U nweaving regulatory networks: Automated extraction from literature and statistical analysis
Overview of the talk <ul><li>Introduction: project participants & jigsaw puzzle analogy </li></ul><ul><li>Project motivati...
Our project is set up as a collaboration of three departments of Columbia University
Interdisciplinary Collaboration: Department of Medical Informatics ,  Columbia University (Carol Friedman, Pauline Kra, Mi...
Studying living organisms  is not unlike playing with a jigsaw puzzle…
Starting point: before sequence data were available
“Stamp collecting”: some regularities start to emerge...
Defining families of sequences
Beginning assembly of pieces: where we are now
Future
Overview of the talk <ul><li>Introduction: project participants & jigsaw puzzle analogy </li></ul><ul><li>Project motivati...
Our long-term objective: develop computational tools for automated  compilation  and  analysis  of complex cell regulation...
Problem/Motivation: Currently a search through the PubMed system with the keywords  “cell cycle”  and  “apoptosis”  produc...
We decided ( i ) to develop tools for  automatic retrieval of binary regulatory relationships between molecules from resea...
We call the system GENIES (GENomics Information Extraction System)
An overview of our system.
Application of techniques  of Artificial Intelligence: Natural Language Processing Goal:  to identify  binary relationship...
Overview of the talk <ul><li>Introduction: project participants & jigsaw puzzle analogy </li></ul><ul><li>Project motivati...
The language of regulatory pathways have significant differences with the language of metabolic pathways
Representation We represent a pathway a series of overlapping “links” – substance/action/substance triplets Substance A  ...
Duality  of actions in signal transduction literature
We realized that the current research literature in molecular biology Describes pathways on two different levels: Logical ...
A  activates  B A  inactivates  B A  phoshorylates  B A  methylates  B ... logical biochemical
Dualism: in the  biochemical  representation substance  A  is not  a participant of the action , while  it  is  in the   l...
Both  logical  and  biochemical  descriptions can be combined in the same sentence: Activated raf-1  phosphorylates  and  ...
The paper descibing a “ knowledge model ” (=ontology) will appear in  Bioinformatics
Ontology paper
We represent a pathway a series of overlapping “links” – substance/action/substance triplets Substance A    Substance B  ...
“Actions” are  relatively  scanty: one can provide an  exhaustive  list  of them
Each action comes with a  mechanism  (biochemical representation) and  result  (logical representation)
Gene  and  protein names  are numerous (currently >80,000) and the number is growing
MedLEE (by  Carol Friedman  and colleagues) contains implementation of various grammatical patterns associated with the sa...
MedLEE = Med ical  L anguage  E xtraction and  E ncoding System It is an integral part of Clinical Information Service  at...
For details see, e.g., Friedman, C., G. Hripcsak, W. DuMouchel, S.B. Johnson, and P.D. Clayton.  1995.  Natural language p...
Overview of the talk <ul><li>Introduction: project participants & jigsaw puzzle analogy </li></ul><ul><li>Project motivati...
Term identification:
To give you a feeling of the work of the  complete  conveyer line…
Consider sentence from an actual Science  article
NLP module (term markup + MedLEE) produces <ul><ul><ul><li>[action, inactivate, [protein,   rap1 ],  </li></ul></ul></ul><...
Which is then converted into “shorthand” notation Substance (gene) Action Action on action
Which is then further converted to a format readable by our pathway visualization program Protein{ Name{ &quot; IL-3 &quot...
Which is then visualized...
Example of an actual  human  regulatory network visualized
Corresponding article
Overview of the talk <ul><li>Introduction: project participants & jigsaw puzzle analogy </li></ul><ul><li>Project motivati...
Drawing a complex graph is a separate problem of Computer Science. We are using a  Simulated Annealing  Technique to find ...
What is a good pathway graph? <ul><li>Every gene/protein name is easy to read every </li></ul><ul><li>Easy to trace connec...
Human Cell Cycle / Apoptosis Machinery
~400 nodes
Layered graph layout
Incompleteness of the graph: almost complete lack of feedback loops
Overview of the talk <ul><li>Introduction: project participants & jigsaw puzzle analogy </li></ul><ul><li>Project motivati...
Scale-free networks in biology and outside; mechanism of stochastic birth of scale-free networks (collaboration with Shawn...
Motivation: To understand and describe real networks  we need to come up with biologically sensible model  that is capable...
What is a scale-free network?
k= 0   k= 1  k= 2  k= 3   k= 4  … k in = 0   k in = 1  k in = 2  k in = 3   k in = 4  … k out = 0   k out = 1  k out = 2  ...
Yeast edge distributions
Network topology Albert, et al. Nature 506, 378-382.   (Erd ö s–R é nyi model: most nodes have approximately the same numb...
There are other scale-free networks
References
References
Actor collaboration Power grid World Wide Web
Actor collaboration (see www.nd.edu/~alb)
 
Scale-free connectivity <ul><li>Scale-free networks are often characterized by a  </li></ul><ul><li>power law distribution...
WWW By K. C. Claffy
Summary
Related concepts: Zipf’s laws
Network of English words HAMLET  The body is with the king, but the king is not with the body. The king is a thing-- body ...
Word frequencies in Shakespeare’s plays: http://www.mta.link75.org/curriculum/english/shake/
Hamlet : “incoming connections” The , 1101 And , 898 To , 726 Of , 657 I , 561 You , 544 My , 508 A , 498 In , 414 It , 41...
***1*** <A-Cursing><A-Down-A><A-Making><A-Piece><A-Work><Abate><Abatements><Abhorred><Ability><Able><Abominably><Abridgeme...
 
 
Metabolic networks in bacteria
 
There are networks that are not scale-free
Caenorhabditis elegans “Some 300 of the 959 cells of the adult worm, for example, constitute a nervous system that can det...
Not all biological networks are scale-free
Overview of the talk <ul><li>Introduction: project participants & jigsaw puzzle analogy </li></ul><ul><li>Project motivati...
A stochastic model of evolution of a molecular network
Molecular networks are composed of DNA, RNA, proteins, lipids, small molecules, …
(Over)Simplification: we assume that each node of the network has two domains (not necessary distinct) responsible for the...
A node of a molecular network Each substance has  a pair of “domains,” upstream and downstream, which determine specific  ...
The model would not be appropriate if domain-rich proteins tend to have more network connections than domain-poor proteins
Another way to put the same question: Is the number of domains per protein correlated with the number of network connectio...
Connectivity is NOT affected by domain number
Therefore, it is probably OK to use “two-domain” model in the current setup
Evolutionary events affecting network growth
We assume that network rearrangements arrive independently according to a Poisson process… …which leads to a system of ord...
Armed with resulting equations and programs, we can compute the topological properties of the growing network for any (rea...
Data: signal transduction network in yeast
We therefore can fit the model to the experimental data and estimate parameter values
Estimating parameters:
Fitting data for upstream and downstream connections simultaneously
Fitting data for upstream and downstream connections separately
Estimated parameters Replacement Duplication Innovation
The analysis of the model suggests that the number of domain copies per genome should also follow a power law
Frequency of domain appearances in  E. coli  (closed circles),  S. cerevisiae  (crosses), and  H. sapiens  (open rectangle...
How many distinct domains exist? Number of distinct domains Number of genes Power law constant
For  E. coli  our estimate suggests existence of  D  > 4,600 domains…
For  yeast   D  > 12,900 domains…
( The last !) overview of the talk <ul><li>Introduction: project participants & jigsaw puzzle analogy </li></ul><ul><li>Pr...
Thank you!
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  1. 1. U nweaving regulatory networks: Automated extraction from literature and statistical analysis
  2. 2. Overview of the talk <ul><li>Introduction: project participants & jigsaw puzzle analogy </li></ul><ul><li>Project motivation. </li></ul><ul><li>Duality of signal transduction language. </li></ul><ul><li>How the whole system works. </li></ul><ul><li>Good and ugly graphs. </li></ul><ul><li>-------------------------------------------- </li></ul><ul><li>Scale-free networks in biology and outside; mechanism of stochastic birth of scale-free networks </li></ul>
  3. 3. Our project is set up as a collaboration of three departments of Columbia University
  4. 4. Interdisciplinary Collaboration: Department of Medical Informatics , Columbia University (Carol Friedman, Pauline Kra, Michael Krauthammer, Yu Hong, Andrey Rzhetsky) Department of Computer Science , Columbia University (Vasileios Hatzivassiloglou, Pablo Ariel Duboue, Wubin Weng) Columbia Genome Center , Columbia University (Pavel Morozov, Tomohiro Koike, Shawn Gomez, Sabina Kaplan, Sergey Kalachikov, Jim Russo, Andrey Rzhetsky)
  5. 5. Studying living organisms is not unlike playing with a jigsaw puzzle…
  6. 6. Starting point: before sequence data were available
  7. 7. “Stamp collecting”: some regularities start to emerge...
