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hopscotch", "and a", "a stat", "stat transcription", "transcription factor", "stat92e .

the", ".

the dome", "dome receptor", "like many", "many cytokine", "cytokine receptors", "contains no", "no tyrosine", "tyrosine kinase", "kinase domain.", "it is", "is constitutively", "constitutively associated", "associated with", "with the", "the kinase", "kinase hop.", "the dome", "receptor dimerises", "dimerises at", "at the", "the plasma", "plasma membrane", "membrane whereupon", "whereupon it", "it binds", "binds a", "a upd", "upd ligand.", "this activates", "activates the", "the receptor", "receptor associated", "associated hop", "hop which", "which are", "are now", "now able", "able to", "to phosphorylate", "phosphorylate each", "each other", "other and", "and also", "also the", "the cytoplasmic", "cytoplasmic tail", "tail of", "dome receptor.", "this creates", "creates a", "a docking", "docking site", "site for", "for monomeric", "monomeric cytoplasmic", "cytoplasmic stat92e", "stat92e proteins", "proteins which", "which can", "can bind", "bind via", "via their", "their sh2", "sh2 domains.", "once bound", "bound to", "to the", "receptor complex", "stat92e is", "is itself", "itself phosphorylated.", "it dissociates", "dissociates from", "from the", "complex and", "and dimerises", "the interaction", "interaction stabilised", "stabilised by", "by the", "the sh2", "sh2 domain", "domain of", "of one", "one molecule", "molecule binding", "binding to", "the phospho", "phospho tyr", "tyr of", "the other.", "the dimer", "dimer translocates", "translocates to", "the nucleus", "nucleus where", "where it", "binds to", "to a", "a palindromic", "palindromic dna", "dna sequence", "sequence in", "in the", "the pathway", "pathway target", "target gene", "gene promoters", "promoters to", "to activate", "activate transcription.

there", "transcription.

there are", "are also", "also negative", "negative regulators", "regulators present", "present in", "in this", "this pathway.", "some are", "are present", "nucleus and", "the case", "case of", "of su", "su var", "var 2", "2 10", "10 which", "which is", "is a", "a drosophila", "drosophila pias", "pias or", "or zimp", "zimp protein", "act by", "by binding", "to stat92e", "stat92e dimer.", "such as", "as the", "the bcl6", "bcl6 orthologue", "ken and", "and barbie", "bind to", "to dna", "dna sequences", "sequences on", "on target", "target genes", "genes which", "which overlap", "overlap with", "with stat92e", "stat92e binding", "binding sites.", "there is", "a protein", "protein tyrosine", "tyrosine phosphatase", "that exists", "exists in", "in two", "two differently", "differently spliced", "spliced forms.", "one is", "is active", "active in", "the cytosol", "cytosol and", "and dephosphorylates", "dephosphorylates hop", "hop and", "and stat92e", "stat92e while", "while the", "the other", "other dephosphorylates", "dephosphorylates stat92e", "stat92e in", "the nucleus.

a", "nucleus.

a truncated", "truncated version", "version of", "of stat92e", "that lacks", "lacks the", "the n", "n terminal", "terminal 133", "133 amino", "amino acids", "acids has", "has also", "also been", "been found.", "is believed", "believed this", "this truncated", "truncated stat", "stat forms", "forms homodimers", "homodimers and", "and heterodimers", "heterodimers with", "with full", "full length", "length stat92e.", "increasing the", "the deltanstat92e", "deltanstat92e to", "stat92e ratio", "ratio in", "in overexpression", "overexpression and", "and rnai", "rnai experiments", "experiments results", "results in", "the repression", "repression of", "gene transcription.", "this may", "may be", "be due", "due to", "the truncated", "truncated protein", "protein failing", "failing to", "to attract", "attract coactivators", "coactivators or", "or failing", "to form", "form tetramers", "necessary for", "for activation", "activation of", "of certain", "certain genes", "genes and", "and assembled", "assembled by", "terminal domains", "when two", "two stat", "stat binding", "binding sites", "sites for", "for dimers", "dimers are", "are close", "close together", "henrikson et", "et al", "yan et", "1996 .

in", ".

in mammalian", "mammalian systems", "socs proteins", "proteins negatively", "negatively influence", "influence the", "jak/stat pathway.", "activated stats", "stats stimulate", "stimulate transcription", "transcription of", "the socs", "socs genes", "and the", "the resulting", "resulting socs", "proteins bind", "bind phosphorylated", "phosphorylated jak", "and their", "their receptors", "receptors to", "to turn", "turn off", "off the", "pathway in", "in a", "a simple", "simple negative", "negative feedback", "feedback loop.", "socs can", "can affect", "affect their", "their negative", "negative regulation", "regulation in", "in three", "three ways.", "binding phospho", "tyr on", "on the", "the receptors", "to physically", "physically block", "block stat", "stat recruitment.", "binding directly", "directly to", "to jaks", "jaks or", "or the", "to specifically", "specifically inhibit", "inhibit jak", "jak kinase", "kinase activity.", "by interacting", "interacting with", "with elongin", "elongin bc", "bc complex", "and cullin", "cullin 2", "facilitating the", "the ubiquitination", "ubiquitination of", "of jaks", "jaks and", "the receptors.", "of these", "these targets", "targets decreases", "decreases their", "their stability", "stability by", "by targeting", "targeting them", "them for", "for proteasomal", "proteasomal degradation", "rawlings et", "2004 .

three", ".

three socs", "proteins have", "have been", "been identified", "identified in", "in drosophila:", "drosophila: socs36e", "and socs16d.", "the present", "present time", "is no", "no evidence", "evidence to", "to demonstrate", "demonstrate a", "a physical", "physical interaction", "interaction between", "between drosophila", "drosophila socs", "proteins and", "and another", "another protein", "protein such", "as hop", "hop or", "or a", "a receptor.", "the jak/stat pathway", "jak/stat pathway is", "pathway is one", "is one of", "one of the", "of the main", "the main eukaryotic", "main eukaryotic signalling", "eukaryotic signalling pathways.", "pathways. in", "vertebrates there", "there are several", "are several ligands", "ligands receptors", "receptors jak", "jak kinases and", "kinases and stat", "and stat molecules", "stat molecules making", "molecules making detailed", "making detailed study", "detailed study of", "study of the", "of the system", "the system very", "system very complex.", "complex. in", "drosophila the", "pathway is much", "is much less", "much less redundant", "redundant offering", "offering one set", "one set of", "set of related", "of related ligands", "related ligands upd", "upd os", "os upd2", "upd2 upd3", "a receptor domeless", "domeless dome", "a janus associated", "janus associated kinase", "associated kinase hopscotch", "hopscotch hop", "and a stat", "a stat transcription", "stat transcription factor", "factor stat92e", "stat92e .

the dome", ".

the dome receptor", "receptor like", "like many cytokine", "many cytokine receptors", "receptors contains", "contains no tyrosine", "no tyrosine kinase", "tyrosine kinase domain.", "domain. however", "however it", "it is constitutively", "is constitutively associated", "constitutively associated with", "associated with the", "with the kinase", "the kinase hop.", "hop. the", "the dome receptor", "dome receptor dimerises", "receptor dimerises at", "dimerises at the", "at the plasma", "the plasma membrane", "plasma membrane whereupon", "membrane whereupon it", "whereupon it binds", "it binds a", "binds a upd", "a upd ligand.", "ligand. this", "this activates the", "activates the receptor", "the receptor associated", "receptor associated hop", "associated hop which", "hop which are", "which are now", "are now able", "now able to", "able to phosphorylate", "to phosphorylate each", "phosphorylate each other", "each other and", "other and also", "and also the", "also the cytoplasmic", "the cytoplasmic tail", "cytoplasmic tail of", "tail of the", "of the dome", "the dome receptor.", "receptor. this", "this creates a", "creates a docking", "a docking site", "docking site for", "site for monomeric", "for monomeric cytoplasmic", "monomeric cytoplasmic stat92e", "cytoplasmic stat92e proteins", "stat92e proteins which", "proteins which can", "which can bind", "can bind via", "bind via their", "via their sh2", "their sh2 domains.", "domains. once", "once bound to", "bound to the", "to the receptor", "the receptor complex", "complex stat92e", "stat92e is itself", "is itself phosphorylated.", "phosphorylated. it", "it dissociates from", "dissociates from the", "from the receptor", "receptor complex and", "complex and dimerises", "dimerises the", "the interaction stabilised", "interaction stabilised by", "stabilised by the", "by the sh2", "the sh2 domain", "sh2 domain of", "domain of one", "of one molecule", "one molecule binding", "molecule binding to", "binding to the", "to the phospho", "the phospho tyr", "phospho tyr of", "tyr of the", "of the other.", "other. the", "the dimer translocates", "dimer translocates to", "translocates to the", "to the nucleus", "the nucleus where", "nucleus where it", "where it binds", "it binds to", "binds to a", "to a palindromic", "a palindromic dna", "palindromic dna sequence", "dna sequence in", "sequence in the", "in the pathway", "the pathway target", "pathway target gene", "target gene promoters", "gene promoters to", "promoters to activate", "to activate transcription.

there", "activate transcription.

there are", "transcription.

there are also", "are also negative", "also negative regulators", "negative regulators present", "regulators present in", "present in this", "in this pathway.", "pathway. some", "some are present", "are present in", "present in the", "in the nucleus", "the nucleus and", "and in", "in the case", "the case of", "case of su", "of su var", "su var 2", "var 2 10", "2 10 which", "10 which is", "which is a", "is a drosophila", "a drosophila pias", "drosophila pias or", "pias or zimp", "or zimp protein", "protein act", "act by binding", "by binding to", "binding to stat92e", "to stat92e dimer.", "dimer. others", "others such", "such as the", "as the bcl6", "the bcl6 orthologue", "orthologue ken", "ken and barbie", "barbie ken", "bind to dna", "to dna sequences", "dna sequences on", "sequences on target", "on target genes", "target genes which", "genes which overlap", "which overlap with", "overlap with stat92e", "with stat92e binding", "stat92e binding sites.", "sites. there", "there is a", "is a protein", "a protein tyrosine", "protein tyrosine phosphatase", "phosphatase ptp61f", "ptp61f that", "that exists in", "exists in two", "in two differently", "two differently spliced", "differently spliced forms.", "forms. one", "one is active", "is active in", "active in the", "in the cytosol", "the cytosol and", "cytosol and dephosphorylates", "and dephosphorylates hop", "dephosphorylates hop and", "hop and stat92e", "and stat92e while", "stat92e while the", "while the other", "the other dephosphorylates", "other dephosphorylates stat92e", "dephosphorylates stat92e in", "stat92e in the", "in the nucleus.

a", "the nucleus.

a truncated", "nucleus.

a truncated version", "truncated version of", "version of stat92e", "stat92e deltanstat92e", "deltanstat92e that", "that lacks the", "lacks the n", "the n terminal", "n terminal 133", "terminal 133 amino", "133 amino acids", "amino acids has", "acids has also", "has also been", "also been found.", "found. it", "it is believed", "is believed this", "believed this truncated", "this truncated stat", "truncated stat forms", "stat forms homodimers", "forms homodimers and", "homodimers and heterodimers", "and heterodimers with", "heterodimers with full", "with full length", "full length stat92e.", "stat92e. increasing", "increasing the deltanstat92e", "the deltanstat92e to", "deltanstat92e to stat92e", "to stat92e ratio", "stat92e ratio in", "ratio in overexpression", "in overexpression and", "overexpression and rnai", "and rnai experiments", "rnai experiments results", "experiments results in", "results in the", "in the repression", "the repression of", "of target", "target gene transcription.", "transcription. this", "this may be", "may be due", "be due to", "due to the", "to the truncated", "the truncated protein", "truncated protein failing", "protein failing to", "failing to attract", "to attract coactivators", "attract coactivators or", "coactivators or failing", "or failing to", "failing to form", "to form tetramers", "tetramers necessary", "necessary for activation", "for activation of", "activation of certain", "of certain genes", "certain genes and", "genes and assembled", "and assembled by", "assembled by the", "by the n", "n terminal domains", "domains when", "when two stat", "two stat binding", "stat binding sites", "binding sites for", "sites for dimers", "for dimers are", "dimers are close", "are close together", "together henrikson", "henrikson et al", "al 2002", "2002 yan", "yan et al", "al 1996", "1996 .

