells’ own pluripotency genes become active. Also, Daley’s method of using Large T Antigen and telomerase TERT in addition to Yamanaka’s four iPS reprogramming factors proved rather counterproductive.

Whom to believe? A retracted Soria-Valles paper? Or Daley’s 2008 Nature paper which desperately wanted to prove better than Yamanaka’s iPS discovery? Source: PubPeer.

For someone like Daley, all of this is not the end of the world. There are always new windows of opportunity. Just as Chinese scientist Jiankui He caused a worldwide scandal with his unethical human experiments with CRISPR-modified babies, Daley (and his Harvard colleague George Church) offered a more enthusiastic view: America cannot afford a CRISPR gap to China. Daley suggested that Harvard should take the lead and apply CRISPR eugenics to ensure the survival of the human race:

“There have even been discussions that we as a species need to maintain the flexibility in the face of future threats to take the control of our own heredity.”

Harvard’s CRISPR experiments on human germ line editing are already starting. An Alzheimer’s associated gene is to be edited in human sperm, while Daley announced big plans to design the children of the future to be resistant to various diseases. Ethics is something this Harvard dean is apparently less interested in.

Harvard recently received a $200 million donation to set up a new institute, the money came from a controversial tycoon Leonard Blavatnik with Russian origins, whose lawyers made The Guardian apologise for erroneously calling him a “Putin pal” and an oligarch. 

It is Daley’s Spanish collaborator, the fugitive Lopez-Otin, who is in deep trouble with that retraction now. Lopez-Otin did manage to bring himself into news recently with his new paper (in a Nature -themed journal!) where his Oviedo lab analysed the genome of Lonesome George, the last member of his giant tortoise species who died in 2012. The press release omitted to say whether he spoke from Oviedo or Paris, Lopez-Otin the turtle geriatrics researcher was quoted with:

“We had previously described nine hallmarks of aging, and after studying 500 genes on the basis of this classification, we found interesting variants potentially affecting six of those hallmarks in giant tortoises, opening new lines for aging research” 

Nature now probably deeply regrets having awarded him with a 2017 Mentoring Award. Maybe they can give next one to Daley? Maybe Daley can get Soria-Valles to CRISPR some of those turtle genes to create a new long-lived human race of Homo harvardiensis crispri?


Update 21.12.2018. My article was apparently well received in Harvard, according to this information I was privy to:

“Daley was complaining intensely at lab meeting in front of entire lab and his junior faculty labs (Trista North and Thorsten Schlaeger) about potential lab members who might have leaked Soria-Valles information to the German blogger. It was intense”

I also learned that the now retracted Soria-Valles Nature Cell Biology 2015 paper was originally submitted to Science, were it was rejected due to some statistics issues.

Update 5.01.19. I was recently alerted by a source:

“George [Daley, -LS] has scared the lab members and provoked Stockholm syndrome among members. The Daley lab is trying to figure out who the leaks are now. Some of the members are trying to crash the German website by sending Hakenkreuz images.”

This was exactly what happened. Commenters used several fake identities to post highly defamatory comments about Daley on my site, equalling his research to Macchiarini’s trachea transplants and, indeed, using Nazi Swastika armband photoshopped on a photo of Daley. Exactly same picture was shared by Daley lab members in preparation of the campaign, it was confirmed to me. I deleted all those comments, but made backup, also of IP addresses.

Specifically, those IP addresses were located in US to Connecticut, 06902 Stamford, and New York State, 10022 New York. My source suggested I contact these Daley lab alumni: In-Hyun Park at Yale, CT, and Kitai Kim at MSKCC in NY, as well as the person allegedly orchestrating the campaign, the current Daley postdoc Deepak Jha. None of them replied, but Jha immediately blocked me on Twitter. This is how some grown men behave to please their mighty (ex-)boss. Maybe they should rather relax and read the book by Daley’s wife, Amy C. Edmondson, “The Fearless Organization: Creating Psychological Safety in the Workplace for Learning, Innovation, and Growth“.

Daley will be opening the Blavantik institute in ceremony on February 5th, at 5:30 PM. Come to talk about plans of CRISPR babies!