  8. 8. Defining families of sequences
  9. 9. Beginning assembly of pieces: where we are now
  10. 10. Future
  11. 11. Overview of the talk <ul><li>Introduction: project participants & jigsaw puzzle analogy </li></ul><ul><li>Project motivation. </li></ul><ul><li>Duality of signal transduction language. </li></ul><ul><li>How the whole system works. </li></ul><ul><li>Good and ugly graphs. </li></ul><ul><li>-------------------------------------------- </li></ul><ul><li>Scale-free networks in biology and outside; mechanism of stochastic birth of scale-free networks </li></ul>
  12. 12. Our long-term objective: develop computational tools for automated compilation and analysis of complex cell regulation cascades in vertebrates
  13. 13. Problem/Motivation: Currently a search through the PubMed system with the keywords “cell cycle” and “apoptosis” produced lists of 169,293 and 29,961 articles, respectively. Clearly it is not feasible to scan all these papers “manually” ...
  14. 14. We decided ( i ) to develop tools for automatic retrieval of binary regulatory relationships between molecules from research literature using techniques of natural language processing , and ( ii ) to use extracted knowledge for editing, visualization, and superimposing/comparing homologous networks .
  15. 15. We call the system GENIES (GENomics Information Extraction System)
  16. 16. An overview of our system.
  17. 17. Application of techniques of Artificial Intelligence: Natural Language Processing Goal: to identify binary relationships of the form “ protein A activates protein B” “ protein B inactivates gene C”
  18. 18. Overview of the talk <ul><li>Introduction: project participants & jigsaw puzzle analogy </li></ul><ul><li>Project motivation. </li></ul><ul><li>Duality of signal transduction language. </li></ul><ul><li>How the whole system works. </li></ul><ul><li>Good and ugly graphs. </li></ul><ul><li>--------------------------------------------- </li></ul><ul><li>Scale-free networks in biology and outside; mechanism of stochastic birth of scale-free networks </li></ul>
  19. 19. The language of regulatory pathways have significant differences with the language of metabolic pathways
  20. 20. Representation We represent a pathway a series of overlapping “links” – substance/action/substance triplets Substance A  Substance B  Substance C  Substance D
  21. 21. Duality of actions in signal transduction literature
  22. 22. We realized that the current research literature in molecular biology Describes pathways on two different levels: Logical and Biochemical
  23. 23. A activates B A inactivates B A phoshorylates B A methylates B ... logical biochemical
  24. 24. Dualism: in the biochemical representation substance A is not a participant of the action , while it is in the logical representation Logical Biochemical
  25. 25. Both logical and biochemical descriptions can be combined in the same sentence: Activated raf-1 phosphorylates and activates mek-1. logical biochemical
  26. 26. The paper descibing a “ knowledge model ” (=ontology) will appear in Bioinformatics
  27. 27. Ontology paper
  28. 28. We represent a pathway a series of overlapping “links” – substance/action/substance triplets Substance A  Substance B  Substance C  Substance D
  29. 29. “Actions” are relatively scanty: one can provide an exhaustive list of them
  30. 30. Each action comes with a mechanism (biochemical representation) and result (logical representation)
  31. 31. Gene and protein names are numerous (currently >80,000) and the number is growing
  32. 32. MedLEE (by Carol Friedman and colleagues) contains implementation of various grammatical patterns associated with the same verb: A activates B… A is an activator of B… A appeared to activate B… A is activating B…
  33. 33. MedLEE = Med ical L anguage E xtraction and E ncoding System It is an integral part of Clinical Information Service at Columbia-Presbyterian Medical Center, It routinely processes thousands of patient records a day. MedLEE does semantic analysis of the complete sentence . If it a complete sentence cannot be parsed successfully, MedLEE does re-analysis, trying to extract parts.
  34. 34. For details see, e.g., Friedman, C., G. Hripcsak, W. DuMouchel, S.B. Johnson, and P.D. Clayton. 1995. Natural language processing in an operational clinical system. Natural Language Engineering . 1 (1): 83-108.
  35. 35. Overview of the talk <ul><li>Introduction: project participants & jigsaw puzzle analogy </li></ul><ul><li>Project motivation. </li></ul><ul><li>Duality of signal transduction language. </li></ul><ul><li>How the whole system works. </li></ul><ul><li>Good and ugly graphs. </li></ul><ul><li>--------------------------------------------- </li></ul><ul><li>Scale-free networks in biology and outside; mechanism of stochastic birth of scale-free networks </li></ul>
  36. 36. Term identification:
  37. 37. To give you a feeling of the work of the complete conveyer line…
  38. 38. Consider sentence from an actual Science article
  39. 39. NLP module (term markup + MedLEE) produces <ul><ul><ul><li>[action, inactivate, [protein, rap1 ], </li></ul></ul></ul><ul><ul><ul><li>[action, activate, [complex, T-cell receptor ] </li></ul></ul></ul><ul><ul><ul><li>[action, transcribe, [gene, gene encoding interleukin-2 ]]], </li></ul></ul></ul><ul><ul><ul><li>[parsemode, mode1]] </li></ul></ul></ul>
  40. 40. Which is then converted into “shorthand” notation Substance (gene) Action Action on action
  41. 41. Which is then further converted to a format readable by our pathway visualization program Protein{ Name{ &quot; IL-3 &quot; , } }     LogicalAction{ { UpstreamActionAgent { Protein{ Name{ &quot; IL-3 &quot;, } } }, DownstreamActionAgent { Complex{ Name{ &quot; IL-3R &quot; } } }, Result{ activation } } } Complex{ Name{ &quot; IL-3R &quot; } Composition{ Protein{ Name{ “ IL-3R alph a ” } } Protein{ Name{ “ IL-3R beta ” } } }   }
  42. 42. Which is then visualized...
  43. 43. Example of an actual human regulatory network visualized
  44. 44. Corresponding article
  45. 45. Overview of the talk <ul><li>Introduction: project participants & jigsaw puzzle analogy </li></ul><ul><li>Project motivation. </li></ul><ul><li>Duality of signal transduction language. </li></ul><ul><li>How the whole system works. </li></ul><ul><li>Good and ugly graphs. </li></ul><ul><li>--------------------------------------------- </li></ul><ul><li>Scale-free networks in biology and outside; mechanism of stochastic birth of scale-free networks </li></ul>
  46. 46. Drawing a complex graph is a separate problem of Computer Science. We are using a Simulated Annealing Technique to find an optimum graph layout
  47. 47. What is a good pathway graph? <ul><li>Every gene/protein name is easy to read every </li></ul><ul><li>Easy to trace connections between pairs of molecules </li></ul><ul><li>Easy to read mechanism and result for each action </li></ul><ul><li>Compact </li></ul><ul><li>Shows tissue/stage/species/cell line specificity </li></ul><ul><li>Beautiful </li></ul>
  48. 48. Human Cell Cycle / Apoptosis Machinery
  49. 49. ~400 nodes
  50. 50. Layered graph layout
  51. 51. Incompleteness of the graph: almost complete lack of feedback loops
  52. 52. Overview of the talk <ul><li>Introduction: project participants & jigsaw puzzle analogy </li></ul><ul><li>Project motivation. </li></ul><ul><li>Duality of signal transduction language. </li></ul><ul><li>How the whole system works. </li></ul><ul><li>Good and ugly graphs. </li></ul><ul><li>--------------------------------------------- </li></ul><ul><li>Scale-free networks in biology and outside; stochastic birth of scale-free networks </li></ul>
  53. 53. Scale-free networks in biology and outside; mechanism of stochastic birth of scale-free networks (collaboration with Shawn M. Gomez)
  54. 54. Motivation: To understand and describe real networks we need to come up with biologically sensible model that is capable of generating networks with properties close to those of real networks
  55. 55. What is a scale-free network?
