title: JAK-STAT signaling pathway

text: JAK-STAT signalling is able to interconnect with other cell-signalling pathways, such as the PI3K/AKT/mTOR pathway. When JAKs are activated and phosphorylate tyrosine residues on receptors, proteins with SH2 domains (such as STATs) are able bind to the phosphotyrosines, and the proteins can carry out their function. Like STATs, the PI3K protein also has an SH2 domain, and therefore it is also able to bind to these phosphorylated receptors. As a result, activating the JAK-STAT pathway can also activate PI3K/AKT/mTOR signalling.


title: JAK-STAT signaling pathway

text: JAK-STAT signalling can also integrate with the MAPK/ERK pathway. Firstly, a protein important for MAPK/ERK signalling, called Grb2, has an SH2 domain, and therefore it can bind to receptors phosphorylated by JAKs (in a similar way to PI3K). Grb2 then functions to allow the MAPK/ERK pathway to progress. Secondly, a protein activated by the MAPK/ERK pathway, called MAPK (mitogen-activated protein kinase), can phosphorylate STATs, which can increase gene transcription by STATs. However, although MAPK can increase transcription induced by STATs, one study indicates that phosphorylation of STAT3 by MAPK can reduce STAT3 activity.


title: JAK-STAT signaling pathway

text: One example of JAK-STAT signalling integrating with other pathways is Interleukin-2 (IL-2) receptor signaling in T cells. IL-2 receptors have γ (gamma) chains, which are associated with JAK3, which then phosphorylates key tyrosines on the tail of the receptor. Phosphorylation then recruits an adaptor protein called Shc, which activates the MAPK/ERK pathway, and this facilitates gene regulation by STAT5.


title: JAK-STAT signaling pathway

text: An alternative mechanism for JAK-STAT signalling has also been suggested. In this model, SH2 domain-containing kinases, can bind to phosphorylated tyrosines on receptors and directly phosphorylate STATs, resulting in STAT dimerization. Therefore, unlike the traditional mechanism, STATs can be phosphorylated not just by JAKs, but by other receptor-bound kinases. So, if one of the kinases (either JAK or the alternative SH2-containing kinase) cannot function, signalling may still occur through activity of the other kinase. This has been shown experimentally.


title: JAK-STAT signaling pathway

text: Given that many JAKs are associated with cytokine receptors, the JAK-STAT signalling pathway plays a major role in cytokine receptor signalling. Since cytokines are substances produced by immune cells that can alter the activity of neighbouring cells, the effects of JAK-STAT signalling are often more highly seen in cells of the immune system. For example, JAK3 activation in response to IL-2 is vital for lymphocyte development and function. Also, one study indicates that JAK1 is needed to carry out signalling for receptors of the cytokines IFNγ, IL-2, IL-4 and IL-10.


title: JAK-STAT signaling pathway

text: The JAK-STAT pathway in cytokine receptor signalling can activate STATs, which can bind to DNA and allow the transcription of genes involved in immune cell division, survival, activation and recruitment. For example, STAT1 can enable the transcription of genes which inhibit cell division and stimulate inflammation. Also, STAT4 is able to activate NK cells (natural killer cells), and STAT5 can drive the formation of white blood cells. In response to cytokines, such as IL-4, JAK-STAT signalling is also able to stimulate STAT6, which can promote B-cell proliferation, immune cell survival, and the production of an antibody called IgE.


title: JAK-STAT signaling pathway

text: JAK-STAT signalling plays an important role in animal development. The pathway can promote blood cell division, as well as differentiation (the process of a cell becoming more specialised). In some flies with faulty JAK genes, too much blood cell division can occur, potentially resulting in leukaemia. JAK-STAT signalling has also been associated with excessive white blood cell division in humans and mice.


title: JAK-STAT signaling pathway

text: The signalling pathway is also crucial for eye development in the fruit fly ("Drosophila melanogaster"). When mutations occur in genes coding for JAKs, some cells in the eye may be unable to divide, and other cells, such as photoreceptor cells, have been shown not to develop correctly.


title: JAK-STAT signaling pathway

text: The entire removal of a JAK and a STAT in "Drosophila" causes death of "Drosophila" embryos, whilst mutations in the genes coding for JAKs and STATs can cause deformities in the body patterns of flies, particularly defects in forming body segments. One theory as to how interfering with JAK-STAT signalling might cause these defects is that STATs may directly bind to DNA and promote the transcription of genes involved in forming body segments, and therefore by mutating JAKs or STATs, flies experience segmentation defects. STAT binding sites have been identified on one of these genes, called "even-skipped" ("eve"), to support this theory. Of all the segment stripes affected by JAK or STAT mutations, the fifth stripe is affected the most, the exact molecular reasons behind this are still unknown.


title: JAK-STAT signaling pathway

text: Given the importance of the JAK-STAT signalling pathway, particularly in cytokine signalling, there are a variety of mechanisms that cells possess to regulate the amount of signalling that occurs. Three major groups of proteins that cells use to regulate this signalling pathway are protein inhibitors of activated STAT (PIAS), protein tyrosine phosphatases (PTPs) and suppressors of cytokine signalling (SOCS). Computational models of JAK-STAT signaling based on the laws of chemical kinetics have elucidated the importance of these different regulatory mechanisms on JAK-STAT signaling dynamics.


title: JAK-STAT signaling pathway

text: PIAS are a four-member protein family made of: PIAS1, PIAS3, PIASx, and PIASγ. The proteins add a marker, called SUMO (small ubiquitin-like modifier), onto other proteins – such as JAKs and STATs, modifying their function. The addition of a SUMO group onto STAT1 by PIAS1 has been shown to prevent activation of genes by STAT1. Other studies have demonstrated that adding a SUMO group to STATs may block phosphorylation of tyrosines on STATs, preventing their dimerization and inhibiting JAK-STAT signalling. PIASγ has also been shown to prevent STAT1 from functioning. PIAS proteins may also function by preventing STATs from binding to DNA (and therefore preventing gene activation), and by recruiting proteins called histone deacetylases (HDACs), which lower the level of gene expression.


title: JAK-STAT signaling pathway

text: Since adding phosphate groups on tyrosines is such an important part of how the JAK-STAT signalling pathway functions, removing these phosphate groups can inhibit signalling. PTPs are tyrosine phosphatases, so are able to remove these phosphates and prevent signalling. Three major PTPs are SHP-1, SHP-2 and CD45.


title: JAK-STAT signaling pathway

text: One example of this is seen in the JAK-STAT signalling pathway mediated by the erythropoietin receptor (EpoR). Here, SHP-1 binds directly to a tyrosine residue (at position 429) on EpoR and removes phosphate groups from the receptor-associated JAK2. The ability of SHP-1 to negatively regulate the JAK-STAT pathway has also been seen in experiments using mice lacking SHP-1. These mice experience characteristics of autoimmune diseases and show high levels of cell proliferation, which are typical characteristics of an abnormally high level of JAK-STAT signalling. Additionally, adding methyl groups to the SHP-1 gene (which reduces the amount of SHP-1 produced) has been linked to lymphoma (a type of blood cancer) .


title: JAK-STAT signaling pathway

text: However, SHP-1 may also promote JAK-STAT signalling. A study in 1997 found that SHP-1 potentially allows higher amounts of STAT activation, as opposed to reducing STAT activity. A detailed molecular understanding for how SHP-1 can both activate and inhibit the signalling pathway is still unknown.


title: JAK-STAT signaling pathway

text: Negative regulation by SHP-2 has been reported in a number of experiments - one example has been when exploring JAK1/STAT1 signalling, where SHP-2 is able to remove phosphate groups from proteins in the pathway, such as STAT1. In a similar manner, SHP-2 has also been shown to reduce signalling involving STAT3 and STAT5 proteins, by removing phosphate groups.


title: JAK-STAT signaling pathway

text: Like SHP-1, SHP-2 is also believed to promote JAK-STAT signalling in some instances, as well as inhibit signalling. For example, one study indicates that SHP-2 may promote STAT5 activity instead of reducing it. Also, other studies propose that SHP-2 may increase JAK2 activity, and promote JAK2/STAT5 signalling. It is still unknown how SHP2 can both inhibit and promote JAK-STAT signalling in the JAK2/STAT5 pathway; one theory is that SHP-2 may promote activation of JAK2, but inhibit STAT5 by removing phosphate groups from it.


title: JAK-STAT signaling pathway

text: There are eight protein members of the SOCS family: cytokine-inducible SH2 domain-containing protein (CISH), SOCS1, SOCS2, SOCS3, SOCS4, SOCS5, SOCS6, and SOCS7, each protein has an SH2 domain and a 40-amino-acid region called the SOCS box. The SOCS box can interact with a number of proteins to form a protein complex, and this complex can then cause the breakdown of JAKs and the receptors themselves, therefore inhibiting JAK-STAT signalling. The protein complex does this by allowing a marker called ubiquitin to be added to proteins, in a process called ubiquitination, which signals for a protein to be broken down. The proteins, such as JAKs and the receptors, are then transported to a compartment in the cell called the proteasome, which carries out protein breakdown.


title: JAK-STAT signaling pathway

text: SOCS can also function by binding to proteins involved in JAK-STAT signalling and blocking their activity. For example, the SH2 domain of SOCS1 binds to a tyrosine in the activation loop of JAKs, which prevents JAKs from phosphorylating each other. The SH2 domains of SOCS2, SOCS3 and CIS bind directly to receptors themselves. Also, SOCS1 and SOCS3 can prevent JAK-STAT signalling by binding to JAKs, using segments called kinase inhibitory regions (KIRs) and stopping JAKs binding to other proteins. The exact details of how other SOCS function is less understood.


title: JAK-STAT signaling pathway

text: Since the JAK-STAT pathway plays a major role in many fundamental processes, such as apoptosis and inflammation, dysfunctional proteins in the pathway may lead to a number of diseases. For example, alterations in JAK-STAT signalling can result in cancer and diseases affecting the immune system, such as severe combined immunodeficiency disorder (SCID).


title: JAK-STAT signaling pathway

text: JAK3 can be used for the signalling of IL-2, IL-4, IL-15 and IL-21 (as well as other cytokines); therefore patients with mutations in the JAK3 gene often experience issues affecting many aspects of the immune system. For example, non-functional JAK3 causes SCID, which results in patients having no NK cells, B cells or T cells, and this would make SCID individuals susceptible to infection. Mutations of the STAT5 protein, which can signal with JAK3, has been shown to result in autoimmune disorders.


