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Phylogenetics comes with a rich repertoire of computational methods for likelihood-based inference of phylogenetic trees [246]. Traditionally, these methods are used to reconstruct the evolutionary history of a set of distinct species. However, they can also be applied to cancer cells or subclones (Fig. 4). In this setting, tips of the phylogeny (also called leaves or taxa) represent sampled and sequenced cells or subclones, whereas inner nodes (also called ancestral) represent their hypothetical common ancestors. The input for a phylogenetic inference commonly consists of a multiple sequence alignment (MSA) of molecular sequences for the species of interest. For cancer phylogenies, one would concatenate the SNVs (and possibly other variant types) to assemble the input MSA. The key challenge for phylogenetic method development comprises designing sequence evolution models that are (i) biologically realistic and yet (ii) computationally tractable for the increasingly large number of sequenced cells per patient and study.

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Tho tha lesta kêm er en hloth månniska mith forande twahondred êlephanta thvsend kêmlun tolêden mith wodenbalkum, râpum ånd allerlêja ark vmbe vsa flâtenêi tha Middelsê to tyande. Thåt bisâwd-vs,ånd likt [170]vs bal to, menNêarchus teld vs, sin kêning wilde tha ôtherakêninggar tâna that i weldiger wêre, sâ thakêninggar fon Thyris êr wêsen hêde. Wi skoldonmen mith helpa, sêkur skolde vs thåt nên skâdanavt dva. Wi moston wel swika, ånd Nearchus wiste ella sâpront to birjuchte thåt wi inna Middelsê lêideêr thrja mônatha forby wêron. Tha Alexandre fornomho-t mith sinra onwerp ofkvmen was, wårth er sa vrmêtenthåt er tha drage strête utdiapa wilde Irtha to-n spot. MenWr.alda lêt sine sêle lâs, thêrvmbe vrdronk erinna win ånd in sina ovirmodichhêd, êr thåt erbijinna kvste. After sin dâd wrde thet rik dêlad thrvchsina forsta. Hja skolde alrek en dêl to fara sina svnumwârja, thach hja wêron vnmênis. Elk wilde sindêl bihalda ånd selva formâra. Tha kêm orlochånd wi ne kvste navt omme kêra. Nêarchus wilde nw, wiskolde vs del setta an Phonisi his kâd, men thåt nildenimman navt ne dva. Wi sêide, rêder willath wi wâganêi Fryasland to gâna. Tha brocht-er vs nei thêre nyahâva fon Athenia, hwêr alle åfte Fryas bern formelshin têin wêron. Forth gvngon wi salt-âtha liftochtaånd wêpne fâra. Among tha fêlo forstahêde Nêarchus en frjund mith nôme Antigonus. Thissestrêdon bêde vmb ên dol, sâ hja sêidon asfollistar to fâra-t kêninglike slachte ånd forth vmbealle Krêkalanda hjara alda frydom wither to jêvane.Antigonus hêde among fêlo ôtherum ênnen svn,thi hête Demêtrius, åfter tonômad thenestêda winner. Thisse gvng ênis vpper stêdeSalâmis of. Nêi thåt er thêr en stûtmêi strêden hêde most er mith thêre flâtestrida fon Ptholemeus. Ptholemêus, alsa hête thene forstthêr welda ovir Êgiptaland. Dêmêtrius