# CMAH

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{{Short description|Pseudogene in humans}}
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{{Infobox_gene}}
'''Cytidine monophospho-''N''-acetylneuraminic acid hydroxylase''' ('''Cmah''') is an [enzyme](/source/enzyme) that is encoded by the '''''CMAH''''' [gene](/source/gene).<ref name="pmid76082182">{{cite journal | vauthors = Kawano T, Koyama S, Takematsu H, Kozutsumi Y, Kawasaki H, Kawashima S, Kawasaki T, Suzuki A | title = Molecular cloning of cytidine monophospho-N-acetylneuraminic acid hydroxylase. Regulation of species- and tissue-specific expression of N-glycolylneuraminic acid | journal = The Journal of Biological Chemistry | volume = 270 | issue = 27 | pages = 16458–63 | date = July 1995 | pmid = 7608218 | doi = 10.1074/jbc.270.27.16458 | doi-access = free }}</ref><ref name="pmid96241882">{{cite journal | vauthors = Irie A, Koyama S, Kozutsumi Y, Kawasaki T, Suzuki A | title = The molecular basis for the absence of N-glycolylneuraminic acid in humans | journal = The Journal of Biological Chemistry | volume = 273 | issue = 25 | pages = 15866–71 | date = June 1998 | pmid = 9624188 | doi = 10.1074/jbc.273.25.15866 | doi-access = free }}</ref><ref name="entrez2">{{cite web|url=https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=8418|title=Entrez Gene: CMAH cytidine monophosphate-N-acetylneuraminic acid hydroxylase (CMP-N-acetylneuraminate monooxygenase)}}</ref> In most mammals, the enzyme [hydroxylates](/source/Hydroxylation) [N-acetylneuraminic acid](/source/N-Acetylneuraminic_acid) (Neu5Ac), producing [N-glycolylneuraminic acid](/source/N-Glycolylneuraminic_acid) (Neu5Gc).<ref name="pmid96241882" /> [Neu5Ac](/source/N-Acetylneuraminic_acid) and [Neu5Gc](/source/N-Glycolylneuraminic_acid) are mammalian glycans that compose the [glycocalyx](/source/glycocalyx), especially in [sialoglycoprotein](/source/sialoglycoprotein)s, which are part of the [sialic acid](/source/sialic_acid) family.<ref name="Kwon_2014">{{cite journal | vauthors = Kwon DN, Chang BS, Kim JH | year = 2014| title = Gene Expression and Pathway Analysis of Effects of the CMAH Deactivation on Mouse Lung, Kidney and Heart | journal = PLOS ONE | volume = 9 | issue = 9| pages = 1–13 | doi = 10.1371/journal.pone.0107559 | pmid = 25229777| pmc = 4167996| bibcode = 2014PLoSO...9j7559K| doi-access = free }}</ref> The ''CMAH'' equivalent in humans is a [pseudogene](/source/pseudogene) (CMAHP);<ref>{{Cite web|url=https://www.ncbi.nlm.nih.gov/gene/8418|title=CMAHP cytidine monophospho-N-acetylneuraminic acid hydroxylase, pseudogene [Homo sapiens (human)]|date=12 Oct 2019|website=NCBI GenBank}}</ref> there is no detectable Neu5Gc in normal human tissue.<ref name="pmid96241882" /> This deficiency has a number of proposed effects on humans, including increased brain growth,<ref name="pmid121920862">{{cite journal | vauthors = Chou HH, Hayakawa T, Diaz S, Krings M, Indriati E, Leakey M, Paabo S, Satta Y, Takahata N, Varki A | title = Inactivation of CMP-N-acetylneuraminic acid hydroxylase occurred prior to brain expansion during human evolution | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 18 | pages = 11736–41 | date = September 2002 | pmid = 12192086 | pmc = 129338 | doi = 10.1073/pnas.182257399 | bibcode = 2002PNAS...9911736C | doi-access = free }}</ref> improved self-recognition by the human [immune system](/source/immune_system),<ref name="ajpa100182">{{cite journal | vauthors = Varki A | title = Loss of N-glycolylneuraminic acid in humans: Mechanisms, consequences, and implications for hominid evolution | journal = American Journal of Physical Anthropology | volume = Suppl 33 | pages = 54–69 | year = 2001 | issue = Suppl | pmid = 11786991 | pmc =7159735  | doi = 10.1002/ajpa.10018 }}</ref> and susceptibility to [atherosclerosis](/source/atherosclerosis).<ref name=pnas1902902116>{{cite journal | vauthors = Kawanishi K, Dhar C, Do R, Varki N, Gordts PL, Varki A | title = Human species-specific loss of CMP-''N''-acetylneuraminic acid hydroxylase enhances atherosclerosis via intrinsic and extrinsic mechanisms | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 116 | issue = 32 | pages = 16036–16045 | date = August 2019 | pmid = 31332008 | doi = 10.1073/pnas.1902902116 | doi-access = free | pmc = 6690033 }}</ref> Incorporation of Neu5Gc from red meat and dairy into human tissues has been linked to chronic disease, including [type-2 diabetes](/source/Type_2_diabetes) and [chronic inflammation](/source/chronic_inflammation).<ref name="Padler-Karavani_2008" /><ref name="pnas09146341072" />