  56. 56. k= 0 k= 1 k= 2 k= 3 k= 4 … k in = 0 k in = 1 k in = 2 k in = 3 k in = 4 … k out = 0 k out = 1 k out = 2 k out = 3 k out = 4 … Geometry of a network: frequency, p k , of vertices having exactly k edges
  57. 57. Yeast edge distributions
  58. 58. Network topology Albert, et al. Nature 506, 378-382. (Erd ö s–R é nyi model: most nodes have approximately the same number of connections)
  59. 59. There are other scale-free networks
  60. 60. References
  61. 61. References
  62. 62. Actor collaboration Power grid World Wide Web
  63. 63. Actor collaboration (see www.nd.edu/~alb)
  64. 65. Scale-free connectivity <ul><li>Scale-free networks are often characterized by a </li></ul><ul><li>power law distribution </li></ul>Actor collaboration WWW Power grid
  65. 66. WWW By K. C. Claffy
  66. 67. Summary
  67. 68. Related concepts: Zipf’s laws
  68. 69. Network of English words HAMLET The body is with the king, but the king is not with the body. The king is a thing-- body the is with king but not a thing
  69. 70. Word frequencies in Shakespeare’s plays: http://www.mta.link75.org/curriculum/english/shake/
  70. 71. Hamlet : “incoming connections” The , 1101 And , 898 To , 726 Of , 657 I , 561 You , 544 My , 508 A , 498 In , 414 It , 414 That , 389 Is , 334 Not , 315 This , 296 His , 292 …
  71. 72. ***1*** <A-Cursing><A-Down-A><A-Making><A-Piece><A-Work><Abate><Abatements><Abhorred><Ability><Able><Abominably><Abridgement><Abroad><Absent><Abstinence><Abstract><Abuse><Abused><Abuses><Access><Accidental><Accidents><Accord><Account><Accounted><Accurst><Accuse><Ache><Achievements><Acquaint><Acquaintance><Acquire><Acres><Across><Acted><Acting><Actively><Adam><Adam's><Adders><Addicted><Address><Adheres><Adjoin'd><Admirable><Admittance><Adoption><Adulterate><Advanced><Advantage><Adventurous><Advise><Aeneas><Aery><Afeard><Affairs><Affectation><Affections><Afflict><Afflicts><Affrighted><Affront><Afoot><Afraid><Afternoon><Afterwards><Ago><Agreeing><Aid><Aim><Aim'd><Airs><Airy><Allegiance><Alleys><Allow><Also><Altitude><Altogether><Always><Amaze><Amazed><Ambassador><Amber><Ambiguous><Amble><Amen><Amities><Among><Anchor's><Ancient><Ancle><Anger><Angle><Angry><Animals><Annexment><Annual><Anoint><Another's><Answerest><Answer'd><Antic><Anticipation><Antiquity><An't><Apiece><Apople'xd><Appal><Apparel><Appetite><Applaud><Appliance><Appointment><Appurtenance><Aptly><Ardour><Argues><Aright><Arithmetic><Army><Aroused><Arraign><Arrest><Arrests><Arrived><Arrow><Artery><Articles><Artless><Ashamed><Aside><Asked><Aslant><Asleep><Aspect><Assail><Assault><Assays><Assay'd><Associates><Assure><Astonish><Asunder><As'es><Attend><Attended><Attends><Attent><Attractive><Attribute><Audit><Augury><Aunt-Mother><Auspicious><Authorities><Avouch><Awry><Aye><Babe><Backed><Backward><Bade><Bait><Baker's><Ban><Bands><Baptista><Bar><Barber's><Bare><Barefaced><Barefoot><Bark><Bark'd><Barren><Barr'd><Baseness><Bastard><Bat><Bated><Battalions><Batten><Battery><Battlements><Bawd><Bawdry><Bawds><Bawdy><Be-Netted><Beam><Beards><Bear't><Beaten><Beats><Beauteous><Beautied><Beauties><Beaver><Became><Because><Beck><Beckons><Bed-Rid><Bedded><Beds><Beer-Barrel><Beetles><Befall'n><Befitted><Beget><Beggar'd><Behaved><Behold><Behove><Behoves><Belief><Believed><Bellow><Bellowed><Bells><Beloved><Bended><Beneath><Benefit><Berattle><Beseech'd><Beshrew><Besides><Besmirch><Bespeak><Bestial><Bestowed><Bestow'd><Bet><Beteem><Bethought><Betime><Betimes><Betoken><Better'd><Bevy><Bewept><Bias><Bier><Bilboes><Birds><Bisson><Bites><Blackest><Blanket><Blanks><Blasting><Blastments><Blasts><Blaze><Blazes><Blazon><Bleeding><Blench><Bless'd><Blest><Blister><Bloat><Bloodily><Blossoms><Blue><Blunted><Blurs><Board><Boarded><Bodes><Bodiless><Bodkin><Bodykins><Boisterous><Bonds><Bonnet><Bonny><Books><Borrower><Borrowing><Borrow'd><Botch><Boughs><Bought><Bounded><Bounds><Bounteous><Bounty><Bourn><Bout><Bouts><Bowl><Box><Boys><Brainish><Branches><Brands><Brass'd><Bravery><Bray><Brazen><Breach><Bread><Breadth><Breaking><Breast><Breathes><Breeder><Breeding><Brevity><Bride-Bed><Bringing><Brings><Broken><Brokers><Brooch><Brood><Brothel><Brows><Bruit><Brute><Brutus><Bubbles><Budge><Buffets><Bugs><Build><Built><Bulwark><Bung-Hole><Burnt><Burthen><Busy><Button><Buttons><Buy><Buyer><Buys><Buzzers><C><Cabin><Cain's><Calamity><Calendar><Calf><Calf-Skins><Called><Call'd><Call't><Calmly><Calumnious><Calumny><Calves><Candied><Cannoneer><Cannons><Canon><Canonized><Canopy><Cap-A-Pe><Capability><Capitol><Capons><Caps><Captain><Captains><Carbuncles><Carefully><Careless><Carnal><Carouses><Carp><Carriage><Carries><Carrion><Carrying><Cart><Carters><Carve><Case><Cases><Casual><Cataplasm><Cautel><Caution><Caviare><Celebrated><Cell><Cellarage><Centre><Cerements><Certainty><Chalice><Challenger><Chamber-Door><Chameleon's><Changed><Changeling><Changes><Chanson><Chanted><Chap-Fallen><Chapless><Chariest><Charity><Charm><Chase><Checking><Cherub><Chide><Chiefest><Chiefly><Chopine><Chorus><Chough><Christians><Chronicles><Churches><Churchyards><Churlish><Cicatrice><Circumscribed><Circumstances><Circumvent><Clad><Claim><Clambering><Clamour><Clapped><Claudio><Claw'd><Clear><Clearly><Cleave><Cleft><Clemency><Clepe><Cliff><Climatures><Cloak><Closely><Clothe><Cloud><Clout><Clown><Clowns><Clutch><Coach><Coagulate><Cockle><Coil><Coinage><Collateral><Colleagued><Columbines><Combat><Combated><Combination><Combined><Comfort><Comical-Historical-Pastoral><Comma><Commanded><Commands><Commencement><Commendable><Commended><Comment><Commerce><Commingled><Commune><Commutual><Compact><Companies><Companions><Company><Compare><Compass><Compelled><Compell'd><Competent><Complete><Composed><Compost><Compound><Compounded><Compulsatory><Compulsive><Comrade><Conceal'd><Conceive><Conception><Concernancy><Concernings><Concluded><Conclusions><Condolement><Confederate><Conference><Confined><Confines><Confront><Confusion><Congregation><Congruing><Conjectures><Conjoin'd><Conjunctive><Conjuration><Conjure><Conjures><Conqueror><Conquest><Considered><Consider'd><Consonancy><Constant><Constantly><Consummation><Contagious><Containing><Contend><Contents><Continual><Contract><Contracted><Contraction><Contrary><Contriving><Controversy><Contumely><Convenience><Conveniently><Conversation><Converse><Converted><Convey><Conveyance><Conveyances><Convocation><Convoy><Cool><Coped><Copied><Core><Cornelius><Corner><Coronation><Coronet><Corrupted><Corses><Costly><Coted><Couched><Counsellor><Counter><Counterfeit><Countries><Countrymen><Country's><Couple><Couplets><Courses><Courteous><Courtesy><Courtiers><Courtier's><Covenant><Cowards><Cozenage><Cozen'd><Crab><Crack><Cracked><Cracks><Crafts><Crafty><Crants><Crash><Craven><Craves><Crawling><Creation><Credent><Creep><Crescent><Crib><Crimeful><Croaking><Crocodile><Crook><Cross><Crow-Flowers><Crowing><Crowner><Crowner's><Crowns><Crust><Cuckold><Cudgel><Cue><Cuffs><Cunnings><Cups><Curb><Curd><Cure><Curiously><Curls><Curse><Customary><Cutpurse><Cyclops><Dagger><Daily><Daintier><Daisies><Daisy><Dalliance><Dally><Dallying><Damn><Damnable><Damnation><Damon><Danskers><Dared><Dares><Darest><Dark><Darkest><Daughters><Dawning><Deal><Dealt><Dearth><Death-Bed><Deaths><Debate><Debatement><Debt><Decayer><Deck'd><Declension><Decline><Declining><Deeds><Deeply><Deer><Defeated><Defeats><Defective><Define><Definement><Defy><Deject><Dejected><Delated><Delays><Deliberate><Delivered><Deliver'd><Delve><Delver><Demanded><Demi-Natured><Demonstrated><Denied><Denies><Denote><Depart><Departed><Depend><Depends><Deprive><Deprived><Deserve><Deserved><Design'd><Desirous><Desk><Despised><Despite><Detecting><Determination><Determine><Device><Devices><Devise><Devised><Devotion's><Devoutly><Dews><Dexterity><Diameter><Dicers><Diction><Didest><Dido><Differences><Different><Digested><Digged><Diligence><Dip><Dipping><Dire><Directions><Dirge><Dirty><Disappointed><Disasters><Disclaiming><Disclose><Discomfort><Discord><Discovery><Disease><Diseased><Diseases><Dish><Dishes><Disjoint><Dislike><Dismantled><Dismay><Dispatch'd><Distant><Distempered><Distilled><Distilment><Distinguish><Distract><Distress><Ditchers><Divided><Divine><Divulging><Dizzy><Doctor><Document><Dogs><Doing><Dole><Dominions><Donn'd><Doom><Doom'd><Dotes><Doublet><Doubts><Douts><Down-Gyved><Dowry><Drab><Drabbing><Dragg'd><Drains><Dram><Draughts><Dreaded><Dreadfully><Dreamt><Dressy><Drinking><Drinks><Driven><Drives><Drooping><Drop><Dropping><Droppings><Drowns><Drugs><Drum><Drunk><Drunkards><Due><Dug><Duke's><Duller><Dulls><Dumbshows><Dungeons><Dunks><Dupp'd><Duties><Dwelling><Dye><Dying><Eale><Earnest><Earthly><Easier><Easily><Easing><East><Eastward><Eaten><Eclipse><Edified><Egg-Shell><Eight><Eisel><Elder><Eldest><Element><Eleven><Eloquent><Embark'd><Emperor><Emphasis><Employ><Empty><Emulate><Enactures><Encompassment><Encounter'd><Encumber'd><Endeavour><Ended><Ending><Endure><Engaged><Engineer><England's><Enlarged><Enmity><Enseamed><Enterprises><Entrance><Entreated><Entreatments><Envenom><Envious><Enviously><Equivocation><Err><Erring><Errors><Eruption><Escoted><Especial><Espials><Essentially><Esteem'd><Estimation><Et><Eterne><Eternity><Events><Ever-Preserved><Everlasting><Evermore><Evidence><Exact><Exactly><Examples><Exceed><Exceedingly><Exception><Excitements><Exclaim><Excrements><Excuse><Exercises><Exhort><Expectancy><Expend><Expense><Exploit><Exposing><Expostulate><Express'd><Extant><Extent><Exterior><Extinct><Extolment><Extorted><Extravagant><E'er><Eyases><Eyelids><Faction><Faculties><Faculty><Faded><Fail><Fail'd><Fairly><Fairy><Falconers><Falling><Falling-Off><Falsehood><Falsely><Familiar><Famous><Fang'd><Fantastic><Fardels><Fathoms><Fatness><Fatted><Favourite><Fawning><Fay><Fear-Surprised><Fearful><Fearing><Fear'd><Feather><Feathers><Feats><Feeds><Feel><Feelingly><Feels><Feet><Felicity><Fellies><Fellow-Student><Fellow's><Female><Fencing><Fennel><Fertile><Fiction><Field><Fiends><Fierce><Fifty><Filial><Fill><Film><Find'st><Finger><Finger'd><Fires><Firm><Firmament><Fitness><Fitted><Fitting><Flagon><Flash><Flashes><Flats><Flatter><Flatter'd><Flaw><Flaxen><Flies><Flights><Flints><Flood><Flourishes><Flowers><Flush><Flushing><Foh><Folded><Folk><Followed><Folly><Foolery><Forbear><Forcing><Fordo><Fordoes><Fore><Foreign><Foreknowing><Foresaid><Forest><Forestall><Forestalled><Forfeit><Forgeries><Forgery><Forgetting><Forgiveness><Forgone><Forgotten><Formal><Forthwith><Fortified><Forts><Fought><Foul'd><Fox><Frailty><Francisco><Free-Footed><Freeze><Frenchman><Fret><Fretful><Fretted><Friending><Friendship><Frighted><Frock><Front><Frontier><Frost><Frowningly><Frown'd><Fruitful><Fruits><Fulfill'd><Function><Functions><Furnish><Fust><Gaffs><Gaged><Gain-Giving><Gallant><Gallows-Maker><Galls><Gambol><Gambols><Gape><Garb><Garbage><Gardeners><Garland><Garlands><Garments><Garrison'd><Gates><Gaudy><Gave't><Gem><Gender><Gentlewoman><Gently><German><Gestures><Gets><Ghost's><Giant-Like><Gib><Gibber><Gibes><Gilded><Gins><Girdle><Girl><Gis><Givers><Glares><Glassy><Glean><Gleaned><Glimpses><Globe><Glow><Glow-Worm><Goblin><Goblins><God-A-Mercy><God-Like><Gold><Gonzago's><Goodman><Goose-Quills><Gore><Gorge><Govern><Grained><Grand><Grandsire><Grant><Grass><Grass-Green><Grating><Gratis><Grave-Makers><Grave-Making><Graveness><Grave's><Greatly><Greatness><Greeks><Greenly><Greet><Greeted><Greeting><Greetings><Grew><Grey><Griefs><Grieved><Grieves><Grinding><Grinning><Grizzled><Groan><Groaning><Groans><Groped><Grosser><Grossly><Groundlings><Grounds><Growing><Grunt><Guarded><Guards><Guiltless><Gules><Gulf><Gum><Gyves><Habits><Hail><Halfpenny><Hallow'd><Halt><Hamlets><Hammers><Hams><Handsaw><Handsome><Hap><Happen><Happiness><Haps><Harbingers><Hardly><Hardy><Hark><Harlot><Harlot's><Harmony><Harrow><Harrows><Harshly><Hart><Hasten><Hasty><Hatch><Hatchment><Hate><Haunt><Have't><Havoc><Hawk><Hazard><Heads><Headshake><Healthful><Hearer><Hearsed><Heart-Ache><Heart's><Heathen><Heaven-Kissing><Heaven's><Heaves><Heavily><Heavy-Headed><Hebenon><Hecate's><Hectic><Hedge><Heedful><Height><Heir><Hellish><Helpful><Hems><Hent><Herald><Herb-Grace><Hereafter><Herod><Heroes><He'll><Hey-Day><Hic><Hies><Higher><Highest><Highly><Highness><Hillo><Hilts><Hinges><Hire><Historical-Pastoral><Hoar><Hoist><Holding><Hold'st><Hole><Holla><Hollow><Homage><Honey><Honeying><Honoured><Honours><Honour's><Hoodman-Blind><Hoops><Hoped><Hopes><Horrors><Horseback><Host><Hourly><Houses><House's><Hover><Howe'er><Howling><Howsoever><Hue><Huge><Hugger-Mugger><Hum><Humanity><Humble><Humourous><Hung><Hunts><Hurts><Husbandry><Husbands><Hush><Hymen><Hyperion><Hyperion's><Hypocrite><Hypocrites><Hyrcanian><Idol><Ild><Ilium><Ill-Breeding><Ills><Illume><Illusion><Imaginations><Imagine><Imitated><Immediately><Immortal><Impartment><Impasted><Impatient><Imperfections><Imperial><Imperious><Impetuous><Impious><Implements><Implorators><Important><Importunate><Importuned><Importunity><Imposthume><Impotence><Impotent><Impress><Impression><Imputation><Incapable><Incest><Inch><Inclined><Inclining><Incontinency><Incorporal><Incorpsed><Incorrect><Increase><Indentures><Index><Indict><Indifferently><Indirections><Indiscretion><Individable><Indued><Inexplicable><Infallibly><Infants><Infect><Infected><Infects><Influence><Infusion><Ingenious><Inheritance><Inheritor><Inhibition><Inky><Inmost><Innocent><Innovation><Inoculate><Insert><Insinuation><Insolence><Instance><Instances><Instantly><Instructs><Instrumental><Intend><Intents><Inter><Interim><Interpret><Intil><Intruding><Inurn'd><Inventorially><Inventors><Investments><Invisible><Invite><Invites><Invulnerable><Israel><Italian><I'd><Jade><Jangled><Jaw><Jaw-Bone><Jaws><Jelly><Jester><Jig-Maker><Jocund><John-A-Dreams><Joint