wnthêre kêse, tha navt thrvch sina salt-âtha, menthrvch dam wy him helpen hêde. Thit hêde wi dênthrvch athskip to fâra Nêarchus, hwand wi him far basterdblod bikånde thrvch sin friska hûd ånd blâwaâgon mith [172]wit hêr. Afternêi gvng Dêmêtrius lâs vp Hrodus4thêr hinne brochton wi sina salt-âtha ând liftochtawr. Thâ wi tha leste rêis to Hrodus kêmon, was orlochvrtyan. Dêmêtrius was nêi Athenia fâren. Tha vskêning thåt vnderstande, lêd-er vs tobek. Tha wi andahâve kêmon, wêre êl et thorp in row bidobben.Friso thêr kêning wêr ovir-a flâte, hêdeen svn ånd en toghater tûs, sâ bjustre fres, as jefhja pâs ut Fryasland wêi kvmen wêren, åndsâ wonderskên as nimman mocht hügja. Thjv hropthêrvr gvng vvr alle Krêkalanda ånd kêm in thaâra fon Dêmêtrius. Dêmêtrius wêrevvl ånd vnsêdlik, ånd hi thogte thåt-im ellafry stvnde. Hi lêt thju toghater avbêr skâkja. Thjumoder ne thvrade hjra joi5 navt wachtja, joi nomath thastjurar wiva hira mâna, thåt is blideskip, ak segsath hjaswêthirte. Tha stjurar hêton hjra wiva trâst,ånd fro jefta frow thåt is frü âk frolik,thåt is êlik an frü. Thrvchdam hju hjra man navtwachtja thurade, gvng hju mith hjra svne nêiDêmêtrius ånd bad, hi skolde hja hjra toghater witherjêva. Men as Dêmêtrius hira svn sa, lêt-er thamnêi sinra hove fora, ånd dêde alên mith him,as-er mith tham his suster dên hêde. Anda moder sand hi enbuda gold, thach hju stirt-et in sê. As hju thûs kêm,warth hju wansinnich, allerwêikes run hju vvra strête:nåst min kindar navt sjan, o wach, lêt mi to jow skulsêka, wand min joi wil mi dêja for tha-k sina kindarwêi brocht håv. Tha Dêmêtrius fornom,thåt Friso to honk wêre, sand-i en bodja to him segsande,thåt hi sina bern to him nomen hêde wmbe ra to fora to-nhâge stât vmbe to lânja him to fâra sinathjanesta. Men Friso thêr stolte ånd herdfochtichwêre, sand en bodja mith en brêve nêi sinum bern tha,thêrin mânde hi hjam, hja skolde Dêmêtrius towilla wêsa, vrmithis tham hjara luk jêrde. Thach thenebodja hêde jeta-n ora brêve mith fenin, thêrmêibifâl-er hja skolde thåt innimma, hwand [174]sêid-er-vnwillinglik is thin lifbivvllad, thåt ne skil jow navt to rêkned ni wrde, thachsâhwersa jow jowe sêle bivvlath sa ne skil jow nimmerthe toWalhâlla ne kvma, jow sêle skil thån ovir irthaommewâra, svnder å thet ljucht sja to mugande, lik thaflâramusa ånd nachtula skilstv alra dystik in thina holaskula, thes nachtis utkvma, then vp vsa gråva grâjaånd hûla, thahwila Frya hjra haved fon jow ofwenda mot. Thabern dêde lik-ra bifâlen warth. Dêmêtriuslêt ra likka in sê werpa ånd to tha månniskawrde sêid, thåt hja fljucht wêron. Nw wilde Frisomith alleman nêi Fryasland fâra, thêr-i êrwêst hêde, men tha mêst nilde thåt navt ne dva.Nw gvng Friso to ånd skât thet thorp mith-akêninglika fârrêdskûrum anda brônd. Hjudne kv ni thvrade ninman ne bilywa, ånd alle wêron blyde,that hja bûta wêre, bihalva wif ånd bern hêdonwi ella abefta lêten, thach wi wêron to lêden mithliftochtum ånd orlochtuch.