== Discovery ==

The [biosynthesis](/source/biosynthesis) pathway of Neu5Gc from Neu5Ac was discovered by Shaw and Schauer in 1988,<ref name="Shaw_1988">{{cite journal | vauthors = Shaw L, Schauer R | title = The biosynthesis of N-glycoloylneuraminic acid occurs by hydroxylation of the CMP-glycoside of N-acetylneuraminic acid | journal = Biological Chemistry Hoppe-Seyler | volume = 369 | issue = 6 | pages = 477–86 | date = June 1988 | pmid = 3202954 | doi = 10.1515/bchm3.1988.369.1.477 }}</ref> while the [protein](/source/Protein_primary_structure) and [DNA sequences](/source/Nucleic_acid_sequence) for Neu5Gc, Neu5Ac, and ''CMAHP'' were described by Irie ''et al''. in 1998.<ref name="pmid96241882" />

== Function in other mammals ==
Sialic acids such as Neu5Ac and Neu5Gc are terminal components of the carbohydrate chains of [glycoconjugate](/source/glycoconjugate)s involved in [ligand–receptor](/source/Ligand), [cell–cell](/source/Cell%E2%80%93cell_interaction), and cell–pathogen interactions.<ref name="pmid76082182" /> Neu5Gc has been shown to be involved in a variety of processes in mice, including [protein metabolism](/source/protein_metabolism), [signal transduction](/source/signal_transduction), [metabolism](/source/metabolism) of most organic molecules, and immunity.<ref name="Kwon_2014" />

=== Cat AB blood group ===
{{See also|Blood type (non-human)}}
The [blood type](/source/blood_type) for a cat is mostly covered by the AB blood group system, determined by the CMAH alleles a cat possess. The majority A type seems to be dominant over the recessive B type, which is only found with a higher frequency in some breeds. An "AB" type seems to be expressed by a third recessive allele.<ref>{{cite journal | vauthors = Bighignoli B, Niini T, Grahn RA, Pedersen NC, Millon LV, Polli M, Longeri M, Lyons LA | title = Cytidine monophospho-N-acetylneuraminic acid hydroxylase (CMAH) mutations associated with the domestic cat AB blood group | journal = BMC Genetics | volume = 8 | page = 27 | date = June 2007 | pmid = 17553163 | pmc = 1913925 | doi = 10.1186/1471-2156-8-27 | doi-access = free }}</ref>

