Lieberman, J.; Beutler, E. Elevation of angiotensin-converting enzyme in Gaucher’s disease. N. Engl. J. Med. 1976, 294, 1442–1444. [ Google Scholar] [ CrossRef] Collis, Clark (17 April 2022). "The trailer for Jodie Whittaker's final episode of 'Doctor Who' reveals returning cast members". Entertainment Weekly . Retrieved 17 April 2022. a b c Scott, Cavan; Wright, Mark (2013). Whoology: Doctor Who the Official Miscellany. BBC Books. pp.146–147. ISBN 9781849906197. Samokhodskaya, L.M.; Jain, M.S.; Kurilova, O.V.; Bobkov, A.P.; Kamalov, A.A.; Dudek, S.M.; Danilov, S.M. Blood ACE phenotyping: A necessary approach for precision medicine. J. Appl. Lab. Med. 2021, 6, 1179–1191. [ Google Scholar] [ CrossRef]

Other spin-off media give contradictory versions of Ace's eventual fate. The comic strip in Doctor Who Magazine has Ace killed off just prior to the events of the 1996 television movie ( Ground Zero, DWM #238-#242). In the webcast audio play Death Comes to Time, Ace inherits the mantle of the Time Lords when they become extinct. Molecular Operating Environment (MOE), 2019.0101; Chemical Computing Group Inc.: Montreal, QC, Canada, 2019. If the series had continued, the production team's intent was to have Ace eventually enter the Prydonian Academy on the Doctor's home planet of Gallifrey and train to be a Time Lord. [7] The story Ice Time by Marc Platt, in which this would happen, was never made. [10] When the Seventh Doctor is next seen in the 1996 Doctor Who television movie, he is travelling alone, with no reference made as to what had happened to Ace. [8] In " The Power of the Doctor" (2022), it is said that Ace and the Doctor had some sort of "fallout" which led to her leaving, although what exactly happened is never clarified. Danilov, S.M.; Tikhomirova, V.E.; Metzger, R.; Naperova, I.A.; Bukina, T.M.; Goker-Alpan, O.; Tayebi, N.; Gayfullin, N.M.; Schwartz, D.E.; Samokhodskaya, L.M.; et al. ACE phenotyping in Gaucher disease. Mol. Genet Metab. 2018, 123, 501–510. [ Google Scholar] [ CrossRef] Stec, D.E.; John, K.; Trabbic, C.J.; Luniwal, A.; Hankins, M.W.; Baum, J.; Hinds, T.D., Jr. Bilirubin binding to PPARα inhibits lipid accumulation. PLoS ONE 2016, 11, e0153427. [ Google Scholar] [ CrossRef] [ PubMed]

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McDonagh, A.F. Ex uno plures; the concealed complexity of bilirubin species in the neonatal blood samples. Pediatrics 2006, 118, 1185–1187. [ Google Scholar] [ CrossRef] [ PubMed] Danilov, S.M.; Gordon, K.; Nesterovitch, A.B.; Lünsdorf, H.; Chen, Z.; Castellon, M.; Popova, I.A.; Kalinin, S.; Mendonca, E.; Petukhov, P.A.; et al. An angiotensin I-converting enzyme mutation (Y465D) causes a dramatic increase in blood ACE via accelerated ACE shedding. PLoS ONE 2011, 6, e25952. [ Google Scholar] [ CrossRef] [ PubMed]

Ace appeared in ten stories (32 episodes), and was the final companion in the original run of the classic series. [6] Metzger, R.; Franke, F.; Bohle, R.-M.; Alhenc-Gelas, F.; Danilov, S.M. Heterogeneous distribution of Angiotensin I-converting enzyme (CD143) in the human and rat vascular systems: Vessels, organs and species specificity. Microvasc. Res. 2011, 82, 206–215. [ Google Scholar] [ CrossRef] [ PubMed] Using this genotype-dependent expression pattern as a tracer, we tested if the primary source of circulating ACE is the lung in humans. To do so, we tested ACE levels in serum and lung samples of the same patients in parallel, using techniques developed in our laboratory in the past years [ 17, 18, 20, 27, 28]. Patients with the DD genotype had significantly higher circulating ACE concentrations and activities than patients with the ACE II genotype, while patients with the ACE ID genotype showed intermediate values confirming earlier reports. However, we did not find any correlation of lung tissue ACE expression or activity with the ACE I/D genotype. This finding suggests that ACE expression in the lungs is independent of ACE I/D genotype, and consequently, the genotype-dependent serum ACE secretion must have an alternative source of ACE.

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A recent report on lung ACE reported tissue ACE expression decreases in lung cancer [ 23]. Indeed, a negative correlation between lung cancer and circulating ACE activity was shown half a century ago, in a limited number of patients [ 32]. This study suggested that if lung microcapillaries are being lost in the tumor, then circulating ACE activities will decline. However, none of the previous studies attempted to directly test the relationships between circulating and lung tissue ACE expressions. To the best of our knowledge, this report is the first to do so in a fairly large human population. However, in The Sarah Jane Adventures story Death of the Doctor, Sarah Jane reveals to her companions that she has done research on some of the Doctor's companions. She mentions "that Dorothy something — she runs that charity, 'A Charitable Earth' ("ACE"). She's raised billions." [8] In the same episode, the Eleventh Doctor reveals that his Tenth incarnation looked in on each of his former companions as he prepared for regeneration at the end of " The End of Time". Ahlfors, C.E.; Vreman, H.J.; Wong, R.J.; Bender, G.J.; Oh, W.; Morris, B.H.; Stevenson, D.K.; Subcommittee, T.P. Effects of sample dilution, peroxidase concentration, and chloride ion on the measurement of unbound bilirubin in premature newborns. Clin. Biochem. 2007, 40, 261–267. [ Google Scholar] [ CrossRef] What the Doctor is aware of, but Ace is not, is that her arrival on Iceworld was no accident but part of a larger scheme stretching across the centuries and conceived by Fenric, [6] an evil that had existed since the beginning of the universe. Ace is a "Wolf of Fenric", one of many descendants of a Norseman tainted with Fenric's genetic instructions to help free it from its ancient prison so it can evolve humans into the Vampiric Haemovores, and a pawn in the complex game between it and the Doctor. After Fenric is defeated in 1943, Ace continues to journey with the Doctor. [7] At one point in the story, Ace offers to distract a guard so that the Doctor can free a prisoner. When the Doctor asks how she plans to divert the guard's attention she replies that she is "not a little girl". She proceeds to lead the guard away from his post by intriguing him with a combination of slightly suggestive innuendo towards the guard and cryptic musings about the Doctor's machinations. The scene suggests that she is aware of both her developed sexuality and the Doctor's manipulative tendencies. Wennberg, R.P.; Ahlfors, C.E.; Bhutani, V.K.; Johnson, L.H.; Shapiro, S.M. Toward understanding kernicterus: A challenge to improve the management of jaundiced newborns. Pediatrics 2006, 117, 474–485. [ Google Scholar] [ CrossRef]