in mammalian", ".

in mammalian systems", "systems socs", "socs proteins negatively", "proteins negatively influence", "negatively influence the", "influence the jak/stat", "the jak/stat pathway.", "pathway. activated", "activated stats stimulate", "stats stimulate transcription", "stimulate transcription of", "transcription of the", "of the socs", "the socs genes", "socs genes and", "genes and the", "and the resulting", "the resulting socs", "resulting socs proteins", "socs proteins bind", "proteins bind phosphorylated", "bind phosphorylated jak", "phosphorylated jak kinases", "kinases and their", "and their receptors", "their receptors to", "receptors to turn", "to turn off", "turn off the", "off the pathway", "the pathway in", "pathway in a", "in a simple", "a simple negative", "simple negative feedback", "negative feedback loop.", "loop. socs", "socs can affect", "can affect their", "affect their negative", "their negative regulation", "negative regulation in", "regulation in three", "in three ways.", "ways. first", "first by", "by binding phospho", "binding phospho tyr", "phospho tyr on", "tyr on the", "on the receptors", "the receptors to", "receptors to physically", "to physically block", "physically block stat", "block stat recruitment.", "recruitment. second", "second by", "by binding directly", "binding directly to", "directly to jaks", "to jaks or", "jaks or the", "or the receptors", "receptors to specifically", "to specifically inhibit", "specifically inhibit jak", "inhibit jak kinase", "jak kinase activity.", "activity. third", "third by", "by interacting with", "interacting with elongin", "with elongin bc", "elongin bc complex", "bc complex and", "complex and cullin", "and cullin 2", "2 facilitating", "facilitating the ubiquitination", "the ubiquitination of", "ubiquitination of jaks", "of jaks and", "and presumably", "presumably the", "receptors. ubiquitination", "ubiquitination of these", "of these targets", "these targets decreases", "targets decreases their", "decreases their stability", "their stability by", "stability by targeting", "by targeting them", "targeting them for", "them for proteasomal", "for proteasomal degradation", "degradation rawlings", "rawlings et al", "al 2004", "2004 .

three socs", ".

three socs proteins", "socs proteins have", "proteins have been", "have been identified", "been identified in", "identified in drosophila:", "in drosophila: socs36e", "socs36e socs44a", "socs44a and", "socs16d. at", "at the present", "the present time", "time there", "there is no", "is no evidence", "no evidence to", "evidence to demonstrate", "to demonstrate a", "demonstrate a physical", "a physical interaction", "physical interaction between", "interaction between drosophila", "between drosophila socs", "drosophila socs proteins", "socs proteins and", "proteins and another", "and another protein", "another protein such", "protein such as", "such as hop", "as hop or", "hop or a", "or a receptor.", "the jak/stat pathway is", "jak/stat pathway is one", "pathway is one of", "is one of the", "one of the main", "of the main eukaryotic", "the main eukaryotic signalling", "main eukaryotic signalling pathways.", "signalling pathways. in", "pathways. in vertebrates", "in vertebrates there", "vertebrates there are", "there are several ligands", "several ligands receptors", "receptors jak kinases", "jak kinases and stat", "kinases and stat molecules", "and stat molecules making", "stat molecules making detailed", "molecules making detailed study", "making detailed study of", "detailed study of the", "study of the system", "of the system very", "the system very complex.", "very complex. in", "complex. in drosophila", "in drosophila the", "drosophila the jak/stat", "jak/stat pathway is much", "pathway is much less", "is much less redundant", "less redundant offering", "redundant offering one", "offering one set of", "one set of related", "set of related ligands", "of related ligands upd", "ligands upd os", "upd3 a", "receptor domeless dome", "dome a", "a janus associated kinase", "janus associated kinase hopscotch", "kinase hopscotch hop", "and a stat transcription", "a stat transcription factor", "transcription factor stat92e", "factor stat92e .

the", "stat92e .

the dome receptor", "dome receptor like", "receptor like many", "like many cytokine receptors", "cytokine receptors contains", "receptors contains no", "contains no tyrosine kinase", "no tyrosine kinase domain.", "kinase domain. however", "however it is", "it is constitutively associated", "is constitutively associated with", "constitutively associated with the", "associated with the kinase", "with the kinase hop.", "kinase hop. the", "hop. the dome", "the dome receptor dimerises", "dome receptor dimerises at", "receptor dimerises at the", "dimerises at the plasma", "at the plasma membrane", "the plasma membrane whereupon", "plasma membrane whereupon it", "membrane whereupon it binds", "whereupon it binds a", "it binds a upd", "binds a upd ligand.", "upd ligand. this", "ligand. this activates", "this activates the receptor", "activates the receptor associated", "the receptor associated hop", "receptor associated hop which", "associated hop which are", "hop which are now", "which are now able", "are now able to", "now able to phosphorylate", "able to phosphorylate each", "to phosphorylate each other", "phosphorylate each other and", "each other and also", "other and also the", "and also the cytoplasmic", "also the cytoplasmic tail", "the cytoplasmic tail of", "cytoplasmic tail of the", "tail of the dome", "of the dome receptor.", "dome receptor. this", "receptor. this creates", "this creates a docking", "creates a docking site", "a docking site for", "docking site for monomeric", "site for monomeric cytoplasmic", "for monomeric cytoplasmic stat92e", "monomeric cytoplasmic stat92e proteins", "cytoplasmic stat92e proteins which", "stat92e proteins which can", "proteins which can bind", "which can bind via", "can bind via their", "bind via their sh2", "via their sh2 domains.", "sh2 domains. once", "domains. once bound", "once bound to the", "bound to the receptor", "to the receptor complex", "receptor complex stat92e", "complex stat92e is", "stat92e is itself phosphorylated.", "itself phosphorylated. it", "phosphorylated. it dissociates", "it dissociates from the", "dissociates from the receptor", "from the receptor complex", "the receptor complex and", "receptor complex and dimerises", "and dimerises the", "dimerises the interaction", "the interaction stabilised by", "interaction stabilised by the", "stabilised by the sh2", "by the sh2 domain", "the sh2 domain of", "sh2 domain of one", "domain of one molecule", "of one molecule binding", "one molecule binding to", "molecule binding to the", "binding to the phospho", "to the phospho tyr", "the phospho tyr of", "phospho tyr of the", "tyr of the other.", "the other. the", "other. the dimer", "the dimer translocates to", "dimer translocates to the", "translocates to the nucleus", "to the nucleus where", "the nucleus where it", "nucleus where it binds", "where it binds to", "it binds to a", "binds to a palindromic", "to a palindromic dna", "a palindromic dna sequence", "palindromic dna sequence in", "dna sequence in the", "sequence in the pathway", "in the pathway target", "the pathway target gene", "pathway target gene promoters", "target gene promoters to", "gene promoters to activate", "promoters to activate transcription.

there", "to activate transcription.

there are", "activate transcription.

there are also", "transcription.

there are also negative", "are also negative regulators", "also negative regulators present", "negative regulators present in", "regulators present in this", "present in this pathway.", "this pathway. some", "pathway. some are", "some are present in", "are present in the", "present in the nucleus", "in the nucleus and", "nucleus and in", "and in the", "in the case of", "the case of su", "case of su var", "of su var 2", "su var 2 10", "var 2 10 which", "2 10 which is", "10 which is a", "which is a drosophila", "is a drosophila pias", "a drosophila pias or", "drosophila pias or zimp", "pias or zimp protein", "zimp protein act", "protein act by", "act by binding to", "by binding to stat92e", "binding to stat92e dimer.", "stat92e dimer. others", "others such as", "such as the bcl6", "as the bcl6 orthologue", "bcl6 orthologue ken", "orthologue ken and", "and barbie ken", "ken bind", "bind to dna sequences", "to dna sequences on", "dna sequences on target", "sequences on target genes", "on target genes which", "target genes which overlap", "genes which overlap with", "which overlap with stat92e", "overlap with stat92e binding", "with stat92e binding sites.", "binding sites. there", "sites. there is", "there is a protein", "is a protein tyrosine", "a protein tyrosine phosphatase", "tyrosine phosphatase ptp61f", "ptp61f that exists", "that exists in two", "exists in two differently", "in two differently spliced", "two differently spliced forms.", "spliced forms. one", "forms. one is", "one is active in", "is active in the", "active in the cytosol", "in the cytosol and", "the cytosol and dephosphorylates", "cytosol and dephosphorylates hop", "and dephosphorylates hop and", "dephosphorylates hop and stat92e", "hop and stat92e while", "and stat92e while the", "stat92e while the other", "while the other dephosphorylates", "the other dephosphorylates stat92e", "other dephosphorylates stat92e in", "dephosphorylates stat92e in the", "stat92e in the nucleus.

a", "in the nucleus.

a truncated", "the nucleus.

a truncated version", "nucleus.

a truncated version of", "truncated version of stat92e", "of stat92e deltanstat92e", "deltanstat92e that lacks", "that lacks the n", "lacks the n terminal", "the n terminal 133", "n terminal 133 amino", "terminal 133 amino acids", "133 amino acids has", "amino acids has also", "acids has also been", "has also been found.", "been found. it", "found. it is", "it is believed this", "is believed this truncated", "believed this truncated stat", "this truncated stat forms", "truncated stat forms homodimers", "stat forms homodimers and", "forms homodimers and heterodimers", "homodimers and heterodimers with", "and heterodimers with full", "heterodimers with full length", "with full length stat92e.", "length stat92e. increasing", "stat92e. increasing the", "increasing the deltanstat92e to", "the deltanstat92e to stat92e", "deltanstat92e to stat92e ratio", "to stat92e ratio in", "stat92e ratio in overexpression", "ratio in overexpression and", "in overexpression and rnai", "overexpression and rnai experiments", "and rnai experiments results", "rnai experiments results in", "experiments results in the", "results in the repression", "in the repression of", "repression of target", "of target gene", "gene transcription. this", "transcription. this may", "this may be due", "may be due to", "be due to the", "due to the truncated", "to the truncated protein", "the truncated protein failing", "truncated protein failing to", "protein failing to attract", "failing to attract coactivators", "to attract coactivators or", "attract coactivators or failing", "coactivators or failing to", "or failing to form", "failing to form tetramers", "form tetramers necessary", "tetramers necessary for", "necessary for activation of", "for activation of certain", "activation of certain genes", "of certain genes and", "certain genes and assembled", "genes and assembled by", "and assembled by the", "assembled by the n", "by the n terminal", "the n terminal domains", "terminal domains when", "domains when two", "when two stat binding", "two stat binding sites", "stat binding sites for", "binding sites for dimers", "sites for dimers are", "for dimers are close", "dimers are close together", "close together henrikson", "together henrikson et", "et al 2002", "2002 yan et", "et al 1996", "al 1996 .

in", "1996 .

in mammalian systems", "mammalian systems socs", "systems socs proteins", "socs proteins negatively influence", "proteins negatively influence the", "negatively influence the jak/stat", "influence the jak/stat pathway.", "jak/stat pathway. activated", "pathway. activated stats", "activated stats stimulate transcription", "stats stimulate transcription of", "stimulate transcription of the", "transcription of the socs", "of the socs genes", "the socs genes and", "socs genes and the", "genes and the resulting", "and the resulting socs", "the resulting socs proteins", "resulting socs proteins bind", "socs proteins bind phosphorylated", "proteins bind phosphorylated jak", "bind phosphorylated jak kinases", "phosphorylated jak kinases and", "jak kinases and their", "kinases and their receptors", "and their receptors to", "their receptors to turn", "receptors to turn off", "to turn off the", "turn off the pathway", "off the pathway in", "the pathway in a", "pathway in a simple", "in a simple negative", "a simple negative feedback", "simple negative feedback loop.", "feedback loop. socs", "loop. socs can", "socs can affect their", "can affect their negative", "affect their negative regulation", "their negative regulation in", "negative regulation in three", "regulation in three ways.", "three ways. first", "first by binding", "by binding phospho tyr", "binding phospho tyr on", "phospho tyr on the", "tyr on the receptors", "on the receptors to", "the receptors to physically", "receptors to physically block", "to physically block stat", "physically block stat recruitment.", "stat recruitment. second", "second by binding", "by binding directly to", "binding directly to jaks", "directly to jaks or", "to jaks or the", "jaks or the receptors", "or the receptors to", "the receptors to specifically", "receptors to specifically inhibit", "to specifically inhibit jak", "specifically inhibit jak kinase", "inhibit jak kinase activity.", "kinase activity. third", "third by interacting", "by interacting with elongin", "interacting with elongin bc", "with elongin bc complex", "elongin bc complex and", "bc complex and cullin", "complex and cullin 2", "cullin 2 facilitating", "2 facilitating the", "facilitating the ubiquitination of", "the ubiquitination of jaks", "ubiquitination of jaks and", "jaks and presumably", "presumably the receptors.", "the receptors. ubiquitination", "receptors. ubiquitination of", "ubiquitination of these targets", "of these targets decreases", "these targets decreases their", "targets decreases their stability", "decreases their stability by", "their stability by targeting", "stability by targeting them", "by targeting them for", "targeting them for proteasomal", "them for proteasomal degradation", "proteasomal degradation rawlings", "degradation rawlings et", "et al 2004", "al 2004 .

three", "2004 .

three socs proteins", ".

three socs proteins have", "socs proteins have been", "proteins have been identified", "have been identified in", "been identified in drosophila:", "identified in drosophila: socs36e", "drosophila: socs36e socs44a", "socs44a and socs16d.", "and socs16d. at", "socs16d. at the", "at the present time", "present time there", "time there is", "there is no evidence", "is no evidence to", "no evidence to demonstrate", "evidence to demonstrate a", "to demonstrate a physical", "demonstrate a physical interaction", "a physical interaction between", "physical interaction between drosophila", "interaction between drosophila socs", "between drosophila socs proteins", "drosophila socs proteins and", "socs proteins and another", "proteins and another protein", "and another protein such", "another protein such as", "protein such as hop", "such as hop or", "as hop or a", "hop or a receptor.", "the jak/stat pathway is one", "jak/stat pathway is one of", "pathway is one of the", "is one of the main", "one of the main eukaryotic", "of the main eukaryotic signalling", "the main eukaryotic signalling pathways.", "eukaryotic signalling pathways. in", "signalling pathways. in vertebrates", "in vertebrates there are", "vertebrates there are several", "are several ligands receptors", "ligands receptors jak", "receptors jak kinases and", "jak kinases and stat molecules", "kinases and stat molecules making", "and stat molecules making detailed", "stat molecules making detailed study", "molecules making detailed study of", "making detailed study of the", "detailed study of the system", "study of the system very", "of the system very complex.", "system very complex. in", "very complex. in drosophila", "in drosophila the jak/stat", "drosophila the jak/stat pathway", "the jak/stat pathway is much", "jak/stat pathway is much less", "pathway is much less redundant", "much less redundant offering", "less redundant offering one", "redundant offering one set", "offering one set of related", "one set of related ligands", "set of related ligands upd", "related ligands upd os", "upd os upd2", "os upd2 upd3", "upd3 a receptor", "a receptor domeless dome", "dome a janus", "a janus associated kinase hopscotch", "associated kinase hopscotch hop", "hop and a", "and a stat transcription factor", "stat transcription factor stat92e", "transcription factor stat92e .

the", "factor stat92e .

the dome", ".

the dome receptor like", "dome receptor like many", "receptor like many cytokine", "many cytokine receptors contains", "cytokine receptors contains no", "receptors contains no tyrosine", "contains no tyrosine kinase domain.", "tyrosine kinase domain. however", "domain. however it", "however it is constitutively", "it is constitutively associated with", "is constitutively associated with the", "constitutively associated with the kinase", "associated with the kinase hop.", "the kinase hop. the", "kinase hop. the dome", "hop. the dome receptor", "the dome receptor dimerises at", "dome receptor dimerises at the", "receptor dimerises at the plasma", "dimerises at the plasma membrane", "at the plasma membrane whereupon", "the plasma membrane whereupon it", "plasma membrane whereupon it binds", "membrane whereupon it binds a", "whereupon it binds a upd", "it binds a upd ligand.", "a upd ligand. this", "upd ligand. this activates", "ligand. this activates the", "this activates the receptor associated", "activates the receptor associated hop", "the receptor associated hop which", "receptor associated hop which are", "associated hop which are now", "hop which are now able", "which are now able to", "are now able to phosphorylate", "now able to phosphorylate each", "able to phosphorylate each other", "to phosphorylate each other and", "phosphorylate each other and also", "each other and also the", "other and also the cytoplasmic", "and also the cytoplasmic tail", "also the cytoplasmic tail of", "the cytoplasmic tail of the", "cytoplasmic tail of the dome", "tail of the dome receptor.", "the dome receptor. this", "dome receptor. this creates", "receptor. this creates a", "this creates a docking site", "creates a docking site for", "a docking site for monomeric", "docking site for monomeric cytoplasmic", "site for monomeric cytoplasmic stat92e", "for monomeric cytoplasmic stat92e proteins", "monomeric cytoplasmic stat92e proteins which", "cytoplasmic stat92e proteins which can", "stat92e proteins which can bind", "proteins which can bind via", "which can bind via their", "can bind via their sh2", "bind via their sh2 domains.", "their sh2 domains. once", "sh2 domains. once bound", "domains. once bound to", "once bound to the receptor", "bound to the receptor complex", "the receptor complex stat92e", "receptor complex stat92e is", "complex stat92e is itself", "is itself phosphorylated. it", "itself phosphorylated. it dissociates", "phosphorylated. it dissociates from", "it dissociates from the receptor", "dissociates from the receptor complex", "from the receptor complex and", "the receptor complex and dimerises", "complex and dimerises the", "and dimerises the interaction", "dimerises the interaction stabilised", "the interaction stabilised by the", "interaction stabilised by the sh2", "stabilised by the sh2 domain", "by the sh2 domain of", "the sh2 domain of one", "sh2 domain of one molecule", "domain of one molecule binding", "of one molecule binding to", "one molecule binding to the", "molecule binding to the phospho", "binding to the phospho tyr", "to the phospho tyr of", "the phospho tyr of the", "phospho tyr of the other.", "of the other. the", "the other. the dimer", "other. the dimer translocates", "the dimer translocates to the", "dimer translocates to the nucleus", "translocates to the nucleus where", "to the nucleus where it", "the nucleus where it binds", "nucleus where it binds to", "where it binds to a", "it binds to a palindromic", "binds to a palindromic dna", "to a palindromic dna sequence", "a palindromic dna sequence in", "palindromic dna sequence in the", "dna sequence in the pathway", "sequence in the pathway target", "in the pathway target gene", "the pathway target gene promoters", "pathway target gene promoters to", "target gene promoters to activate", "gene promoters to activate transcription.

there", "promoters to activate transcription.

there are", "to activate transcription.

there are also", "activate transcription.

there are also negative", "transcription.

there are also negative regulators", "are also negative regulators present", "also negative regulators present in", "negative regulators present in this", "regulators present in this pathway.", "in this pathway. some", "this pathway. some are", "pathway. some are present", "some are present in the", "are present in the nucleus", "present in the nucleus and", "the nucleus and in", "nucleus and in the", "and in the case", "in the case of su", "the case of su var", "case of su var 2", "of su var 2 10", "su var 2 10 which", "var 2 10 which is", "2 10 which is a", "10 which is a drosophila", "which is a drosophila pias", "is a drosophila pias or", "a drosophila pias or zimp", "drosophila pias or zimp protein", "or zimp protein act", "zimp protein act by", "protein act by binding", "act by binding to stat92e", "by binding to stat92e dimer.", "to stat92e dimer. others", "dimer. others such", "others such as the", "such as the bcl6 orthologue", "the bcl6 orthologue ken", "bcl6 orthologue ken and", "orthologue ken and barbie", "ken and barbie ken", "ken bind to", "bind to dna sequences on", "to dna sequences on target", "dna sequences on target genes", "sequences on target genes which", "on target genes which overlap", "target genes which overlap with", "genes which overlap with stat92e", "which overlap with stat92e binding", "overlap with stat92e binding sites.", "stat92e binding sites. there", "binding sites. there is", "sites. there is a", "there is a protein tyrosine", "is a protein tyrosine phosphatase", "protein tyrosine phosphatase ptp61f", "phosphatase ptp61f that", "ptp61f that exists in", "that exists in two differently", "exists in two differently spliced", "in two differently spliced forms.", "differently spliced forms. one", "spliced forms. one is", "forms. one is active", "one is active in the", "is active in the cytosol", "active in the cytosol and", "in the cytosol and dephosphorylates", "the cytosol and dephosphorylates hop", "cytosol and dephosphorylates hop and", "and dephosphorylates hop and stat92e", "dephosphorylates hop and stat92e while", "hop and stat92e while the", "and stat92e while the other", "stat92e while the other dephosphorylates", "while the other dephosphorylates stat92e", "the other dephosphorylates stat92e in", "other dephosphorylates stat92e in the", "dephosphorylates stat92e in the nucleus.

a", "stat92e in the nucleus.

a truncated", "in the nucleus.

a truncated version", "the nucleus.

a truncated version of", "nucleus.

a truncated version of stat92e", "version of stat92e deltanstat92e", "stat92e deltanstat92e that", "deltanstat92e that lacks the", "that lacks the n terminal", "lacks the n terminal 133", "the n terminal 133 amino", "n terminal 133 amino acids", "terminal 133 amino acids has", "133 amino acids has also", "amino acids has also been", "acids has also been found.", "also been found. it", "been found. it is", "found. it is believed", "it is believed this truncated", "is believed this truncated stat", "believed this truncated stat forms", "this truncated stat forms homodimers", "truncated stat forms homodimers and", "stat forms homodimers and heterodimers", "forms homodimers and heterodimers with", "homodimers and heterodimers with full", "and heterodimers with full length", "heterodimers with full length stat92e.", "full length stat92e. increasing", "length stat92e. increasing the", "stat92e. increasing the deltanstat92e", "increasing the deltanstat92e to stat92e", "the deltanstat92e to stat92e ratio", "deltanstat92e to stat92e ratio in", "to stat92e ratio in overexpression", "stat92e ratio in overexpression and", "ratio in overexpression and rnai", "in overexpression and rnai experiments", "overexpression and rnai experiments results", "and rnai experiments results in", "rnai experiments results in the", "experiments results in the repression", "results in the repression of", "the repression of target", "repression of target gene", "of target gene transcription.", "target gene transcription. this", "gene transcription. this may", "transcription. this may be", "this may be due to", "may be due to the", "be due to the truncated", "due to the truncated protein", "to the truncated protein failing", "the truncated protein failing to", "truncated protein failing to attract", "protein failing to attract coactivators", "failing to attract coactivators or", "to attract coactivators or failing", "attract coactivators or failing to", "coactivators or failing to form", "or failing to form tetramers", "to form tetramers necessary", "form tetramers necessary for", "tetramers necessary for activation", "necessary for activation of certain", "for activation of certain genes", "activation of certain genes and", "of certain genes and assembled", "certain genes and assembled by", "genes and assembled by the", "and assembled by the n", "assembled by the n terminal", "by the n terminal domains", "n terminal domains when", "terminal domains when two", "domains when two stat", "when two stat binding sites", "two stat binding sites for", "stat binding sites for dimers", "binding sites for dimers are", "sites for dimers are close", "for dimers are close together", "are close together henrikson", "close together henrikson et", "together henrikson et al", "henrikson et al 2002", "al 2002 yan", "2002 yan et al", "yan et al 1996", "et al 1996 .