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204 comments on “Lopez-Otin and Daley retract Nature Cell Biology paper

    • Harvard Medical School Dean George Q. Daley failed to disclose competing financial interest with MPM capital @MPMCapital.
      Daley has been a partner and scientific advisor of MPM capital since 2003 till 2016 when he took Dean position. MPM capital invests in stem cells and cancer in which Daley lab research has focused. Example, MPM capital invests Daley’s latest company 28-7.
      The only paper in which Daley disclosed MPM COI was Nature 2010 (Kim et al.). “Competing interests. G.Q.D. is a member of the Scientific Advisory Boards of MPM Capital, Inc., Epizyme, Inc., and iPierian, Inc.”
      None of other papers around the time did (2003-2010).

      Like

  1. Elisabeth M Bik commented Harvard Medical School Dean George Daley on PubPeer.
    Intrestingly, two of earlier anonymous comments were censored.

    The Lin28/let-7 axis regulates glucose metabolism
    Cell (2011) – 5 Comments
    pubmed: 21962509 doi: 10.1016/j.cell.2011.08.033 issn: 1097-4172 issn: 0092-8674

    Hao Zhu , Ng Shyh-Chang , Ayellet V. Segrè , Gen Shinoda , Samar P. Shah , William S. Einhorn , Ayumu Takeuchi , Jesse M. Engreitz , John P. Hagan , Michael G. Kharas , Achia Urbach , James E. Thornton , Robinson Triboulet , Richard I. Gregory , David Altshuler , George Q. Daley , David Altshuler , George Q Daley

    https://pubpeer.com/publications/9FFA7E2C80B6F11BDF006C3E6A1C1D

    “Could the authors please clarify two Western blots that look very similar? From the description, they appear to represent different experiments, but it is not immediately clear.
    Figure 3D: “Western blot analysis of the effects of Lin28a overexpression on PI3K-mTOR signaling in C2C12 myoblasts, under serum-fed (fed), 18 hr serum starved (SS) or insulin-stimulated (Ins) conditions. Insulin stimulation was performed in serum-starved myoblasts with 10 mg/mL insulin for 5 min. Prior to insulin stimulation, serum-starved myoblasts were treated with either DMSO or 20 ng/mL rapamycin for 1 hr.”
    Figure 4D: “Western blot analysis of Lin28a, Irs2, and tubulin in C2C12 myoblasts with and without Lin28a overexpression” (nothing stated about rapamycin treatment, serum starvation, or insulin stimulation).
    The Lin28a (red boxes) and Tubulin panels (blue boxes) look unexpectedly similar. I would very much appreciate it if the authors could clarify if these were the same experiments.”

    “In addition, Figure 5A shows that differently treated mice appear to have a different size. The legend reads: “Rapamycin (left 2 mice) and vehicle (right 2 mice) treated wild-type and Lin28a Tg mice shows relative size differences.”
    However, it is a bit hard to see that the mice have different sizes, since the 2 photos appear to show a sharp transition in the middle. This is most notable looking at the hind paws of the mice, which appear to be cut off. Since the 4 mice shown here are shown in (what appears to be) 4 different photos, it is hard to judge if they are different in size. Could the authors please show us the complete, uncropped, unspliced photos?”

    Like

  2. Elisabeth M Bik commented Harvard Medical School Dean George Daley on PubPeer.
    Image duplication and potential intentional manipulation.

    Signaling axis involving Hedgehog, Notch, and Scl promotes the embryonic endothelial-to-hematopoietic transition
    Proceedings of the National Academy of Sciences (2013) – 1 Comment
    pubmed: 23236128 doi: 10.1073/pnas.1214361110 issn: 0027-8424 issn: 1091-6490

    Peter Geon Kim , Colleen E Albacker , Yi-fen Lu , I.-h. Jang , Yoowon Lim , Garrett C Heffner , Natasha Arora , Teresa V Bowman , Michelle I Lin , M William Lensch , Alejandro De Los Angeles , Leonard I Zon , Sabine Loewer , George Q Daley

    https://pubpeer.com/publications/1AEEA38E82AE9DB70C6B4EEB3871AC

    “Supplemental Figure 11A shows embryos at different developmental stages and treatments. However, two of the lateral views (shown in red boxes) and two dorsal view photos (shown with green boxes) appear to look very similar. Could the authors please clarify if these are showing the same embryos?
    Unexpectedly, with the dorsal views, part of the photos (green boxes) share similarities, but other parts do not.”