title: JAK-STAT signaling pathway

text: It has been suggested that patients with mutations in STAT1 and STAT2 are often more likely to develop infections from bacteria and viruses. Also, STAT4 mutations have been associated with rheumatoid arthritis, and STAT6 mutations are linked to asthma.


title: JAK-STAT signaling pathway

text: Patients with a faulty JAK-STAT signalling pathway may also experience skin disorders. For example, non-functional cytokine receptors, and overexpression of STAT3 have both been associated with psoriasis (an autoimmune disease associated with red, flaky skin). STAT3 plays an important role in psoriasis, as STAT3 can control the production of IL-23 receptors, and IL-23 can help the development of Th17 cells, and Th17 cells can induce psoriasis. Also, since many cytokines function through the STAT3 transcription factor, STAT3 plays a significant role in maintaining skin immunity. In addition, because patients with JAK3 gene mutations have no functional T cells, B cells or NK cells, they would more likely to develop skin infections.


title: JAK-STAT signaling pathway

text: Cancer involves abnormal and uncontrollable cell growth in a part of the body. Therefore, since JAK-STAT signalling can allow the transcription of genes involved in cell division, one potential effect of excessive JAK-STAT signalling is cancer formation. High levels of STAT activation have been associated with cancer; in particular, high amounts of STAT3 and STAT5 activation is mostly linked to more dangerous tumours. For example, too much STAT3 activity has been associated with increasing the likelihood of melanoma (skin cancer) returning after treatment and abnormally high levels of STAT5 activity have been linked to a greater probability of patient death from prostate cancer.


title: JAK-STAT signaling pathway

text: Altered JAK-STAT signalling can also be involved in developing breast cancer. JAK-STAT signalling in mammary glands (located within breasts) can promote cell division and reduce cell apoptosis during pregnancy and puberty, and therefore if excessively activated, cancer can form. High STAT3 activity plays a major role in this process, as it can allow the transcription of genes such as "BCL2" and "c-Myc", which are involved in cell division.


title: JAK-STAT signaling pathway

text: Mutations in JAK2 can lead to leukaemia and lymphoma. Specifically, mutations in exons 12, 13, 14 and 15 of the JAK2 gene are proposed to be a risk factor in developing lymphoma or leukemia. Additionally, mutated STAT3 and STAT5 can increase JAK-STAT signalling in NK and T cells, which promotes very high proliferation of these cells, and increases the likelihood of developing leukaemia. Also, a JAK-STAT signalling pathway mediated by erythropoietin (EPO), which usually allows the development of red blood cells, may be altered in patients with leukemia.


title: JAK-STAT signaling pathway

text: The Janus kinase (JAK)/signal transducer and the activator of the transcription (STAT) pathway were at the centre of attention for driving hyperinflammation in COVID-19, i.e., the SARS-CoV-2 infection triggers hyperinflammation through the JAK/STAT pathway, resulting in the recruitment of dendritic cells, macrophages, and natural killer (NK) cells, as well as differentiation of B cells and T cells progressing towards cytokine storm.


title: JAK-STAT signaling pathway

text: Since excessive JAK-STAT signalling is responsible for some cancers and immune disorders, JAK inhibitors have been proposed as drugs for therapy. For instance, to treat some forms of leukaemia, targeting and inhibiting JAKs could eliminate the effects of EPO signalling and perhaps prevent the development of leukaemia. One example of a JAK inhibitor drug is Ruxolitinib, which is used as a JAK2 inhibitor. STAT inhibitors are also being developed, and many of the inhibitors target STAT3. It has been reported that therapies which target STAT3 can improve the survival of patients with cancer. Another drug, called Tofacitinib, has been used for psoriasis and rheumatoid arthritis treatment, and has been approved for treatment of Crohn's disease and ulcerative colitis.


The Official Marvel Graphic Novel Collection (also referred to as The Ultimate Graphic Novels Collection) is a fortnightly partwork magazine published by Hachette Partworks. The series is a collection of special edition hardback graphic novel, collecting all the parts in a story-arc for one of Marvel's best known superheroes, often a fan-favourite or "important" story from Marvel comics lore.


title: The Official Marvel Graphic Novel Collection

text: The series is published in the UK, Russia, Ireland, Australia, New Zealand and South Africa by Hachette Partworks, in Poland by Hachette Polska, in the Czech Republic and Slovakia by Panini Fascicule, in Argentina, Brazil, Colombia, Perú and Chile by Editorial Salvat, in Bulgaria by Hachette Fascicoli and in France and Germany by the French mother company of Hachette Collections.


text: The first English-language issue was published in December 2011 priced at £2.99 (R29.95 in SA, $7.95 in AU) issue 2 was £6.99 (R79.95 in SA, $12.95 in AU) and from issue 3 onwards it was its normal price of £9.99 (R109.95 in SA, $19.95 in AU).


text: The series proved so successful for publisher Hachette Partworks that they launched a second series of 130 fortnightly graphic novel hardbacks entitled "Marvel's Mightiest Heroes Graphic Novel Collection" and a third (non-Marvel) series of 90 fortnightly graphic novel hardbacks entitled "", a fourth series of 100 fortnightly graphic novel hardbacks called "Transformers: The Definitive G1 Collection" (featuring strips from Marvel US and UK, Dreamwave and IDW) and a fifth series of 80 fortnightly graphic novel hardbacks entitled "". It also inspired a similar partwork line from DC Comics and Eaglemoss Collections, the "DC Comics Graphic Novel Collection" and one featuring "Star Trek" comics from the sixties up until modern comics called "Star Trek Graphic Novel Collection", and at the end of 2017 an even newer collection also by Eaglemoss "DC Comics – The Legend Of Batman".


text: The collection was later re-released with alternative numbering in 2016, which concluded with Issue 170 in September 2022.


text: As well as the comic strip, each book features an introduction to the book, information on the character, writer and artist plus some of the artist's draft board sketches. 60 books are required to build up a panoramic picture on the spine by artist Gabriele Dell'Otto. In April 2014, a flyer accompanying issue #62 revealed the artwork by Dell'Otto had been extended to cover 120 volumes rather than the original 60.


text: Each issue number of the collection is not the same as the books volume number (e.g. issue #1 is volume 21) as the volume number is the chronological release order of the original publication, whereas the issue number is the order in which they were released within this collection. Issue #1 was launched twice in the UK. Early subscribers to issue #1 (volume 21) may have received an edition with a different spine from those that subscribed to the subsequent launch. The panoramic artwork on the spine of this edition does not align with the volumes 20 or 22.


text: The first issue came with an extra magazine which contained information on the collection and short descriptions on some characters which will feature in the upcoming books. It also included some character history. The magazine also folded out into a giant poster depicting Marvel universe heroes drawn by Leinil Francis Yu.


text: Below is a list of the books from each issue in published date order. Only the first six issues were officially announced, but each issue features a further reading section which advertised future books and their volume number, though not release number. Early into the run, customer support provided a list of books to be published from issue seven onwards which was unverified, but proved to be accurate for sometime. The full list of issues was confirmed on the Hachette Partworks website but later removed as the order for some issues altered slightly. Subsequently, via the collections official website the set was announced to continue for a further 60 issues. The release order for issues #73–120 was later verified via BookDepository.com In April 2016, the May catalogue for PreviewsUK confirmed that an issue #121 would be released as part of the original collection. Subsequently, via the official Facebook page, it was confirmed that the original collection would now continue for a further 20 issues, therefore extending the set to 140. In reply to a comment on the collection's facebook page in May 2017, confirmation was made that the collection will now expand to 170 titles. Later in December, in reply to an email, a Facebook user was told that this has now been expanded, yet again with no prewarning to subscribers, to 200.


text: The collection has been confirmed as being extended again to 220 issues, with zero notification, in reply to a query as to the end number on one of Hatchetts Facebook posts in July 2019. The exact phrasing was to run to 220, not that it will end at 220. In April 2020, in response to a Facebook comment, the collection has been extended to 250 issues.


text: In a Facebook post in June 2021, Hachette confirmed that the Original Marvel Graphic Novel Collection (2011) would be extended to 280 issues and the more recent Marvel Graphic Novel Collection (2016) would be extended to 170 issues.


text: In a post by British Comic Heroes via Facebook in June 2022 it was said that Hachette were calling time on the Marvel - The Ultimate Graphic Novel Collection at issue 280, however in later post, British Comic Heroes clarified that that the Hatchette announcement did not actually confirm this.


text: Subscribers to the more recent Marvel Graphic Novel Collection (2016) received a letter with their package containing issue 170 advising the collection had now ended. This confirmed the 2016 collection would be ending 110 graphic novels short of the original 2012 collection.


text: The table below contains the full list of issues as per the original printing of the collection beginning in December 2011. The final volume (280) was released in October, 2022 after nearly eleven years.


text: The following books were only released in Ireland, Czech Republic, Poland, Germany, Brazil, Russia, France, Perú, Argentina, Greece, Hungary and Bulgaria.


text: In Germany "Astonishing X-Men: Gifted" and "Fear Itself (Part 1)" were released with different covers.


text: "Winter Soldier (Part 1)" was released in Germany with a picture, which was in other countries used for "Winter Soldier (Part 2)", on the cover.


text: In Poland, the collection was titled Wielka Kolekcja Komiksów Marvela (The Great Marvel Comics Collection) and was published in 170 issues from August 2012 to May 2019.


text: The same collection is being published in the Czech Republic and Slovakia from January 2013 as Ultimátní komiksový komplet (The Ultimate Comics Collection), with 199 KČ / 9.99 EUR per book from issue 3 onwards. The price increased to 219 KČ / 9.99 EUR per book from issue 38 onwards and then to 249 KČ / 9.99 EUR per book from issue 56 onwards. The books (at least according to first 4 books) come in slightly different order than the one in table above. The books are sold in Czech republic first and after 4 months the unsold books are distributed in Slovakia. The collection continues with issues 61–120, none of the books is marked as "Classic".


text: The collection debuted in Germany under the title Die offizielle Marvel-Comic-Sammlung (The Official Marvel Comic Collection) in January 2013.


text: In September 2013, after an initial test run, the collection was made available in Brazil by Editora Salvat as A Coleção Oficial de Graphic Novels Marvel (The Official Marvel Graphic Novel Collection), priced at R$29,90 from issue 3 onwards.