== Function in humans ==
Neu5Gc has been found in normal human tissue, with larger amounts found in fetal<ref name="ajpa100182" /> and cancerous<ref name="Malykh_2001">{{cite journal | vauthors = Malykh YN, Schauer R, Shaw L | year = 2001 | title = N-Glycolylneuraminic Acid in Human Tumours | journal = Biochimie | volume = 83 | issue = 7| pages = 623–34 | doi = 10.1016/s0300-9084(01)01303-7 | pmid = 11522391 }}</ref> tissues. Studies suggest that Neu5Gc could be an excellent cancer cell marker.<ref name="Malykh_2001" /> Since Neu5Gc can only be made by functional ''CMAH,'' which is not present in humans, researchers have searched for alternative sources of Neu5Gc in humans.<ref name="Tangvoranuntakul_2003">{{cite journal | vauthors = Tangvoranuntakul P, Gagneux P, Diaz S, Bardor M, Varki N, Varki A, Muchmore E | title = Human uptake and incorporation of an immunogenic nonhuman dietary sialic acid | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 100 | issue = 21 | pages = 12045–50 | date = October 2003 | pmid = 14523234 | pmc = 218710 | doi = 10.1073/pnas.2131556100 | bibcode = 2003PNAS..10012045T | doi-access = free }}</ref> Current research indicates that Neu5Gc is incorporated into human tissues through consumption of red meats and dairy.<ref name="Tangvoranuntakul_2003" /><ref name="Padler-Karavani_2008">{{cite journal | vauthors = Padler-Karavani V, Yu H, Cao H, Chokhawala H, Karp F, Varki N, Chen X, Varki A | title = Diversity in specificity, abundance, and composition of anti-Neu5Gc antibodies in normal humans: potential implications for disease | journal = Glycobiology | volume = 18 | issue = 10 | pages = 818–30 | date = October 2008 | pmid = 18669916 | doi = 10.1093/glycob/cwn072 | pmc = 2586336 | doi-access = free }}</ref> This incorporation process involves [macropinocytosis](/source/Pinocytosis), delivery to the [lysosome](/source/lysosome), and export of free Neu5Gc to the [cytosol](/source/cytosol) via the sialin transporter.<ref name="Tangvoranuntakul_2003" /><ref name="pnas09146341072">{{cite journal | vauthors = Varki A | title = Colloquium paper: uniquely human evolution of sialic acid genetics and biology | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 Suppl 2 | issue = suppl. 2 | pages = 8939–46 | date = May 2010 | pmid = 20445087 | pmc = 3024026 | doi = 10.1073/pnas.0914634107 | bibcode = 2010PNAS..107.8939V | doi-access = free }}</ref>

Because Neu5Gc differs from Neu5Ac by only one oxygen, it is handled like a native sialic acid by human [biochemical pathways](/source/Metabolic_pathway).<ref name="pnas09146341072" /> The immune system does not work the same way, however; all humans have varying amounts of a diverse spectrum of anti-Neu5Gc antibodies.<ref name="Padler-Karavani_2008" /> If Neu5Gc is constantly being incorporated into tissues due to a diet heavy in red meats and dairy, anti-Neu5Gc antibodies cause chronic inflammation, especially in blood vessels and the linings of hollow organs.<ref name="Padler-Karavani_2008" /> These sites are also common places for [atherosclerosis](/source/atherosclerosis) and [epithelial carcinomas](/source/Carcinoma), both of which are associated with red meat and dairy consumption and are aggravated by chronic inflammation.<ref name="s107192">{{cite journal | vauthors = Varki A | s2cid = 13169985 | title = Multiple changes in sialic acid biology during human evolution | journal = Glycoconjugate Journal | volume = 26 | issue = 3 | pages = 231–45 | date = April 2009 | pmid = 18777136 | pmc =7087641  | doi = 10.1007/s10719-008-9183-z }}</ref> Red meat ingestion and chronic inflammation have also been associated with diseases like type-2 diabetes and age-dependent [macular degeneration](/source/macular_degeneration), so Neu5Gc may be linked to the development of these disorders as well.<ref name="Padler-Karavani_2008" /><ref name="pnas09146341072" />

Recent data suggests that the [hypoxic](/source/Hypoxia_(medical)) conditions in [carcinoma](/source/carcinoma)s can up-regulate the expression of the lysosomal sialic acid transporter necessary for Neu5Gc incorporation into human tissues.<ref name="s107192" /><ref name="pnas09146341072" /> In addition, [growth factor](/source/growth_factor)s may activate enhanced macropinocytosis, which can increase Neu5Gc incorporation.<ref name="pnas09146341072" /> Studies have shown that fetal tissues are also capable of taking up Neu5Gc from maternal dietary sources, which may explain elevated levels of Neu5Gc in the human fetus.<ref name="s107192" />

