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In 2020, BBC Books published At Childhood's End ( ISBN 9781785944994), a novel by Aldred featuring Ace, decades after her travels with the Doctor and now running the "A Charitable Earth" charity. The novel also features the Thirteenth Doctor and her companions. Like the charity, the title of the novel forms the acronym "ACE". 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] 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] 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]
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. Another finding of this study is the endogenous regulation of ACE activity by inhibitors. The first results on potential endogenous inhibitors of ACE were reported as early as 1979 [ 35]. Later human results also suggested the existence of endogenous ACE inhibitors in the heart [ 36] as well as in the serum by identifying C-type natriuretic peptide [ 37]. Moreover, it was also shown that dilution can be a valuable tool to investigate the endogenous inhibition of ACE [ 38], suggesting that ACE is generally inhibited in rat tissues. Our previous reports on the endogenous inhibition of circulating ACE activity [ 17] by serum albumin [ 18] were confirmed in the present study. Applying the same technique, we observed a significantly higher endogenous inhibition (approximately 70%) in lung tissue than in blood. These ACE inhibitory levels were comparable in patients with and without ACE inhibitory medications, suggesting a negligible effect of the drug on tissue ACE activities. The concentration of human serum albumin is too low in the lung tissue samples to provide significant ACE inhibition [ 18], and thus, this implicates an alternative mechanism for ACE inhibition in the present study. These findings were in accordance to that found in the rat, suggesting at least 85% endogenous ACE inhibition in the lung [ 38]. Further studies are required to identify the molecular nature of the endogenous ACE inhibitor in human lung tissue.
McAlpine, Fraser (29 July 2011). "A Companion to the Doctor's Companions". Anglophenia. BBC America . Retrieved 28 April 2015. Danilov, S.M.; Tikhomirova, V.E.; Kryukova, O.V.; Balatsky, A.V.; Bulaeva, N.I.; Golukhova, E.Z.; Bokeria, L.A.; Samokhodskaya, L.M.; Kost, O.A. Conformational fingerprint of blood and tissue ACEs: Personalized approach. PLoS ONE 2018, 13, e0209861. [ Google Scholar] [ CrossRef]
Huber, A.H.; Zhu, B.; Kwan, T.; Kampf, J.P.; Hegyi, T.; Kleinfeld, A.M. Fluorescence sensor for the quantification of unbound bilirubin concentration. Clin. Chem. 2012, 58, 869–876. [ Google Scholar] [ CrossRef] [ PubMed] 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". In Tales of the TARDIS, Ace reunited with an aged Seventh Doctor and discussed their adventures. They also discussed the meeting with Fenric and both apologised to each other falling out. Danilov, S.; Savoie, F.; Lenoir, B.; Jeunemaitre, X.; Azizi, M.; Tarnow, L.; Alhenc-Gelas, F. Development of enzyme-linked immunoassays for human angiotensin I converting enzyme suitable for large-scale studies. J. Hypertens. 1996, 14, 719–727. [ Google Scholar] [ CrossRef] Lieberman, J.; Beutler, E. Elevation of angiotensin-converting enzyme in Gaucher’s disease. N. Engl. J. Med. 1976, 294, 1442–1444. [ Google Scholar] [ CrossRef]
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] 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] 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. According to a widely accepted consensus, ACE is expressed primarily by endothelial cells, particularly those of the lung [ 14], and subsequently released into the circulation. However, the human heart also expresses ACE [ 15], suggesting that the lung is probably not the only organ contributing to circulating ACE in humans. Moreover, levels of ACE expressions in kidneys and in small intestines were also found to be comparable to those in the lung [ 16].
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] The renin-angiotensin-aldosterone system (RAAS) plays a crucial role in the fluid and salt homeostasis. One of the key biochemical steps within the RAAS is conversion of the inactive angiotensin I decapeptide (AngI) to active angiotensin II (AngII) octapeptide by angiotensin converting enzyme (ACE). ACE was first identified in 1956 by Skeggs et al. [ 1], and ACE inhibitors were subsequently introduced in clinical practice. They represent a first line therapy for a wide range of cardiovascular maladies, including hypertension [ 2, 3] and heart failure [ 4]. It is important to note that AngII generation by ACE is reversed by its isoform ACE2 (which eliminates AngII). Therefore, the physiological level of AngII is usually determined by the balance between ACE and ACE2 activities in tissues. This balance is important in cardiovascular diseases [ 5, 6, 7], and also in COVID-19. Regarding the latter, ACE2 is the cellular receptor for the SARS-CoV-2 [ 8] and it is proposed that some symptoms of COVID-19 are mediated by disrupted ACE/ACE2 balance [ 9, 10]. Ace appeared in ten stories (32 episodes), and was the final companion in the original run of the classic series. [6] Alhenc-Gelas, F.; Richard, J.; Courbon, D.; Warnet, J.M.; Corvol, P. Distribution of plasma angiotensin I-converting enzyme levels in healthy men: Relationship to environmental and hormonal parameters. J. Lab. Clin. Med. 1991, 117, 33–39. [ Google Scholar] Vlaming, M.L.; Pala, Z.; van Esch, A.; Wagenaar, E.; de Waart, D.R.; van de Wetering, K.; van der Kruijssen, C.M.; Oude Elferink, R.P.; van Tellingen, O.; Schinkel, A.H. Functionally overlapping roles of Abcg2 (Bcrp1) and Abcc2 (Mrp2) in the elimination of methotrexate and its main toxic metabolite 7-hydroxymethotrexate in vivo. Clin. Cancer Res. 2009, 15, 3084–3093. [ Google Scholar] [ CrossRef] [ PubMed]
Ching, S.F.; Hayes, L.W.; Slakey, L.L. Angiotensin-converting enzyme in cultured endothelial cells. Synthesis, degradation, and transfer to culture medium. Arteriosclerosis 1983, 3, 581–588. [ Google Scholar] [ CrossRef] [ PubMed] 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] Ace was also featured in the Doctor Who Magazine comic strip sporadically, one of the few television companions to appear in it. This prospective study was done involving patients with lung surgeries at the clinical ward of the University of Debrecen and patients undergoing heart transplantation at the Heart and Vascular Center at Semmelweis University, Budapest. The study was authorized by the Medical Research Council of Hungary (20753-7/2018/EÜIG for patients undergoing lung surgery and ETT TUKEB 7891/2012/EKU (119/PI/12.) for patients with heart transplantation). Tissue and blood samples were obtained from patients undergoing thoracic-surgical interventions (lung samples) or heart transplantation (pseudonymized explanted heart samples from the left ventricular anterior wall and blood plasma samples were obtained from the Transplantation Biobank of the Heart and Vascular Center at Semmelweis University, Budapest, Hungary). All enrolled patients gave their individual informed consents according to the Declaration of Helsinki.McDonagh, A.F.; Vreman, H.J.; Wong, R.J.; Stevenson, D.K. Photoisomers: Obfuscating factors in clinical peroxidase measurements of unbound bilirubin? Pediatrics 2009, 123, 67–76. [ 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. Watchko, J.F.; Tiribelli, C. Bilirubin-induced neurologic damage-mechanisms and management approaches. N. Engl. J. Med. 2013, 369, 2021–2030. [ Google Scholar] [ CrossRef] A promotional video made to advertise the Blu-ray release of Doctor Who's twenty-sixth season shows Ace as the head of A Charitable Earth. [11]
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