multiple sequence alignment multiple sequence alignment sequence alignment biological sequences generally protein dna cases input set sequences assumed evolutionary relationship share lineage descended common ancestor resulting sequence phylogenetic analysis conducted assess sequences shared evolutionary origins visual depictions alignment image right illustrate events point single acid changes appear differing characters single alignment column gaps appear sequences alignment multiple sequence alignment assess sequence conservation protein domains secondary structures individual multiple sequence alignment refers process sequence set sequences relevant length difficult time consuming align hand produce analyze require sophisticated alignment complex multiple sequence alignment programs use methods global identifying optimal alignment sequences moderate length expensive dynamic programming complexity direct method producing uses dynamic programming technique identify globally optimal alignment solution proteins method usually involves sets parameters gap penalty matrix assigning scores alignment possible pair based similarity chemical properties evolutionary probability sequences similar gap penalty simpler matrix identical matches considered typical scores matrix positive mix positive negative case global alignment positive negative case local alignment individual sequences naive method requires constructing dimensional equivalent matrix formed standard sequence alignment search space increases increasing strongly dependent sequence length expressed big commonly measure complexity takes time produce find global sequences way shown complete problem based introduced practical method uses dimensional search space approach dynamic programming performed pair sequences set space near dimensional intersection searched way alignment program sum pairs characters position alignment called sum pair score implemented software program constructing multiple sequence progressive alignment construction widely approach multiple sequence uses search known progressive technique known tree method developed ben progressive alignment builds final combining beginning similar pair progressing related progressive alignment methods require stages stage relationships sequences represented tree called guide tree second step built adding sequences growing according guide tree initial guide tree determined efficient method neighbor joining use distances based number identical letter sub sequences dynamic programming alignment progressive guaranteed globally optimal primary problem errors stage growing errors propagated final result performance particularly bad sequences set related modern progressive methods modify scoring function secondary function assigns scaling factors individual members set fashion based phylogenetic distance nearest neighbors non random selection sequences given alignment program progressive alignment methods efficient implement large scale sequences progressive alignment services commonly available publicly accessible web users need locally install applications interest popular progressive alignment method family especially weighted variant access provided large number web including different vary user interface different parameters accessible user extensively phylogenetic tree construction spite author explicit warnings studies input protein structure prediction modeling current version family announced expired august recommend performs based seeded guide trees profile profile techniques protein offer different tools progressive dna multiple alignment fast transform common progressive alignment method called coffee slower derivatives generally produces accurate related sequence sets coffee combining direct alignment pair indirect sequence pair sequence uses output local alignment program finds multiple regions local alignment sequences resulting alignment phylogenetic tree guide produce new accurate factors progressive methods guaranteed converge global alignment quality difficult evaluate true biological significance obscure semi progressive method improves alignment quality use running time implemented program methods set methods produce reducing errors inherent progressive methods classified work similarly progressive methods repeatedly initial sequences adding new sequences growing reason progressive methods strongly dependent high quality initial alignment fact incorporated final result sequence aligned alignment considered improves efficiency cost accuracy contrast methods return previously calculated sub incorporating sequence means general objective function finding high quality alignment score variety subtly different iteration methods implemented available software packages reviews comparisons useful generally refrain choosing best technique software package uses hill climbing alignment score alignment weights locally regions growing performs best alignment previously constructed faster method program takes unusual approach focusing narrowly local sub segments sequence motifs introducing gap penalty alignment individual motifs achieved matrix representation similar dot matrix plot alignment alternative method uses fast local anchor points seeds slower global alignment procedure implemented chaos suite popular iteration based method called muscle multiple sequence alignment log expectation improves progressive methods accurate distance measure assess sequences distance measure updated iteration stages original form muscle contained depending enabled consensus methods consensus methods attempt find optimal multiple sequence alignment given multiple different set sequences commonly consensus methods coffee coffee uses multiple sequence generated seven different methods generate consensus capable generating consensus number input generated different models sequence evolution different methods multiple sequence alignment default option consensus alignment generated different models protein sequence evolution hidden models hidden models models assign possible combinations gaps matches determine likely set possible produce single highest scoring output generate family possible evaluated biological significance produce global local based methods developed relatively recently offer significant improvements speed especially sequences contain overlapping regions typical based methods work representing form directed known partial order consists series representing possible entries columns representation column absolutely sequences share particular character particular position coded single outgoing connections possible characters column alignment terms typical hidden model observed states individual alignment columns hidden states represent presumed ancestral sequence sequences set descended efficient search variant dynamic programming method known generally align growing sequence set produce new distinct progressive alignment methods alignment prior sequences updated new sequence addition like progressive methods technique influenced order sequences set integrated alignment especially sequences related software programs available variants based methods implemented noted efficiency properly method complex common progressive methods simplest partial order alignment similar method implemented packages sam sequence alignment modeling system sam source protein structure prediction participate structure prediction experiment develop database predicted proteins species software package detection remotely related protein sequences based comparison running far fastest best automatic structure prediction structure prediction competitions genetic simulated standard techniques computer science inspired directly reproduce physical processes attempt efficiently produce quality technique genetic production attempt broadly simulate evolutionary process gave rise divergence set method works breaking series possible fragments repeatedly fragments introduction gaps varying positions general objective function simulation generally sum pairs function introduced dynamic programming based methods technique protein sequences implemented software program saga sequence alignment genetic equivalent called technique simulated existing produced method refined series designed find better regions alignment space input alignment occupies like genetic method simulated objective function like sum pairs function simulated uses temperature factor determines rate proceed likelihood typical usage periods high rates relatively low likelihood explore distant regions alignment space periods lower rates higher thoroughly explore local near newly regions approach implemented program multiple sequence alignment simulated phylogeny aware methods multiple sequence alignment methods try minimize number gaps consequence produce compact causes problems sequences aligned contain non regions gaps phylogeny analysis problems common newly produced sequences poorly contain frame shifts wrong domains non method developed authors released software package called prank prank improves present runs slowly compared progressive methods developed years new phylogeny aware tools appeared called pagan developed team prank developed software packages developed independently share common features notably use improve recognition non regions improvement code making software faster prank motif finding motif finding known profile analysis method locating sequence motifs global means producing better means producing scoring matrix use searching sequences similar motifs variety methods motifs developed based identifying short highly patterns larger alignment constructing matrix similar matrix reflects acid composition position motif alignment refined standard profile analysis matrix includes entries possible character entries gaps alternatively statistical pattern finding identify motifs precursor cases set contains small number sequences contains highly related sequences added distribution reflected scoring matrix particular zero probability entries matrix values small blocks analysis method motif finding motifs regions alignment blocks generated extracted sequences set common motifs previously generated known gene families block scoring generally relies high frequency characters calculation explicit matrix blocks provides interactive method locate motifs sequences statistical pattern matching implemented expectation common motif finding tools known uses expectation hidden methods generate motifs search tools companion mast combined suite mast non multiple sequence alignment non dna regions especially necessarily related non common ancestors assumptions align protein sequences dna regions inherently different hold sequences meaningful align dna regions sequences operators alignment binding site