text: In Russia the series was launched in January 2014, under the title Marvel. Официальная коллекция комиксов (Marvel. Ofitsialnaya kollektsiya komiksov — Marvel. The Official Comics Collection). The collection is issued by the Russian branch of the Hachette in cooperation with the Panini Comics providing translation and page layout.


text: In March 2014 the collection started in France under the title Marvel Comics: La Collection de Référence


text: In Argentina, the collection started May 2014 under the title Colección Definitiva de Novelas Gráficas de Marvel. The same edition began to be sold in Peru beginning in September 2015.


text: In March 2016 a test run of four titles was launched in Romania under the title Colecţia Oficială de Romane Grafice Marvel but it wasn't picked up for a full run.


text: In September 2019 the collection started in Greece under the title Η Επίσημη Συλλογή Graphic Novels της Marvel.


text: In September 2020 the collection started in Bulgaria under the title Върховна колекция графични романи Марвел.


text: The second series from Hachette Partworks began in January 2013, with each issue focussing on a different heroic Marvel character. This time the books built up a panoramic picture on the spine by artist Marko Djurdjević. The format featured a relatively recent story as the volume's main feature story (billed first on the front cover), preceded by the first appearance story and in some cases another early appearance (e.g. Hawkeye's first appearance as a solo character plus his first appearance with The Avengers). Although the first four titles were announced, only three were published and subscribers were told the series had been postponed. However, the series was relaunched in January 2014 beginning with the same four issues, but this time the books built up a panoramic picture on the spine by artist Adi Granov. This means collectors who had purchased the original three volumes would have to purchase them again to complete the spine art.


text: Two further Marvel Collections were market trialed by Hachette, an Avengers series in 2018 and an X-Men series in 2019. The Avengers series did not go to a full release and remaining market trial stock was added to the Hachette webstore in early 2019 including oversized variants of the 3 trial books. In late October 2019 remaining market trial stock from the X-Men trial and an "Alien" and "Predator" series that had been trialed in late 2018 were also added to the webstore indicating that they were unlikely to go to a full launch. The Collection has been launched in France in October 2020.


text: A new collection on sale on the french version of Hachette site. This has been tested 10 months ago, and starts now, on August 2022.


text: It seems that the collection will be edited in order, starting with the oldest comics around 1961-1962 and estimated to arrive around the late sixties.


text: It seems also that the volumes follows the italian collection which contains 300 issues in softcover. The first issues seem to be the exact replica, except for the hardcover.


title: Erewhon

text: Erewhon: or, Over the Range () is a novel by English writer Samuel Butler, first published anonymously in 1872, set in a fictional country discovered and explored by the protagonist. The book is a satire on Victorian society.


title: Erewhon

text: The first few chapters of the novel dealing with the discovery of Erewhon are in fact based on Butler's own experiences in New Zealand, where, as a young man, he worked as a sheep farmer on Mesopotamia Station for about four years (1860–64), and explored parts of the interior of the South Island and wrote about in his "A First Year in Canterbury Settlement" (1863).


title: Erewhon

text: The novel is one of the first to explore ideas of artificial intelligence, as influenced by Darwin's recently published "On the Origin of Species" (1859) and the machines developed out of the Industrial Revolution (late 18th to early 19th centuries). Specifically, it concerns itself, in the three-chapter "Book of the Machines", with the potentially dangerous ideas of machine consciousness and self-replicating machines.


title: Erewhon

text: The greater part of the book consists of a description of Erewhon. The nature of this nation is intended to be ambiguous. At first glance, Erewhon appears to be a Utopia, yet it soon becomes clear that this is far from the case. Yet for all the failings of Erewhon, it is also clearly not a dystopia, such as that depicted in 1949 in George Orwell's "Nineteen Eighty-Four".


title: Erewhon

text: As a satirical utopia, "Erewhon" has sometimes been compared to "Gulliver's Travels" (1726), a classic novel by Jonathan Swift; the image of Utopia in this latter case also bears strong parallels with the self-view of the British Empire at the time. It can also be compared to the William Morris novel, "News from Nowhere" (1890).


title: Erewhon

text: "Erewhon" satirises various aspects of Victorian society, including criminal punishment, religion, and anthropocentrism. For example, according to Erewhonian law, offenders are treated as if they were ill, whereas ill people are looked upon as criminals. Another feature of Erewhon is the absence of machines; this is due to the widely shared perception by the Erewhonians that machines are potentially dangerous.


title: Erewhon

text: Butler developed the three chapters of "Erewhon" that make up "The Book of the Machines" from a number of articles he had contributed to "The Press", which had just begun publication in Christchurch, New Zealand, beginning with "Darwin among the Machines" (1863). Butler was the first to write about the possibility that machines might develop consciousness by natural selection.


title: Erewhon

text: Many dismissed this as a joke, but, in his preface to the second edition, Butler wrote, "I regret that reviewers have in some cases been inclined to treat the chapters on Machines as an attempt to reduce Mr Darwin's theory to an absurdity. Nothing could be further from my intention, and few things would be more distasteful to me than any attempt to laugh at Mr Darwin."


title: Erewhon

text: In a 1945 broadcast, George Orwell praised the book and said that when Butler wrote "Erewhon" it needed "imagination of a very high order to see that machinery could be dangerous as well as useful." He recommended the novel, though not its sequel, "Erewhon Revisited".


title: Erewhon

text: The French philosopher Gilles Deleuze used ideas from Butler's book at various points in the development of his philosophy of difference. In "Difference and Repetition" (1968), Deleuze refers to what he calls "Ideas" as "Erewhon". "Ideas are not concepts", he argues, but rather "a form of eternally positive differential multiplicity, distinguished from the identity of concepts." "Erewhon" refers to the "nomadic distributions" that pertain to simulacra, which "are not universals like the categories, nor are they the "hic et nunc" or "nowhere", the diversity to which categories apply in representation." "Erewhon", in this reading, is "not only a disguised "no-where" but a rearranged "now-here"."


title: Erewhon

text: In his collaboration with Félix Guattari, "Anti-Oedipus" (1972), Deleuze draws on Butler's "The Book of the Machines" to "go beyond" the "usual polemic between vitalism and mechanism" as it relates to their concept of "desiring-machines":


title: Erewhon

text: C. S. Lewis alludes to the book in his essay, "The Humanitarian Theory of Punishment" in the posthumously published collection, "God in the Dock" (1970).


title: Erewhon

text: Aldous Huxley alludes to the book in his novel "Island" (1962), as does Agatha Christie in "Death on the Nile" (1937).


title: Erewhon

text: In 1994, a group of ex-Yugoslavian writers in Amsterdam, who had established the PEN centre of Yugoslav Writers in Exile, published a single issue of a literary journal "Erewhon".


title: Erewhon

text: New Zealand sound art organisation, the Audio Foundation, published in 2012 an anthology edited by Bruce Russell named "Erewhon Calling" after Butler's book.


title: Erewhon

text: In 2014, New Zealand artist Gavin Hipkins released his first feature film, titled "Erewhon" and based on Butler's book. It premiered at the New Zealand International Film Festival and the Edinburgh Art Festival.


title: Erewhon

text: In "Smile", the second episode of the 2017 season of "Doctor Who", the Doctor and Bill explore a spaceship named "Erehwon". Despite the slightly different spelling, the episode writer Frank Cottrell-Boyce confirmed that this was a reference to Butler's novel.


title: Erewhon

text: The book The Open Society and Its Enemies, by Karl Popper, reproduces on its first page the following citation of Butler: ""It will be seen ... that the Erewhonians are a meek and long-suffering people easily led by the nose, and quick to offer up common sense at the shrine of logic, when a philosopher arises among them who carries them away ... by convincing them that their existing institutions are not based on the strictest principles of morality"."


title: Erewhon

text: 'Erewhon' is the unofficial name US astronauts gave Regan Station, a military space station in David Brin's 1990 novel Earth.


title: Erewhon

text: The 'Butlerian Jihad' is the name of the crusade to wipe out 'thinking machines' in the novel, "Dune", by Frank Herbert.


title: Erewhon

text: 'Erewhon' is the name of Los Angeles-based natural foods grocery store originally founded in Boston in 1966.


title: Erewhon

text: 'Erewhon' is also the name of an independent speculative fiction publishing company founded in 2018 by Liz Gorinsky.


title: 2005–06 Real Madrid CF season

text: The 2005–06 Real Madrid C.F. season was the club's 75th season in La Liga. This article lists all matches that the club played in the 2005–06 season, and also shows statistics of the club's players.


title: 2005–06 Real Madrid CF season

text: For the second consecutive season, Real Madrid did not win any competition. This was their first consecutive trophyless seasons since 1982–83 to 1983–84.


title: 2005–06 Real Madrid CF season

text: In June 2005, president Florentino Pérez presented the "2005 Real Madrid World Tour", which included 6 friendly matches in North America and Asia. Two more matches were played in Central Europe during the second stage of the pre-season, including a homage to Ferenc Puskás, which was held in Hungary. The last match, an annual Trofeo Santiago Bernabéu, was played on home soil.


title: Hong Kong 97 (video game)

text: Hong Kong 97 is an unlicensed shoot 'em up video game developed and published by HappySoft, a doujin game developer, for the Super Famicom. It was released in Japan in 1995, being sold as cartridges and floppy disks. Designed by the Japanese game journalist Kowloon Kurosawa, who claims the game is a satire of the video game industry, "Hong Kong 97" was made in two days with the help of his friend.


title: Hong Kong 97 (video game)

text: The game takes place in China in 1997, during the handover of Hong Kong from the United Kingdom. Facing increased crime rate due to immigration from Mainland China, the Hong Kong government hires Chin, a super-powerful relative of Bruce Lee, to kill the entire population of China. At the same time, the deceased Tong Shau Ping is resurrected by a secret project conducted by the Chinese government as an "ultimate weapon". After defeating Tong Shau Ping, the game is repeated indefinitely until Chin dies. "Hong Kong 97" sold around 30 copies due to its underground bootleg release, and it has since gained a cult following for its notoriously poor quality. In retrospect, it is considered by critics and journalists to be among the worst games ever made.