Thahwila Adel to Texland inna lêre wêre, was thêrtefta en êlle ljawe fâm in vpper burch. Hju kêm fonut tha Saxanamarkum wêi, fon ut-êre stâtha thêris kêthen Svôbaland thêr thrvch wårth hju toTexland Svôbene1 hêten, afskên[210]hjra nôme Ifkja wêre. Adelhêde hja ljaf krêjen ånd hju hêde Adel ljaf,men sin tåt bêd-im hi skolde jet wachtja. Adel washêrich, men alsa ring sin tât fallen was ånd hisêten, sand hi bistonda bodon nei Berth-holda hira tât hin,as-er sine toghter to wif håva machte. Bertholda wêr-neforste fon vnforbastere sêd, hi hêde Ifkja nêiTexland inna lêre svnden inner hâpe that hja ênis toburchfâm kêre wrde skolde in sine åjn land. Thach hihêde hjara bêder gêrte kånna lêred,thêrvmbe gvng-er to ånd jef hjam sina sêjen. Ifkjawêr-ne kante Fryas. Far sa fêre ik hja håvkånna lêred, heth hju alôn wrocht ånd wrot tilthju Fryasbern wither kvma machte vndera selva êwa åndvnder ênen bôn. Vmbe tha månniska vppa hira syd tokrêjande, was hju mith hira frjudelf fon of hira tât thrvchalle Saxanamarka fâren and forth nêiGêrtmånnja. Gêrtmannja alsa hêdon thaGêrtmanna hjara stât hêten, thêr hja thrvchGosa hira bijeldinga krêjen hêde. Dâna gvngen hja neitha Dênemarka. Fon tha Dênemarka gvngon hja skip neiTexland. Fon Texland gvngon hja nêi Westflyland en sa allingentha sê nêi Walhallagâra hin. Fon Walhallagârabrûdon hja allingen thêra sûder Hrênum al onthja mith grâta frêse boppa thêre Rêne bi thaMarsâta kêmon2 hwêrfon vsaApollânja skrêven heth. Tho hja thêr en stûtwêst hêde, gvngon hja wither nêi tha delta3. As hja nw en tid lông nêi thadelta offâren wêron al ont hja inna strêk fonthêre alda burch Aken4 kêmon, sind thêrvnwarlinga fjuwer skalka morth and naked uteklât. Hja wêronen lith åfter an kvmen. Min brother thêr vral by washêde hja often vrbêden, thach hja nêde navt nehêred. Tha bônar thêr thåt dên hêdewêron Twisklândar thêr juddêga drist wêiovira Hrêna kvma to morda and to râwande. ThaTwislândar thåt sind bannane ånd wêi britneFryasbern, [212]men hjara wiva håvath hja fon thaTartarum râwet. Tha Tartara is en brûn Findas folk, althushêten thrvchdam hja alle folka to strida uttarta. Hja send alhrutar ånd râwar. Thêr fon send tha Twisklândaralsa blod thorstich wrden. Tha Twisklândar tham thjuårgnise dên hêde, hêton hjara selva Frya jefthaFranka. Ther wêron sêide min brother râda brunaånd wita mong. Thêre thêr râd jeftha brunwêron biton hjara hêre mith sjalkwêter5wit. Nêidam hjara ônthlita thêr brun by wêr,alsa wrdon hja thesto lêdliker thêr thrvch. Êvin asApollânja biskojadon hja åfternêi Lydasburchånd et Aldergâ. Dâna tâgon hju in overStâverens wrde by hjara ljuda rond. Alsa minlik hêdon hjahjara selva anståled that tha månniska ra allerwêikeshalda wilde. Thrê mônatha forther sand Adel bodon nêialle âthum thêr hi biwnnen hêde ånd lêttham bidda, hja skoldon inna Minna mônath lichta ljuda to himsenda.6 [214]

Launched in 2167, Fornax magazine described itself as "the galaxy's finest xenophilia." By its fifth year, Fornax became the first human magazine to offer full five-sensory stimulation, a previously-unaffordable magazine technology made profitable by the economy of scale. With a monthly publishing run of 127 million available in both in [sic] hard-copy and direct download, Fornax offers a range of alien models with particular emphasis on the unisexual asari, although both genders of quarians, drell, batarians, and volus are regularly depicted. Specialty editions such as Genit-elcor and Krogasm service devoted but smaller markets.

A game company spends money developing a game, paying the engineers and the artists along the way, and then it sells the game. It might not even physically exist on a DVD/ROM cartridge/whatever. This might be a digital download. However, the sales pay for its development. 041b061a72