The presence of Neu5Gc in various [biotherapeutic](/source/biotherapeutic)s derived from animal products may impact human health and is still being studied.<ref name="Padler-Karavani_2008" /> Some complications could include [immune hypersensitivity reactions](/source/Immune_hypersensitivity), reduced [half-life](/source/half-life) of the biotherapeutic in circulation, [immune complex](/source/immune_complex) formation, increase of Neu5Gc antibody concentration, enhanced [immunoreactivity](/source/immunoreactivity) against the biotherapeutic polypeptide, and directly loading more Neu5Gc into tissues.<ref name="s107192" />

=== Animal model ===
Mice with ''Cmah'' knocked out display many human-like traits when it comes to running endurance<ref name="Okerblom_2018" /> and cardiovascular vulnerabilities, especially in reaction to the consumption of red meat. Knockout mice do not automatically generate anti-Neu5Gc antibodies, however; this is thought to be due to a lack of stimulation from bacteria that have taken Neu5Gc into their [lipopolysaccharide](/source/lipopolysaccharide) shell, which naturally happens in humans. Manual immunization with Neu5Gc-laden red blood cells is required to generate these kind of antibodies.<ref name=pnas1902902116/>

== Evolution ==
Genomic analyses indicate that ''CMAH'' genes are present only in [deuterostome](/source/deuterostome)s, some unicellular [algae](/source/algae) and some [bacteria](/source/bacteria).<ref name="Peri_2018">{{cite journal | vauthors = Peri S, Kulkarni A, Feyertag F, Berninsone PM, Alvarez-Ponce D | title = Phylogenetic Distribution of CMP-Neu5Ac Hydroxylase (CMAH), the Enzyme {{sic|nolink=y|reason=error in source|Synthetizing}} the Proinflammatory Human Xenoantigen Neu5Gc | journal = Genome Biology and Evolution | volume = 10 | issue = 1 | pages = 207–219 | date = January 2018 | pmid = 29206915 | pmc = 5767959 | doi = 10.1093/gbe/evx251 }}</ref> ''CMAH'' relatives have been lost in many other deuterostome lineages, including [tunicate](/source/tunicate)s, many groups of fish, the [axolotl](/source/axolotl), most reptiles, and all birds.<ref name="Peri_2018" /> Among mammals, the gene is missing or nonfunctional in New World monkeys, the European hedgehog, ferrets, some bats, the sperm whale, and the platypus.<ref name="Peri_2018" /> These animals lacking a functional ''CMAH'' gene do not express Neu5Gc.<ref name="Peri_2018" />

=== Human evolution ===
The absence of Neu5Gc in humans is due to a 92-bp [deletion](/source/Deletion_(genetics)) of an [exon](/source/exon) of the human gene ''CMAH''.<ref name="pmid96241882" /> Sequences encoding mouse, pig, and chimpanzee ''CMAH'' have been examined using [cDNA](/source/Complementary_DNA) cloning techniques and were found to be highly similar.<ref name="Peri_2018" /> However, the [homologous](/source/Homology_(biology)) human cDNA differs from these cDNAs by a 92-bp deletion in the 5' region.<ref name="Peri_2018" /> This deletion, corresponding to exon 5 of the mouse hydroxylase gene, causes a [frameshift mutation](/source/frameshift_mutation) and premature termination of the [polypeptide chain](/source/polypeptide_chain) in humans.<ref name="pmid96241882" /> Neu5Gc seems to be undetectable in human tissues because the truncated version of human hydroxylase [mRNA](/source/Messenger_RNA) cannot encode for an active enzyme.<ref name="Shaw_1988" />

The deletion that deactivated this gene occurred approximately 3.2 [mya](/source/Mya_(unit)), after the divergence of humans from the African [great apes](/source/great_apes), and quickly swept to [fixation](/source/Fixation_(population_genetics)) in the human population.<ref name="pmid121920862" />  The lineage of this pseudogene in humans indicates another deep split in Africa dating to 2.9 mya, with a complex subsequent history.<ref name="pmid121920862" />