sequences factor rely evolutionary related operations similarly evolutionary operator point define edit distance sequences little meaning sequences sequence variation maintain certain level binding site function specifically important trying align known sequences build supervised models predict unknown locations multiple sequence alignment methods need adjust underlying evolutionary hypothesis operators work published incorporating neighbouring base information align binding sites searching lowest alignment binding site alignment quality control necessary use multiple alignment means arbitrary set proteins good chance alignment contain errors example evaluation leading alignment programs found pairs aligned incorrectly aligned errors arise unique regions sequences complex evolutionary process leading proteins align easily sequence number sequence divergence increases errors simply nature multiple sequence alignment viewers enable visually reviewed quality alignment functional sites sequences enable alignment edited correct usually minor errors order obtain optimal alignment suitable use phylogenetic analysis comparative modeling number sequences increases especially wide studies involve impossible manually furthermore manual finally best expert align ambiguous cases highly diverged sequences cases common practice use automatic procedures exclude aligned regions purpose phylogeny reconstruction program widely remove alignment blocks suspect low quality according number sequences alignment columns criteria excessively filter regions events aligned reliably regions desirable purposes detection positive selection alignment output site specific scores allow selection high confidence regions service offered soap program tests column parameters popular alignment program coffee program uses library construction final output colored according confidence scores reflect agreement different library aligned extension consistency score uses coffee libraries evaluate party projections produced fast slow methods allowing trade speed accuracy alignment program output confidence scores uses statistical model allows calculation uncertainty alignment hot heads tails score measure site specific alignment uncertainty existence multiple optimal solutions guidance program similar site specific confidence measure based alignment uncertainty guide tree progressive alignment programs alternative justified approach assess alignment uncertainty use evolutionary models joint phylogeny alignment approach allows calculation posterior estimated phylogeny alignment measure confidence estimates case posterior probability calculated site alignment approach implemented program free available programs multiple sequence use multiple sequence create phylogenetic tree possible reasons functional domains known sequences alignment non sequences regions known important found makes possible multiple sequence analyze find evolutionary relationships sequences point events called detected multiple sequence identify important sites binding sites active sites sites corresponding key functions locating domains looking multiple sequence useful consider different aspects sequences comparing sequences aspects include identity similarity identity means sequences identical respective positions hand similarity sequences compared having similar example terms sequences considered similar similarity ultimately leads similar sequences closer similarity sequences help find common ancestry survey articles multiple alignment structural functional phylogenetic analyses sequences taylor sequence structure oxford oxford_university press recent progresses multiple sequence alignment survey thompson comprehensive comparison multiple sequence alignment programs research wallace multiple sequence recent multiple sequence alignment biology lecture notes courses multiple sequence alignment lectures max institute molecular lecture notes practical exercises multiple sequence molecular lecture notes molecular evolution lecture notes


wide association study genetic wide association study study known association study study examination common genetic variants different individuals variant associated trait typically focus associations single traits like major diseases studies compare dna participants having varying particular trait disease participants study people disease cases similar people controls people different particular trait example blood pressure approach known participants classified clinical manifestation opposed person gives sample dna millions genetic variants read type variant frequent people disease variant said associated disease associated considered mark region human influence risk disease contrast methods specifically test genetic regions studies investigate entire approach said non candidate driven contrast gene specific candidate driven studies studies identify variants dna associated disease specify genes successful published investigated patients age related found significantly altered frequency compared healthy controls hundreds thousands individuals tested human studies examined diseases traits associations found studies received criticism important quality control steps rendering findings invalid modern publications address issues opponents background human differ millions different ways small variations individual larger variations copy number variations cause alterations individual traits disease risk physical properties height year prior introduction studies primary method investigation inheritance studies genetic families approach proven highly useful single gene disorders common complex diseases results genetic studies proved hard reproduce suggested alternative studies genetic association study study type asks genetic variant found expected individuals interest disease studied early calculations statistical power indicated approach better studies detecting weak genetic effects addition conceptual framework additional factors enabled studies advent human genetic material greatly reduced cost difficulty collecting sufficient numbers biological specimens study international project identified majority common interrogated study structure identified project allowed focus describe variation development methods important methods common approach studies case control setup compares large groups individuals healthy control group case group affected disease individuals group majority common known exact number depends technology typically million investigated frequency significantly altered case control group fundamental unit reporting effect sizes odds ratio odds ratio ratio odds context studies odds disease individuals having specific odds disease individuals frequency case group higher control group odds ratio higher vice versa lower frequency additionally value significance odds ratio typically calculated simple squared test finding odds significantly different objective study shows associated disease variations case control approach common alternative case control studies analysis data height concentrations gene expression likewise alternative statistics designed dominance patterns calculations typically software include support alternative statistics earlier focused effect individual evidence shows complex interactions contribute complex diseases researchers tries integrate data biological data protein protein interaction network extract results key step majority studies chip study process greatly increases number tested association increases power study analysis distinct carried statistical methods combine data reference panel methods advantage sharing individuals short stretches sequence existing software packages include addition calculation association common account potentially results sex age common examples known genetic variations associated geographical historical populations arose association studies account geographical background participants controlling called population odds values calculated common approach create manhattan plot context studies plot shows negative value function location significant association stands plot usually points structure importantly value threshold significance corrected multiple testing issues exact threshold varies study conventional threshold significant face hundreds thousands millions tested studies typically perform analysis discovery followed significant independent results attempts creating comprehensive identified studies associated diseases numbered thousands study conducted compared patients age related healthy controls identified significantly altered frequency groups located gene complement factor unexpected finding research findings studies subsequently prompted functional research manipulation complement system landmark publication history studies trust case control consortium study largest study conducted time publication included cases seven common diseases individuals heart disease type diabetes type diabetes disease disorder shared controls study successful new disease genes underlying diseases landmark studies general trends larger larger sample sizes end largest sample sizes range individuals reason drive reliably detecting risk smaller odds lower frequency trend use narrowly defined blood similar called intermediate analyses value functional research central point debate studies variations found studies associated small increased risk disease small value median odds ratio risk showing odds considered small explain variation variation known studies based twins example known height studies account minority clinical applications challenge future successful study apply findings way drug development including better integration genetic studies drug development process focus role genetic variation maintaining health blueprint designing new drugs studies looked use risk markers means directly improving accuracy found accuracy improves report minor benefits use generally problem direct approach small effects observed small effect ultimately translates poor separation cases controls small improvement accuracy alternative application potential studies success related identifying genetic variant associated response anti virus treatment treated combined study shown near human gene associated significant differences response treatment later report demonstrated genetic variants associated natural clearance virus major findings facilitated development medicine allowed physicians medical decisions based patient goal led increased interest association risk gene expression nearby genes called expression trait studies reason studies identify risk risk genes specification genes step closer drug targets result major studies typically included extensive analysis strongest effects observed identified risk functional follow studies small