title: Hong Kong 97 (video game)

text: The player controls Chin, who must shoot and evade the Chinese populace and police officers moving downwards from the top of the screen. When shot, the enemies explode in mushroom clouds, leaving behind a flashing corpse and items for instant death or temporary invincibility. After a while, cars start appearing from the sides, moving horizontally across the screen as obstacles. After thirty enemies have been defeated by the player, the final boss, the "ultimate weapon" Tong Shau Ping appears. Once he is defeated, the game repeats itself. The game shows static photos as the background, which alternate between pictures of Maoist propaganda, Guilin, the logo for Asia Television, the logo for Chinese Coca-Cola or Mao Zedong in monochrome.


title: Hong Kong 97 (video game)

text: Sporadically, a syringe appears as a power-up, which grants Chin temporary invincibility. The player has no health points: if Chin is hit by anything other than an item, the game is immediately over, unless Chin is under invincibility. The game over screen contains the superimposed words "Chin IS DEAD!!" in English and grammatically incorrect Chinese "" () over a still graphic image of what is believed to be either the dead body of Leszek Błażyński or a victim of the Bosnian War, both dated to 1992. The game then goes to the credits (listing the Embassy of Canada as a cooperation partner) and back to the title screen.


title: Hong Kong 97 (video game)

text: Upon turning on the game, the first three measures of the chorus of an upbeat rock-style rendition of "I Love Beijing Tiananmen" can be heard, which loop endlessly throughout the game. The game has no other music or sound effects. It can be played in English, Japanese or traditional Chinese.


title: Hong Kong 97 (video game)

text: "Hong Kong 97" begins with a short cutscene which places the game around the transfer of sovereignty over Hong Kong in 1997. People from Mainland China (described in the English script as "fuckin' ugly reds" and in the Japanese script as "dirty people spitting sputum") started immigrating to Hong Kong, causing a large increase in the crime rate. As a countermeasure, the Hong Kong government (represented in-game by the governor Chris Patten) hires Chin (portrayed by Hong Kong actor and martial artist Jackie Chan), an unspecified relative of Bruce Lee, to "wipe out" all 1.2 billion of the "red communists" in China. Meanwhile, a secret project in Mainland China has succeeded in resurrecting Tong Shau Ping as the "ultimate weapon".


title: Hong Kong 97 (video game)

text: The Chinese translation of the game refers to Chin as "Mr. Chan" (), alluding to the fact that a picture of Jackie Chan was used to depict the character. The back of the insert of the game notes that Chin is a heroin addict.


title: Hong Kong 97 (video game)

text: In January 2018, Yoshihisa "Kowloon" Kurosawa finally broke his silence on the development of the game to the "South China Morning Post". He stated that his goal was to make the worst game possible as a mockery of the game industry. Since Kurosawa did not have much programming skill, he had an Enix employee help him out, with the game being made in two days. He later asked a friend with basic knowledge of English to translate the story into this language, as well as an exchange student from Hong Kong to translate it into Chinese. Kurosawa took the music, an audio clip from "I Love Beijing Tiananmen", from a second-hand LaserDisc he got in Shanghai Street, and the main character sprite, depicting Jackie Chan, was taken from a movie poster of "Wheels on Meals", a 1984 Hong Kong martial arts film.


title: Hong Kong 97 (video game)

text: With the game completed, Kurosawa used a game backup device that could copy Super Famicom games onto floppy disks, which he found whilst wandering through the computer malls of Sham Shui Po. Due to game backup devices being illegal in Japan at the time, Kurosawa could only advertise his game through articles written under pseudonyms for underground gaming magazines. He set up a mail-order service to sell the game on floppy discs and cartridges, for ¥2,000 – ¥2,500 ($20–$25 in USD). It sold only about 30 copies, despite him having printed several hundred copies of the insert, which he later threw away. He eventually forgot about the game, until he became aware that it was gaining some unwanted attention in the late 2000s. Eventually, his Facebook account was discovered and was bombarded with questions about the game.


title: Hong Kong 97 (video game)

text: In an advertisement in the underground magazine "Game Urara" for another HappySoft title, "The Story of Kamikuishiki Village", "Hong Kong 97"s poor quality is acknowledged, with the advert referring to the game as "dreadful" and "incomprehensible". It also claims that bootleg copies of the game were sold in Hong Kong and Bangkok.


title: Hong Kong 97 (video game)

text: In retrospective reviews, "Hong Kong 97" was met with overwhelmingly negative reception, with many calling it one of the worst video games ever made. The game has garnered a "so bad, it's good" cult following in Japan and Taiwan, the West after it became the subject of an "Angry Video Game Nerd" episode, and Thailand.


Missouri University of Science and Technology, or Missouri S&T, is a public research university in Rolla, Missouri. It is a member institution of the University of Missouri System. Most of its 7,645 students (fall 2020) study engineering, business, sciences, and mathematics. Known primarily for its engineering school, Missouri S&T offers degree programs in business and management systems, information science and technology, sciences, social sciences, humanities, and arts. Its Carnegie classification is as a "STEM-dominant", R2 doctoral university with "high research activity".


title: Missouri University of Science and Technology

text: Missouri S&T was founded in 1870 as the Missouri School of Mines and Metallurgy (MSM), the first technological learning institution west of the Mississippi River. Early in its history, the School of Mines was focused primarily on mining and metallurgy. Rolla is located close to the Southeast Missouri Lead District which produces about 70% of the U.S. primary supply of lead as well as significant amounts of the nation's zinc.


text: The school was founded under the auspices of the University of Missouri in Columbia in order to take advantage of the Morrill Land-Grant Acts to "teach such branches of learning as are related to agriculture and the mechanic arts, in such manner as the legislatures of the States may respectively prescribe, in order to promote the liberal and practical education of the industrial classes in the several pursuits and professions in life." The act endowed Missouri a federal land grant of 30,000 acres for each of the state's two senators and nine representatives at the time—or . The endowment said that the land could not be sold for less than $1.25/acre and as such was a minimum endowment of $412,500 for Missouri. There was an intense debate in the state over the location and number of schools before it was finally decided to have one school in Columbia and a branch in the mining area of southeast Missouri.


text: Iron County, Missouri (Ironton) and Phelps County, Missouri (Rolla) made bids for the school. Iron County's bid was valued at $112,545 and Phelps County's bid was $130,545 so the Phelps bid was officially approved on December 20, 1870.


text: Classes began on November 23, 1871, in a new building that the city of Rolla had just built. The college had an enrollment of 28 and three graduates in 1874. The college bought what is now called the "Rolla Building" for $25,000 in January 1875. That building is now used as the Mathematics and Statistics Department's library, chair's office, part of the main office, and other faculty offices following a $2 million renovation in 1995.


text: Initially, the school only offered degrees in civil engineering, metallurgy, and mining engineering. However, by the late 1920s, the school had added degrees in ceramic engineering, chemical engineering, electrical engineering, and mechanical engineering. The school became home to Missouri's first operational nuclear reactor in 1961.


text: In June 2018, the school was approved by the state's Coordinating Board for Higher Education for designation as "highly selective" in its undergraduate admission criteria, joining only Truman State University among the state's public universities at that level. As such, first-time, full-time students seeking degrees are generally only admitted if they have a "percentile score" of 140 points or greater, a combination of their high school class and college testing (ACT or SAT) percentile ranks. Missouri Department of Higher Education guidelines state that schools in this category may admit up to ten percent of students with lower percentile scores, and will automatically admit those with an ACT (or equivalent SAT) score of 27 or better.


text: Until 1964, the school was considered an offsite department of MU's School of Agriculture and Mechanical Arts, reporting to the main campus in Columbia (although it began fielding sports teams in 1935 in the Mid-America Intercollegiate Athletics Association). As such, its presiding officer was originally called a director (1871–1941), then a dean (1941–1964). In 1963 the University of Missouri System was created with the additions of standalone campuses in Kansas City and St. Louis. A year later, MSM was upgraded to an autonomous standalone campus as the University of Missouri at Rolla and its presiding officer, like that of its sister schools, was granted the title of chancellor. The curriculum was expanded to include most of the science and engineering disciplines, as well as social sciences and liberal arts such as psychology and history. In 1968, the campus name was slightly altered to the University of Missouri–Rolla, thus conforming to the naming scheme of the other three campuses. Business and management programs were gradually added in the following years. On January 1, 2008, UMR became known as Missouri University of Science and Technology or Missouri S&T for short.


text: In making the case for changing the name, then Chancellor John F. Carney III noted that Rolla in 2007 was "one of the few technological research universities in the nation. A technological research university (polytechnic university or institute of technology) may be defined as one in which a majority of students are enrolled in engineering, the sciences, business or mathematics; the graduate and research programs in those fields are robust; and exceptional academic programs in the liberal arts, humanities and social sciences complement and provide context to the technological strengths of the institution."


text: He noted that more than 70 percent of its enrollment was in engineering and more than 90 percent was in engineering, business, science and math—significantly higher than engineering schools such as the Massachusetts Institute of Technology, Georgia Institute of Technology, and Rensselaer Polytechnic Institute. He noted "The university's name, however, does not reflect the distinctive nature of the campus. Often, UMR is viewed as a 'satellite' or 'branch' campus due to its name or as a 'feeder' campus for the University of Missouri-Columbia (commonly referred to as the University of Missouri). This branch-campus designation hinders many of our efforts to achieve national recognition and a strong reputation as a technological research university."


text: He noted, "Of the 1.1 million seniors in the nation who took the ACT in 2006, only 551 non-Missouri seniors – or .05 percent – sent their scores to UMR." He also noted that the school's acronym of UMR got it confused with the University of Minnesota Rochester.


text: Among the other names that were considered were Missouri University of Science and Engineering, Missouri Technological University, and Missouri Science and Engineering University.


text: The naming structure for the head of the university has changed reflecting its changes through the years. The head currently reports to the University of Missouri System.


text: The chancellor lives on campus at the Chancellor Residence (constructed in 1889 as the "Club House" dormitory, converted to a room house, before becoming the Missouri State Geological Survey headquarters and finally becoming the residence for the then-director in 1905).


text: In August 2018, a committee was announced to lead a nationwide search for the next chancellor, the office having been filled on an interim basis since May 2017. In May 2019, Mohammad Dehghani of Stevens Institute of Technology was announced as the next Missouri S&T chancellor, to begin service in August 2019. Dehghani had previously held leadership positions at the Lawrence Livermore National Laboratory, the Applied Physics Laboratory, and the Johns Hopkins University Systems Institute, at which he was a founding director.