[Sexual selection](/source/Sexual_selection) may have contributed to the fixation of nonfunctional ''CMAH'' in humans.<ref name="Ghaderi_2011">{{cite journal | vauthors = Ghaderi D, Springer SA, Ma F, Cohen M, Secrest P, Taylor RE, Varki A, Gagneux P | year = 2011 | title = Sexual Selection by Female Immunity against Paternal Antigens Can Fix Loss of Function Alleles | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 108 | issue = 43| pages = 17743–48 | doi = 10.1073/pnas.1102302108 | pmid = 21987817 | pmc = 3203784 | bibcode = 2011PNAS..10817743G | doi-access = free }}</ref> This hypothesis has been tested in mice, with females carrying nonfunctional ''CMAH'' exhibiting reproductive incompatibility with males carrying functional ''CMAH'' due to anti-Neu5Gc [antibodies](/source/Antibody) migrating to the female reproductive tract and destroying Neu5Gc-positive sperm.<ref name="Ghaderi_2011" />

==== Implications for human evolution ====
Pseudogenes such as ''CMAH'' can be used to study [allele](/source/allele) fixation and [demographic history](/source/demographic_history).<ref name="Hayakawa_2005">{{cite journal | vauthors = Hayakawa T, Aki I, Varki A, Satta Y, Takahata N | year = 2005| title = Fixation of the Human-Specific CMP-N-Acetylneuraminic Acid Hydroxylase Pseudogene and Implications of Haplotype Diversity for Human Evolution | journal = Genetics | volume = 172 | issue = 2| pages = 1139–46 | doi = 10.1534/genetics.105.046995 | pmid = 16272417 | pmc = 1456212 }}</ref> Analyses of ''CMAH'' [haplotype](/source/haplotype) diversity have been used to examine human demographic history during the [Plio-Pleistocene](/source/Plio-Pleistocene).<ref name="Hayakawa_2005" />

The functional loss of ''CMAH'' after the divergence of humans from the great apes has several implications for its role in human development, including less constrained brain growth and increased running endurance, two traits thought to be important to human evolution.<ref name="pmid121920862" /><ref name="Okerblom_2018">{{cite journal | vauthors = Okerblom J, Fletes W, Patel HH, Schenk S, Varki A, Breen EC | year = 2018| title = Human-like Cmah Inactivation in Mice Increases Running Endurance and Decreases Muscle Fatigability: Implications for Human Evolution | journal = Proceedings of the Royal Society B: Biological Sciences | volume = 285 | issue = 1886| article-number = 20181656 | doi = 10.1098/rspb.2018.1656 | pmid = 30209232| pmc = 6158528| doi-access = free }}</ref> In most mammals, ''CMAH'' [expression](/source/Gene_expression) is down-regulated in the brain, and experimental up-regulation of ''CMAH'' is lethal in mice.<ref name="pmid121920862" /> Experimental ''CMAH'' loss in mice increases running endurance and decreases muscle fatigue, which could have been beneficial to ancestral ''[Homo](/source/Homo)'' during the gene's fixation.<ref name="Okerblom_2018" />

==== Implications for pathogenicity ====
The loss of Neu5Gc in humans may have contributed to resistance to generalist [pathogen](/source/pathogen)s and increased [pathogenicity](/source/pathogenicity) of human-specific pathogens.<ref name="Alisson-Silva_2018">{{cite journal | vauthors = Alisson-Silva F, Liu JZ, Diaz SL, Deng L, Gareau MG, Marchelletta R, Chen X | year = 2018| title = Human Evolutionary Loss of Epithelial Neu5Gc Expression and Species-Specific Susceptibility to Cholera | journal = PLOS Pathogens | volume = 14 | issue = 6| pages = 1–20 | doi = 10.1371/journal.ppat.1007133 | pmid = 29912959 | pmc = 6023241 | doi-access = free }}</ref> Human-specific [cholera](/source/cholera), which employs host sialic acids to trigger a gastrointestinal response, preferentially uses Neu5Ac and is inhibited by Neu5Gc.<ref name="Alisson-Silva_2018" />

[Nonfunctionialization](/source/Nonfunctionalization) of ''CMAH'' has made humans more susceptible to some [virus](/source/virus)es by decreasing sialic acid diversity.<ref name="ajpa100182" /> Viruses that bind to Neu5Ac before entering the cell are enhanced by the high density of Neu5Ac, which would be reduced if other sialic acids were present on human [cell membrane](/source/cell_membrane)s.<ref name="ajpa100182" /> For example, the most serious form of [malaria](/source/malaria) in humans, ''[P. falciparum](/source/Plasmodium_falciparum),'' binds to Neu5Ac on the membrane of [red blood cell](/source/red_blood_cell)s.<ref name="ajpa100182" /><ref name="s107192" />