in", "al 1996 .

in mammalian", ".

in mammalian systems socs", "mammalian systems socs proteins", "systems socs proteins negatively", "socs proteins negatively influence the", "proteins negatively influence the jak/stat", "negatively influence the jak/stat pathway.", "the jak/stat pathway. activated", "jak/stat pathway. activated stats", "pathway. activated stats stimulate", "activated stats stimulate transcription of", "stats stimulate transcription of the", "stimulate transcription of the socs", "transcription of the socs genes", "of the socs genes and", "the socs genes and the", "socs genes and the resulting", "genes and the resulting socs", "and the resulting socs proteins", "the resulting socs proteins bind", "resulting socs proteins bind phosphorylated", "socs proteins bind phosphorylated jak", "proteins bind phosphorylated jak kinases", "bind phosphorylated jak kinases and", "phosphorylated jak kinases and their", "jak kinases and their receptors", "kinases and their receptors to", "and their receptors to turn", "their receptors to turn off", "receptors to turn off the", "to turn off the pathway", "turn off the pathway in", "off the pathway in a", "the pathway in a simple", "pathway in a simple negative", "in a simple negative feedback", "a simple negative feedback loop.", "negative feedback loop. socs", "feedback loop. socs can", "loop. socs can affect", "socs can affect their negative", "can affect their negative regulation", "affect their negative regulation in", "their negative regulation in three", "negative regulation in three ways.", "in three ways. first", "ways. first by", "first by binding phospho", "by binding phospho tyr on", "binding phospho tyr on the", "phospho tyr on the receptors", "tyr on the receptors to", "on the receptors to physically", "the receptors to physically block", "receptors to physically block stat", "to physically block stat recruitment.", "block stat recruitment. second", "recruitment. second by", "second by binding directly", "by binding directly to jaks", "binding directly to jaks or", "directly to jaks or the", "to jaks or the receptors", "jaks or the receptors to", "or the receptors to specifically", "the receptors to specifically inhibit", "receptors to specifically inhibit jak", "to specifically inhibit jak kinase", "specifically inhibit jak kinase activity.", "jak kinase activity. third", "activity. third by", "third by interacting with", "by interacting with elongin bc", "interacting with elongin bc complex", "with elongin bc complex and", "elongin bc complex and cullin", "bc complex and cullin 2", "and cullin 2 facilitating", "cullin 2 facilitating the", "2 facilitating the ubiquitination", "facilitating the ubiquitination of jaks", "the ubiquitination of jaks and", "of jaks and presumably", "and presumably the", "the receptors. ubiquitination of", "receptors. ubiquitination of these", "ubiquitination of these targets decreases", "of these targets decreases their", "these targets decreases their stability", "targets decreases their stability by", "decreases their stability by targeting", "their stability by targeting them", "stability by targeting them for", "by targeting them for proteasomal", "targeting them for proteasomal degradation", "for proteasomal degradation rawlings", "proteasomal degradation rawlings et", "degradation rawlings et al", "rawlings et al 2004", "et al 2004 .

three", "al 2004 .

three socs", "2004 .

three socs proteins have", ".

three socs proteins have been", "socs proteins have been identified", "proteins have been identified in", "have been identified in drosophila:", "been identified in drosophila: socs36e", "in drosophila: socs36e socs44a", "socs36e socs44a and", "and socs16d. at the", "socs16d. at the present", "the present time there", "present time there is", "time there is no", "there is no evidence to", "is no evidence to demonstrate", "no evidence to demonstrate a", "evidence to demonstrate a physical", "to demonstrate a physical interaction", "demonstrate a physical interaction between", "a physical interaction between drosophila", "physical interaction between drosophila socs", "interaction between drosophila socs proteins", "between drosophila socs proteins and", "drosophila socs proteins and another", "socs proteins and another protein", "proteins and another protein such", "and another protein such as", "another protein such as hop", "protein such as hop or", "such as hop or a", "as hop or a 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"fruitfly_protein_pathways_reactome", "fieldtype": "text", "phraselist": [ "imd pathway", "the imd", "pathway mediates", "mediates the", "the response", "response of", "of drosophila", "drosophila to", "to the", "the presence", "presence of", "of diaminopimelic", "diaminopimelic acid", "acid type", "type peptidoglycan", "dap pgn", "found in", "in all", "all gram", "gram negative", "negative and", "and many", "many gram", "gram positive", "positive bacteria", "over lysine", "lysine type", "type pgn", "pgn found", "in gram", "positive bacteria.", "it operates", "operates in", "in the", "the fat", "fat body", "body and", "and hemocytes", "hemocytes in", "in response", "response to", "to a", "a systemic", "systemic infection", "infection and", "and is", "is activated", "activated upon", "upon recognition", "recognition of", "of dap", "pgn by", "by the", "the pgrp", "pgrp lc/le", "lc/le receptors", "which leads", "leads to", "to activation", "activation of", "of the", "the nfkappab", 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et", "hedengren et", "and ird5", "silverman et", "rutschmann et", "lu et", "vidal et", "gesellchen et", "kleino et", "zhuang et", "inhibitor of", "of apoptosis", "apoptosis 2", "flies lacking", "lacking these", "these genes", "genes are", "are viable", "viable but", "but are", "are highly", "highly susceptible", "susceptible to", "to gram", "negative bacterial", "bacterial infection", "lemaitre et", "1995 .", ". it", "it is", "is not", "not clear", "clear if", "if this", "this pathway", "plays another", "another role", "role beside", "beside immunity", "immunity but", "but overactivation", "overactivation of", "pathway induces", "induces strong", "strong lethality", "lethality due", "due to", "to apoptosis", "2001 .", "it should", "should also", "also be", "be noted", "noted that", "that the", "pathway is", "is present", "present and", "and functional", "functional in", "in almost", "almost all", "all epithelial", "epithelial cells.", "the responses", "responses in", "in these", "these tissues", "tissues are", "are not", "not identical", "identical to", "to those", "those observed", "observed in", "or in", "in cell", "cell culture", "culture .", "in particular", "the outputs", "outputs of", "of imd", "imd signalling", "signalling are", "are significantly", "significantly modified", "modified in", "the gut.", "during imd", "signalling in", "the gut", "gene targets", "targets producing", "producing pgn", "pgn digesting", "digesting pgrp", "pgrp lb", "lb and", "sc proteins", "proteins are", "are expressed", "expressed but", "but other", "other rel", "rel target", "target genes", "especially the", "the amp", "amp genes", "are mostly", "mostly silent.

in", "silent.

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in", "peptides.

in addition", "addition to", "to being", "being a", "a key", "key component", "tak1 kinase", "kinase is", "is involved", "involved in", "in triggering", "triggering a", "a jnk", "jnk kinase", "kinase signalling", "signalling cascade", "starting with", "the phosphorylation", "phosphorylation of", "the jnkk", "hep .", "this binds", "binds to", "a scaffolding", "scaffolding protein", "connector of", "of kinase", "kinase to", "to ap", "ap 1", "bringing into", "into close", "close proximity", "proximity the", "the jnk", "jnk protein", "which is", "is phosphorylated", "phosphorylated by", "by hep.", "cka is", "is also", "also phosphorylated", "phosphorylated which", "which results", "results in", "the dissociation", "dissociation of", "of bsk", "bsk which", "which translocates", "the nucleus.", "here it", "it binds", "binds with", "with a", "a nuclear", "nuclear residing", "residing cka", "cka molecule", "molecule which", "which additionally", "additionally recruits", "recruits the", "the ap", "1 transcription", "transcription factor", "factor consisting", "consisting of", "the c", "c jun", "jun orthologue", "and the", "c fos", "fos orthologue", "kay .", "bsk may", "may phosphorylate", "phosphorylate both", "both jra", "jra and", "and kay", "kay which", "which dissociate", "dissociate from", "from cka", "cka and", "genes involved", "the early", "early immune", "response thought", "thought to", "to be", "be involved", "in wound", "wound repair", "repair and", "and stress", "stress mechanisms.", "the gene", "gene responsible", "for encoding", "encoding the", "the phosphatase", "phosphatase puckered", "activated which", "is responsible", "for dephosphorylating", "dephosphorylating bsk", "an example", "example of", "of a", "a negative", "negative regulatory", "regulatory loop.

the", "loop.

the imd", "the immune", "response against", "against gram", "bacteria infection.", "during immune", "immune challenge", "jnk pathway", "activated prior", "prior to", "the activation", "imd pathway.", "this early", "response does", "does not", "not require", "require rel", "rel activity", "in fact", "it has", "has been", "been proposed", "proposed that", "the main", "main target", "target of", "pathway activation", "inhibits the", "of rel", "rel dependent", "dependent genes.", "once rel", "activated the", "early response", "is terminated", "terminated and", "and a", "a sustained", "sustained immune", "is active.

in", "active.

in addition", "to these", "these core", "core components", "many new", "new gene", "gene products", "products have", "been linked", "linked to", "pathway but", "but their", "their function", "function have", "have not", "not been", "been fully", "fully established:

", "amidase pgrps:", "pgrps: recently", "been shown", "shown that", "is down", "down regulated", "the amidase", "amidase pgrps", "and pgrp", "pgrp sc1.", "they exert", "exert their", "their action", "action extracellularly", "extracellularly by", "by scavenging", "scavenging peptidoglycan", "peptidoglycan into", "into non", "non immune", "immune stimulatory", "stimulatory fragments.
", "pgrp le:", "le: pgrp", "le participates", "participates with", "with pgrp", "lc in", "the sensing", "sensing of", "pgn and", "and may", "may play", "play a", "a role", "of monomeric", "monomeric pgn", "pgn in", "the cytosol.
", "pgrp lf:", "lf: pgrp", "pgrp lf", "lf appears", "appears to", "to block", "block pgrp", "lc mediated", "mediated activation", "the imd/jnk", "imd/jnk pathway", "pathway possibly", "possibly by", "by interaction", "interaction with", "lc at", "or by", "by sequestering", "sequestering pgn", "pgn away", "away from", "from pgrp", "maillet et", "2008 .
", "negative regulators", "regulators of", "imd pathway:", "pathway: caspar", "plenty of", "of sh3s", "posh .
", "scf complex", "complex components", "components may", "may be", "the processing", "processing of", "of rel:", "rel: skpa", "and slimb", "khush et", "2002 .
", "components of", "the ubiquitin", "ligase complex:", "complex: bendless", "and uev1a", "zhou et", "2005 .
", "jnk: the", "pathway can", "can activate", "activate the", "jnkk hemipterous", "the level", "level of", "of tak1", "2003 .
", "factor akirin", "aka bhringi", "goto et", "and gata", "gata zinc", "zinc finger", "finger transcription", "senger et", "synergize with", "with relish", "activate transcription.", "the imd pathway", "imd pathway mediates", "pathway mediates the", "mediates the response", "the response of", "response of drosophila", "of drosophila to", "drosophila to the", "to the presence", "the presence of", "presence of diaminopimelic", "of diaminopimelic acid", "diaminopimelic acid type", "acid type peptidoglycan", "peptidoglycan dap", "found in all", "in all gram", "all gram negative", "gram negative and", "negative and many", "and many gram", "many gram positive", "gram positive bacteria", "bacteria over", "over lysine type", "lysine type pgn", "type pgn found", "pgn found in", "found in gram", "in gram positive", "gram positive bacteria.", "bacteria. it", "it operates in", "operates in the", "in the fat", "the fat body", "fat body and", "body and hemocytes", "and hemocytes in", "hemocytes in response", "in response to", "response to a", "to a systemic", "a systemic infection", "systemic infection and", "infection and is", "and is activated", "is activated upon", "activated upon recognition", "upon recognition of", "recognition of dap", "of dap pgn", "dap pgn by", "pgn by the", "by the pgrp", "the pgrp lc/le", "pgrp lc/le receptors", "receptors which", "which leads to", "leads to activation", "to activation of", "activation of the", "of the nfkappab", "the nfkappab like", "nfkappab like transactivator", "like transactivator relish", "relish rel", ". elements", "elements regulated by", "regulated by the", "by the pathway", "the pathway during", "pathway during a", "during a systemic", "systemic infection have", "infection have been", "have been identified", "been identified by", "identified by microarray", "by microarray and", "microarray and include", "and include a", "include a large", "a large set", "large set of", "set of antibacterial", "of antibacterial peptides", "antibacterial peptides genes", "genes de", "de gregorio et", "gregorio et al.", "al. 2002", "2002 boutros", "boutros et al.", ". in", "addition the", "imd pathway plays", "pathway plays an", "plays an important", "an important role", "important role in", "role in the", "in the relationship", "the relationship many", "relationship many epithelia", "many epithelia have", "epithelia have with", "have with the", "with the external", "the external world", "world where", "where it mediates", "it mediates the", "mediates the local", "the local inducible", "local inducible immune", "inducible immune response", "response tzou", "tzou et al.", "al. 2000", "2000 zaidman", "zaidman remy et", "remy et al.", "al. 2006", ". the", "the canonical component", "canonical component of", "component of the", "of the imd", "imd pathway contains:", "pathway contains: pgrp", "contains: pgrp lc", "lc gottar", "gottar et al.", "2002 choe", "choe et al.", "2002 ramet", "ramet et al.", "imd georgel", "georgel et al.", "al. 2001", "dfadd bg4", "leulier et al.", "2002 naitza", "naitza et al.", "dredd leulier", "rel hedengren", "hedengren et al.", "al. 1999", "kenny key", "key and", "ird5 silverman", "silverman et al.", "2000 rutschmann", "rutschmann et al.", "2000 lu", "lu et al.", "tak1 vidal", "vidal et al.", "2001 silverman", "al. 2003", "tab2 gesellchen", "gesellchen et al.", "al. 2005", "2005 kleino", "kleino et al.", "2005 zhuang", "zhuang et al.", "inhibitor of apoptosis", "of apoptosis 2", "2 iap2", "2005 leulier", ". flies", "flies lacking these", "lacking these genes", "these genes are", "genes are viable", "are viable but", "viable but are", "but are highly", "are highly susceptible", "highly susceptible to", "susceptible to gram", "to gram negative", "gram negative bacterial", "negative bacterial infection", "infection lemaitre", "lemaitre et al.", "al. 1995", "1995 . it", ". it is", "it is not", "is not clear", "not clear if", "clear if this", "if this pathway", "this pathway plays", "pathway plays another", "plays another role", "another role beside", "role beside immunity", "beside immunity but", "immunity but overactivation", "but overactivation of", "overactivation of the", "imd pathway induces", "pathway induces strong", "induces strong lethality", "strong lethality due", "lethality due to", "due to apoptosis", "apoptosis georgel", "it should also", "should also be", "also be noted", "be noted that", "noted that the", "that the imd", "imd pathway is", "pathway is present", "is present and", "present and functional", "and functional in", "functional in almost", "in almost all", "almost all epithelial", "all epithelial cells.", "cells. however", "however the", "the responses in", "responses in these", "in these tissues", "these tissues are", "tissues are not", "are not identical", "not identical to", "identical to those", "to those observed", "those observed in", "observed in the", "body or", "or in cell", "in cell culture", "cell culture .", "particular the", "the outputs of", "outputs of imd", "of imd signalling", "imd signalling are", "signalling are significantly", "are significantly modified", "significantly modified in", "modified in the", "in the gut.", "gut. during", "during imd signalling", "imd signalling in", "signalling in the", "in the gut", "gut gene", "gene targets producing", "targets producing pgn", "producing pgn digesting", "pgn digesting pgrp", "digesting pgrp lb", "pgrp lb and", "and sc", "sc proteins are", "proteins are expressed", "are expressed but", "expressed but other", "but other rel", "other rel target", "rel target genes", "genes especially", "especially the amp", "the amp genes", "amp genes are", "genes are mostly", "are mostly silent.

in", "mostly silent.

in response", "silent.

in response to", "response to infection", "to infection by", "infection by gram", "by gram negative", "gram negative bacteria", "negative bacteria the", "bacteria the imd", "imd pathway of", "pathway of the", "of the innate", "the innate immunity", "innate immunity response", "immunity response is", "response is activated.", "activated. dap", "pgns found", "found on gram", "on gram negative", "bacteria are", "are recognised and", "recognised and bind", "and bind to", "bind to the", "to the pgrp", "the pgrp lc", "pgrp lc receptor", "lc receptor at", "receptor at the", "at the plasma", "the plasma membrane", "plasma membrane or", "membrane or intracellularly", "or intracellularly bind", "intracellularly bind to", "the pgrp le", "pgrp le receptor.", "receptor. this", "this causes the", "causes the receptor", "the receptor to", "receptor to dimerise/multimerise", "to dimerise/multimerise and", "dimerise/multimerise and activate", "and activate resulting", "activate resulting in", "resulting in the", "in the recruitment", "the recruitment of", "recruitment of the", "of the adaptor", "the adaptor proteins", "adaptor proteins imd", "proteins imd and", "imd and dfadd", "bg4 along", "along with the", "with the caspase", "the caspase 8", "caspase 8 orthologue", "8 orthologue dredd.", "dredd. meanwhile", "meanwhile the", "the ser/thr mapk", "ser/thr mapk kinase", "mapk kinase kinase", "kinase tak1", "tak1 and its", "and its partner", "its partner tab2", "partner tab2 are", "tab2 are activated", "are activated possibly", "activated possibly through", "possibly through the", "through the iap2:bendless", "iap2:bendless ben", "ben :uev1a ubiquitin", ":uev1a ubiquitin e3", "ubiquitin e3 ligase", "e3 ligase complex.", "complex. tak1", "tak1 and tab2", "tab2 in", "in turn phosphorylate", "turn phosphorylate the", "phosphorylate the ikkbeta", "the ikkbeta orthologue", "ikkbeta orthologue ird5.", "ird5. activated", "ird5 in", "in complex with", "complex with ikkgamma", "with ikkgamma orthologue", "ikkgamma orthologue kenny", "phosphorylates the nfkappab", "the nfkappab orthologue", "nfkappab orthologue relish", ". rel", "rel consists of", "consists of an", "of an n", "an n terminal", "n terminal nuclear", "terminal nuclear factor", "nuclear factor containing", "factor containing domain", "68 and", "and an inhibitory", "an inhibitory c", "inhibitory c terminal", "c terminal domain", "49 responsible", "responsible for anchoring", "for anchoring rel", "anchoring rel in", "rel in the", "in the cytoplasm.", "cytoplasm. rel", "rel is then", "is then cleaved", "then cleaved by", "cleaved by the", "by the caspase", "caspase dredd", "dredd releasing", "releasing the n", "the n terminal", "n terminal domain", "terminal domain rel", "domain rel 68.", "68. this", "this translocates to", "translocates to the", "to the nucleus", "the nucleus where", "nucleus where it", "where it is", "it is able", "is able to", "able to activate", "to activate transcription", "activate transcription of", "transcription of genes", "of genes encoding", "genes encoding antimicrobial", "encoding antimicrobial peptides.

in", "antimicrobial peptides.

in addition", "peptides.

in addition to", "addition to being", "to being a", "being a key", "a key component", "key component of", "pathway tak1", "tak1 kinase is", "kinase is involved", "is involved in", "involved in triggering", "in triggering a", "triggering a jnk", "a jnk kinase", "jnk kinase signalling", "kinase signalling cascade", "cascade starting", "starting with the", "with the phosphorylation", "the phosphorylation of", "phosphorylation of the", "of the jnkk", "hemipterous hep", ". this", "this binds to", "binds to a", "to a scaffolding", "a scaffolding protein", "protein connector", "connector of kinase", "of kinase to", "kinase to ap", "to ap 1", "1 cka", "bringing into close", "into close proximity", "close proximity the", "proximity the jnk", "the jnk protein", "protein basket", "basket bsk", "which is phosphorylated", "is phosphorylated by", "phosphorylated by hep.", "hep. cka", "cka is also", "is also phosphorylated", "also phosphorylated which", "phosphorylated which results", "which results in", "results in the", "in the dissociation", "the dissociation of", "dissociation of bsk", "of bsk which", "bsk which translocates", "which translocates to", "to the nucleus.", "nucleus. here", "here it binds", "it binds with", "binds with a", "with a nuclear", "a nuclear residing", "nuclear residing cka", "residing cka molecule", "cka molecule which", "molecule which additionally", "which additionally recruits", "additionally recruits the", "recruits the ap", "the ap 1", "ap 1 transcription", "1 transcription factor", "transcription factor consisting", "factor consisting of", "consisting of the", "of the c", "the c jun", "c jun orthologue", "orthologue jra", "and the c", "the c fos", "c fos orthologue", "orthologue kayak", "kayak kay", ". bsk", "bsk may phosphorylate", "may phosphorylate both", "phosphorylate both jra", "both jra and", "jra and kay", "and kay which", "kay which dissociate", "which dissociate from", "dissociate from cka", "from cka and", "cka and activate", "and activate transcription", "of genes involved", "genes involved in", "involved in the", "in the early", "the early immune", "early immune response", "immune response thought", "response thought to", "thought to be", "to be involved", "be involved in", "involved in wound", "in wound repair", "wound repair and", "repair and stress", "and stress mechanisms.", "mechanisms. additionally", "additionally the", "the gene responsible", "gene responsible for", "responsible for encoding", "for encoding the", "encoding the phosphatase", "the phosphatase puckered", "puckered puc", "puc is", "is activated which", "activated which is", "which is responsible", "is responsible for", "responsible for dephosphorylating", "for dephosphorylating bsk", "bsk an", "an example of", "example of a", "of a negative", "a negative regulatory", "negative regulatory loop.

the", "regulatory loop.

the imd", "loop.