text: In October 2020, the university received the largest single gift to any university, public or private, in the state of Missouri. The $300 million gift from June and Fred Kummer established a new foundation to establish the Kummer Institute for Student Success, Research and Economic Development. The gift also will establish a new college of innovation and entrepreneurship at Missouri S&T, develop new areas for research, provide scholarships and fellowships for students, and bolster the Rolla region's economy.


text: Military service has long been a tradition at the college. Beginning with the American Civil War, students and faculty have served in all major American conflicts.


text: Three individuals: James Abert, George D. Emerson, and Robert W. Douthat served in the American Civil War and as faculty.


text: When the United States entered WWI in April, 1917, a total of 65 members of the university, students and faculty, entered into the service for First Officers Training Camp. Almost half of the enrolled student population was involved in The Great War in some capacity, as the total enrollment was 186, down from 301 students. In total, nine men from the university sacrificed their lives. Two men received the Distinguished Service Cross from General John J. Pershing. One man, H. F. Allison, is credited with the first shot fired in France from a member of the American Expeditionary Force.


text: In 1920, the college started its Reserve Officer Training Corps. An integral part of university life, at least half of all students made ROTC a part of their curriculum from 1924 to 1940. Of the 931 students enrolled in 1940, 534 were also ROTC Cadets. Two cadets from these inter-war years eventually made the rank of general: Byron E. Peebles and Walter P. Leber, from the classes of 1936 and 1940, respectively.


text: After the bombing of Pearl Harbor, MSM faced the repeated challenge of students seeking to immediately enlist to help the war effort as had occurred in 1917. The 1941–42 administration, including Curtis Laws Wilson, instead encouraged the student body to finish their training as that would make them more useful to the military.


text: Bertlsmeyer Hall is located at the intersection of 11th street and State Street. The construction of Bertelsmeyer Hall broke ground in April 2013. It was named after James E. Bertelsmeyer (BS ChemE 1966), who contributed $5 million towards its construction. The building was dedicated in October 2014 and is the current home of the Chemical and Biochemical Engineering Department.


text: Castleman Hall, completed in March 1991, was dedicated in October 1991 as a new home for the alumni and development offices, and the music and theater departments. Featuring a 660-seat performing arts center, the building occupies the city block between Main and State Streets, and Tenth and Eleventh Streets. The alumni and music offices had been in Harris Hall since the 1970s. The Alumni Association moved to the Hasselmann building in 2015.


text: The Curtis Laws Wilson Library is the main academic library on campus. Wilson served as dean of the school from 1941 to 1963. The library's third floor is strictly a quiet study area with multiple rooms circling around the main area. The IT Helpdesk Walk-In Center is located on the first floor. The Miner Break Cafe (currently a Starbucks) is also located in the front right corner of the first floor.


text: The basement of the library is a quiet study area and is also home to several campus organizations, including:


text: Harris Hall opened in 1940 after Director William Chedsey was able to secure $80,000 from the Works Progress Administration and $50,000 in state funding. Harris Hall housed the Civil degree program for nearly two decades. As of April 2021, parts of the building are used by the Army ROTC Stonehenge Battalion, and Air Force ROTC Detachment 442. The building is named after Elmo Golightly Harris, one of the university's first directors, and the first chair of the department of civil engineering. Harris also led the first class held in the building.


text: The Hasselmann Alumni house was dedicated in 2015 as the home for the Miner Alumni Association and as a venue for campus and community events. It is named for Karl Hasselmann, a 1925 graduate in mining engineering, who had a prominent career in the oil industry. The Miner Alumni Association was organized in 1921 and publishes the "Missouri S&T Magazine" (formerly the "MSM Alumnus"). Alumni and other professionals also support the institution through discipline-specific academies which elect members for contributions to their professions and to the campus. These S&T groups serve an advisory role and include the Academy of Chemical Engineers, the Academy of Civil Engineers, the Academy of Computer Science, the Academy of Electrical and Computer Engineering, the Academy of Engineering Management, the Academy of Mechanical and Aerospace Engineers, the Academy of Miner Athletics, and the Mines and Metallurgy Academy.


text: The Havener Center is a multipurpose campus center for student life and activity. It is named for entrepreneur Gary Havener, a 1962 graduate in mathematics. It was dedicated in 2005 to house the Student Life offices, the campus bookstore, a food court, a gameroom, meeting space, etc.


text: Leach Theatre is located in Castleman Hall and has a maximum seating capacity of 650 audience members. The theatre was opened in 1991 and plays host to approximately 100 events each academic year, including campus events and touring performances of groups such as the St. Louis Symphony Orchestra, the Russian National Ballet, Stomp, as well as off-Broadway shows such as "Cats", "Evita", and "42nd Street".


text: The university developed a new way to make deep cuts in granite and worked with artist Edwina Sandys who used the method to create the Millennium Arch sculpture. The Arch is a single trilithon with the stylized silhouettes of a man and a woman cut from the two uprights. The figures cut from the uprights stand nearby as freestanding statues. The work, which is located on 10th Street facing Castleman Hall, was developed as a project of the High Pressure Waterjet Laboratory of the Rock Mechanics & Explosive Research Center at Missouri S&T.


text: There are two similar but smaller megaliths, showing the same silhouette, on each side of the sidewalk entrance to the Rock Mechanics & Explosive Research Center.


text: Missouri S&T Stonehenge is a partial reconstruction of the original Stonehenge monument located on Salisbury Plain, in southern England. Missouri S&T's version of the ancient structure is located on the northwest corner of campus, and was dedicated on June 20, 1984, during the summer solstice. It features a diameter ring of 30 stones around a horseshoe of five trilithons through which various sightings of sunrise and sunset can be made. About 160 tons of granite were used to construct the monument. The rock was cut by Missouri S&T's water jet cutter equipment, which used two waterjets cutting at a pressure of 15,000 pounds of force per square inch (103 MPa), slicing across the surface just like a conventional saw. The cutter moved at a speed of about 10 feet per minute (50 mm/s) and cut between one-quarter and one-half inch (6 and 13 mm) on each pass.


text: After completion, Missouri S&T Stonehenge received an award from the National Society of Professional Engineers for being one of 1985's Ten Outstanding Engineering Achievements.


text: The school operates the 200 kW Missouri S&T nuclear reactor on-campus for educational, training, and research purposes. It became the first nuclear reactor to have become operational in Missouri, and first achieved criticality in 1961.


text: The construction of Parker Hall was completed in 1912. The building housed the campus library until the opening of the Curtis Laws Wilson Library. Parker Hall is one of three buildings (The Rolla building and Norwood Hall being the other two) that are from the school's first 50 years. As of April 2021, Parker Hall holds the Visitor Center, Admissions Office, Registrar, Student Financial Assistance, Accounting and Cashier's Office, and administrative offices.


text: The Jack Carney Puck and Plaza is a small, circular stage in the center of the campus. It is used for many student events, and is particularly active during St. Patrick's Day festivities. The Puck is a common gathering area, and tours given to new students often start at the landmark. The stage is recarpeted each year to reflect the next "Best Ever" St. Patrick's Day. Reconstruction of the area around the Puck began in late 2020 to renovate the landmark in honor of former Chancellor John F. "Jack" Carney III. The campus landmark's dedication was celebrated in October 2021.


text: Originally known as the New Chemistry Building and built in 1940, Schrenk Hall is home to the Chemistry and Biological Sciences departments.


text: Officially opened in December 2010, the Solar Village consists of four entries by Missouri S&T in the U.S. Department of Energy Solar Decathlon. Students, staff, faculty, and donors of Missouri S&T designed, constructed, and competed homes in each of the first four Decathlons including the Solar House in 2002, the Prairie House in 2005, the Solar House in 2007, and the Show-Me House in 2009. In 2012, the Solar Village was one of two highlights in a video short that won recognition from Second Nature and a Climate Leadership Award for the campus. In 2014, the Solar Village was expanded to include a microgrid system and an electric car charging station, and in 2016, Missouri S&T announced a second, EcoVillage, composed of Decathlon entries including the 2013 Chameleon House and the 2015 Nest Home.


text: The Kummer Design Center was dedicated on May 20, 2011. It was named after Fred and June Kummer who donated $1.25 million of the $2.75 million project, which was funded entirely by private gifts to the university. Fred Kummer is an alumnus of the university. The Kummer Design Center was initially a building. The building formerly housed the Student Rec Center, and before that it was a Holsum Bread Bakery.


text: The Kummer Design Center is located at 1051 N Bishop Avenue in Rolla, and is home to the SDELC, short for Student Design and Experiential Learning Center. The SDELC contains offices, a conference room, a machine shop, labs, a computer lab, and an iGEM lab. Twenty of the university's design teams are housed inside of the SDELC. There are approximately twelve hundred students involved on said design teams, and they have 24/7 access to the design center. These students get to use their experiences on the design teams for the university-required experiential learning. The Kummer Design Center is also home to American Pie Company and Spoon Me (frozen yogurt) fast food restaurants.


text: On April 26, 2019, a Mars Rover designed by S&T's Mars Rover Team broke ground on an expansion for the Kummer Design Center. The expansion added of new labs, manufacturing, and fabrication bays. In addition it expanded the waterjet, welding, and composites labs. The expansion doubled the size of the previous SDELC. Brinkmann Constructors is the company that built the addition onto the design center. The expansion's highest-level donors were Richard and Nancy Arnold, Brinkmann Constructors, Roger and Karen LaBoude, and Fred and June Kummer. The new expansion was dedicated on September 11, 2020, to a virtual audience.


text: In the beginning of the COVID-19 pandemic, students and staff used the design center to make PPE for Phelps Health and other surrounding medical facilities. The design center utilized 3D printers to print prototype face shield brackets and face masks. Some of the prototype files were released for the public to print.


text: The Electromagnetic Compatibility (EMC) Laboratory supports related research. The Missouri University of Science and Technology Electromagnetic Compatibility Consortium is a broad partnership of digital electronics companies committed to funding electromagnetic compatibility research through this facility.


text: This limestone mine is located near the main campus and is used for the teaching and research activities of the Department of Mining Engineering. The facilities, which cover , include the mine and adjacent surface dolomite quarries. The mine supports student competition teams, such as the mine rescue team, and the annual "Haunted Mine" Halloween event. The mine has been used by the school since 1921.