    Like

  3. Elisabeth M Bik commented Harvard Medical School Dean George Daley on PubPeer.
    Image duplication.

    Induction of multipotential hematopoietic progenitors from human pluripotent stem cells via respecification of lineage-restricted precursors
    Cell stem cell (2013) – 1 Comment
    pubmed: 24094326 doi: 10.1016/j.stem.2013.09.002 issn: 1934-5909 issn: 1875-9777

    Sergei Doulatov , Linda T. Vo , Stephanie S. Chou , Peter G. Kim , Natasha Arora , Hu Li , Brandon K. Hadland , Irwin D. Bernstein , James J. Collins , Leonard I. Zon , George Q. Daley

    https://pubpeer.com/publications/0CAD83E2393AC807F18A1246FF919E

    “Supplemental Figure 1D, SOX4 panel. The first 2 lanes look unexpectedly similar, and there is a sharp transition visible between them. Shown with red arrows. Image made darker to bring out details. Would the authors be so kind to explain if these 2 lanes were supposed to look similar?”

    Like

  4. Elisabeth M Bik commented Harvard Medical School Dean George Daley on PubPeer.
    Image duplication.

    Embryonic stem cell-derived hematopoietic stem cells
    Proceedings of the National Academy of Sciences (2005) – 1 Comment
    pubmed: 16357205 doi: 10.1073/pnas.0506127102 issn: 0027-8424 issn: 1091-6490

    Yuan Wang , Frank Yates , Olaia Naveiras , Patricia Ernst , George Q Daley

    https://pubpeer.com/publications/C3B95A2B8FB9250B3426F7140930CA

    “Could the authors please check Supporting Figure 10? The same FACS plot appears to be visible 4 times, and it is not clear from the description if they show the same experiment.
    Shown with red boxes.”

    Like

  5. Russian oligarch Blavatnik, a member of Harvard Medical School Board of Fellows, who donated $200 million to the same school, is a litmus test of ethics.

    Is Harvard Whitewashing a Russian Oligarch’s Fortune?

    “To be clear, Mr. Blavatnik is not accused of any crimes, in the United States or in Russia. But he is undoubtedly a Kremlin insider, someone who has made an enormous fortune trading on his political connections to a deeply corrupt circle of oligarchs and a criminal Russian state.

    Mr. Blavatnik is entitled to spend his money how he pleases. But institutions like the Hudson Institute and Harvard, which at least in principle stand for the ethical pursuit of knowledge, sully themselves by accepting it.”

    Like

  6. More comments on Harvard Medical School Dean George Daley.
    Image manipulation. This DNA fingerprint is the most important evidence to support their conclusion of making multiclonal hematopoietic stem cells from mouse ESCs. According to the paper, “Such clonal extinction, clonal succession, and lineage restriction is an expected feature of HSC dynamics”

    Embryonic stem cell-derived hematopoietic stem cells
    Proceedings of the National Academy of Sciences of the United States of America (2005) – 5 Comments
    pubmed: 16357205 doi: 10.1073/pnas.0506127102 issn: 0027-8424 issn: 1091-6490

    Yuan Wang , Frank Yates , Olaia Naveiras , Patricia Ernst , George Q Daley

    https://pubpeer.com/publications/C3B95A2B8FB9250B3426F7140930CA

    “Southern Blots in Fig. 5B has multiple splicings. The DNA fingerprint, in which native location of bands are crucial, is difficult to assess accurately. ”

    Like

  7. PubPeer reader pointed out an additional concern on Zhu et al. Cell (2011) paper from Harvard Medical School Dean George Daley.

    The Lin28/let-7 axis regulates glucose metabolism
    Cell (2011) – 7 Comments
    pubmed: 21962509 doi: 10.1016/j.cell.2011.08.033 issn: 1097-4172 issn: 0092-8674

    Hao Zhu , Ng Shyh-Chang , Ayellet V. Segrè , Gen Shinoda , Samar P. Shah , William S. Einhorn , Ayumu Takeuchi , Jesse M. Engreitz , John P. Hagan , Michael G. Kharas , Achia Urbach , James E. Thornton , Robinson Triboulet , Richard I. Gregory , David Altshuler , George Q. Daley , David Altshuler , George Q Daley

    https://pubpeer.com/publications/9FFA7E2C80B6F11BDF006C3E6A1C1D

    “#3 If figure 4D experiment is the same as figure 3D, the 2nd and 4th lanes have insulin, which phosphorylates IRS2 to cause its electrophoretic shift. However, IRS2 bands in figure 4D, except for minor shift in the 4th lane, do not show shifting.
    Reference. IRS2 shift after insulin exposure. https://www.ncbi.nlm.nih.gov/pubmed/14596677