><Joint-Labourer><Jointly><Jointress><Journeymen><Journeys><Jowls><Joyfully><Judges><Judicious><Juggled><Juice><Justice><Kettle><Kettle-Drum><Key><Kibe><Kick><Kin><Kindless><Kingly><Kissed><Kissing><Kites><Knaves><Knee><Knew'st><Knife><Knight><Knock><Knocked><Knocking><Knotted><Knowest><Knowledge><Know't><La><Laboursome><Labour'd><Lacks><Lack'd><Lads><Ladyship><Lady's><Lain><Lament><Lamond><Lank><Lapsed><Lapwing><Large><Larger><Lash><Lawful><Law's><Lawyer><Lazar-Like><Leads><Lean><Leans><Leaping><Learning><Lecherous><Lecture><Led><Legs><Lender><Lends><Lenten><Leperous><Lesser><Lesson><Lethe><Letter><Levied><Lewdness><Liar><Liberal-Conceited><Libertine><Licence><Lick><Lids><Lief><Liegemen><Life-Rendering><Life's><Lifted><Lightest><Lightness><Likelihood><Likeness><Likewise><Limed><Lingers><Link'd><Lion's><Liquid><Lisp><Lists><Littlest><Livest><Load><Loan><Loathsome><Locks><Lodge><Lodged><Lofty><Loggats><Loins><Loneliness><Longed><Looked><Looking><Loosed><Lord's><Loser><Loses><Losing><Loss><Lot><Loudly><Lover><Low><Lowest><Lucianus><Lug><Lunacies><Luxury><Lying><Machine><Magic><Maid's><Maimed><Mainly><Maintains><Malefactions><Mallecho><Mandate><Manner><Mantle><Marble><Margent><Market><Marriage-Vows><Marriages><Marrow><Mars><Marshal><Mars's><Mart><Martial><Marvel><Massy><Masterly><Master's><Match><Match'd><Matin><Matron's><Mattering><Mayst><Mazzard><Meaning><Meantime><Meats><Medicine><Meditation><Meed><Mellow><Melodious><Mend><Mercury><Mermaid-Like><Merriment><Mess><Message><Messenger><Messengers><Met><Metal><Metals><Method><Mettle><Mew><Miching><Midnight><Mightier><Mightiest><Milch><Mildew'd><Milk><Milky><Million><Millions><Mincing><Mineral><Mines><Mining><Minister><Ministering><Ministers><Minute><Minutes><Miraculous><Mischief><Miss><Mistook><Mixture><Moan><Mockery><Model><Moderate><Modesties><Moiety><Moist><Monarchs><Monday><Monster><Monsters><Monstrous><Monument><Mood><Moods><Moons><Moor><Mope><Moral><Moreover><Morrow><Mortised><Mote><Mothers><Mould><Moult><Mountebank><Mourn><Mourning><Mourn'd><Mouse-Trap><Mouthed><Mouths><Moved><Moves><Moving><Mows><Muddied><Muddy><Muddy-Mettled><Multitude><Murdering-Piece><Murderous><Murder'd><Musty><Mute><Mutes><Mutine><Mutines><Mystery><Name's><Napkin><Narrow><Nasty><Nations><Natures><Nave><Necessaries><Necessity><Neglect><Negligence><Neighbour><Neighbour'd><Nemean><Nephew><Nephews><Nero><Nerve><Nettles><Neutral><New-Hatch'd><New-Lighted><Newborn><Newly><Nick-Name><Niggard><Nighted><Nightly><Night's><Nill><Niobe><Nipping><Nobility><Nobler><Noblest><Nods><Nomination><Non><Nonce><Normandy><North-North-West><Northerly><Noted><Notes><Nothing's><Now-A-Days><Noyance><Nut><Nymph><Oaths><Obeys><Object><Objects><Oblivion><Obscure><Obsequies><Obsequious><Observance><Observant><Observation><Observed><Observers><Obstinate><Occasions><Occulted><Occurrents><Ocean><Offal><Offences><Offence's><Offend><Offendendo><Offender's><Offends><Offer'd><Office><Olympus><Omen><Ominous><Ope><Oped><Open'd><Operant><Opinion><Opposing><Opposite><Opposites><Oppression><Oppressor's><Oppress'd><Orb><Orbed><Orderly><Ordinant><Ordnance><Ore><Orisons><Ossa><Ostentation><Out-Herods><Outbreak><Outface><Outlive><Outlives><Outrageous><Outstretched><Over-Happy><Overcame><Overcome><Overpeering><Overthrown><Owl><Owner><Ownself><O'er-Crows><O'er-Leavens><O'er-Raught><O'er-Reaches><O'er-Sized><O'er-Teemed><O'erbears><O'erdoing><O'ergrowth><O'erhanging><O'erhasty><O'erhear><O'ermaster><O'errule><O'erstep><O'ersways><O'erthrown><O'ertook><O'ertop><O'erweigh><O'erwhelm><Packet><Packing><Paddling><Paddock><Pagan><Pah><Paid><Pain><Paint><Painting><Paintings><Pajock><Pales><Pall><Palmy><Palpable><Panders><Pangs><Pansies><Paradox><Paragon><Parching><Parchment><Pardon't><Paris><Parle><Parley><Partial><Partisan><Party><Passages><Passes><Passeth><Passionate><Passion's><Pastoral><Pastoral-Comical><Pastors><Pat><Patches><Path><Patiently><Patrick><Pays><Peace-Parted><Peak><Pearl><Pebbles><Peculiar><Peevish><Pelican><Pelion><Pendent><Penetrable><People><Perceive><Perceived><Perdition><Perdy><Perfect><Perfections><Pe ***2*** <A-Down><Absolute><Absurd><Accent><According><Actions><Actors><Acts><Admit><Advancement><Alarm><Allowance><Allow'd><All's><Aloof><Amazement><Amiss><Antique><Apart><Ape><Apparition><Apprehension><Approve><Apt><Armed><Arm'd><Arrant><Arrows><Article><Ask><Asking><Assigns><Assistant><Assurance><Assured><Author><Awake><Awe><Axe><Baby><Baked><Barbary><Baser><Basket><Bearers><Bears><Beasts><Beautified><Beggars><Begins><Beguile><Behavior><Belike><Bell><Below><Beware><Beyond><Bird><Blank><Blast><Blasted><Bleed><Blown><Blows><Blush><Book><Breaks><Breathing><Breed><Broad><Broke><Brook><Brothers><Builds><Bulk><Burn><Burning><Burns><Buz><By'r><Caesar><Calm><Camel><Canker><Cap><Capable><Capital><Card><Carpenter><Cat><Catch><Caught><Cease><Celestial><Chamber><Chance><Chances><Chapel><Character><Charitable><Cheek><Cheerfully><Child><Choler><Church><City><Clothes><Coldly><Collected><Collection><Comedy><Comest><Comply><Confine><Confound><Consider><Contagion><Continent><Contrive><Convert><Cost><Couch><Coward><Craft><Creature><Crew><Cruel><Currents><Cut><Daggers><Dearest><Dearly><Deceived><Defeat><Defect><Defence><Delay><Delicate><Deliver><Demand><Demands><Deny><Desert><Desperation><Destroy><Diadem><Diet><Difference><Dig><Dignity><Directly><Dirt><Disclosed><Dishonour><Dismal><Dispatch><Distraction><Distrust><Divide><Divinity><Dog><Doubtful><Dove><Draws><Drive><Drowned><Eager><Easiness><Easy><Eats><Effects><Em><Embrace><Empire><Employment><Enact><Ends><Enemies><Enterprise><Entreaty><Envenom'd><Envy><Epitaph><Equal><Escape><Especially><Eternal><Event><Evil><Exchange><Exercise><Expel><Extremity><Faces><Fall'n><Fame><Fares><Farm><Fate><Fates><Fathers><Favours><Fears><Feature><Fed><Fellowship><Fetch><Fetters><Fighting><Finding><Finds><Fines><Fish><Fishmonger><Fits><Five><Flame><Flames><Flaming><Flourish><Foe><Foil><Follow'd><Fond><Food><Fools><Forbid><Forced><Forehead><Forged><Forgive><Former><Fortunes><Forty><Forward><For's><For't><Frankly><Fruit><Gait><Gall><Galled><Garden><Gentry><Glass><Going><Goodness><Got><Graces><Grapple><Grave-Maker><Graves><Green><Grieve><Guest><Guts><Hair><Hall><Haply><Happily><Harsh><Hat><Having><Havior><Ha't><Hearers><Hearts><Heavenly><Heed><Heel><Held><Helps><Heraldry><Hey><Hid><Hideous><History><Hitherto><Hobby-Horse><Holy><Horrid><Horridly><Horses><Hours><Hundred><Hurt><Husband's><Ice><If't><Immediate><Imminent><Imponed><Inclination><Inform><Inquire><Instrument><Intent><Issue><Its><It's><I've><Jealousy><Jig><Join><Jot><Jove><Joys><Julius><Jump><Just><Keen><Killed><Kills><Kings><Kisses><Knavery><Knavish><Knees><Knowing><Know'st><Labour><Lap><Larded><Lasting><Lawless><Laying><Least><Leaves><Level><Levies><Liberal><Likely><Limbs><Line><Lips><Liquor><Lived><Living><Loam><Lobby><Lock><