text: The Student Design & Experiential Learning Center (SDELC) was established in 2000 to better support the various multi-disciplinary student design teams. In 2004, the center's mission expanded to provide experiential learning in academic courses, identify and support student service learning projects within the curriculum, and support ad hoc student teams in specialty academic events involving multi-disciplinary student research.


text: By 2006, the SDELC had expanded to ten student design teams. The center's expanded mission involved better funding and offering support and resources to multi-disciplinary project teams that had a research base to their activities. The SDELC provided academic credit opportunities in the form of three, one-hour classes on design, leadership and communication. The center also offers a half-credit course on experiential design through the Residential College (RC) program which has a per-semester enrollment of over 100 students engaged in hands-on learning projects. The SDELC's student design teams, research teams and projects, and academic courses are the foundation of experiential learning at Missouri S&T.


text: The Missouri S&T athletic teams are named the Miners and Lady Miners. The university is a member of the Division II level of the National Collegiate Athletic Association (NCAA), primarily competing in the Great Lakes Valley Conference (GLVC) for most of its sports since the 2005–06 academic year; while its men's swimming team competes in the New South Intercollegiate Swim Conference (NSISC). The Miners and Lady Miners previously competed in the Mid-America Intercollegiate Athletics Association (MIAA) from 1935–36 to 2004–05; and in the Missouri College Athletic Union (MCAU) of the National Association of Intercollegiate Athletics (NAIA) from 1924–25 to 1932–33.


text: Missouri S&T competes in 17 intercollegiate varsity sports (10 for men, 7 for women): Men's sports include baseball, basketball, cross country, football, golf, soccer, swimming, track & field (indoor and outdoor) and volleyball; while women's sports include basketball, cross country, soccer, softball, track & field (indoor and outdoor), volleyball and spirit squad. Former sports included women's golf. As of July 2022, men's volleyball became the 17th varsity sport in the 2023 spring season (2022–23 school year).


text: The name comes from the university's history as a mining school. Intercollegiate competition began with a baseball game in 1892 with the first football game in the following year.


text: Club sports associated with Missouri S&T include ultimate frisbee, lacrosse, rugby union, roller hockey, trap and skeet, tennis, baseball, and water polo.


text: Intramural sports have a very large following at the Missouri S&T. With over 60 men's teams and over 10 women's teams, sports are arranged into divisions. Thirty different sports are contested each year: golf, softball, swimming, ultimate, flag football, billiards, badminton, volleyball, racquetball, bowling, basketball, table tennis, tennis, track, weightlifting, and soccer.


text: There are over 200 student organizations at Missouri S&T, including student government, professional societies, community service organizations, and religious and cultural groups.


text: The student-run newspaper at Missouri S&T, "The Missouri Miner", is published every Thursday during the school year and can be read online, with ongoing digitization of each issue since the first in 1915. In February 2007, the paper threatened to sue the school because the university cut funding. After a one-school-year break for many reasons including a funding cut, "The Missouri Miner" continued publication in the fall semester of 2009.


text: Production of the university's "RollaMo" yearbook is handled by undergraduate students. Amateur radio station, WØEEE, founded in 1931 and run by the Amateur Radio Club, was the first campus club at MSM and is one of the oldest student/college amateur stations in the US. The club is located in Emerson Electrical Company Hall.


text: Two broadcast radio stations are associated with Missouri S&T: KMNR, previously known as KMSM, is a student-run, freeform radio station whose music playlist varies with the mood and inclination of the DJ, with some playing caller requests. Every year KMNR hosts two concerts – Freakers Ball in the fall and MasqueRave (formerly Glitter Ball) in the spring. KMST, previously known as KUMR, is a member-supported public radio station, typically playing classical, bluegrass and jazz and National Public Radio programs. On July 16, 2007, KUMR officially changed its call letters to KMST, in advance of the change of name from "University of Missouri–Rolla" to the "Missouri University of Science and Technology". In 2017, KMST's broadcast operations were transferred to the University of Missouri–St. Louis.


text: There are 19 fraternities and 5 sororities, which collectively raise over $125,000 annually toward various philanthropies.


text: The Beta-Eta chapter of Tau Kappa Epsilon was founded at the Missouri School of Mines and Metallurgy on March 8, 1947 – the fraternity's 55th chapter. It remains active at Missouri S&T and has a chartered alumni association. As of fall 2022, the chapter had initiated 1,259 members and received 69 international awards. The Beta-Eta chapter has been recognized internationally nine times as a "Top TKE Chapter", the fraternity's highest recognition for a chapter, most recently for the 2021–2022 academic year. In 2017, the Tau Kappa Epsilon chapter at Missouri S&T completed construction of a new chapter house on Fraternity Row where the old Delta Sigma Phi round house was located. The former TKE house was demolished in 2020 after asbestos abatement in 2019.


text: The Christian Campus Fellowship also provides university-approved housing just off campus for 64 residents.


text: Most of the former Quadrangle residence hall buildings were razed and replaced with a parking lot in the late 2010s.


text: St. Patrick's Day is the largest annual celebration and predominant cultural event at Missouri S&T, with each year's observance touted as the "Best Ever!". During St. Pat's, students wear green sweatshirts (which are sold as fund-raisers throughout the season), carry shillelaghs and party (including drinking green beer). One tradition, observed primarily among fraternities, is the "killing" of rubber snakes in commemoration of St. Patrick's mythical banishing of snakes from Ireland.


text: Along with the snake invasion comes the tradition of Follies. Students meet daily at "the Puck" (a short cylindrical stage bearing a large shamrock) to hear jokes and participate in short competitions. On the third day of Follies, students move to the town's band-shell to participate in the ceremonial arrival of St. Pat's Court. The day after Follies, students participate in "Gonzo and Games". Gonzo and Games are two days of elaborate games in which different organizations compete. Friday of St. Pat's week is concluded with Coronation, a ceremony where the Queen of Love and Beauty is announced. The final event of St. Pat's week is a Saturday morning parade on Pine Street, which is painted green by St. Pat's Board Alumni. This parade is known throughout the United States and boasts well over one hundred floats and participating groups.


text: Such recognition of St. Patrick began in 1903 when the engineering students of the University of Missouri in Columbia claimed St. Patrick's Day to be a holiday for engineers. The tradition continues and has been adopted by many other schools across the nation. A bronze statue of St. Patrick, by St. Louis sculptor Rudolph Edward Torrini, is located on the Wilson Library Plaza. St. Patrick's Day 2008 marked the one hundredth consecutive year of the holiday's celebration at Missouri S&T. The university cancelled all school-sanctioned St. Patrick's Day celebrations for the first time in 2020 due to the COVID-19 pandemic. 2021 included "part virtual and part socially distanced" events for the holiday.


title: Second Bank of the United States

text: The Second Bank of the United States was the second federally authorized Hamiltonian national bank in the United States. Located in Philadelphia, Pennsylvania, it was chartered from February 1816 to January 1836. The Bank's formal name, according to section 9 of its charter as passed by Congress, was "The President Directors and Company of the Bank of the United States". While other banks in the US were chartered by and only allowed to have branches in a single state, it was authorized to have branches in multiple states and lend money to the US government.


title: Second Bank of the United States

text: A private corporation with public duties, the Bank handled all fiscal transactions for the U.S. Government, and was accountable to Congress and the U.S. Treasury. Twenty percent of its capital was owned by the federal government, the Bank's single largest stockholder. Four thousand private investors held 80 percent of the Bank's capital, including three thousand Europeans. The bulk of the stocks were held by a few hundred wealthy Americans. In its time, the institution was the largest monied corporation in the world.


title: Second Bank of the United States

text: The essential function of the Bank was to regulate the public credit issued by private banking institutions through the fiscal duties it performed for the U.S. Treasury, and to establish a sound and stable national currency. The federal deposits endowed the Bank with its regulatory capacity.


title: Second Bank of the United States

text: Modeled on Alexander Hamilton's First Bank of the United States, the Second Bank was chartered by President James Madison, who in 1791 had attacked the First Bank as unconstitutional, in 1816 and began operations at its main branch in Philadelphia on January 7, 1817, managing 25 branch offices nationwide by 1832.


title: Second Bank of the United States

text: The efforts to renew the Bank's charter put the institution at the center of the general election of 1832, in which the Bank's president Nicholas Biddle and pro-bank National Republicans led by Henry Clay clashed with the "hard-money" Andrew Jackson administration and eastern banking interests in the Bank War. Failing to secure recharter, the Second Bank became a private corporation in 1836, and underwent liquidation in 1841.


title: Second Bank of the United States

text: The political support for the revival of a national banking system was rooted in the early 19th century transformation of the country from simple Jeffersonian agrarianism towards one interdependent with industrialization and finance. In the aftermath of the War of 1812, the federal government suffered from the disarray of an unregulated currency and a lack of fiscal order; business interests sought security for their government bonds. A national alliance arose to legislate a national bank to address these needs.


title: Second Bank of the United States

text: The political climate—dubbed the Era of Good Feelings—favored the development of national programs and institutions, including a protective tariff, internal improvements and the revival of a Bank of the United States. Southern and western support for a bank, led by Republican nationalists John C. Calhoun of South Carolina and Henry Clay of Kentucky, was decisive in the successful chartering effort. The charter was signed into law by James Madison on April 10, 1816. Subsequent efforts by Calhoun and Clay to earmark the Bank's $1.5 million establishment "bonus", and annual dividends estimated at $650,000, as a fund for internal improvements, were vetoed by President Madison, on strict constructionist grounds.


title: Second Bank of the United States

text: Opposition to a new bank emanated from two interests. Old Republicans, represented by John Taylor of Caroline and John Randolph of Roanoke, characterized the Second Bank as both constitutionally illegitimate and a direct threat to Jeffersonian agrarianism, state sovereignty and the institution of slavery, expressed by Taylor's statement that "...if Congress could incorporate a bank, it might emancipate a slave." Hostile to the regulatory effects of the national bank, private banks—proliferating with or without state charters—had scuttled rechartering of the First Bank in 1811. These interests played significant roles in undermining the institution during the administration of U.S. President Andrew Jackson (1829–1837).


title: Second Bank of the United States

text: The Second Bank was a national bank. However, it did not serve the functions of a modern central bank: It did not set monetary policy, regulate private banks, hold their excess reserves, or act as a lender of last resort.