the imd pathway", "mediates the immune", "the immune response", "immune response against", "response against gram", "against gram negative", "negative bacteria infection.", "infection. during", "during immune challenge", "challenge the", "the jnk pathway", "jnk pathway is", "pathway is activated", "is activated prior", "activated prior to", "prior to the", "to the activation", "the activation of", "the imd pathway.", "pathway. this", "this early immune", "immune response does", "response does not", "does not require", "not require rel", "require rel activity", "activity in", "fact it", "it has been", "has been proposed", "been proposed that", "proposed that the", "that the main", "the main target", "main target of", "target of the", "of the jnk", "jnk pathway activation", "activation the", "factor inhibits", "inhibits the activation", "activation of rel", "of rel dependent", "rel dependent genes.", "genes. however", "however once", "once rel is", "rel is activated", "is activated the", "activated the early", "the early response", "early response is", "response is terminated", "is terminated and", "terminated and a", "and a sustained", "a sustained immune", "sustained immune response", "immune response of", "response of the", "pathway is active.

in", "is active.

in addition", "active.

in addition to", "addition to these", "to these core", "these core components", "components many", "many new gene", "new gene products", "gene products have", "products have been", "have been linked", "been linked to", "linked to the", "to the imd", "imd pathway but", "pathway but their", "but their function", "their function have", "function have not", "have not been", "not been fully", "been fully established:

", "established:

amidase", "amidase pgrps: recently", "recently it", "has been shown", "been shown that", "shown that the", "pathway is down", "is down regulated", "down regulated by", "by the amidase", "the amidase pgrps", "pgrps pgrp", "lb and pgrp", "and pgrp sc1.", "sc1. they", "they exert their", "exert their action", "their action extracellularly", "action extracellularly by", "extracellularly by scavenging", "by scavenging peptidoglycan", "scavenging peptidoglycan into", "peptidoglycan into non", "into non immune", "non immune stimulatory", "immune stimulatory fragments.
", "fragments.
pgrp", "pgrp le: pgrp", "le: pgrp le", "pgrp le participates", "le participates with", "participates with pgrp", "with pgrp lc", "pgrp lc in", "lc in the", "in the sensing", "the sensing of", "sensing of dap", "dap pgn and", "pgn and may", "and may play", "may play a", "play a role", "a role in", "sensing of monomeric", "of monomeric pgn", "monomeric pgn in", "pgn in the", "in the cytosol.
", "cytosol.
pgrp", "pgrp lf: pgrp", "lf: pgrp lf", "pgrp lf appears", "lf appears to", "appears to block", "to block pgrp", "block pgrp lc", "pgrp lc mediated", "lc mediated activation", "mediated activation of", "of the imd/jnk", "the imd/jnk pathway", "imd/jnk pathway possibly", "pathway possibly by", "possibly by interaction", "by interaction with", "interaction with pgrp", "pgrp lc at", "lc at the", "membrane or by", "or by sequestering", "by sequestering pgn", "sequestering pgn away", "pgn away from", "away from pgrp", "from pgrp lc", "lc maillet", "maillet et al.", "al. 2008", ".
negative", "negative regulators of", "regulators of the", "the imd pathway:", "imd pathway: caspar", "caspar plenty", "plenty of sh3s", "sh3s posh", ".
scf", "scf complex components", "complex components may", "components may be", "may be involved", "in the processing", "the processing of", "processing of rel:", "of rel: skpa", "skpa cullin1", "cullin1 lin19", "slimb slmb", "khush et al.", ".
components", "components of the", "of the ubiquitin", "the ubiquitin e3", "e3 ligase complex:", "ligase complex: bendless", "bendless ben", "ben and", "uev1a zhou", "zhou et al.", ".
jnk:", "jnk: the imd", "imd pathway can", "pathway can activate", "can activate the", "activate the jnk", "pathway through", "through the jnkk", "the jnkk hemipterous", "at the level", "the level of", "level of tak1", "tak1 boutros", "2002 silverman", ".
nuclear", "nuclear factor akirin", "akirin aka", "bhringi bhr", "goto et al.", "2008 and", "and gata zinc", "gata zinc finger", "zinc finger transcription", "finger transcription factor", "factor serpent", "serpent srp", "senger et al.", "al. 2004", "2004 synergize", "synergize with relish", "rel and", "and activate transcription.", "the imd pathway mediates", "imd pathway mediates the", "pathway mediates the response", "mediates the response of", "the response of drosophila", "response of drosophila to", "of drosophila to the", "drosophila to the presence", "to the presence of", "the presence of diaminopimelic", "presence of diaminopimelic acid", "of diaminopimelic acid type", "diaminopimelic acid type peptidoglycan", "type peptidoglycan dap", "peptidoglycan dap pgn", "dap pgn found", "found in all gram", "in all gram negative", "all gram negative and", "gram negative and many", "negative and many gram", "and many gram positive", "many gram positive bacteria", "positive bacteria over", "bacteria over lysine", "over lysine type pgn", "lysine type pgn found", "type pgn found in", "pgn found in gram", "found in gram positive", "in gram positive bacteria.", "positive bacteria. it", "bacteria. it operates", "it operates in the", "operates in the fat", "in the fat body", "the fat body and", "fat body and hemocytes", "body and hemocytes in", "and hemocytes in response", "hemocytes in response to", "in response to a", "response to a systemic", "to a systemic infection", "a systemic infection and", "systemic infection and is", "infection and is activated", "and is activated upon", "is activated upon recognition", "activated upon recognition of", "upon recognition of dap", "recognition of dap pgn", "of dap pgn by", "dap pgn by the", "pgn by the pgrp", "by the pgrp lc/le", "the pgrp lc/le receptors", "lc/le receptors which", "receptors which leads", "which leads to activation", "leads to activation of", "to activation of the", "activation of the nfkappab", "of the nfkappab like", "the nfkappab like transactivator", "nfkappab like transactivator relish", "transactivator relish rel", "relish rel .", "rel . elements", ". elements regulated", "elements regulated by the", "regulated by the pathway", "by the pathway during", "the pathway during a", "pathway during a systemic", "during a systemic infection", "a systemic infection have", "systemic infection have been", "infection have been identified", "have been identified by", "been identified by microarray", "identified by microarray and", "by microarray and include", "microarray and include a", "and include a large", "include a large set", "a large set of", "large set of antibacterial", "set of antibacterial peptides", "of antibacterial peptides genes", "peptides genes de", "genes de gregorio", "de gregorio et al.", "et al. 2002", "2002 boutros et", "al. 2002 .", "2002 . in", ". in addition", "in addition the", "addition the imd", "the imd pathway plays", "imd pathway plays an", "pathway plays an important", "plays an important role", "an important role in", "important role in the", "role in the relationship", "in the relationship many", "the relationship many epithelia", "relationship many epithelia have", "many epithelia have with", "epithelia have with the", "have with the external", "with the external world", "external world where", "world where it", "where it mediates the", "it mediates the local", "mediates the local inducible", "the local inducible immune", "local inducible immune response", "immune response tzou", "response tzou et", "et al. 2000", "2000 zaidman remy", "zaidman remy et al.", "et al. 2006", "al. 2006 .", "2006 . the", ". the canonical", "the canonical component of", "canonical component of the", "component of the imd", "of the imd pathway", "the imd pathway contains:", "imd pathway contains: pgrp", "pathway contains: pgrp lc", "pgrp lc gottar", "lc gottar et", "2002 choe et", "2002 ramet et", "2002 imd", "imd georgel et", "et al. 2001", "2001 dfadd", "bg4 leulier", "2002 naitza et", "2002 dredd", "dredd leulier et", "2000 rel", "rel hedengren et", "et al. 1999", "1999 kenny", "key and ird5", "and ird5 silverman", "ird5 silverman et", "2000 rutschmann et", "2000 lu et", "2001 tak1", "tak1 vidal et", "2001 silverman et", "et al. 2003", "2003 tab2", "tab2 gesellchen et", "et al. 2005", "2005 kleino et", "2005 zhuang et", "2006 inhibitor", "inhibitor of apoptosis 2", "apoptosis 2 iap2", "iap2 gesellchen", "2005 leulier et", "2006 . flies", ". flies lacking", "flies lacking these genes", "lacking these genes are", "these genes are viable", "genes are viable but", "are viable but are", "viable but are highly", "but are highly susceptible", "are highly susceptible to", "highly susceptible to gram", "susceptible to gram negative", "to gram negative bacterial", "gram negative bacterial infection", "bacterial infection lemaitre", "infection lemaitre et", "et al. 1995", "al. 1995 .", "1995 . it is", ". it is not", "it is not clear", "is not clear if", "not clear if this", "clear if this pathway", "if this pathway plays", "this pathway plays another", "pathway plays another role", "plays another role beside", "another role beside immunity", "role beside immunity but", "beside immunity but overactivation", "immunity but overactivation of", "but overactivation of the", "overactivation of the imd", "the imd pathway induces", "imd pathway induces strong", "pathway induces strong lethality", "induces strong lethality due", "strong lethality due to", "lethality due to apoptosis", "to apoptosis georgel", "apoptosis georgel et", "al. 2001 .", "2001 . it", ". it should", "it should also be", "should also be noted", "also be noted that", "be noted that the", "noted that the imd", "that the imd pathway", "the imd pathway is", "imd pathway is present", "pathway is present and", "is present and functional", "present and functional in", "and functional in almost", "functional in almost all", "in almost all epithelial", "almost all epithelial cells.", "epithelial cells. however", "however the responses", "the responses in these", "responses in these tissues", "in these tissues are", "these tissues are not", "tissues are not identical", "are not identical to", "not identical to those", "identical to those observed", "to those observed in", "those observed in the", "observed in the fat", "fat body or", "body or in", "or in cell culture", "in cell culture .", "culture . in", ". in particular", "in particular the", "particular the outputs", "the outputs of imd", "outputs of imd signalling", "of imd signalling are", "imd signalling are significantly", "signalling are significantly modified", "are significantly modified in", "significantly modified in the", "modified in the gut.", "the gut. during", "gut. during imd", "during imd signalling in", "imd signalling in the", "signalling in the gut", "the gut gene", "gut gene targets", "gene targets producing pgn", "targets producing pgn digesting", "producing pgn digesting pgrp", "pgn digesting pgrp lb", "digesting pgrp lb and", "lb and sc", "and sc proteins", "sc proteins are expressed", "proteins are expressed but", "are expressed but other", "expressed but other rel", "but other rel target", "other rel target genes", "target genes especially", "genes especially the", "especially the amp genes", "the amp genes are", "amp genes are mostly", "genes are mostly silent.

in", "are mostly silent.

in response", "mostly silent.

in response to", "silent.