Lock'd><Lunacy><Lungs><Lust><Maggots><Maiden><Maids><Majestical><Majesties><Malicious><Manners><Marvellous><Mason><Matters><Meeting><Melancholy><Melt><Merely><Merit><Merry><Middle><Mighty><Minds><Mind's><Mirror><Mirth><Mischance><Mole><Moment><Money><Mount><Mountains><Mouse><Naked><Nature's><Naught><Nearer><Necessary><Neck><Needful><Neglected><Nephew's><Neptune's><New><Norman><Nose><Numbers><Oath><Obedience><Obligation><Odd><Officers><Often><Ones><Open><Opinions><Opposed><Opposition><Orchard><Origin><Ours><Overdone><Pace><Painted><Pair><Palm><Pardon'd><Passage><Pastime><Patch><Peasant><Peep><Perform'd><Perfume><Pestilent><Petty><Philosophy><Picked><Picture><Plague><Platform><Played><Player><Playing><Pleased><Pleasures><Plots><Plucks><Pole><Potent><Praise><Praised><Prayer><Prayers><Precedent><Precepts><Precious><Pregnant><Prepare><Pretty><Prevent><Prisoner><Proceed><Proclaim><Proclaims><Prodigal><Profound><Promised><Pronounced><Proper><Prophesy><Propose><Providence><Puff'd><Purging><Purposed><Purposes><Pursue><Quarrel><Quit><Ranker><Rapiers><Rat><Rate><Re-Deliver><Reasons><Rebellious><Recorders><Recoveries><Red><Regard><Region><Relieved><Relish><Remove><Repair><Reply><Requite><Respect><Rewards><Rhenish><Richer><Rights><Ring><Rise><Rites><Roar><Roman><Rome><Room><Rotten><Roughly><Rub><Rude><Rue><Rugged><Run><Runs><Sable><Sables><Safe><Safely><Sailors><Salvation><Sat><Say'st><Sblood><Scale><Scandal><Scape><Scarce><Sconce><Scourge><Scripture><Seat><Secure><Seeks><Seeming><Seem'd><Sending><Senseless><Sensible><Serpent><Servants><Serve><Served><Serves><Sets><Shake><Shell><She'll><She's><Ship><Shipwright><Shoes><Shoulder><Shouldst><Shown><Shuffling><Sickly><Sickness><Side><Signify><Sin><Sinews><Single><Slightly><Smile><Smooth><Soil><Soldier><Sometime><Songs><Sooner><Source><Spoke><Spoken><Spokes><Spread><Spurns><Stamp><Station><Step><Sting><Stone><Stoops><Stops><Strangely><Straw><Streets><Strength><Strict><Strike><Strumpet><Substance><Succession><Sultry><Sum><Summit><Supper><Suppress><Swearing><Sweat><Sweep><Swift><Tables><Taken><Talk><Talk'd><Tardy><Tedious><Teeth><Term><Thither><Thou'lt><Throne><Thrown><Thunder><To-Day><Toe><Toy><Trace><Trade><Tragedy><Trail><Translate><Travel><Treacherous><Treachery><Treble><Tremble><Tribute><Trouble><Troubles><Truant><Trust><Tune><Tush><Twain><Twixt><Unbated><Unction><Undertake><Union><Unknown><Unworthy><Upon't><Used><Valiant><Vantage><Variable><Vengeance><Venom><View><Violets><Virtues><Voltimand><Vouchers><Vow><Voyage><Vulgar><Wag><Wait><Walks><Want><Wants><War><Wars><Wary><Wash><Wax><Waxes><Weak><Weakness><Weapon><Wears><Weary><Weasel><Weigh><Weigh'd><Whale><Whereof><Where's><Whips><Whisper><Whoreson><Who's><Wildly><Willing><Willingly><Wings><Wipe><Wise><Wisely><Witchcraft><Witness><Wittingly><Wonderful><Wonted><Working><World's><Wrong'd><Wrote><Yield><Yonder> ***3*** <Aboard><Accident><Actor><Addition><Admiration><Advice><Affliction><Alack><Along><Ambassadors><Ambitious><Angels><Appear><Appears><Appear'd><Argal><Armour><Arras><Assay><Avoid><Beating><Becomes><Beggar><Bend><Bent><Bitter><Bless><Blow><Bold><Born><Borne><Bow><Boy><Brave><Burst><Canst><Carry><Ceremony><Change><Chaste><Cheer><Chief><Children><Clay><Close><Complexion><Confession><Content><Corruption><Corse><Counsel><Count><Country><Courtier><Creatures><Cried><Crimes><Cup><Defend><Delight><Delights><Denmark's><Desires><Dew><Dies><Distemper><Distracted><Doomsday><Doors><Dozen><Dreadful><Dreams><Dry><Ducats><Edge><Election><Encounter><Enemy><Enter><Entreat><Estate><Excellence><Except><Express><Faithful><Fancy><Fantasy><Faults><Feast><Fee><Feeling><Fellows><Few><Fiery><Fight><Fi'xd><Flat><Foolish><Foot><Force><Forms><Four><Gain><Gallows><Gaming><Gather><Generous><Giving><Gods><God's><Golden><Gonzago><Goodly><Gross><Guard><Guilt><Hadst><Hangers><Happy><Hears><Heartily><Heels><Hercules><Hill><Hits><Honourable><Horse><House><Idle><Ignorance><Ignorant><Importing><Incensed><Indifferent><Inward><I'm><Jephthah><Jest><Judge><Judgments><Justly><Knows><Ladies><Left><Lets><Liege><Liest><Likes><Lines><Livery><Lo><Look'd><Loose><Loud><Loving><Making><March><Married><Masters><Men's><Mere><Mistress><Mobled><Morn><Mountain><Murderer><Nation><Ne'er><Nights><Nine><Nonny><Observe><Odds><Offended><Offer><Order><Organ><Osric><Otherwise><Ourself><Outward><Parts><Passing><Past><Patient><Pious><Pipe><Pit><Piteous><Pith><Placed><Pluck><Poison'd><Poland><Powers><Presence><Present><Prince><Process><Profit><Proud><Prove><Proved><Pure><Purse><Puts><Rage><Rapier><Rash><Received><Recover><Remains><Repent><Revenged><Reynaldo><Rich><Rogue><Rouse><Royal><Ruled><Sail><Saint><Salt><Scene><Scope><Seal><Secrecy><Seeing><Shadow><Shapes><Sides><Sirs><Skill><Sleeps><Slow><Smiling><Solemn><Sore><Sort><Sovereign><Special><Sponge><Sport><Spring><Stage><Start><Stay'd><Steel><Stick><Stole><Story><Stuff><Subject><Suffer><Suffers><Suit><Suits><Sworn><Swounds><Tame><Ta'en><Tear><Tempt><Tenders><Theme><Thick><Third><Thirty><Tongues><Touching><Trial><Trick><Tricks><Turn'd><Understanding><Unfold><Unless><Unseen><Uses><Vice><Visitation><Vouchsafe><Wanton><Was't><Waves><Ways><Wed><Wheel><Wherefore><Win><Winds><Wisest><Wish><Withdraw><Wonder><Wondrous><Wont><Worm><Worse><Worth><Wretch><Years> ***4*** <Above><Affair><Affection><Angel><Argument><Ass><Assume><Begun><Bestow><Birth><Blame><Bones><Bore><Bosom><Breathe><Brow><Burial><Calls><Cannon><Censure><Certain><Closes><Closet><Clouds><Commandment><Commend><Consent><Consequence><Cousin><Cries><Cunning><Cursed><Deep><Didst><Died><Direct><Discretion><Door><Drift><Dumb><Ease><Eat><Elsinore><Entertainment><Fain><Favour><Fingers><Fly><Follows><Forget><Frame><Freely><Funeral><Gainst><Gifts><Glad><Grown><Habit><Hang><Heat><Hecuba><Hence><Herein><High><Honour'd><Horrible><Image><Imagination><Imports><Incestuous><Infinite><Instant><Kept><Kill><Lands><Lead><Leisure><Lend><Length><Lest><Lights><Lives><Main><Meant><Methought><Mock><Modesty><Month><Months><Mortal><Motion><Native><Need><Occasion><Others><Over><Pate><Pause><Pay><Person><Piece><Pity><Pleasure><Poison><Polack><Possible><Practise><Priam><Prithee><Prologue><Property><Quality><Quantity><Quite><Ready><Remembrance><Return'd><Rose><Save><Secret><Send><Sends><Shalt><Shortly><Shot><Sick><Sigh><Silence><Sith><Sits><Six><Slave><Sleeping><Snow><Sometimes><Sorry><Spade><Speed><Stars><Stop><Straight><Strong><Stronger><Tale><Ten><Tend><Tender><Thence><Thinking><Thrice><Thrift><Throat><To-Morrow><Took><Treasure><Twenty><Twice><Twill><Under><Unnatural><Violence><Violent><Warrant><Wear><Weeds><Weep><Whereto><Whilst><White><Wi><Wide><Wild><Wits><Wittenberg><Wretched><Yea><You'll> ***5*** <Alexander><Anon><Arm><Audience><Base><Bernardo><Blessing><Bodies><Bound><Brains><Brief><Carriages><Choose><Cock><Colour><Commission><Conceit><Countenance><Course><Crown><Cry><Damn'd><