    Like

  8. The Southern Blots from Harvard Medical School Dean George Daley contain more than a mere splicing.

    Embryonic stem cell-derived hematopoietic stem cells
    Proceedings of the National Academy of Sciences of the United States of America (2005) – 7 Comments
    pubmed: 16357205 doi: 10.1073/pnas.0506127102 issn: 0027-8424 issn: 1091-6490

    Yuan Wang , Frank Yates , Olaia Naveiras , Patricia Ernst , George Q Daley

    https://pubpeer.com/publications/C3B95A2B8FB9250B3426F7140930CA

    “Contrast adjusted figure 5B tells more than a mere splicing. For better detection, someone would do ImageJ eventually. And where is background of SBlot? ”

    Like

  9. More PubPeer comment on Wang Blot. Contrast adjustment revealed splicing. What’s more (worse), there was no background of blots. It implies that individual lane or even ‘unit of bands’ came separetely from different sources.

    Embryonic stem cell-derived hematopoietic stem cells
    Proceedings of the National Academy of Sciences of the United States of America (2005) – 8 Comments
    pubmed: 16357205 doi: 10.1073/pnas.0506127102 issn: 0027-8424 issn: 1091-6490

    Yuan Wang , Frank Yates , Olaia Naveiras , Patricia Ernst , George Q Daley

    https://pubpeer.com/publications/C3B95A2B8FB9250B3426F7140930CA

    Figure 5C with adjusted contrast.
    background of blots cannot be seen.
    splicing indicated by a box.

    Like

  10. More PubPeer comment on Wang Blot from the Daley lab. Comparison with the newer blotts produced in the same lab indicates that Wang Blot may have something going on.

    Embryonic stem cell-derived hematopoietic stem cells
    Proceedings of the National Academy of Sciences of the United States of America (2005) – 9 Comments
    pubmed: 16357205 doi: 10.1073/pnas.0506127102 issn: 0027-8424 issn: 1091-6490

    Yuan Wang , Frank Yates , Olaia Naveiras , Patricia Ernst , George Q Daley

    https://pubpeer.com/publications/C3B95A2B8FB9250B3426F7140930CA

    “Southern Blot analysis normaly gives certain background, like smear and spots. These spots and smear can be extended from lane to lane. Lu et al. 2016 from the same lab shows the clear example here. Note that some of big spots in lanes left M, 6th and right M are spreading over neighboring lanes. Saying that, could the authors provide uncropped blots of Wang et al. 2005 that had zero background? Initially I thought that the blots were developed in enough low exposure, so eliminated any chance of producing background (considering the technology level in 2005, it is hard to practice though). But there are actually certain smears left inside a lane, example in 3rd and 4th lanes of panel B, that these never spread to neighboring lanes.”

    Like

  11. M. William Lensch, who was involved in Gustavo German’s dispute, was demoted from the Chief of Staff of Harvard Medical School Dean Geroge Q. Daley. Now a lawyer whose expertise is handling Title IX replaced his position.
    https://hms.harvard.edu/about-hms/leadership

    Like

  12. Soria-Valles Nature Cell Biology paper, co-authored with Daley, both established and abolished the Mentor Award to Lopez-Otin.
    More papers of Lopez-Otin are under investigation.
    “we have alerted the journals concerned in the new cases.”

    https://retractionwatch.com/2019/09/25/nature-walks-back-mentorship-prize-for-spanish-scientist-with-nine-retractions/

    Like

  13. Pingback: Carlos Lopez-Otin and the revoked Nature Mentoring Award – For Better Science

  14. Cancer Res. 2005 Dec 15;65(24):11572-80.Novel role for PDEF in epithelial cell migration and invasion.Gunawardane RN1, Sgroi DC, Wrobel CN, Koh E, Daley GQ, Brugge JS.

    Author information1Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.

    Figure 5C. Much more similar than you would expect.

    Like

  15. Pingback: Losing research ethics and mental health in Daley lab – For Better Science

  16. Pingback: The Island of Dr Izpusua Belmonte – For Better Science

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