interfering gene knock mice shed light low density important clinical implications disease limitations studies issues limitations taken care proper quality control study setup lack defined case control groups insufficient sample size control multiple testing control population common problems particularly statistical issue multiple testing noted approach problematic massive number statistical tests performed presents unprecedented potential false positive results ignoring issues cited contributing general sense problems addition easily problems subtle important issues surfaced high profile study investigated individuals long life spans identify associated longevity example publication came scrutiny type array case control group caused falsely highlighted associated longevity study subsequently retracted addition issues studies attracted fundamental criticism mainly assumption common genetic variation plays large role explaining variation common disease aspect studies attracted criticism known studies ultimately worth expenditure alternative strategies suggested involve analysis recently rapidly decreasing price complete provided realistic alternative array based studies discussed use new technique referred study high potential step shortcomings non fine mapping designed rely provide coverage entire variants reported associated variants unlikely actual variants associated regions contain hundreds variants spanning large regions encompassing different genes making biological interpretation difficult fine mapping process lists associated variants credible set likely include variant fine mapping requires variants associated region dense coverage stringent quality control resulting high quality large sample sizes sufficient separating highly signals different methods perform fine mapping methods produce posterior probability variant requirements difficult satisfy limited examples methods generally applied


plant involved wound response family plant proven having isolated leaves group led ryan similar functions identified outside rich found tobacco plant found found cell walls plant cells insect damage processed produce mature thought uncertain signal processes occur similar immune response animals early experiments showed travelled plant insects damaged plant acquired resistance thought increases production acid causing result main function coordinate defensive responses insect affect plant development production protect insect activate modify root growth shown affect plants responses salt stress radiation shown affect resistance allow distinguish different stopped involved defensive roles instead affect flower morphology discovery structure research group led ryan isolated acid leaves induced production proteins response wounding experiments synthetic radio labelled forms demonstrated able travel plant induce production leaves nature wounding signal named found function plants found tissues plant roots later studies identified members including potato black bell pepper identified members family tobacco respond wounding producing similar functions active rich isolated tobacco activated production similar way tomatoes structurally unrelated similar function resulted named rich following initial discovery found black found outside sweet potato sequence analysis identified coffee highly species contain rich central domain acid isolated found activate components innate immune response unlike post modified precursor identified rice wheat activity tested predicted structures varied contain sequence motif identified species varied contain components sequence motif found cell precursor acid contain signal sequence suggesting free precursor acid lacks signal sequence precursor present low levels leaves wounding particularly cells surrounding elements mid veins precursor exclusively cells leaves wounding precursor potato similar manner suggesting cell type specific regulation species cell wall precursor tobacco acid structural precursor structural properties containing indicate system precursor acid exclusively leaves associated cells unlike primarily associated cell wall appear represent distinct subfamily rich proteins found cell walls wounding thought cell wall matrix processes precursor producing active processing processed yield active terminus precursor speculated processed disease resistance processed active tobacco processed sweet potato possibly long precursor sweet potato longest precursor described production multiple signalling precursor common feature found animals small amounts active concentrations sufficient response plant level making potent gene identified identified rich repeat like isolated found similar structure cell membrane found able involved defensive developmental responses recent studies found initial conclusion incorrect stop present domain prevents correctly lacks domain required signalling respond producing causing response led suggest mechanism perceived investigation showed binding cause suggesting signal plants similar able respond normally strengthening view found protein cell membrane protein structure similar like led ryan suggest instead involved processing active form degradation synthetic forms substituted predicted site remained stable cell cultures longer native form later studies noted responsible processing remain unidentified research reported protein date gene identified far reported thought perceived cell membrane identified named active concentrations analysis structure shown member subfamily includes transforming tobacco cell cultures allowed respond normal tobacco response associated found proposed function protein required proper functioning hybrid shown closest analog interact signal remain poorly understood better understanding signal occurs bound acid essential albeit late component wound signalling pathways signal activated protein compromised defence response insect larvae compared wild type plants genes decreased production acid acid dependent defence genes applying plants rescued indicating signal responsible causing changes gene expression downstream effect signalling processing applying change minutes perception concentration increases acid released cell membranes activated acid converted acid acid defensive genes production induced precursor genes creating feedback loop defensive signal volatile activate acquired resistance neighbouring plants preparing defences attack signalling events analogous immune response animals response activated animals activated turn activate membrane converted acid acid pathways early experiments demonstrated transported plants thought signal activated acquired resistance view challenged experiments showed acid perception unable activate acquired resistance thought acid signal pathways acid synthesis functions defence plays critical role defence signalling promotes synthesis defence related proteins mainly proteins signaling proteins expression resulted significant decrease larvae damage indicating high level protection superior defence mechanism continuous activation costly affecting growth physiology reproductive success plants production severely impaired larvae feeding plants grew times fast caused similar changes gene expression tobacco example activity increased tobacco leaves caused decrease activity days wounding expressed tobacco larvae feeding plants weighed half days feeding feeding normal plants concentration hydrogen increased tissues production induced involved initiating acquired resistance plants expressing accumulated precursor indicating controlled able activate synthesis accumulation production induced wounding compared wild type plants indicating required strong defence response applied cut induce production instead increased expression gene produces protein membranes forming expression induced plants expressing produced volatile organic compounds normal plants found attractive expression genes involved production active response crucial defences effective predators developing insects consume plant material completing development likely production different pathways including acid function wound healing different allow distinguish different fungus increases expression varied depending resistant affect ability black resist competing normal plants plants produced ground regulated black contrast regulated contrast regulated activated synthesis regulation associated increased root mass decrease shoot mass demonstrating cause developmental changes result allowing plant tolerate directly resist attack roots affected root growth increasing high concentrations resources roots plants attack thought store carbon use grow attack ends increased root shoot stress resistance found improve plants tolerance stress including salt stress radiation expressed plants lower normal plants grown salt solutions plants higher lower leaf concentrations acid higher findings suggest allowed plants adapt salt stress efficiently perceived environment similarly wounded plants susceptible salt stress plants wounding decreases growth plant toxic roots analysis salt induced changes gene expression found differences measured normal plants accounted changes conventional salt stress induced pathways instead suggested activation acid determines state directs resources production compounds active pre plants minimize water loss effects achieved negatively regulating production force plants invest additional resources counteract water loss secondary effect plants grown light resistant insect compared plants grown filters exclude radiation plants exposed pulse radiation weakly wounded accumulate plant radiation weak wounding sufficient induce accumulation cell cultures respond similarly acting activate short cause medium development known involved defence insect expression affect feeding performance larvae compared normal plants found caused changes flower morphology reduced efficiency self flowers similar plants lack measurement levels flowers revealed lower normal plants authors suggested function defence related involved controlling flower morphology signalling processes remain similar increases root growth suggesting play role plant development


