Test system for systems biology

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Test system for systems biology

• Four distinct types of global datasets were
  generated and analyzed
• Proteome analysis quantitative proteomics (ICAT
  technology) to analyze 300 proteins in wild-type
  yeast with the system turned on and off
• Thirty of these proteins changed in the
  transition between these two biological states
• the mRNA and protein changes went in different
  directions for 15 of these examples
• post-transcription control mechanisms must
  regulate protein synthesis in half of the examples

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Test system for systems biology

• Four distinct types of global datasets were
  generated and analyzed
• Kinetic analysis of global mRNA concentrations
  change across the physiological time span of
  activation of the galactose biomodule
• Kinetic data provide powerful new approaches to
  understanding the temporal operation of the
  galactose biomodule and its temporal connections
  to other biomodules in the yeast cell

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Test system for systems biology

• Endomesodermal development in sea urchin
• The architecture of a gene regulatory network is
  specified by the DNA binding sites, for these
  establish the linkages of the transcription
  factors that coordinate the behaviors of genes
  throughout the gene regulatory networks.
• The gene regulatory networks contribute to
  determine the behavior of the peripheral
  (structural) genes in the network.
• The peripheral genes ultimately execute the
  specific development functions that underlie
  particular aspects of development.

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• The green panel depicts primarily transcription
  factors and their interactions with the control
  regions of other transcription factors.
• Genes are indicated by horizontal lines.
• Arrowheads indicate activation.
• I indicate repression
• The yellow (lower) panel indicates peripheral
  genes that carry out the functions of endodermal
  development.

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• The 2.1-kb promoter region of the endo16 gene is
  enlarged here and depicts 34 DNA binding sites
  (rectangles) and 13 different transcription
  factors and cofactors (rectangles or lollipops
  connected by lines to the DNA binding sites).
• Experiments indicate that there are six modules
  (AG) that carry out discrete functions for the
  developmental regulation of endo 16.
• The ultimate objective is to convert this logic
  diagram into a mathematical formulation that
  accurately represents the subtle complexities of
  this developmental circuit.

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• A logical diagram depicting the functions of the
  A and B modules throughout endomesodermal
  development.
• This logic then embodies a mathematical
  relationship between the control segments.

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Hostpathogen systems biology

• For tryptophan biosynthesis C. psittaci obtains
  an alternative source of anthranilate by
  hijacking the hosts tryptophan depletion pathway
  by intercepting the byproduct kynurenine.
• the tryptophan depletion pathway of the host is
  activated by inducing indoleamine-2,3-dioxygenase
  using IFN-?
• C. psittaci uses host kynurenine through kynU to
  produce its own tryptophan, enabling
  intracellular growth and causing chronic
  infections.

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Hostpathogen systems biology

• Group A Streptococcus, the causative agent of
  mild infections and life-threatening invasive
  diseases, produces many virulence factors that
  promote survival in humans.
• A two component regulatory system, designated
  covRS (cov, control of virulence csrRS),
  negatively controls expression of five proven or
  putative virulence factors (capsule, cysteine
  protease, streptokinase, streptolysin S, and
  streptodornase)
• Inactivation of covRS results in enhanced
  virulence in mouse models of invasive disease

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• GAS CovR gene regulation network delineated by
  microarray expression analysis. CovRS respond to
  unknown environmental signals and modulate
  expression of several broad categories of GAS
  genes involved in growth and adaptation by a
  phosphorelay mechanism. CovR-regulated gene
  products influence hostpathogen interactions,
  including capsular polysaccharide (capsule), cell
  proteins anchored via LPXTG motifs (surface
  proteins), cytosolic and membrane proteins
  involved in environmental adaptation (adaptation
  response), and extracellular proteins containing
  secretion signals (secreted proteins).
• Several two-component systems (ovals) and other
  transcriptional regulators (squares) are also
  CovR-regulated, but their downstream regulatory
  consequences are unknown. Red lines,
  down-regulation green lines, up-regulation. PG,
  peptidoglycan, secreted proteins surface solid
  rectangles, secreted proteins with LPXTG motifs.
  Numbers denote SPy numbers assigned for serotype
  M1 GAS strain SF370 ORFs.

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Hostpathogen systems biology

• Systems biology in malaria research integrating
  genomics, transcriptomics and proteomics, we can
• classify and annotate genes by their expression
  profiles
• detect evidence of posttranscriptional gene
  silencing in the murine malaria species.
• Metabolic pathway reconstruction by expression
  analysis

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• Metabolic pathway reconstruction by expression
  analysis.
• (a) Table showing representation of protein
  expression from the glycolytic and TCA pathways,
  color coded by protein sequence coverage
  identified through proteomics experiments (see
  key). The sequence coverage values in the table
  serve as a crude measurement of protein
  abundance. Values are from Ref. 1. During
  asexual blood stages, the glycolytic pathway is
  active, resulting in the production of lactate,
  whereas there is no evidence of a complete TCA
  cycle during these stages.
• (b) Pathway glyph representation of the activity
  of metabolic pathways, as determined by their
  proteomics expression profiles.Red indicates
  active pathways and gray indicates inactive
  pathways.

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Hostpathogen systems biology

• Systems biology in Schistosoma research
  integrating genomics, transcriptomics and
  proteomics
• Reconstruction and in silico analysis of the MAPK
  and WNT signaling pathways in Schistosoma
  japonicum
• MAPK signaling pathways regulating
  proliferation and differentiation processes in
  Schistosoma

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Hostpathogen systems biology

• The global molecular interaction architecture of
  the immune system
• molecular interactions of the immune system
  actually consist of a nested tandem bow-tie
  architecture
• This architecture can be recognized both in
  intracellular signal transduction pathways and in
  intercellular signaling processes

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• Nested bow-tie architecture in immune system.
  Salient features of the immune system network are
  nested bow-tie structures and extensive feedback
  loops. The bow-tie structure of intercellular
  interactions

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• The bow-tie architecture also exists at the
  signal transduction level

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Future directions or open issues in systems
biology

• Nanotechnology
• integration across disciplines
• Modeling

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