title: Second Bank of the United States

text: The Bank was launched in the midst of a major global market readjustment as Europe recovered from the Napoleonic Wars. It was charged with restraining uninhibited private bank note issue—already in progress—that threatened to create a credit bubble and the risks of a financial collapse. Government land sales in the West, fueled by European demand for agricultural products, ensured that a speculative bubble would form. Simultaneously, the national bank was engaged in promoting a democratized expansion of credit to accommodate laissez-faire impulses among eastern business entrepreneurs and credit-hungry western and southern farmers.


title: Second Bank of the United States

text: Under the management of its first president William Jones, the Bank failed to control paper money issued from its branch banks in the West and South, contributing to the post-war speculative land boom. When the U.S. markets collapsed in the Panic of 1819—a result of global economic adjustments—the Bank came under withering criticism for its belated tight money policies—policies that exacerbated mass unemployment and plunging property values. Further, it transpired that branch directors for the Baltimore office had engaged in fraud and larceny.


title: Second Bank of the United States

text: Resigning in January 1819, Jones was replaced by Langdon Cheves, who continued the contraction in credit in an effort to stop inflation and stabilize the Bank, even as the economy began to correct. The Bank's reaction to the crisis—a clumsy expansion, then a sharp contraction of credit—indicated its weakness, not its strength. The effects were catastrophic, resulting in a protracted recession with mass unemployment and a sharp drop in property values that persisted until 1822. The financial crisis raised doubts among the American public as to the efficacy of paper money, and in whose interests a national system of finance operated. Upon this widespread disaffection the anti-bank Jacksonian Democrats would mobilize opposition to the Bank in the 1830s. The Bank was in general disrepute among most Americans when Nicholas Biddle, the third and last president of the Bank, was appointed by President James Monroe in 1823.


title: Second Bank of the United States

text: Under Biddle's guidance, the Bank evolved into a powerful institution that produced a strong and sound system of national credit and currency. From 1823 to 1833, Biddle expanded credit steadily, but with restraint, in a manner that served the needs of the expanding American economy. Albert Gallatin, former Secretary of the Treasury under Thomas Jefferson and James Madison, wrote in 1831 that the Bank was fulfilling its charter expectations.


title: Second Bank of the United States

text: By the time of Jackson's inauguration in 1829, the Bank appeared to be on solid footing. The Supreme Court had affirmed its constitutionality in "McCulloch v. Maryland", the 1819 case which Daniel Webster had argued successfully on its behalf a decade earlier, the Treasury recognized the useful services it provided, and the American currency was healthy and stable. Public perceptions of the national bank were generally positive. The Bank first came under attack by the Jackson administration in December 1829, on the grounds that it had failed to produce a stable national currency, and that it lacked constitutional legitimacy. Both houses of Congress responded with committee investigations and reports affirming the historical precedents for the Bank's constitutionality and its pivotal role in furnishing a uniform currency. Jackson rejected these findings, and privately characterized the Bank as a corrupt institution, dangerous to American liberties.


title: Second Bank of the United States

text: Biddle made repeated overtures to Jackson and his cabinet to secure a compromise on the Bank's rechartering (its term due to expire in 1836) without success. Jackson and the anti-bank forces persisted in their condemnation of the Bank, provoking an early recharter campaign by pro-bank National Republicans under Henry Clay. Clay's political ultimatum to Jackson—with Biddle's financial and political support—sparked the Bank War and placed the fate of the Bank at center of the 1832 presidential election.


title: Second Bank of the United States

text: Jackson mobilized his political base by vetoing the recharter bill and, the veto sustained, easily won reelection on his anti-bank platform. Jackson proceeded to destroy the Bank as a financial and political force by removing its federal deposits, and in 1833, federal revenue was diverted into selected private banks by executive order, ending the regulatory role of the Second Bank.


title: Second Bank of the United States

text: In hopes of extorting a rescue of the Bank, Biddle induced a short-lived financial crisis that was initially blamed on Jackson's executive action. By 1834, a general backlash against Biddle's tactics developed, ending the panic, and all recharter efforts were abandoned.


title: Second Bank of the United States

text: In February 1836, the Bank became a private corporation under Pennsylvania law. A shortage of hard currency ensued, causing the Panic of 1837 and lasting approximately seven years. The bank suspended payment from October 1839 to January 1841, and permanently in February 1841. It then started a lengthy liquidation process, complicated by lawsuits, that ended in 1852 when it assigned its remaining assets to trustees and surrendered the state charter.


title: Second Bank of the United States

text: The Second Bank was America's national bank, comparable to the Bank of England and the Bank of France, with one key distinction – the United States government owned one-fifth (20 percent) of its capital. Whereas other national banks of that era were wholly private, the Second Bank was more characteristic of a government bank.


title: Second Bank of the United States

text: Under its charter, the Bank had a capital limit of $35 million, $7.5 million of which represented the government-owned share. It was required to remit a "bonus" payment of $1.5 million, payable in three installments, to the government for the privilege of using the public funds, interest free, in its private banking ventures. The institution was answerable for its performance to the U.S. Treasury and Congress and subject to Treasury Department inspection.


title: Second Bank of the United States

text: As exclusive fiscal agent for the federal government, it provided a number of services as part of its charter, including holding and transfer of all U.S. deposits, payment and receipt of all government transactions, and processing of tax payments. In other words, the Bank was "the depository of the federal government, which was its principal stockholder and customer."


title: Second Bank of the United States

text: The chief personnel for the Bank comprised 25 directors, five of whom were appointed by the President of the United States, subject to Senate approval. Federally appointed directors were barred from acting as officials in other banks. Two of the three Bank presidents, William Jones and Nicholas Biddle, were chosen from among these government directors.


title: Second Bank of the United States

text: Headquartered in Philadelphia, the Bank was authorized to establish branch offices where it deemed suitable, and these were immune from state taxation.


title: Second Bank of the United States

text: The primary regulatory task of the Second Bank, as chartered by Congress in 1816, was to restrain the uninhibited proliferation of paper money (bank notes) by state or private lenders, which was highly profitable to these institutions. In this capacity, the Bank would preside over this democratization of credit, contributing to a vast and profitable disbursement of bank loans to farmers, small manufacturers and entrepreneurs, encouraging rapid and healthy economic expansion. Historian Bray Hammond describes the mechanism by which the bank exerted its anti-inflationary influence:


title: Second Bank of the United States

text: Under this banking regime, the impulse towards over-speculation, with the risks of creating a national financial crisis, would be avoided, or at least mitigated. It was just this mechanism that the local private banks found objectionable, because it yoked their lending strategies to the fiscal operations of the national government, requiring them to maintain adequate gold and silver reserves to meet their debt obligations to the U.S. Treasury. The proliferation of private-sector banking institutions – from 31 banks in 1801 to 788 in 1837 – meant that the Second Bank faced strong opposition from this sector during the Jackson administration.


title: Second Bank of the United States

text: The architect of the Second Bank was William Strickland (1788–1854), a former student of Benjamin Latrobe (1764–1820), the man who is often called the first professionally trained American architect. Latrobe and Strickland were both disciples of the Greek Revival style. Strickland went on to design many other American public buildings in this style, including financial structures such as the Mechanics National Bank (also in Philadelphia). He also designed the second building for the main U.S. Mint in Philadelphia in 1833, as well as the New Orleans, Dahlonega, and Charlotte branch mints in the mid-to-late 1830s.


title: Second Bank of the United States

text: Strickland's design for the Second Bank is in essence based on the Parthenon in Athens, and is a significant early and monumental example of Greek Revival architecture. The hallmarks of the Greek Revival style can be seen immediately in the north and south façades, which use a large set of steps leading up to the main level platform, known as the stylobate. On top of these, Strickland placed eight severe Doric columns, which are crowned by an entablature containing a triglyph frieze and simple triangular pediment. The building appears much as an ancient Greek temple, hence the stylistic name. The interior consists of an entrance hallway in the center of the north façade flanked by two rooms on either side. The entry leads into two central rooms, one after the other, that span the width of the structure east to west. The east and west sides of the first large room are each pierced by a large arched fan window. The building's exterior uses Pennsylvania blue marble, which, due to the manner in which it was cut, has begun to deteriorate due to weak parts of the stone being exposed to the elements. This phenomenon is most visible on the Doric columns of the south façade. Construction lasted from 1819 to 1824.


title: Second Bank of the United States

text: The Greek Revival style used for the Second Bank contrasts with the earlier, Federal style in architecture used for the First Bank of the United States, which also still stands and is located nearby in Philadelphia. This can be seen in the more Roman-influenced Federal structure's ornate, colossal Corinthian columns of its façade, which is also embellished by Corinthian pilasters and a symmetric arrangement of sash windows piercing the two stories of the façade. The roofline is also topped by a balustrade, and the heavy modillions adorning the pediment give the First Bank an appearance much more like a Roman villa than a Greek temple.


title: Second Bank of the United States

text: Since the Bank's closing in 1841, the edifice has performed a variety of functions. Today, it is part of Independence National Historical Park in Philadelphia. The structure is open to the public free of charge and serves as an art gallery, housing a large collection of portraits of prominent early Americans painted by Charles Willson Peale and many others.


title: Second Bank of the United States

text: The building was designated a National Historic Landmark in 1987 for its architectural and historic significance.


title: Second Bank of the United States

text: The Wall Street branch in New York City was converted into the United States Assay Office before it was demolished in 1915. The federal-style façade was saved and installed in the American Wing of the Metropolitan Museum of Art in 1924.


title: Second Bank of the United States

text: The Second Bank building was described by Charles Dickens in a chapter of his 1842 travelogue "American Notes for General Circulation", Philadelphia, and its solitary prison: We reached the city, late that night. Looking out of my chamber-window, before going to bed, I saw, on the opposite side of the way, a handsome building of white marble, which had a mournful ghost-like aspect, dreary to behold. I attributed this to the sombre influence of the night, and on rising in the morning looked out again, expecting to see its steps and portico thronged with groups of people passing in and out. The door was still tight shut, however; the same cold cheerless air prevailed: and the building looked as if the marble statue of Don Guzman could alone have any business to transact within its gloomy walls. I hastened to inquire its name and purpose, and then my surprise vanished. It was the Tomb of many fortunes; the Great Catacomb of investment; the memorable United States Bank.