addition tail messenger tail consists multiple words stretch bases process produces mature messenger translation forms larger process gene expression process begins gene terminates segment newly pre set proteins proteins tail end genes proteins add tail possible sites produce single gene alternative similar alternative tail important nuclear export translation stability tail shortened time short degraded cell types short tails stored later activation contrast occurs bacteria promotes degradation case non molecules tails generally shorter molecules background information messenger type large biological molecules individual building blocks called tail acid tail reflects way abbreviated letter base contains produced dna template convention sequences written direction end end end tail found messenger region acts template protein synthesis translation rest regions tune active translated called non like regions non regulatory roles nuclear function nuclear tail added end tail protects degradation aids termination export nucleus translation exception animal dependent lack tail ending instead stem loop structure followed rich sequence termed downstream element directs cut end formed non end small tail seen forms mature ends removed processing notable ones long seemingly large group regulatory example includes tail mature mechanism complex nucleus works products precursor multi protein complex components right newly produced end produced occurs downstream binding site site signal sequence variants weakly exist proteins add binding rich region downstream site recognises site set sequences mammals recruit sequence missing signal sequence motif recognised complex varies groups human sites contain sequence sequence common plants fungi typically termination poorly understood mechanism signals slip involves protein unknown site associated signal vary starts builds tail adding units protein new short tail increases affinity tail approximately long longer stops determining length tail contact allowing signal terminate reaches termination sequence dna template primary end signaled machinery physically linked complex removes downstream effects tail acts binding site protein protein promotes export nucleus translation degradation protein tail prior export nucleus recruits tail allows export protein exported exported degraded protein recruit proteins affect translation initiation turn recruits tail required translation cells tail gradually shorter shorter tail translated degraded sooner hours degraded degradation process accelerated region immature egg cells shortened tails degraded instead stored translated activated egg activation animals cap remove tail level access cap tail important controlling soon degraded bound initiation factors cap tail translation reduces rate regulated binding proteins tail removed complex removes cap leading degradation involved identified alternative protein genes site gene code differ end alternative changes length region change binding sites region contains tend translation promote degradation examples alternative region making code different protein common shortening region choice site influenced depends expression proteins example expression factor increases response group compounds trigger immune response results selection weak sites shorter removes regulatory elements regions defense related products like longer half lives produce proteins binding proteins machinery affect site dna near signal animal cell types line early post sites nerve cells tail shortened tail translated shortened tails lengthened early mouse embryo maternal egg cell allows cell survive grow start middle cell stage cell stage human brain active learning play role long term strengthening signal transmission nerve cell response nerve important learning memory formation requires binding proteins involve binding proteins like depending cell type type nuclear process degradation non including way marking degradation nucleus complex maintains tail long end degraded tails found human fragments form tails bacteria non tail promotes degradation contains end extension provided tail allows secondary structure block end successive rounds degradation end allows overcome secondary structures tail recruit cut tails long different groups animals contain tails targets tails long average ones start stop stop complete plant bacteria type performed found bacteria constituent extension vast majority bases like bacteria promotes degradation likely evolution seen organisms universal wide distribution modification fact present organisms domains life implies universal common ancestor living organisms presumed form system organisms implies lost evolution examples lack known salt tolerant lack modification ancient closely related complexes attacking bond breaking reaction extend tail added rich choice likely result higher concentrations result energy currency making likely incorporated tail early suggested involvement rich tails degradation prompted later evolution produce tails ancient separately evolved bacteria adding completes ends domain presumed horizontal transfer adding allowed like adding switch function like evolved history identified activity extracts cell identified types cells activity known function sequences found function sequences thought protection end later specific roles nuclear export translation identified responsible characterized 1960s 1970s large number proteins control process discovered early 1990s


circular proteins circular relationship proteins proteins changed order sequence result protein structure different overall similar dimensional shape pair proteins discovered proteins known circular occur result evolutionary events modifications artificially engineered main models proposed explain evolution proteins fusion occurs gene undergoes form tandem repeat redundant sections protein removed relationship found fusion occurs partial proteins fuse form single circular routinely engineered laboratory improve activity investigate properties original protein traditional sequence alignment structure alignment able detect circular proteins new non linear approaches developed overcome able detect independent similarities history bruce colleagues discovered instance protein nature determining sequence protein noticed similarity known protein ends later work confirmed circular pair showed post unusual protein discovery natural protein researchers looked way emulate process david thomas able create version protein termini create protein introducing new termini colleagues introduced genetic method making circular carefully dna method allowed introduced arbitrary sites despite early discovery post circular suggestion possible genetic mechanism evolving circular pair genes discovered class proteins involved presentation humans chris robert russell identified version inserted plant nicknamed known case natural genes related circular hundreds examples protein pairs related circular subsequently discovered nature produced laboratory february circular database contains protein pairs known structures known structures database collects proteins variants wild type proteins database contains collection hand manual proteins non trivial relationships circular evolution main models currently explain evolution proteins fusion models compelling examples supporting relative contribution model evolution debate common mechanisms proposed cut paste earliest model proposed evolution circular mechanism model precursor gene undergoes fusion form large tandem repeat start stop introduced corresponding locations gene removing redundant sections protein surprising prediction mechanism intermediate occur instance version protein functional evolution quickly select proteins likewise partially terminus truncated functional extensively documented protein families dna example relationship highly approximately acid long forming alpha structure nearly identical placement sites sequence codes called precursor products domains likely arose tandem ancestral gene repeat suggests mechanism evolution relationship plant specific insert psi psi domain exclusively found plants consisting approximately found plant belongs like protein family termini swapped order compared leading fusion model evolution circular fusion model process starts partial proteins represent independent parts originally halves single protein underwent event proteins later fuse form single regardless protein comes fusion protein similar function fusion proteins occurs twice evolution species different species different order resulting fusion proteins related circular evidence particular protein having evolved fusion mechanism provided observing halves independent related species demonstrating halves function separate example fusion mechanism found membrane bound transfer reaction coupled consist major functional units iii found different arrangement bacteria higher phylogenetic analysis suggests groups domain arrangements acquired fused independently processes lead circular post modification evolutionary models mentioned describe ways genes resulting proteins post modification underlying gene circular happen spontaneously case alternately require restriction role circular protein engineering proteins termini located close space possible design circular proteins today circular generated routinely lab standard techniques sites prevent protein folding correctly created nearly identical structure function original protein motivation creating circular protein vary scientists want improve property protein reduce rate proteins broken large impact activity cells termini accessible designing protein accessible termini increase lifespan protein cell improve activity protein increase rate chemical reaction leading efficient proteins alter substrate binding protein result loss substrate binding occasionally lead novel binding activity altered substrate improve making proteins active wider range temperatures conditions improve utility alternately scientists interested properties original protein fold order determining order different parts protein fold challenging extremely fast time scales involved versions proteins fold different order providing information folding original protein essential structural elements artificial proteins allow parts protein deleted gives insight structural elements essential modify structure proteins shown different structure wild type proteins find sites proteins protein domain protein useful instance green protein allowed researchers measure activity split regions tolerate introduction circular likely accept addition protein retaining function proteins design novel introducing circular design proteins specific chemical reactions detect presence certain molecules proteins instance fusion described detect level calcium sample detection circular sequence alignment protein structure alignment developed assuming linear data representations able detect circular proteins examples frequently methods problems correctly proteins related circular dynamic programming hidden models alternative number built non linear approaches able detect independent similarities employ modifications allowing limitations dynamic programming table collection methods classified according type input require sequence based require sequence proteins order create alignment sequence methods generally fast suitable searching pairs proteins structure based methods require structures proteins considered slower sequence based methods able detect circular related proteins low sequence similarity structural methods independent meaning able detect complex circular