In contrast to these negative effects, losing ''CMAH'' should actually protect humans against any pathogen that targets Neu5Gc, such as those that cause [diarrheal diseases](/source/diarrheal_diseases) in livestock,<ref name="ajpa100182" /> [''E. coli'' K99](/source/Pathogenic_Escherichia_coli), [transmissible gastroenteritis coronavirus](/source/transmissible_gastroenteritis_virus) (TGEV),<ref name="s107192" /> and [simian virus 40](/source/SV40) (SV40).<ref name="s107192" />

== References ==
{{reflist}}

== Further reading ==
{{refbegin | 2}}
* {{cite journal | vauthors = Varki A | title = N-glycolylneuraminic acid deficiency in humans | journal = Biochimie | volume = 83 | issue = 7 | pages = 615–22 | date = July 2001 | pmid = 11522390 | doi = 10.1016/S0300-9084(01)01309-8 }}
* {{cite journal | vauthors = Bonaldo MF, Lennon G, Soares MB | title = Normalization and subtraction: two approaches to facilitate gene discovery | journal = Genome Research | volume = 6 | issue = 9 | pages = 791–806 | date = September 1996 | pmid = 8889548 | doi = 10.1101/gr.6.9.791 | doi-access = free }}
* {{cite journal | vauthors = Irie A, Suzuki A | title = CMP-N-Acetylneuraminic acid hydroxylase is exclusively inactive in humans | journal = Biochemical and Biophysical Research Communications | volume = 248 | issue = 2 | pages = 330–3 | date = July 1998 | pmid = 9675135 | doi = 10.1006/bbrc.1998.8946 }}
* {{cite journal | vauthors = Chou HH, Takematsu H, Diaz S, Iber J, Nickerson E, Wright KL, Muchmore EA, Nelson DL, Warren ST, Varki A | title = A mutation in human CMP-sialic acid hydroxylase occurred after the Homo-Pan divergence | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 95 | issue = 20 | pages = 11751–6 | date = September 1998 | pmid = 9751737 | pmc = 21712 | doi = 10.1073/pnas.95.20.11751 | bibcode = 1998PNAS...9511751C | doi-access = free }}
* {{cite journal | vauthors = Muchmore EA, Diaz S, Varki A | title = A structural difference between the cell surfaces of humans and the great apes | journal = American Journal of Physical Anthropology | volume = 107 | issue = 2 | pages = 187–98 | date = October 1998 | pmid = 9786333 | doi = 10.1002/(SICI)1096-8644(199810)107:2<187::AID-AJPA5>3.0.CO;2-S }}
* {{cite journal | vauthors = Hayakawa T, Satta Y, Gagneux P, Varki A, Takahata N | title = Alu-mediated inactivation of the human CMP- N-acetylneuraminic acid hydroxylase gene | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 20 | pages = 11399–404 | date = September 2001 | pmid = 11562455 | pmc = 58741 | doi = 10.1073/pnas.191268198 | bibcode = 2001PNAS...9811399H | doi-access = free }}
* {{cite journal | vauthors = Chou HH, Hayakawa T, Diaz S, Krings M, Indriati E, Leakey M, Paabo S, Satta Y, Takahata N, Varki A | title = Inactivation of CMP-N-acetylneuraminic acid hydroxylase occurred prior to brain expansion during human evolution | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 18 | pages = 11736–41 | date = September 2002 | pmid = 12192086 | pmc = 129338 | doi = 10.1073/pnas.182257399 | bibcode = 2002PNAS...9911736C | doi-access = free }}
{{refend}}

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Adapted from the Wikipedia article [CMAH](https://en.wikipedia.org/wiki/CMAH) by Wikipedia contributors ([contributor history](https://en.wikipedia.org/wiki/CMAH?action=history)). Available under [Creative Commons Attribution-ShareAlike 4.0 International](https://creativecommons.org/licenses/by-sa/4.0/). Changes may have been made.