Lieberman, J. Elevation of serum angiotensin-converting enzyme level in sarcoidosis. Am. J. Med. 1975, 59, 365–372. [ Google Scholar] [ CrossRef] Kost, O.A.; Grinshtein, S.V.; Nikolskaya, I.; Shevchenko, A.; Binevski, P.V. Purification of soluble and membrane forms of somatic angiotensin-converting enzyme by cascade affinity chromatography. Biochemistry 1997, 62, 321–328. [ Google Scholar] a b c Scott, Cavan; Wright, Mark (2013). Whoology: Doctor Who the Official Miscellany. BBC Books. pp.146–147. ISBN 9781849906197.

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] 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. Ace's relationship with the Doctor remains strained for some time, boiling over in Blood Heat when the Doctor destroys an unstable parallel Earth (where Manisha is still alive) and under the influence of an alien creature she stabs him through one of his hearts in The Left-Handed Hummingbird. In No Future (also by Cornell) the Meddling Monk tries to manipulate her into betraying the Doctor, which she seemingly does, again stabbing him and leaving him alone on an ice planet. In reality she stabbed him with a pantomime knife from the TARDIS wardrobe and she is playing her own game (partly to teach him what it feels like to be manipulated). When the Monk and his chained Chronovore offer her a chance to return Jan to life, she refuses and rejoins the TARDIS crew, her issues with the Doctor resolved. In Set Piece by Kate Orman, Ace becomes stranded in Ancient Egypt and comes to realise that she can survive without the Doctor, but that she also increasingly sees the world as he does. At the book's end she leaves the Doctor again to become Time's Vigilante, using a short-range time hopper mounted on a motorcycle to patrol a particular segment of time; in effect doing what the Doctor does, but on a smaller scale. She appears in later books, notably Head Games, Happy Endings, and Lungbarrow. Warner, Sam (31 May 2018). "Doctor Who spin-off Class returning at Big Finish". Digitalspy.com . Retrieved 6 October 2018.

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] 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] Petrov, M.N.; Shilo, V.Y.; Tarasov, A.V.; Schwartz, D.E.; Garcia, J.G.N.; Kost, O.A.; Danilov, S.M. Conformational changes of blood ACE in uremia. PLoS ONE 2012, 7, e49290. [ Google Scholar] [ CrossRef]

Sawahata, M.; Sugiyama, Y.; Nakamura, Y.; Nakayama, M.; Mato, N.; Yamasawa, H.; Bando, M. Age-related and historical changes in the clinical characteristics of sarcoidosis in Japan. Resp. Med. 2015, 109, 272–278. [ Google Scholar] [ CrossRef] [ PubMed] 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] 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]. Kumagai, A.; Ando, R.; Miyatake, H.; Greimel, P.; Kobayashi, T.; Hirabayashi, Y.; Shimogori, T.; Miyawaki, A. A bilirubin-inducible fluorescent protein from eel muscle. Cell 2009, 153, 1602–1611. [ Google Scholar] [ CrossRef] In 2018, Ace was confirmed to appear in Big Finish Production's audio drama based on Doctor Who spin-off Class, with Aldred reprising her role alongside the show's main cast. [13] The story released that August.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] Our data suggest that the source of circulating ACE is independent of lung capillaries. In line with that, the human heart was identified as an alternative source for circulating ACE. Additional ACE expressing and secreting cells can also be found in the apical surface of epithelial cells in the proximal tubule of kidney, the mucosa of small intestine, the syncytial trophoblast of placenta and the choroid plexus, in addition to various regions within the central nervous system [ 24]. Moreover, ACE was also found to be expressed by macrophages [ 33]. While the role of these potential ACE sources in the circulating ACE levels is unknown, it is well established that circulating ACE level increases in sarcoidosis [ 34]. We also confirmed elevated circulating ACE levels in patients with sarcoidosis and proposed that it can be used as a biomarker for sarcoidosis [ 27, 28]. Using a similar approach to ours, an independent study reported genotype-dependent ACE expression in the human heart [ 15] in full accordance with our findings in the present study, suggestive of a relationship between serum and cardiac ACE activities. Molecular Operating Environment (MOE), 2019.0101; Chemical Computing Group Inc.: Montreal, QC, Canada, 2019. 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].