temperature sensitive non gene expression regulate genes required heat shock cold shock response implicated regulatory roles starvation general operate changing secondary structure response temperature fluctuations structural transition expose important regions binding site affects translation rate nearby protein gene examples support world hypothesis theory proposes sole acid present cells replaced current dna protein system examples include regulatory element rose element discovery temperature sensitive element reported prior research upstream start site found affect level translation protein protein involved selection life cycle high concentrations promoting study upstream region identified alternative secondary structures experimental study found structures dependent concentration temperature thought encourage entry cycle heat stress order rapidly replicate escape host cell term coined applied element identified recently searches employed uncover novel candidate traditional sequence based searches inefficient secondary structure element acid sequence distribution known located region messenger heat shock proteins suggested fact sampling bias inherent difficulties detecting short sequences data predominantly found potential found mammals including humans candidate heat shock heat shock factor protective proteins cell temperature exceeds body temperature preventing cells structure structurally simple short sequences smallest found heat shock protein species generally elements range length typically contain small number base pairs reduce stability structure allowing easier response temperature increase detailed structural analysis rose revealed bases actually engaged preserves structure figure unusual consist pairs base pairs relatively unstable increased temperature causes local melting structure region exposing shine sequence significantly complex single case region found thought contain multiple synthetic designed simple single structure primary sequence short sensitive single base change render inactive mechanism found messenger upstream protein gene able binding site prevent translation protein temperature increases structure melt expose shine sequence permit binding small translation machinery start typically found downstream shine sequence signals beginning protein gene translated product addition acting mechanism lone example trans acting found thought involved starvation response specific example motif found exposed temperatures stem loop base pairs opposite shine sequence allows enter translation occur concentration shown affect stability studied found gene heat shock proteins high temperatures specialised heat shock factor typically associated heat induced protein expression regulate cold shock proteins example expression proteins regulated similar mechanism identified sensitive temperatures activate infection specific genes example key genes demonstrated dna green protein gene gene fusion promoter observed implications world hypothesis world hypothesis states carrier hereditary information active different sequences acting sensors hypothesis proposes modern dna protein based life evolved selection replaced majority roles thought ancient wide scale distribution related organisms proposed world responsible temperature dependent regulation molecules modern organisms molecular fossils hint previously widespread importance world examples regulatory element increasing translation rate heat shock protein high temperatures predicted contain operative rose element found respectively exist heat shock protein translation temperatures


matrix liquid found inside cells constitutes fluid separated compartments membranes example mitochondrial matrix separates compartments cell cell membrane comprises internal structures cell nucleus separate liquid matrix chemical reactions place place membranes space pathways occur contained complex mixture substances dissolved water water forms large majority structure properties cells understood concentrations potassium different fluid differences levels important processes cell signaling generation action cells nerve muscle cells contains large amounts alter molecules behave thought simple solution molecules multiple levels organization include concentration small molecules calcium large complexes act carry pathways protein complexes separate parts definition term introduced initially referred liquid produced breaking cells apart components cell extract identical cell usually called fraction term refer liquid phase intact cell contained possibility confusion use word refer extracts cells intact cells phrase describe liquid contents living cells properties composition proportion cell volume varies example compartment forms bulk cell structure bacteria plant cells main compartment large central consists water dissolved small molecules large water molecules proteins majority non protein molecules molecular mass mixture small molecules complex variety molecules involved immense example different small molecules plants present species single cell estimates number single cells baker predict water water makes total volume typical cell fluid human ranges usually higher cell growing roughly pure water small molecules liquid slower pure water collisions large numbers studies shrimp examined water affects cell functions saw reduction water cell decreasing progressively cell activity halting water level reaches normal water vital life structure water understood methods nuclear magnetic resonance information average structure water measure local variations microscopic scale structure pure water poorly understood ability water form structures water clusters hydrogen bonds classic view water cells water strongly bound water majority structure pure water water active different properties dissolved molecules excluded concentrated argue effects high concentrations cells extend water cells differently water solutions ideas include proposal cells contain zones low high density water widespread effects structures functions parts cell use advanced nuclear magnetic resonance methods directly measure mobility water living cells idea suggests cell water acts like pure water remainder mobile probably bound concentrations different fluid contains higher amounts charged proteins outside cell structure contrast fluid high concentration potassium low concentration difference concentrations critical levels inside cell outside water enter constantly levels inside cells higher levels outside instead expelled potassium taken potassium flow concentration gradient potassium selection channels loss positive charge creates negative membrane potential balance potential difference negative exit cell selective channels loss effect higher concentration organic molecules inside cell cells deal larger changes accumulating molecules allow cells survive completely dried allow organism enter state suspended animation called state glass like solid helps stabilize proteins cell membranes damaging effects low concentration calcium allows calcium function second messenger calcium signaling signal action potential opens calcium channels calcium floods sudden increase calcium signalling molecules protein potassium signaling functions understood protein molecules cell membranes dissolved protein cells extremely high approaches occupying volume measuring precisely protein dissolved intact cells difficult proteins appear weakly associated membranes cells released solution cell experiments membrane cells carefully disrupted damaging cell membranes quarter cell protein released cells able proteins given implying bound idea majority proteins cells tightly bound network called seen unlikely contains cell structure known irregular mass dna associated proteins control held cell nucleus separated nuclear pores block free larger diameter high concentration causes effect called effective concentration increased volume effect produce large changes rates position chemical reactions particularly important ability alter favoring association multiple proteins come form protein complexes dna binding proteins targets organization components separated regions cell membranes components mix randomly levels organization specific molecules defined sites concentration small molecules rapidly concentration produced compartment studied example calcium sparks produced short period region open calcium channel diameter sparks merge form larger called calcium waves concentration small molecules oxygen produced cells clusters understood protein complexes proteins associate form protein complexes contain set proteins similar functions carry steps organization allow substrate product passed directly released solution rapid efficient randomly distributed prevent release unstable reaction wide variety pathways involve tightly bound involve loosely associated complexes difficult study outside cell consequently importance complexes general remains unclear protein compartments protein complexes contain large central cavity isolated remainder example enclosed compartment set form hollow barrel containing proteins damaging mixed freely remainder barrel capped set regulatory proteins recognize proteins signal directing degradation tag feed cavity large class protein compartments protein shell compartments typically proteins understood example contains involved carbon presence network large particles cell example studies particles larger size excluded parts edges cell nucleus excluding compartments contain remainder influence distribution large structures excluding areas concentrating function single function instead site multiple cell processes examples processes include signal cell membrane sites cell cell nucleus compartment site processes breakdown nuclear membrane major function transport site production relatively simple water molecules rapidly molecules transported specific binding proteins shuttle molecules cell membranes molecules taken cell way transported inside small spheres moved motor proteins site large proportion instance mammals half proteins cell localized complete data available indicate majority processes occur major pathways occur animals protein localization pathways different organisms instance acid synthesis occurs plants


