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Co-factors

Polymerization and complex assembly. Energy & materials. Autocatalytic feedback. Taxis and transport. Proteins. Core metabolism. Sugars. Catabolism. Amino Acids. Nucleotides. Precursors. Nutrients. Trans*. Fatty acids. Genes. Co-factors. Carriers. DNA replication.

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Co-factors

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  1. Polymerization and complex assembly Energy & materials Autocatalytic feedback Taxis and transport Proteins Core metabolism Sugars Catabolism Amino Acids Nucleotides Precursors Nutrients Trans* Fatty acids Genes Co-factors Carriers DNA replication Regulation & control? E. coli genome

  2. Polymerization and complex assembly Autocatalytic feedback Taxis and transport Proteins Core metabolism Sugars Catabolism Amino Acids Nucleotides Precursors Nutrients Trans* Fatty acids Genes Co-factors Carriers DNA replication Regulation & control E. coli genome

  3. Polymerization and complex assembly Autocatalytic feedback Taxis and transport Proteins Core metabolism Sugars Catabolism Amino Acids Not to scale Nucleotides Precursors Regulation & control Nutrients Trans* Fatty acids Genes Co-factors Carriers DNA replication Regulation & control

  4. Gene networks? essential: 230 nonessential: 2373 unknown: 1804 total: 4407 http://www.shigen.nig.ac.jp/ecoli/pec

  5. Polymerization and complex assembly Autocatalytic feedback Taxis and transport Proteins Core metabolism Sugars Catabolism Amino Acids Nucleotides Precursors Nutrients Trans* Fatty acids Genes Co-factors Carriers DNA replication Regulation & control E. coli genome

  6. Steering Brakes Anti-skid Wipers Mirrors Cruise control GPS Radio Traction control Shifting Headlights Electronic ignition Temperature control Seats Electronic fuel injection Seatbelts Fenders Bumpers Airbags Suspension (control)

  7. Knockouts often lethal Steering Brakes Anti-skid Wipers Mirrors Knockouts often lose robustness, not minimal functionality Cruise control GPS Radio Traction control Shifting Headlights Electronic ignition Temperature control Seats Electronic fuel injection Seatbelts Fenders Bumpers Airbags Suspension (control)

  8. Polymerization and complex assembly Autocatalytic feedback Taxis and transport Proteins Core metabolism Sugars Catabolism Amino Acids Nucleotides Precursors Nutrients Trans* Knockouts often lethal Fatty acids Genes Co-factors Carriers DNA replication Knockouts often lose robustness, not minimal functionality Regulation & control

  9. Polymerization and complex assembly Autocatalytic feedback Taxis and transport Proteins Core metabolism Sugars Catabolism Amino Acids Nucleotides Precursors Nutrients Trans* Fatty acids Genes Co-factors Carriers DNA replication Complexity is dominated by regulation & control

  10. Transmitter Receiver Variety of Ligands & Receptors Variety of responses Regulation of protein action Regulation of protein levels Core metabolism Sugars Fatty acids Co-factors Catabolism Precursors Amino Acids Nucleotides Genes Proteins Carriers Trans* DNA replication

  11. Gly G1P G6P F6P F1-6BP Gly3p ATP 13BPG 3PG TCA Oxa ACA 2PG PEP Pyr NADH Cit S Stoichiometry matrix

  12. Gly G1P G6P F6P F1-6BP Gly3p Regulation of enzyme levels by transcription/translation/degradation 13BPG 3PG TCA Oxa ACA 2PG PEP Pyr Cit

  13. Gly G1P G6P F6P F1-6BP Gly3p Allosteric regulation of enzymes ATP 13BPG 3PG TCA Oxa ACA 2PG PEP Pyr NADH Cit

  14. Gly G1P G6P Allosteric regulation of enzymes F6P F1-6BP Regulation of enzyme levels Gly3p ATP 13BPG 3PG TCA Oxa ACA 2PG PEP Pyr NADH Cit

  15. Gly Fast G1P G6P Allosteric regulation of enzymes F6P F1-6BP Regulation of enzyme levels Gly3p ATP 13BPG Slow 3PG TCA Oxa ACA 2PG PEP Pyr NADH Cit

  16. Regulatory hourglass Huge variety of environments, metabolisms, functions Regulation of protein action Regulation of protein levels Huge variety of components

  17. Huge variety Environments, metabolisms, functions Standardized mechanisms Highly conserved Regulation of protein action Regulation of protein levels Huge variety Components (genes) Variety is within a specie (across time and space) and of course between species.

  18. Lego Huge variety Standardized mechanisms Highly conserved control assembly Huge variety

  19. Polymerization and complex assembly Autocatalytic feedback Proteins Regulation & control Trans* Genes DNA replication

  20. motif rpoH Other operons See El-Samad, Kurata, et al… PNAS, PLOS CompBio DnaK Lon

  21. degradation motif Heat rpoH folded unfolded Other operons DnaK Lon DnaK Lon

  22. Heat rpoH  mRNA  Other operons DnaK RNAP Lon  RNAP DnaK FtsH Lon

  23. Heat rpoH  mRNA   DnaK Other operons  DnaK DnaK RNAP ftsH Lon  RNAP DnaK FtsH Lon

  24. Heat rpoH  mRNA   DnaK Other operons  DnaK DnaK ftsH RNAP Lon  RNAP DnaK FtsH Lon

  25. Heat rpoH  mRNA Regulation of protein action Regulation of protein levels   DnaK  DnaK DnaK ftsH RNAP Lon  RNAP DnaK FtsH Lon