Danger><Danish><Dare><Disposition><Dread><Drown><Drown'd><Ecstasy><Fast><Fault><Figure><Flesh><Foils><Forgot><Fortune's><Found><France><French><Gentle><Grows><Half><Hard><Hearing><Hide><Holds><Honesty><Humbly><Ill><Impart><In's><Keeps><Kill'd><Kingdom><Knave><Knew><Land><Liberty><Man's><Marriage><Mass><Mercy><Methinks><Moon><Morning><Motive><Natural><Next><Nunnery><Pass><Patience><Perchance><Perhaps><Polonius><Presently><Prison><Quiet><Rather><Read><Report><Return><Safety><Seems><Short><Sing><Slain><Soldiers><Souls><Sound><Spirits><Stands><Stir><Sudden><Swear><Table><Teach><Terms><Themselves><Throw><Thyself><Told><Treason><Trumpet><Twas><Twelve><Vile><Visage><Visit><Vows><Warlike><Went><Whereon><Woo't><Ye><Year><Yes> form><Performance><Perilous><Periwig-Pated><Permanent><Pernicious><Perpend><Persever><Personal><Persons><Persuade><Perturbed><Perusal><Peruse><Pester><Pestilence><Petard><Petition><Phoebus><Physic><Pick-Axe><Pickers><Pictures><Pierce><Pigeon-Liver'd><Pile><Pinch><Pin's><Pioner><Pirate><Pitied><Pitiful><Places><Plain><Planets><Plastering><Plausive><Plautus><Plays><Play'd><Pleasant><Pleasing><Pledge><Plentiful><Plot><Plum-Tree><Plunge><Plurisy><Ply><Pocket><Pocky><Poem><Poet><Points><Poisoning><Poisons><Polacks><Policy><Politic><Politician><Poll><Pomp><Ponderous><Poniards><Pooh><Popp'd><Porches><Porpentine><Portal><Portentous><Portraiture><Positively><Possess><Possession><Possess'd><Posset><Post><Post-Haste><Postscript><Posy><Potency><Potently><Potion><Pound><Pour><Poured><Powerfully><Pox><Practises><Praises><Pranks><Prate><Prating><Praying><Pray'st><Preaching><Preceding><Precisely><Precurse><Prenominate><Preparation><Preparations><Prepared><Presentment><Pressure><Pressures><Prettiness><Prey><Priam's><Prick><Prick'd><Pride><Priest><Primal><Primrose><Primy><Princes><Prison-House><Private><Privates><Privy><Prize><Probation><Proceeded><Proceeding><Proclaim'd><Profane><Profanely><Profession><Profoundest><Progress><Project><Prolongs><Promise><Promise-Crammed><Promontory><Prompted><Pronounce><Pronouncing><Prophetic><Proportions><Proposer><Props><Prosperously><Protests><Proverb><Provide><Provided><Provincial><Provoke><Public><Pull'd><Pulse><Punish><Punish'd><Puppets><Purchases><Purer><Purgation><Purged><Purples><Purport><Pursued><Pursuest><Pursy><Push><Puzzles><Quaintly><Quake><Qualifies><Quarrelling><Quarry><Quarter'd><Quest><Questionable><Quickly><Quickness><Quicksilver><Quiddities><Quietly><Quietus><Quillets><Quills><Quintessence><Quoted><Quoth><Rabble><Rack><Radiant><Rages><Rags><Rain><Rain'd><Raised><Range><Rankly><Rant><Rare><Rareness><Rascal><Rashly><Rashness><Ratified><Ratifiers><Ravel><Raven><Raves><Raw><Rawer><Razed><Re-Speaking><Re-Word><Reach><Reaches><Readiness><Reading><Reads><Really><Realm><Rear><Rebellion><Rebels><Rebuke><Receives><Reckless><Reckon><Reckoning><Recks><Recognizances><Reconcilement><Records><Recount><Recovery><Rede><Reechy><Reels><Reform><Reformed><Refrain><Regards><Reigns><Relative><Relief><Religion><Religious><Remain><Remainder><Remedy><Remember'd><Remembrances><Remiss><Remorse><Remorseless><Removed><Rend><Render><Rendezvous><Repast><Repel><Repentance><Replication><Replies><Repose><Repugnant><Repulsed><Reputation><Request><Requiem><Resemble><Resembles><Reserve><Reserved><Residence><Resolutes><Resolution><Resolve><Resort><Respects><Responsive><Restore><Restrain'd><Rests><Retain><Retirement><Retrograde><Returneth><Returns><Reveal><Revel><Revels><Revengeful><Revenue><Reverend><Reverted><Revisit'st><Revolution><Rhapsody><Rheum><Rhymed><Riband><Rightly><Rims><Riotous><Ripe><Rises><Rite><Rivals><River><Rivet><Roars><Roasted><Robe><Robin><Robustious><Rock><Romage><Rood><Roof><Roots><Roscius><Rosemary><Roses><Rot><Rough-Hew><Row><Royally><Ruin><Rule><Running><Russet><Rusty><S><Sacred><Sadly><Sadness><Salary><Sale><Sallets><Sanctified><Sanctuarize><Sandal><Sanity><Sans><Sate><Satirical><Satisfaction><Satisfied><Satyr><Savageness><Saviour's><Savoury><Saws><Saw't><Saying><Scann'd><Scant><Scanter><Scapes><Scarcely><Scarf'd><Scenes><Scent><Scholar><Scholars><Scholar's><School><Schoolfellows><Scorn><Scorns><Scratch'd><Screen'd><Scrimers><Scruple><Scullion><Se><Sea-Fight><Sea-Gown><Seals><Search><Seas><Seasons><Season'd><Seated><Secrets><Seduce><Seed><Seeming-Virtuous><Sees><Seest><See't><Seized><Select><Self-Slaughter><Semblable><Seneca><Sepulchre><Sequel><Sequent><Sere><Sergeant><Serious><Servant><Settled><Seven><Several><Sewing><Sexton><Sexton's><Shadows><Shadow's><Shaking><Shameful><Shards><Share><Shark'd><Sharp><Shatter><Sheen><Sheep><Sheepskins><Sheet><Sheeted><Sheets><Shelf><Shent><Shepherds><Shift><Shine><Shipped><Shipwrights><Shirt><Shocks><Shoe><Shook><Shoon><Shoot><Shortens><Shove><Shovel><Showers><Showing><Shreds><Shrewdly><Shrill-Sounding><Shriving-Time><Shroud><Shrouding><Shrunk><Shuffled><Shut><Sicklied><Siege><Sift><Sighs><Signet><Silver'd><Simple><Simples><Singeing><Singeth><Sings><Sinners><Sins><Sin's><Sipping><Sirrah><Sister's><Sitting><Sixteen><Sized><Skin><Skirts><Skyish><Slander><Slanders><Slaughter><Slaughters><Slave's><Slay><Sledded><Slender><Slight><Slings><Slips><Sliver><Small><Smart><Smear'd><Smelling><Smells><Smelt><Smiles><Smoothness><Smote><Snatches><Snuff><Soaks><Sober><Society><Soever><Soe'er><Softly><Soil'd><Sold><Soldier's><Sole><Soles><Solicited><Solicitings><Solid><Solidity><Something-Settled><Somewhat><Song><Sons><Son's><Soon><Sorrows><Sorts><Soul's><Sounded><Southerly><Sovereignty><Space><Spacious><Spake><Spark><Sparrow><Spectators><Speeches><Speechless><Speedier><Speedy><Spend><Spendthrift><Spent><Sphere><Spheres><Spies><Spills><Spilt><Spite><Splenitive><Split><Spots><Springe><Springes><Springs><Sprinkle><Sprung><Spur><Squeak><Squeezing><Staff><Stages><Stain'd><Stairs><Stake><Stale><Stalk><Stalks><Standing><Started><Starts><Stately><Statists><Statutes><Stays><Steal><Stealers><Stealing><Steals><Steep><Steep'd><Steps><Sterile><Sterling><Stern><Steward><Stew'd><Sticks><Stiff><Stiffly><Stirring><Stirr'd><Stithy><Stock><Stockings><Stomach><Stones><Stooping><Stopping><Storm><Stoup><Stowed><Stranger><Straws><Stream><Strengthen><Strew><Strewments><Strew'd><Stricken><Strife><Strikes><Striking><Strings><Strokes><Strongest><Struggling><Strutted><Stubborn><Stubbornness><Stuck><Study><Stung><Sty><Subscribed><Successive><Such-A-One><Such-A-One's><Such-Like><Sucked><Suck'd><Suddenly><Suffered><Suffering><Sugar><Suiting><Sullies><Sulphurous><Summons><Sunday><Sundays><Superfluous><Supervise><Suppliance><Supply><Supposal><Surely><Surmise><Surrender><Survivor><Suspiration><Sustain><Swaddling-Clouts><Swaggering><Swallowed><Swear't><Sweaty><Sweets><Swinish><Switzers><Swoopstake><Swords><Swore><Synod><Table-Book><Taint><Taints><Tanned><Tanner><Target><Tarre><Task><Taste><Tatters><Tax><Ta'xd><Tediousness><Tells><Tellus><Temperance><Temperately><Temper'd><Tempest><Temple><Tenable><Tenantless><Tenants><Tennis><Tent><Tenures><Termagant><Test><Tether><Tetter><Thaw><Theatre><Theft><Thereabout><Therein><Thereof><Thereon><Thereto><Thereunto><Thews><They'll><Thicker><Thieves><Thin><Thing's><Think'st><Think't><Thirties><Thorns><Thorny><Thoroughly><Thought-Sick><Thou'rt><Thrall'd><Threaten><Threatening><Threats><Throwing><Thumb><Thunders><Tickled><Timber'd><Tinct><Tithe><Toil><Toils><Tokens><Tomb><Topp'd><Tormenting><Torrent><Total><Touches><Touch'd><Towering><Town-Crier><Toys><Traduced><Tragedians><Tragical-><Tragical-Historical><Trains><Traitorous><Transform><Transformation><Transports><Trappings><Traveller><Tread><Treads><Tree><Trespass><Tributary><Trick'd><Tried><Trifle><Trifling><Trip><Trippingly><Tristful><Triumph><Trivial><Trophies><Trophy><Tropically><True-Love><Truepenny><Truncheon's><Truster><Tumbled><Tunes><Turbulent><Turf><Turk><Turned><Turneth><Turns><Turn'st><Tutor><Tweaks><Tween><Twentieth><Two-Fold><Twould><Tyrannically><Tyrannous><Tyrant><Ubique><Ugly><Ulcer><Ulcerous><Umbrage><Unanel'd><Unbraced><Uncharge><Uncle-Father><Uncle's><Uncurrent><Undergo><Undertakings><Undiscover'd><Undo><Uneffectual><Unequal><Unfellowed><Unfledged><Unforced><Unfortified><Ungalled><Ungarter'd><Ungored><Ungracious><Unhand><Unhappily><Unholy><Unhousel'd><Unimproved><Unite><University><Unkennel><Unkind><Unknowing><Unlimited><Unmanly><Unmannerly><Unmask><Unmaster'd><Unmatch'd><Unmi'xd><Unnerved><Unpack><Unpeg><Unpolluted><Unpregnant><Unprevailing><Unprofitable><Unproportioned><Unreclaimed><Unrighteous><Unripe><Unsanctified><Unsatisfied><Unschool'd><Unseal><Unshaken><Unshaped><Unsifted><Unsinew'd><Unskilful><Unsmirched><Unsure><Until><Untimely><Unused><Unvalued><Unwatch'd><Unweeded><Unwholesome><Unworthiest><Unwrung><Unyoke><Up-Spring><Uphoarded><Upshot><Usual><Usurp><Usurp'st><Utter><Utterance><Utter'd><Vacancy><Vailed><Vain><Valenced><Valentine><Valentine's><Validity><Valour><Vanish'd><Vanquisher><Vapours><Varnish><Vast><Venom'd><Ventages><Verity><Verse><Vial><Vicious><Videlicet><Vienna><Vigour><Villanies><Villanous><Villany><Violet><Virgin><Vision><Volley><Volume><Vouch><Vulcan's><Wagered><Waist><Waits><Wake><Walk'd><Wall><Wandering><Wann'd><Wantonness><Wards><Warms><Warning><Warrantise><Wart><Wassail><Waste><Watchman><Watch'd><Water-Fly><Waving><Weaker><Weakest><Weal><Wealth><Weapons><Wearing><Wedding><Weed><Weedy><Week><Weeping><Weeps><Weighing><Weight><Well-Took><West><Westward><Wharf><Whatsoever><Wheaten><Whence><Whensoever><Whereat><Whet><Whiff><Whiles><Whine><Whipped><Whipping><Whirling><Whirlwind><Whispers><Whit><Whore><Whored><Wick><Widow><Wildness><Wilfully><Willow><Wills><Wince><Windlasses><Window><Windy><Wine><Wing><Winking><Winks><Winner><Winnowed><Winter><Wisdoms><Wiseness><Wishes><Wish'd><Witch><Witching><Withdrew><Withered><Withers><Wit's><Woman's><Womb><Women's><Won><Wonder-Wounded><Woo><Wood><Woodcock><Woodcocks><Wore><Works><Worlds><Worms><Worm's><Worn><Worser><Worst><Worthy><Wot><Wounded><Woundless><Wrap><Wrath><Wreck><Wring><Wringing><Wrinkled><Wrist><Write><Writers><Wrung><Yard><Yaughan><Yaw><Yawn><Yeoman's><Yesterday><Yesternight><Yesty><Yielding><Yon><Yond><Yorick><Yorick's><Younger><Yourselves><Zone>
  72. 75. Metabolic networks in bacteria
  73. 77. There are networks that are not scale-free
  74. 78. Caenorhabditis elegans “Some 300 of the 959 cells of the adult worm, for example, constitute a nervous system that can detect odor, taste, and respond to temperature and touch.”
  75. 79. Not all biological networks are scale-free
  76. 80. Overview of the talk <ul><li>Introduction: project participants & jigsaw puzzle analogy </li></ul><ul><li>Project motivation. </li></ul><ul><li>Duality of signal transduction language. </li></ul><ul><li>How the whole system works. </li></ul><ul><li>Good and ugly graphs. </li></ul><ul><li>--------------------------------------------- </li></ul><ul><li>Scale-free networks in biology and outside; mechanism of stochastic birth of scale-free networks </li></ul>
  77. 81. A stochastic model of evolution of a molecular network
  78. 82. Molecular networks are composed of DNA, RNA, proteins, lipids, small molecules, …
  79. 83. (Over)Simplification: we assume that each node of the network has two domains (not necessary distinct) responsible for the upstream and downstream connections
  80. 84. A node of a molecular network Each substance has a pair of “domains,” upstream and downstream, which determine specific upstream and downstream network connections.
  81. 85. The model would not be appropriate if domain-rich proteins tend to have more network connections than domain-poor proteins
  82. 86. Another way to put the same question: Is the number of domains per protein correlated with the number of network connections per protein?
  83. 87. Connectivity is NOT affected by domain number
  84. 88. Therefore, it is probably OK to use “two-domain” model in the current setup
  85. 89. Evolutionary events affecting network growth
  86. 90. We assume that network rearrangements arrive independently according to a Poisson process… …which leads to a system of ordinary differential equations corresponding to a continuous-time Markov model…
  87. 91. Armed with resulting equations and programs, we can compute the topological properties of the growing network for any (reasonable) combination of parameter values
  88. 92. Data: signal transduction network in yeast
  89. 93. We therefore can fit the model to the experimental data and estimate parameter values
  90. 94. Estimating parameters:
  91. 95. Fitting data for upstream and downstream connections simultaneously
  92. 96. Fitting data for upstream and downstream connections separately
  93. 97. Estimated parameters Replacement Duplication Innovation
  94. 98. The analysis of the model suggests that the number of domain copies per genome should also follow a power law
  95. 99. Frequency of domain appearances in E. coli (closed circles), S. cerevisiae (crosses), and H. sapiens (open rectangles).
  96. 100. How many distinct domains exist? Number of distinct domains Number of genes Power law constant
  97. 101. For E. coli our estimate suggests existence of D > 4,600 domains…
  98. 102. For yeast D > 12,900 domains…
  99. 103. ( The last !) overview of the talk <ul><li>Introduction: project participants & jigsaw puzzle analogy </li></ul><ul><li>Project motivation. </li></ul><ul><li>Duality of signal transduction language. </li></ul><ul><li>How the whole system works. </li></ul><ul><li>Good and ugly graphs. </li></ul><ul><li>--------------------------------------------- </li></ul><ul><li>Scale-free networks in biology and outside; stochastic birth of scale-free networks </li></ul>
  100. 104. Thank you!
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