structural alignment structural alignment attempts establish structures based shape dimensional process usually applied protein structures large molecules contrast simple structural equivalent structures known structural alignment requires knowledge equivalent positions structural alignment valuable tool comparison proteins low sequence similarity evolutionary relationships proteins easily detected standard sequence alignment techniques structural alignment imply evolutionary relationships proteins share little common sequence caution results evidence shared evolutionary ancestry possible effects evolution multiple unrelated acid sequences converge common structure structural compare sequences multiple sequences rely information sequences dimensional method sequences structures known usually found ray possible perform structural alignment structures produced structure prediction methods evaluating predictions requires structural alignment model true known structure assess model quality structural especially useful analyzing data structural efforts comparison points evaluate produced purely sequence based methods structural alignment atomic coordinate sets minimal root mean square structures aligned structures indicates divergence structural alignment complicated existence multiple protein domains input structures changes relative orientation domains structures aligned artificially data produced structural alignment minimum information produced successful structural alignment set dimensional coordinates input structure note input element fixed reference coordinates change fitted structures mutual values sophisticated measures structural similarity global distance test metric structural alignment implies corresponding dimensional sequence alignment sequence identity percentage identical input structures calculated measure closely sequences related types comparisons protein structures composed chains linked common protein backbone number different possible protein producing structural alignment calculating corresponding values structures different sequences chain generally taken account identities differ aligned reason common structural alignment methods use default backbone included bond simplicity efficiency alpha carbon positions considered bond variant structures aligned highly similar identical meaningful align chain positions case reflects protein backbone states chains comparison criteria reduce noise bolster positive matches include secondary structure assignment native contact maps interaction patterns measures chain packing measures hydrogen bond retention structural basic possible comparison protein structures makes attempt align input structures requires alignment input determine sequence intended considered calculation structural commonly compare multiple protein case alignment necessary sequences evaluate quality produced sequence information sequences structures known method traditionally uses simple squares fitting optimal translations found sum squared distances structures recently maximum likelihood methods greatly increased accuracy estimated translations based modified developed identify relationships protein structures need alignment successfully identified canonical bundle method sufficiently correct relative domain structural complexity optimal solution optimal protein sequence known structure production optimal multiple sequence alignment shown complete imply structural alignment problem complete strictly speaking optimal solution protein structure alignment problem known certain protein structure similarity measures measures protein structure prediction experiments measures capable number proteins superimposed distance unfortunately optimal solution practical running time depends lengths geometry input proteins approximate solution approximate time structural alignment produce family optimal solutions given scoring function developed theoretically classify approximate protein structure alignment problem expensive large scale protein structure analysis consequence practical converge global solutions alignment given scoring function exist guarantee convergence local scoring functions practical developed representation structures protein structures represented coordinate independent space comparable typically achieved constructing sequence sequence matrix series encompass comparative absolute distances relative fixed coordinate space intuitive representation distance matrix dimensional matrix containing distances structure alpha matrix increases number structures simultaneously aligned increases reducing protein coarse metric secondary structure elements structural fragments produce sensible despite loss information distances noise discarded choosing representation facilitate critical developing efficient alignment mechanism methods structural alignment techniques comparing individual structures sets structures production comparison measure divergence pair structures present protein data bank classify proteins fold common popular structural alignment method distance alignment matrix method breaks input structures fragments distance matrix evaluating contact patterns successive fragments secondary structure features involve sequence appear matrix main diagonal matrix reflect spatial contacts near sequence parallel main diagonal features represent parallel perpendicular features representation memory intensive features square matrix symmetrical redundant main diagonal proteins distance share similar features approximately positions said similar similar length loops connecting secondary structure elements actual alignment process requires similarity search proteins distance built normally conducted series overlapping size matches final alignment standard score original version simulation maximize structural similarity score function distances corresponding particular distant corresponding features reduce effects noise introduced loop mobility minor structural variations relies distance matrix account possibility structurally aligned features appear different orders sequences compared method construct database known fold classification based structure structure alignment proteins families structurally similar proteins known protein structures aligned determine structural neighbors fold classification database based downloadable program web search based standalone version known extension extension method similar breaks structure set series fragments attempts complete alignment series combinations fragments called aligned fragment pairs define similarity matrix optimal path generated identify final alignment meet given criteria local similarity included matrix means reducing necessary search space increasing efficiency number similarity possible original definition method included structural inter distances expanded include local environmental properties secondary structure exposure hydrogen bonding patterns angles alignment path calculated optimal path similarity matrix progressing sequences extending alignment possible high scoring pair initial pair alignment occur point sequence matrix extensions proceed meets given distance criteria restricting alignment low gap sizes size maximum gap size required input parameters usually set determined values respectively like construct fold classification database known protein structures recently released updated version protein comparison tool provides new variation detect circular protein structures structure alignment program method uses double dynamic programming produce structural alignment based structure space instead alpha typically structural alignment beta method takes account state location backbone works constructing series inter distance nearest non neighbors protein series constructed containing differences neighbors pair constructed dynamic programming applied resulting matrix determines series optimal local summed summary matrix dynamic programming applied determine overall structural alignment originally produced extended multiple applied fashion produce fold classification scheme known class architecture construct protein structure classification database recent developments improvements structural alignment methods constitute active area research new modified methods proposed claimed offer advantages older widely distributed techniques recent example align uses novel method distance matrix standard dynamic programming applied proposed accelerate convergence dynamic programming correct effects arising alignment lengths study align reported improve speed accuracy improvements computer performance erased purely technical deficiencies older approaches clear universal criterion optimal structural alignment align instance particularly robust comparisons sets proteins great sequence lengths indirectly captures hydrogen bonding secondary structure order conservation better alignment related proteins recent developments focused particular attributes speed scores alternative gold standards tolerance structural data structural models alternative gaining popularity use consensus methods proteins structural similarities structural alignment structural alignment techniques traditionally applied exclusively proteins primary biological assume characteristic dimensional structures large molecules form characteristic structures primarily hydrogen bonds formed base pairs base similar molecules especially difficult extract data structure strongly sequence proteins limited alphabet decreases information content given given position increasing interest structures growth number determined structures structure similarity methods developed recently methods structure smaller parts called general secondary structure units subsequently aligned partial merged final structure alignment scored method implemented recent method structural alignment sequences low sequence identity published implemented program method truly analogous protein structural alignment techniques structures input sequences requiring determined structures input prediction protein folding process particularly successful date structures predicted free energy based scoring methods account base pairing software choosing software tool structural alignment challenge large variety available packages differ significantly reliability partial solution problem presented publicly accessible complete list currently available freely distributed structural alignment software found structural alignment software properties structural alignment software packages summarized tested examples structural alignment tools