  26. Heat rpoH Regulation of protein action  mRNA Regulation of protein action Regulation of protein levels  Regulation of protein levels  DnaK  DnaK DnaK ftsH RNAP Gly Lon G1P  RNAP G6P DnaK FtsH Lon F6P F1-6BP Gly3p ATP 13BPG 3PG TCA Oxa ACA 2PG PEP Pyr NADH Cit Layered control architectures Allosteric Trans*

  27. Heat rpoH  mRNA   DnaK Other operons  DnaK DnaK ftsH RNAP Lon  RNAP DnaK FtsH Lon

  28. motif rpoH Other operons DnaK Lon

  29. Heat rpoH Regulation of protein action  mRNA Regulation of protein action Regulation of protein levels  Regulation of protein levels  DnaK  DnaK DnaK ftsH RNAP Gly Lon G1P  RNAP G6P DnaK FtsH Lon F6P F1-6BP Allosteric regulation of enzymes Gly3p ATP 13BPG Regulation of enzyme levels 3PG TCA Oxa ACA 2PG PEP Pyr NADH Cit

  30. The Internet hourglass Applications Web FTP Mail News Video Audio ping napster Ethernet 802.11 Power lines ATM Optical Satellite Bluetooth Linktechnologies

  31. The Internet hourglass Applications Web FTP Mail News Video Audio ping napster TCP IP Ethernet 802.11 Power lines ATM Optical Satellite Bluetooth Linktechnologies

  32. IP on everything The Internet hourglass Applications IP under everything Web FTP Mail News Video Audio ping napster TCP IP Ethernet 802.11 Power lines ATM Optical Satellite Bluetooth Linktechnologies

  33. Link Applications Top of “waist” provides robustness to variety and uncertainty above TCP/ AQM Bottom of “waist” provides robustness to variety and uncertainty below IP

  34. Application Application Application TCP TCP TCP IP IP IP IP IP Routing Provisioning Vertical decomposition Protocol Stack

  35. Application Application Application TCP TCP TCP Horizontal decomposition Each level is decentralized and asynchronous IP IP IP IP IP Routing Provisioning

  36. “FAST” TCP/AQM theory • Arbitrarily complex network • Topology • Number of routers and hosts • Nonlinear • Delays Routers • Short proof • Global stability • Equilibrium optimizes aggregate user utility Hosts Papachristodoulou, Li packets

  37. Layering as optimization decomposition application transport network link physical Application: utility Phy: power IP: routing Link: scheduling • Each layer is abstracted as an optimization problem • Operation of a layer is a distributed solution • Results of one problem (layer) are parameters of others • Operate at different timescales

  38. Examples application transport network link physical Optimal web layer: Zhu, Yu, Doyle ’01 HTTP/TCP: Chang, Liu ’04 TCP: Kelly, Maulloo, Tan ’98, …… TCP/IP: Wang et al ’05, …… TCP/MAC: Chen et al ’05, …… TCP/power control: Xiao et al ’01, Chiang ’04, …… Rate control/routing/scheduling: Eryilmax et al ’05, Lin et al ’05, Neely, et al ’05, Stolyar ’05, this paper detailed survey in Proc. of IEEE, 2006

  39. I2LSR, SC2004 Bandwidth Challenge “FAST” TCP/AQM implementation OC48 Harvey Newman’s group, Caltech http://dnae.home.cern.ch/dnae/lsr4-nov04 OC192 November 8, 2004 Caltech and CERN transferred • 2,881 GBytes in one hour (6.86Gbps) • between Geneva - US - Geneva (25,280 km) • through LHCnet/DataTag, Abilene and CENIC backbones • using 18 FAST TCP streams

  40. TCP/IP Metabolism/biochem 5:Apps:supply and demand of nutrients and products 5:Apps: Supply and demand of packet flux 4:Allosteric regulation of enzymes: robust to changing supply/demand 4:TCP: robustness to changing supply/demand, and packet losses 3:IP: routes on physical network, rerouting for router losses 3:Transcriptional regulation of enzyme levels 2:Physical: Raw physical network 2:Genome: Raw potential stoichiometry network 1:Hardware catalog: DNA, genes, enzymes, carriers,… 1:Hardware catalog: routers, links, servers, hosts,…

  41. Lego Huge variety Standardized mechanisms Highly conserved control assembly Huge variety

  42. Lego Huge variety Limited environmental uncertainty needs minimal control assembly Huge variety

  43. Lego Uncertain environments Require additional layers control assembly Huge variety

  44. NXT controller Variety of actuators Variety of sensors Real- time control

  45. TCP/IP Metabolism/biochem • This provides the raw physical network • But it is not functional without some control 2:Physical: Raw physical network 2:Genome: Raw potential stoichiometry network 1:Hardware catalog: DNA, genes, enzymes, carriers,… 1:Hardware catalog: routers, links, servers, hosts,…

  46. This layer provides a minimally functional network • It provides robustness and evolvability to changes in the layers below. • In an environment lacking uncertainty (which is rare), this level of regulation is largely adequate. 3:IP: routes on physical network, rerouting for router losses 3:Transcriptional regulation of enzyme levels 2:Physical: Raw physical network 2:Genome: Raw potential stoichiometry network 1:Hardware catalog: DNA, genes, enzymes, carriers,… 1:Hardware catalog: routers, links, servers, hosts,…

  47. TCP/IP Metabolism/biochem 5:Apps:supply and demand of nutrients and products 5:Apps: Supply and demand of packet flux • The presence of fluctuating demand and evolving applications requires additional layers of control 3:IP: routes on physical network, rerouting for router losses 3:Transcriptional regulation of enzyme levels 2:Physical: Raw physical network 2:Genome: Raw potential stoichiometry network 1:Hardware catalog: DNA, genes, enzymes, carriers,… 1:Hardware catalog: routers, links, servers, hosts,…

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