title: Second Bank of the United States

text: The stoppage of this bank, with all its ruinous consequences, had cast (as I was told on every side) a gloom on Philadelphia, under the depressing effect of which it yet laboured. It certainly did seem rather dull and out of spirits.


title: Lesch–Nyhan syndrome

text: Lesch–Nyhan syndrome (LNS) is a rare inherited disorder caused by a deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT). This deficiency occurs due to mutations in the "HPRT1" gene located on the X chromosome. LNS affects about 1 in 380,000 live births. The disorder was first recognized and clinically characterized by American medical student Michael Lesch and his mentor, pediatrician William Nyhan, at Johns Hopkins.


title: Lesch–Nyhan syndrome

text: The HGPRT deficiency causes a build-up of uric acid in all body fluids. The combination of increased synthesis and decreased utilization of purines leads to high levels of uric acid production. This results in both high levels of uric acid in the blood and urine, associated with severe gout and kidney problems. Neurological signs include poor muscle control and moderate intellectual disability. These complications usually appear in the first year of life. Beginning in the second year of life, a particularly striking feature of LNS is self-mutilating behaviors, characterized by lip and finger biting. Neurological symptoms include facial grimacing, involuntary writhing, and repetitive movements of the arms and legs similar to those seen in Huntington's disease. The cause of the neurological abnormalities remains unknown. Because a lack of HGPRT causes the body to poorly utilize vitamin B, some males may develop megaloblastic anemia.


title: Lesch–Nyhan syndrome

text: LNS is inherited in an X-linked recessive manner; the gene mutation is usually carried by the mother and passed on to her son, although one-third of all cases arise "de novo" (from new mutations) and do not have a family history. LNS is present at birth in baby boys. Most, but not all, persons with this deficiency have severe mental and physical problems throughout life. Cases in females are very rare.


title: Lesch–Nyhan syndrome

text: The symptoms caused by the buildup of uric acid (gout and kidney symptoms) respond well to treatment with medications such as allopurinol that reduce the levels of uric acid in the blood. The mental deficits and self-mutilating behavior do not respond well to treatment. There is no cure, but many affected people live to adulthood. Several new experimental treatments may alleviate symptoms.


title: Lesch–Nyhan syndrome

text: LNS is characterized by three major hallmarks: neurologic dysfunction, cognitive and behavioral disturbances including self-mutilation, and uric acid overproduction (hyperuricemia). Damage to the basal ganglia causes affected individuals to adopt a characteristic fencing stance due to the nature of the lesion. Some may also have macrocytic anemia due to the faulty DNA synthesis, most likely due to deficient purine synthesis that leads to a lag of cell division with respect to increases in cell mass. Virtually all patients are male; males experience delayed growth and puberty, and most develop shrunken testicles or testicular atrophy. Female carriers are at an increased risk for gouty arthritis but are usually otherwise unaffected.


title: Lesch–Nyhan syndrome

text: One of the first symptoms of the disease is the presence of sand-like crystals of uric acid in the diapers of the affected infant. Overproduction of uric acid may lead to the development of uric acid crystals or stones in the kidneys, ureters, or bladder. Such crystals deposited in joints later in the disease may produce gout-like arthritis, with swelling and tenderness. The overproduction of uric acid is present at birth, but may not be recognized by routine clinical laboratory testing methods. The serum uric acid concentration is often normal, as the excess purines are promptly eliminated in the urine. The crystals usually appear as an orange grainy material, or they may coalesce to form either multiple tiny stones or distinct large stones that are difficult to pass. The stones, or calculi, usually cause hematuria (blood in the urine) and increase the risk of urinary tract infection. Some affected people have kidney damage due to such kidney stones. Stones may be the presenting feature of the disease, but can go undetected for months or even years.


title: Lesch–Nyhan syndrome

text: The periods before and surrounding birth are typically normal in individuals with LNS. The most common presenting features are abnormally decreased muscle tone (hypotonia) and developmental delay, which are evident by three to six months of age. Affected individuals are late in sitting up, while most never crawl or walk. Lack of speech is also a very common trait associated with LNS.


title: Lesch–Nyhan syndrome

text: Irritability is most often noticed along with the first signs of nervous system impairment. Within the first few years of life, extrapyramidal involvement causes abnormal involuntary muscle contractions such as loss of motor control (dystonia), writhing motions (choreoathetosis), and arching of the spine (opisthotonus). Signs of pyramidal system involvement, including spasticity, overactive reflexes (hyperreflexia) and extensor plantar reflexes, also occur. The resemblance to athetoid cerebral palsy is apparent in the neurologic aspects of LNS. As a result, most individuals are initially diagnosed as having cerebral palsy. The motor disability is so extensive that most individuals never walk, and become lifelong wheelchair users.


title: Lesch–Nyhan syndrome

text: Persons affected are cognitively impaired and have behavioral disturbances that emerge between two and three years of age. The uncontrollable self-injury associated with LNS also usually begins at three years of age. The self-injury begins with biting of the lips and tongue; as the disease progresses, affected individuals frequently develop finger biting and headbanging. The self-injury can increase during times of stress. Self-harm is a distinguishing characteristic of the disease and is apparent in 85% of affected males.


title: Lesch–Nyhan syndrome

text: The majority of individuals are cognitively impaired, which is sometimes difficult to distinguish from other symptoms because of the behavioral disturbances and motor deficits associated with the syndrome. In many ways, the behaviors may be seen as a psychological extension of the compulsion to cause self-injury, and include rejecting desired treats or travel, repaying kindness with coldness or rage, failing to answer test questions correctly despite study and a desire to succeed, and provoking anger from caregivers when affection is desired.


title: Lesch–Nyhan syndrome

text: Compulsive behaviors also occur, including aggressiveness, vomiting, spitting, and coprolalia (involuntary swearing). The development of this type of behavior is sometimes seen within the first year, or in early childhood, but others may not develop it until later in life.


title: Lesch–Nyhan syndrome

text: While carrier females are generally an asymptomatic condition, they do experience an increase in uric acid excretion, and some may develop symptoms of hyperuricemia, and experience gout in their later years. Testing in this context has no clinical consequence, but it may reveal the possibility of transmitting the trait to male children. Women may also require testing if a male child develops LNS. In this instance, a negative test means the son's disease is the result of a new mutation, and the risk in siblings is not increased.


title: Lesch–Nyhan syndrome

text: Females who carry one copy of the defective gene are carriers with a 50% chance of passing the disease on to their sons. In order for a female to be affected, she would need to have two copies of the mutated gene, one of which would be inherited from her father. Males affected with LNS do not usually have children due to the debilitating effects of the disease. It is possible for a female to inherit an X chromosome from her unaffected father, who carries a new mutation of the HGPRT gene. Under these circumstances, a girl could be born with LNS, and though there are a few reports of this happening, it is very rare. The overwhelming majority of patients with LNS are male.


title: Lesch–Nyhan syndrome

text: A less severe, related disease, partial HPRT deficiency, is known as Kelley–Seegmiller syndrome (Lesch–Nyhan syndrome involves total HPRT deficiency). Symptoms generally involve less neurological involvement but the disease still causes gout and kidney stones.


title: Lesch–Nyhan syndrome

text: LNS is due to mutations in the "HPRT1" gene, so named because it codes for the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT or HGPRT, ). This enzyme is involved in the biochemical pathways the body uses to produce purines, one of the components of DNA and RNA. Defects of this enzyme lead to increased production of uric acid. Since the "HPRT" gene is located on the X chromosome, LNS is an X-linked inherited disease.


title: Lesch–Nyhan syndrome

text: The father of an affected male will not be the carrier of the mutant allele, and will not have the disease. An obligate carrier would be a woman who has an affected son and one other affected relative in the maternal line.


title: Lesch–Nyhan syndrome

text: If a woman is the first in her family with an affected son, Haldane's rule predicts a 2/3 chance that she is a carrier and a 1/3 chance that the son has a new germline mutation.


title: Lesch–Nyhan syndrome

text: The risk to siblings of an affected individual depends upon the carrier status of the mother herself. A 50% chance is given to any female who is a carrier to transmit the HPRT1 mutation in each pregnancy. Sons who inherit the mutation will be affected while daughters who inherit the mutation are carriers. Therefore, with each pregnancy, a carrier female has a 25% chance of having a male that is affected, a 25% chance of having a female that is a carrier, and a 50% chance of having a normal male or female.


title: Lesch–Nyhan syndrome

text: Males with LNS do not reproduce due to the characteristics of the disease. However, if a male with a less severe phenotype reproduces, all of his daughters are carriers, and none of his sons will be affected.


title: Lesch–Nyhan syndrome

text: As in other X-linked diseases, males are affected because they only have one copy of the X chromosome. In Lesch–Nyhan syndrome, the defective gene is that for hypoxanthine-guanine phosphoribosyltransferase (HGPRT), a participant in the 'recycling' of purine nucleotides. Female carriers have a second X chromosome, which contains a "normal" copy of HPRT, preventing the disease from developing, though they may have increased risk of hyperuricemia.


title: Lesch–Nyhan syndrome

text: A large number of mutations of HPRT are known. Mutations that only mildly decrease the enzyme's function do not normally cause the severe form of LNS, but do produce a milder form of the disease which still features purine overproduction accompanied by susceptibility to gout and uric acid nephrolithiasis.


title: Lesch–Nyhan syndrome

text: Formation of DNA (during cell division) requires nucleotides, molecules that are the building blocks for DNA. The purine bases (adenine and guanine) and pyrimidine bases (thymine and cytosine) are bound to deoxyribose and phosphate and incorporated as necessary. Normally, the nucleotides are synthetized "de novo" from amino acids and other precursors. A small part, however, is 'recycled' from degraded DNA of broken-down cells. This is termed the "salvage pathway".


title: Lesch–Nyhan syndrome

text: HGPRT is the "salvage enzyme" for the purines: it channels hypoxanthine and guanine back into DNA synthesis. Failure of this enzyme has two results:


title: Lesch–Nyhan syndrome

text: It was previously unclear whether the neurological abnormalities in LNS were due to uric acid neurotoxicity or to a relative shortage in "new" purine nucleotides during essential synthesis steps. Genetic mutations affecting the enzymes of the "de novo" synthesis pathway may possibly contribute to the disease, although these are rare or unknown. Uric acid has been suggested as a possible cause of neurotoxicity but this is unproven.