contracted organic chemical families plays important roles brain body synthesized removing group precursor chemical synthesized brain synthesized plants animals brain functions chemical released nerve cells send signals nerve cells brain includes distinct pathways plays major role reward motivated behavior types reward increase level brain addictive drugs increase activity brain pathways involved motor control controlling release pathways cell groups form system outside central nervous system functions parts peripheral nervous system local chemical messenger blood vessels release acts normal concentrations increases output reduces production digestive system reduces protects immune system reduces activity exception blood vessels peripheral systems synthesized locally effects near cells release important diseases nervous system associated system key treat work altering effects disease condition causing motor caused loss area called precursor manufactured pure form marketed widely treatment condition evidence involves altered levels activity drugs treat antagonists reduce activity similar antagonist drugs effective anti agents restless legs syndrome attention deficit disorder associated decreased activity addictive high lower treat available manufactured medication injection reach brain peripheral effects useful treatment heart failure shock especially newborn babies structure consists structure ring groups group attached chain simplest possible family includes presence ring attachment makes substituted family includes numerous drugs like organic base base generally acidic environments acid base reaction form highly water relatively stable exposed oxygen basic environments free base form water highly increased stability water form supplied chemical use salt created combined acid dry form fine powder synthesis synthesized restricted set cell types mainly cells direct precursor synthesized indirectly essential acid directly non essential acid found nearly protein readily available food common found types food incapable crossing blood brain barrier surrounds protects brain synthesized inside brain perform activity converted molecular oxygen converted iron converted acid known precursor synthesis converted acid converted require synthesis required acid synthesis degradation broken inactive set acting sequence effectively different breakdown pathways exist main end product acid known biological activity acid filtered clinical research measurements acid estimate levels activity brain difficulty approach separating high level acid contributed normally broken susceptible direct reaction oxygen yielding plus free products rate increased presence iron factors free produced poison cells evidence mechanism contribute cell loss occurs disease conditions functions cellular effects effects binding cell surface mammals identified labeled function protein coupled meaning exert effects complex second messenger system divided families known like like located nervous system ultimate effect like activation opening channels opening potassium channels ultimate effect like activation usually target consequently incorrect describe effect target depends types present membrane internal responses second messenger camp numerous human nervous system present significantly lower levels storage release inside brain functions controlled set mechanisms common synthesis transported carrier stored ejected cases release occurs process called caused action caused activity trace associated high affinity trace certain substituted located membranes cell activation regulate signaling producing firing diverse set mechanisms located located membrane terminal action potential molecules quickly absorbed cell membrane broken making available future release brain level mechanisms transmission release like release nervous system driven directly action containing cells transmission occurs small amounts released preceded action transmission regulated variety factors including activity nervous system inside brain plays important roles executive functions motor control motivation reinforcement reward lower level functions including sexual cell groups pathways system producing nerve cells comparatively number total human brain cell bodies confined groups relatively small brain areas project brain areas exert powerful effects targets cell groups mapped assigned labels starting letter scheme areas contain contain areas identified groups ventral area group posterior group nucleus group group nucleus group small area forms component basal parts input area called output area found mainly cell group nearby group humans projection dorsal termed plays significant role control motor function learning new motor skills especially vulnerable damage large number die result syndrome ventral area area prominent group projects smaller group projects nucleus pathways collectively termed projection sends projections play central role reward aspects motivation posterior project spinal cord function established evidence area plays role restless legs syndrome condition people difficulty sleeping overwhelming constantly parts body especially legs nucleus nucleus form important projection goes influences primary anterior produced nucleus portal system median supplies cells produce absence continuously context regulating occasionally called factor grouped projects areas control releasing necessary activate development male female reproductive systems following additional group found eye cells meaning release medium specifically active daylight hours silent night acts enhance activity cone cells suppressing rod cells result increase sensitivity color contrast bright light conditions cost reduced sensitivity light dim basal largest important sources brain ventral area structures closely related similar respects components basal complex network structures located mainly base largest component basal sends projection dorsal ventral area sends similar type projection ventral progress understanding functions basal slow popular broadly stated propose basal play central role action selection action selection theory simplest form proposes person animal situation behaviors possible activity basal determines executed releasing response continuing motor systems activated generate competing behaviors basal concept responsible initiating behaviors determining details carried words essentially form decision making system basal divided sectors involved controlling particular types actions ventral sector basal containing ventral ventral area operates highest level hierarchy selecting actions organism level dorsal sectors containing dorsal operate lower levels selecting specific muscles movements implement given behavior pattern contributes action selection process important ways sets threshold initiating actions higher level activity lower impetus required evoke given behavior consequence high levels lead high levels motor activity behavior low levels lead slowed reactions disease levels circuit greatly reduced characterized difficulty initiating movement people disease confronted strong threat reactions vigorous healthy person opposite direction drugs increase release cocaine produce heightened levels activity including extreme movements second important effect teaching signal action followed increase activity basal circuit altered way makes response easier evoke similar situations arise future form conditioning plays role reward signal reward reward system reward attractive property behavior known approach behavior behavior rewarding potential cause approach choice consume pleasure learning classical conditioning approach behavior main functions reward aspect reward pleasure provides definition reward rewarding rewarding rewards like money desirable aspect rewarding reflected approach behavior induce component rewards derived behavior acquiring model distinguishes components rewarding incentive model wanting desire commonly seeking corresponds approach behavior liking pleasure corresponds behavior human drug wanting liking desire use addictive drug increases pleasure obtained consuming decreases drug tolerance brain functions partly global reward signal initial response rewarding information value context reward context reward related learning functions reward prediction error signal degree value reward unexpected according hypothesis rewards expected produce second response certain cells rewards unexpected greater expected produce short lasting increase omission expected reward actually causes release drop background level prediction error hypothesis drawn particular interest influential learning method known temporal difference learning makes heavy use signal prediction error confluence theory data led fertile interaction computer scientists interested machine learning evidence recordings brains animals shows ventral area strongly activated wide variety rewarding events reward responsive crucial reward related serve central component reward system function varies projection example nucleus shell projection assigns incentive want rewarding associated cues projection updates value different goals accordance incentive projections consolidation reward related memories nucleus core dorsal pathways involved learning motor responses facilitate acquisition rewarding activity projections appears associated reward prediction central role wanting associated approach responses rewarding detailed studies shown simply liking pleasure reflected response involved aspects pleasure related pleasure centers identified system nucleus shell outside system ventral nucleus example direct electrical pathways brain experienced types animals willing work obtain drugs treat reduce levels tend cause diminished ability experience pleasure types experiences sex enjoying food playing video games increase release addictive drugs directly indirectly affect nucleus drugs increase drug wanting leading drug use repeatedly taken high presumably incentive drugs increase release include cocaine produce increases wanting behaviors greatly alter expressions pleasure change levels drugs heroin produce increases expressions liking wanting behaviors animals ventral system rendered inactive seek food death left food placed mouths consume expressions indicative pleasure outside nervous system cross blood brain barrier synthesis functions peripheral areas large degree independent synthesis functions brain substantial functions entirely clear found blood levels comparable humans form produced acting free bulk produced surrounds parts digestive system production thought mechanism food produced digestive process levels typically rise fold meal known biological functions relatively small quantity produced sympathetic nervous system digestive system possibly organs act peripheral tissues converted beta released located walls act release responses activated released body conditions low oxygen arterial perform useful functions known role blood flow peripheral systems limited area performs function peripheral systems plays important role include immune system immune system acts present immune cells especially affect immune cells bone system addition synthesized released immune cells main effect reduce activation level functional significance system unclear possible route interactions nervous system immune system relevant disorders system located cells kidney present synthesized cells discharged tubular fluid actions include increasing blood supply increasing rate increasing defects function lead reduced consequently result development high blood pressure strong evidence faults production result number including stress genetic essential stress cause defects system caused genetic factors high blood pressure role somewhat complex consists parts component digestive substances including small function enters small clearly established possibilities include protecting damage reducing rate content moves digestive system including evidence beta cells contain acts reduce release source input clearly established come derives sympathetic nervous system synthesized locally types cells medical uses manufactured medication sold trade names world health organization list essential commonly drug treatment severe low blood pressure slow heart rate cardiac arrest especially important treating newborn given half life short approximately minute adults minutes newborn minutes usually given continuous single injection effects depending include increase increase output increase heart rate increase blood pressure low acts sympathetic nervous system increase heart muscle force heart rate increasing cardiac output blood pressure higher cause increases blood pressure older literature describes low thought improve kidney function consequences recent reviews concluded low levels effective harmful effects result prominent effects result acting effects include negative effects kidney function irregular lethal dose expected prove fatal population found mouse administered mouse administered rat administered dog administered form known available use assess function disease disorders system plays central role significant medical conditions including disease attention deficit disorder addiction aside important drugs act systems parts brain body medical recreational purposes developed variety research drugs high affinity specific types effects affect aspects physiology including aging brain number studies reported age related decline synthesis density number brain decline shown occur regions decreases documented reduction aging thought responsible symptoms increase frequency age decreased arm swing increased changes levels cause age related changes flexibility decline output aging disease disease age related disorder characterized movement disorders body slowing movement limbs use advanced stages progresses eventually death main symptoms caused loss cells cells especially vulnerable damage variety insults including depicted book movie repeated sports related forms chemical poisoning lead substantial cell loss producing syndrome similar main features disease cases disease meaning cause cell death identified widely treatment administration precursor converted brain parts body unlike capable crossing blood brain barrier administered peripheral reduce converted periphery increase enters brain administered regularly long time period variety unpleasant effects begin appear considered best available long term treatment option cases disease treatment restore cells lost causes remaining cells produce loss degree advanced stages treatment begins fail cell loss severe remaining ones produce regardless levels drugs enhance function treat cases appears best trade positive effects negative effects treat disease associated development syndrome involves medication medication induced engagement natural rewards like gambling sexual activity behaviors similar observed individuals addiction drug addiction cocaine substituted including marketed exert effects primarily partly increasing levels brain variety mechanisms cocaine non resulting increased concentrations like cocaine substituted increase concentration different mechanisms effects include increases heart rate body temperature improvements attention endurance increases pleasure produced rewarding events higher anxiety loss contact reality drugs group high addiction potential effects reward system brain useful lower treating attention deficit disorder important factor onset duration action cocaine effect seconds injected free base form effects minutes rapid brief action makes effects easily perceived consequently gives high addiction potential taken form contrast hours reach peak levels depending effects hours slow sustained actions reduce addiction potential useful treating variety addictive drugs produce increase reward related activity cocaine promote increased levels appear primary factor causing addiction addictive drugs heroin increased levels reward system play minor role addiction people addicted withdrawal experience physical suffering associated alcohol withdrawal withdrawal instead experience intense desire drug characterized symptoms brought psychological dependence system plays crucial role aspects addiction earliest stage genetic differences alter expression brain predict person find appealing consumption produces increases brain levels minutes hours finally chronic elevation comes repetitive high dose consumption wide ranging set structural changes brain responsible characterize addiction treatment addiction difficult consumption comes psychological withdrawal extinct emerge faced associated drug friends locations situations association networks brain greatly drugs early 1950s discovered class drugs known typical known major effective reducing symptoms introduction widely 1950s led release patients institutions years followed 1970s researchers understood typical worked antagonists realization led called hypothesis largely caused brain systems hypothesis drew additional support observation symptoms intensified enhancing drugs produce healthy people taken large following decades fewer effects developed newer drugs act directly instead produce alterations activity indirectly drugs treat drugs broadly effect types active behavior particularly reduce agitated behavior characteristic overt remains substantial dispute improvement patient experiences drugs later observations caused hypothesis lose popularity simple original form thing patients typically increased levels brain activity drugs notably act produce symptoms importantly drugs reduce activity imperfect treatment reduce symptoms producing severe short term long term effects continue believe involves sort system hypothesis evolved time sorts tended increasingly subtle complex widespread use drugs long controversial reasons drugs perceived people produce general thought suppress ability experience pleasure second difficult act specifically behaviors merely suppressing types active behavior produce range effects including weight gain diabetes fatigue sexual changes type movement disorder known effects continue long cessation drug use permanently attention deficit disorder altered implicated attention deficit disorder condition associated impaired control turn leading problems regulating attention control behaviors control things missing details working memory problems genetic links addition links important relationship involves drugs treat effective agents drugs increase levels brain clinical effects treating indirect activation specifically pain plays role pain processing multiple levels central nervous system including spinal cord gray basal decreased levels associated painful symptoms frequently occur disease occur painful clinical conditions including burning mouth syndrome restless legs syndrome largely determined activity area region known trigger zone area contains large population type consequently drugs activate high potential cause group includes administered disease cases antagonists useful anti drugs comparative biology evolution reports detected types bacteria called importantly types bacteria contain animals use proposed animals derived machinery bacteria horizontal gene transfer occurred relatively late evolutionary time result incorporation bacteria cells gave rise animals animals single report presence indication function reported nervous systems species including dates emergence earliest appearance nervous system million years ago era functions types worm type animal examined seen modify motor behavior model organism reduces increases food movements produces screw like movements swimming promotes crawling wide range effect behavior switching response selection comparable effect mammals consistently shown play role reward learning animal groups invertebrates common fruit flies trained repeat action consistently followed increase levels long believed exception seen having adverse effect reward seen instead closely related recent studies shown play reward learning fruit flies found rewarding effect set previously accessed research plants plants including variety food plants varying degrees highest concentrations observed fruit pulp red yellow contains levels parts million weight potatoes brussels contain levels million tomatoes beans plants contain concentrations million plants synthesized acid mechanisms similar animals use variety ways producing variety functions plant clearly established evidence play role response infection act growth promoting factors situations modify way actions identified mechanisms activate consumed food act brain cross blood brain barrier variety plants contain precursor highest concentrations found leaves pods plants genus especially velvet beans source drug plant containing substantial amounts plant produces beans known broad beans level beans lower pod shells parts plant seeds trees contain substantial amounts species marine green algae major component present high concentrations estimated dry weight evidence functions anti defense reducing consumption precursor family dark substances found wide range organisms closely related type known synthesized human skin type synthesized uses precursor substantial evidence gives dark color brain derived probably appears biological systems plants likely precursor complex patterns appear butterfly wings black white stripes bodies insect larvae thought caused structured history development synthesized george james laboratories london england identified human brain named precursor synthesis function recognized laboratory chemical national heart institute sweden awarded nobel prize physiology medicine showing precursor adrenaline research motivated proteins led discovery wide variety materials placed solution slightly basic coated layer referred forms spontaneous reaction formally type synthesis usually involves reaction base water structure unknown form objects ranging size large surfaces layers chemical properties potential extremely useful numerous studies examined possible applications simplest level protection damage light form drug delivery sophisticated level properties useful active