in response to infection", "response to infection by", "to infection by gram", "infection by gram negative", "by gram negative bacteria", "gram negative bacteria the", "negative bacteria the imd", "bacteria the imd pathway", "the imd pathway of", "imd pathway of the", "pathway of the innate", "of the innate immunity", "the innate immunity response", "innate immunity response is", "immunity response is activated.", "is activated. dap", "activated. dap pgns", "dap pgns found", "pgns found on", "found on gram negative", "on gram negative bacteria", "negative bacteria are", "bacteria are recognised", "are recognised and bind", "recognised and bind to", "and bind to the", "bind to the pgrp", "to the pgrp lc", "the pgrp lc receptor", "pgrp lc receptor at", "lc receptor at the", "receptor at the plasma", "at the plasma membrane", "the plasma membrane or", "plasma membrane or intracellularly", "membrane or intracellularly bind", "or intracellularly bind to", "intracellularly bind to the", "to the pgrp le", "the pgrp le receptor.", "le receptor. this", "receptor. this causes", "this causes the receptor", "causes the receptor to", "the receptor to dimerise/multimerise", "receptor to dimerise/multimerise and", "to dimerise/multimerise and activate", "dimerise/multimerise and activate resulting", "and activate resulting in", "activate resulting in the", "resulting in the recruitment", "in the recruitment of", "the recruitment of the", "recruitment of the adaptor", "of the adaptor proteins", "the adaptor proteins imd", "adaptor proteins imd and", "proteins imd and dfadd", "and dfadd bg4", "bg4 along with", "along with the caspase", "with the caspase 8", "the caspase 8 orthologue", "caspase 8 orthologue dredd.", "orthologue dredd. meanwhile", "meanwhile the ser/thr", "the ser/thr mapk kinase", "ser/thr mapk kinase kinase", "kinase kinase tak1", "kinase tak1 and", "tak1 and its partner", "and its partner tab2", "its partner tab2 are", "partner tab2 are activated", "tab2 are activated possibly", "are activated possibly through", "activated possibly through the", "possibly through the iap2:bendless", "the iap2:bendless ben", "iap2:bendless ben :uev1a", "ben :uev1a ubiquitin e3", ":uev1a ubiquitin e3 ligase", "ubiquitin e3 ligase complex.", "ligase complex. tak1", "complex. tak1 and", "and tab2 in", "tab2 in turn", "in turn phosphorylate the", "turn phosphorylate the ikkbeta", "phosphorylate the ikkbeta orthologue", "the ikkbeta orthologue ird5.", "orthologue ird5. activated", "ird5. activated ird5", "activated ird5 in", "ird5 in complex", "in complex with ikkgamma", "complex with ikkgamma orthologue", "with ikkgamma orthologue kenny", "orthologue kenny key", "key phosphorylates", "phosphorylates the nfkappab orthologue", "the nfkappab orthologue relish", "orthologue relish rel", "rel . rel", ". rel consists", "rel consists of an", "consists of an n", "of an n terminal", "an n terminal nuclear", "n terminal nuclear factor", "terminal nuclear factor containing", "nuclear factor containing domain", "containing domain rel", "domain rel 68", "rel 68 and", "68 and an", "and an inhibitory c", "an inhibitory c terminal", "inhibitory c terminal domain", "domain rel 49", "rel 49 responsible", "49 responsible for", "responsible for anchoring rel", "for anchoring rel in", "anchoring rel in the", "rel in the cytoplasm.", "the cytoplasm. rel", "cytoplasm. rel is", "rel is then cleaved", "is then cleaved by", "then cleaved by the", "cleaved by the caspase", "the caspase dredd", "dredd releasing the", "releasing the n terminal", "the n terminal domain", "n terminal domain rel", "terminal domain rel 68.", "rel 68. this", "68. this translocates", "this translocates to the", "translocates to the nucleus", "to the nucleus where", "the nucleus where it", "nucleus where it is", "where it is able", "it is able to", "is able to activate", "able to activate transcription", "to activate transcription of", "activate transcription of genes", "transcription of genes encoding", "of genes encoding antimicrobial", "genes encoding antimicrobial peptides.

in", "encoding antimicrobial peptides.

in addition", "antimicrobial peptides.

in addition to", "peptides.

in addition to being", "addition to being a", "to being a key", "being a key component", "a key component of", "key component of the", "imd pathway tak1", "pathway tak1 kinase", "tak1 kinase is involved", "kinase is involved in", "is involved in triggering", "involved in triggering a", "in triggering a jnk", "triggering a jnk kinase", "a jnk kinase signalling", "jnk kinase signalling cascade", "signalling cascade starting", "cascade starting with", "starting with the phosphorylation", "with the phosphorylation of", "the phosphorylation of the", "phosphorylation of the jnkk", "hemipterous hep .", "hep . this", ". this binds", "this binds to a", "binds to a scaffolding", "to a scaffolding protein", "scaffolding protein connector", "protein connector of", "connector of kinase to", "of kinase to ap", "kinase to ap 1", "ap 1 cka", "cka bringing", "bringing into close proximity", "into close proximity the", "close proximity the jnk", "proximity the jnk protein", "jnk protein basket", "bsk which is", "which is phosphorylated by", "is phosphorylated by hep.", "by hep. cka", "hep. cka is", "cka is also phosphorylated", "is also phosphorylated which", "also phosphorylated which results", "phosphorylated which results in", "which results in the", "results in the dissociation", "in the dissociation of", "the dissociation of bsk", "dissociation of bsk which", "of bsk which translocates", "bsk which translocates to", "which translocates to the", "translocates to the nucleus.", "the nucleus. here", "nucleus. here it", "here it binds with", "it binds with a", "binds with a nuclear", "with a nuclear residing", "a nuclear residing cka", "nuclear residing cka molecule", "residing cka molecule which", "cka molecule which additionally", "molecule which additionally recruits", "which additionally recruits the", "additionally recruits the ap", "recruits the ap 1", "the ap 1 transcription", "ap 1 transcription factor", "1 transcription factor consisting", "transcription factor consisting of", "factor consisting of the", "consisting of the c", "of the c jun", "the c jun orthologue", "jun orthologue jra", "jra and the", "and the c fos", "the c fos orthologue", "fos orthologue kayak", "kayak kay .", "kay . bsk", ". bsk may", "bsk may phosphorylate both", "may phosphorylate both jra", "phosphorylate both jra and", "both jra and kay", "jra and kay which", "and kay which dissociate", "kay which dissociate from", "which dissociate from cka", "dissociate from cka and", "from cka and activate", "cka and activate transcription", "and activate transcription of", "transcription of genes involved", "of genes involved in", "genes involved in the", "involved in the early", "in the early immune", "the early immune response", "early immune response thought", "immune response thought to", "response thought to be", "thought to be involved", "to be involved in", "be involved in wound", "involved in wound repair", "in wound repair and", "wound repair and stress", "repair and stress mechanisms.", "stress mechanisms. additionally", "additionally the gene", "the gene responsible for", "gene responsible for encoding", "responsible for encoding the", "for encoding the phosphatase", "encoding the phosphatase puckered", "phosphatase puckered puc", "puc is activated", "is activated which is", "activated which is responsible", "which is responsible for", "is responsible for dephosphorylating", "responsible for dephosphorylating bsk", "dephosphorylating bsk an", "bsk an example", "an example of a", "example of a negative", "of a negative regulatory", "a negative regulatory loop.

the", "negative regulatory loop.

the imd", "regulatory loop.

the imd pathway", "loop.

the imd pathway mediates", "pathway mediates the immune", "mediates the immune response", "the immune response against", "immune response against gram", "response against gram negative", "against gram negative bacteria", "gram negative bacteria infection.", "bacteria infection. during", "infection. during immune", "immune challenge the", "challenge the jnk", "the jnk pathway is", "jnk pathway is activated", "pathway is activated prior", "is activated prior to", "activated prior to the", "prior to the activation", "to the activation of", "the activation of the", "activation of the imd", "of the imd pathway.", "imd pathway. this", "pathway. this early", "this early immune response", "early immune response does", "immune response does not", "response does not require", "does not require rel", "not require rel activity", "rel activity in", "activity in fact", "in fact it", "fact it has", "it has been proposed", "has been proposed that", "been proposed that the", "proposed that the main", "that the main target", "the main target of", "main target of the", "target of the jnk", "of the jnk pathway", "the jnk pathway activation", "pathway activation the", "activation the ap", "transcription factor inhibits", "factor inhibits the", "inhibits the activation of", "the activation of rel", "activation of rel dependent", "of rel dependent genes.", "dependent genes. however", "however once rel", "once rel is activated", "rel is activated the", "is activated the early", "activated the early response", "the early response is", "early response is terminated", "response is terminated and", "is terminated and a", "terminated and a sustained", "and a sustained immune", "a sustained immune response", "sustained immune response of", "immune response of the", "response of the imd", "imd pathway is active.

in", "pathway is active.

in addition", "is active.

in addition to", "active.

in addition to these", "addition to these core", "to these core components", "core components many", "components many new", "many new gene products", "new gene products have", "gene products have been", "products have been linked", "have been linked to", "been linked to the", "linked to the imd", "to the imd pathway", "the imd pathway but", "imd pathway but their", "pathway but their function", "but their function have", "their function have not", "function have not been", "have not been fully", "not been fully established:

", "fully established:

amidase", "established:

amidase pgrps:", "pgrps: recently it", "recently it has", "it has been shown", "has been shown that", "been shown that the", "shown that the imd", "imd pathway is down", "pathway is down regulated", "is down regulated by", "down regulated by the", "regulated by the amidase", "by the amidase pgrps", "amidase pgrps pgrp", "pgrps pgrp lb", "pgrp lb and pgrp", "lb and pgrp sc1.", "pgrp sc1. they", "sc1. they exert", "they exert their action", "exert their action extracellularly", "their action extracellularly by", "action extracellularly by scavenging", "extracellularly by scavenging peptidoglycan", "by scavenging peptidoglycan into", "scavenging peptidoglycan into non", "peptidoglycan into non immune", "into non immune stimulatory", "non immune stimulatory fragments.
", "stimulatory fragments.
pgrp", "fragments.
pgrp le:", "pgrp le: pgrp le", "le: pgrp le participates", "pgrp le participates with", "le participates with pgrp", "participates with pgrp lc", "with pgrp lc in", "pgrp lc in the", "lc in the sensing", "in the sensing of", "the sensing of dap", "sensing of dap pgn", "of dap pgn and", "dap pgn and may", "pgn and may play", "and may play a", "may play a role", "play a role in", "a role in the", "role in the sensing", "the sensing of monomeric", "sensing of monomeric pgn", "of monomeric pgn in", "monomeric pgn in the", "pgn in the cytosol.
", "the cytosol.
pgrp", "cytosol.
pgrp lf:", "pgrp lf: pgrp lf", "lf: pgrp lf appears", "pgrp lf appears to", "lf appears to block", "appears to block pgrp", "to block pgrp lc", "block pgrp lc mediated", "pgrp lc mediated activation", "lc mediated activation of", "mediated activation of the", "activation of the imd/jnk", "of the imd/jnk pathway", "the imd/jnk pathway possibly", "imd/jnk pathway possibly by", "pathway possibly by interaction", "possibly by interaction with", "by interaction with pgrp", "interaction with pgrp lc", "with pgrp lc at", "pgrp lc at the", "lc at the plasma", "plasma membrane or by", "membrane or by sequestering", "or by sequestering pgn", "by sequestering pgn away", "sequestering pgn away from", "pgn away from pgrp", "away from pgrp lc", "pgrp lc maillet", "lc maillet et", "et al. 2008", "al. 2008 .
", "2008 .
negative", ".
negative regulators", "negative regulators of the", "regulators of the imd", "of the imd pathway:", "the imd pathway: caspar", "pathway: caspar plenty", "caspar plenty of", "of sh3s posh", "sh3s posh .
", "posh .
scf", ".
scf complex", "scf complex components may", "complex components may be", "components may be involved", "may be involved in", "be involved in the", "involved in the processing", "in the processing of", "the processing of rel:", "processing of rel: skpa", "rel: skpa cullin1", "lin19 and", "and slimb slmb", "slmb khush", "al. 2002 .
", "2002 .
components", ".
components of", "components of the ubiquitin", "of the ubiquitin e3", "the ubiquitin e3 ligase", "ubiquitin e3 ligase complex:", "e3 ligase complex: bendless", "complex: bendless ben", "ben and uev1a", "and uev1a zhou", "uev1a zhou et", "al. 2005 .
", "2005 .
jnk:", ".
jnk: the", "jnk: the imd pathway", "the imd pathway can", "imd pathway can activate", "pathway can activate the", "can activate the jnk", "activate the jnk pathway", "jnk pathway through", "pathway through the", "through the jnkk hemipterous", "jnkk hemipterous hep", "hep at", "at the level of", "the level of tak1", "of tak1 boutros", "tak1 boutros et", "2002 silverman et", "al. 2003 .
", "2003 .
nuclear", ".
nuclear factor", "factor akirin aka", "akirin aka bhringi", "aka bhringi bhr", "2008 and gata", "and gata zinc finger", "gata zinc finger transcription", "zinc finger transcription factor", "transcription factor serpent", "srp senger", "et al. 2004", "2004 synergize with", "with relish rel", "rel and activate", "the imd pathway mediates the", "imd pathway mediates the response", "pathway mediates the response of", "mediates the response of drosophila", "the response of drosophila to", "response of drosophila to the", "of drosophila to the presence", "drosophila to the presence of", "to the presence of diaminopimelic", "the presence of diaminopimelic acid", "presence of diaminopimelic acid type", "of diaminopimelic acid type peptidoglycan", "acid type peptidoglycan dap", "type peptidoglycan dap pgn", "dap pgn found in", "pgn found in all", "found in all gram negative", "in all gram negative and", "all gram negative and many", "gram negative and many gram", "negative and many gram positive", "and many gram positive bacteria", "gram positive bacteria over", "positive bacteria over lysine", "bacteria over lysine type", "over lysine type pgn found", "lysine type pgn found in", "type pgn found in gram", "pgn found in gram positive", "found in gram positive bacteria.", "gram positive bacteria. it", "positive bacteria. it operates", "bacteria. it operates in", "it operates in the fat", "operates in the fat body", "in the fat body and", "the fat body and hemocytes", "fat body and hemocytes in", "body and hemocytes in response", "and hemocytes in response to", "hemocytes in response to a", "in response to a systemic", "response to a systemic infection", "to a systemic infection and", "a systemic infection and is", "systemic infection and is activated", "infection and is activated upon", "and is activated upon recognition", "is activated upon recognition of", "activated upon recognition of dap", "upon recognition of dap pgn", "recognition of dap pgn by", "of dap pgn by the", "dap pgn by the pgrp", "pgn by the pgrp lc/le", "by the pgrp lc/le receptors", "pgrp lc/le receptors which", "lc/le receptors which leads", "receptors which leads to", "which leads to activation of", "leads to activation of the", "to activation of the nfkappab", "activation of the nfkappab like", "of the nfkappab like transactivator", "the nfkappab like transactivator relish", "like transactivator relish rel", "transactivator relish rel .", "rel . elements regulated", ". elements regulated by", "elements regulated by the pathway", "regulated by the pathway during", "by the pathway during a", "the pathway during a systemic", "pathway during a systemic infection", "during a systemic infection have", "a systemic infection have been", "systemic infection have been identified", "infection have been identified by", "have been identified by microarray", "been identified by microarray and", "identified by microarray and include", "by microarray and include a", "microarray and include a large", "and include a large set", "include a large set of", "a large set of antibacterial", "large set of antibacterial peptides", "set of antibacterial peptides genes", "antibacterial peptides genes de", "peptides genes de gregorio", "genes de gregorio et", "gregorio et al. 2002", "al. 2002 boutros", "2002 boutros et al.", "boutros et al. 2002", "et al. 2002 .", "2002 . in addition", "in addition the imd", "addition the imd pathway", "the imd pathway plays an", "imd pathway plays an important", "pathway plays an important role", "plays an important role in", "an important role in the", "important role in the relationship", "role in the relationship many", "in the relationship many epithelia", "the relationship many epithelia have", "relationship many epithelia have with", "many epithelia have with the", "epithelia have with the external", "have with the external world", "the external world where", "external world where it", "world where it mediates", "where it mediates the local", "it mediates the local inducible", "mediates the local inducible immune", "the local inducible immune response", "inducible immune response tzou", "immune response tzou et", "response tzou et al.", "tzou et al. 2000", "al. 2000 zaidman", "2000 zaidman remy et", "remy et al. 2006", "et al. 2006 .", "2006 . the canonical", ". the canonical component", "the canonical component of the", "canonical component of the imd", "component of the imd pathway", "of the imd pathway contains:", "the imd pathway contains: pgrp", "imd pathway contains: pgrp lc", "contains: pgrp lc gottar", "pgrp lc gottar et", "lc gottar et al.", "gottar et al. 2002", "al. 2002 choe", "2002 choe et al.", "choe et al. 2002", "al. 2002 ramet", "2002 ramet et al.", "ramet et al. 2002", "imd georgel et al.", "georgel et al. 2001", "bg4 leulier et", "leulier et al. 2002", "al. 2002 naitza", "2002 naitza et al.", "naitza et al. 2002", "dredd leulier et al.", "leulier et al. 2000", "rel hedengren et al.", "hedengren et al. 1999", "kenny key and", "and ird5 silverman et", "ird5 silverman et al.", "silverman et al. 2000", "al. 2000 rutschmann", "2000 rutschmann et al.", "rutschmann et al. 2000", "al. 2000 lu", "2000 lu et al.", "lu et al. 2001", "tak1 vidal et al.", "vidal et al. 2001", "al. 2001 silverman", "2001 silverman et al.", "silverman et al. 2003", "tab2 gesellchen et al.", "gesellchen et al. 2005", "al. 2005 kleino", "2005 kleino et al.", "kleino et al. 2005", "al. 2005 zhuang", "2005 zhuang et al.", "zhuang et al. 2006", "2006 inhibitor of", "of apoptosis 2 iap2", "iap2 gesellchen et", "al. 2005 leulier", "2005 leulier et al.", "leulier et al. 2006", "2006 . flies lacking", ". flies lacking these", "flies lacking these genes are", "lacking these genes are viable", "these genes are viable but", "genes are viable but are", "are viable but are highly", "viable but are highly susceptible", "but are highly susceptible to", "are highly susceptible to gram", "highly susceptible to gram negative", "susceptible to gram negative bacterial", "to gram negative bacterial infection", "negative bacterial infection lemaitre", "bacterial infection lemaitre et", "infection lemaitre et al.", "lemaitre et al. 1995", "et al. 1995 .", "al. 1995 . it", "1995 . it is not", ". it is not clear", "it is not clear if", "is not clear if this", "not clear if this pathway", "clear if this pathway plays", "if this pathway plays another", "this pathway plays another role", "pathway plays another role beside", "plays another role beside immunity", "another role beside immunity but", "role beside immunity but overactivation", "beside immunity but overactivation of", "immunity but overactivation of the", "but overactivation of the imd", "overactivation of the imd pathway", "of the imd pathway induces", "the imd pathway induces strong", "imd pathway induces strong lethality", "pathway induces strong lethality due", "induces strong lethality due to", "strong lethality due to apoptosis", "due to apoptosis georgel", "to apoptosis georgel et", "apoptosis georgel et al.", "et al. 2001 .", "2001 . it should", ". it should also", "it should also be noted", "should also be noted that", "also be noted that the", "be noted that the imd", "noted that the imd pathway", "that the imd pathway is", "the imd pathway is present", "imd pathway is present and", "pathway is present and functional", "is present and functional in", "present and functional in almost", "and functional in almost all", "functional in almost all epithelial", "in almost all epithelial cells.", "all epithelial cells. however", "cells. however the", "however the responses in", "the responses in these tissues", "responses in these tissues are", "in these tissues are not", "these tissues are not identical", "tissues are not identical to", "are not identical to those", "not identical to those observed", "identical to those observed in", "to those observed in the", "those observed in the fat", "observed in the fat body", "the fat body or", "fat body or in", "body or in cell", "or in cell culture .", "cell culture . in", "culture . in particular", "in particular the outputs", "particular the outputs of", "the outputs of imd signalling", "outputs of imd signalling are", "of imd signalling are significantly", "imd signalling are significantly modified", "signalling are significantly modified in", "are significantly modified in the", "significantly modified in the gut.", "in the gut. during", "the gut. during imd", "gut. during imd signalling", "during imd signalling in the", "imd signalling in the gut", "in the gut gene", "the gut gene targets", "gut gene targets producing", "gene targets producing pgn digesting", "targets producing pgn digesting pgrp", "producing pgn digesting pgrp lb", "pgn digesting pgrp lb and", "pgrp lb and sc", "lb and sc proteins", "and sc proteins are", "sc proteins are expressed but", "proteins are expressed but other", "are expressed but other rel", "expressed but other rel target", "but other rel target genes", "rel target genes especially", "target genes especially the", "genes especially the amp", "especially the amp genes are", "the amp genes are mostly", "amp genes are mostly silent.

in", "genes are mostly silent.

in response", "are mostly silent.

in response to", "mostly silent.

in response to infection", "silent.

in response to infection by", "response to infection by gram", "to infection by gram negative", "infection by gram negative bacteria", "by gram negative bacteria the", "gram negative bacteria the imd", "negative bacteria the imd pathway", "bacteria the imd pathway of", "the imd pathway of the", "imd pathway of the innate", "pathway of the innate immunity", "of the innate immunity response", "the innate immunity response is", "innate immunity response is activated.", "response is activated. dap", "is activated. dap pgns", "dap pgns found on", "pgns found on gram", "found on gram negative bacteria", "gram negative bacteria are", "negative bacteria are recognised", "bacteria are recognised and", "are recognised and bind to", "recognised and bind to the", "and bind to the pgrp", "bind to the pgrp lc", "to the pgrp lc receptor", "the pgrp lc receptor at", "pgrp lc receptor at the", "lc receptor at the plasma", "receptor at the plasma membrane", "at the plasma membrane or", "the plasma membrane or intracellularly", "plasma membrane or intracellularly bind", "membrane or intracellularly bind to", "or intracellularly bind to the", "intracellularly bind to the pgrp", "bind to the pgrp le", "to the pgrp le receptor.", "pgrp le receptor. this", "le receptor. this causes", "receptor. this causes the", "this causes the receptor to", "causes the receptor to dimerise/multimerise", "the receptor to dimerise/multimerise and", "receptor to dimerise/multimerise and activate", "to dimerise/multimerise and activate resulting", "dimerise/multimerise and activate resulting in", "and activate resulting in the", "activate resulting in the recruitment", "resulting in the recruitment of", "in the recruitment of the", "the recruitment of the adaptor", "recruitment of the adaptor proteins", "of the adaptor proteins imd", "the adaptor proteins imd and", "adaptor proteins imd and dfadd", "imd and dfadd bg4", "dfadd bg4 along", "bg4 along with the", "along with the caspase 8", "with the caspase 8 orthologue", "the caspase 8 orthologue dredd.", "8 orthologue dredd. meanwhile", "dredd. meanwhile the", "meanwhile the ser/thr mapk", "the ser/thr mapk kinase kinase", "mapk kinase kinase tak1", "kinase kinase tak1 and", "kinase tak1 and its", "tak1 and its partner tab2", "and its partner tab2 are", "its partner tab2 are activated", "partner tab2 are activated possibly", "tab2 are activated possibly through", "are activated possibly through the", "activated possibly through the iap2:bendless", "through the iap2:bendless ben", "the iap2:bendless ben :uev1a", "iap2:bendless ben :uev1a ubiquitin", "ben :uev1a ubiquitin e3 ligase", ":uev1a ubiquitin e3 ligase complex.", "e3 ligase complex. tak1", "ligase complex. tak1 and", "complex. tak1 and tab2", "tak1 and tab2 in", "and tab2 in turn", "tab2 in turn phosphorylate", "in turn phosphorylate the ikkbeta", "turn phosphorylate the ikkbeta orthologue", "phosphorylate the ikkbeta orthologue ird5.", "ikkbeta orthologue ird5. activated", "orthologue ird5. activated ird5", "activated ird5 in complex", "ird5 in complex with", "in complex with ikkgamma orthologue", "complex with ikkgamma orthologue kenny", "ikkgamma orthologue kenny key", "key phosphorylates the", "phosphorylates the nfkappab orthologue relish", "nfkappab orthologue relish rel", "orthologue relish rel .", "rel . rel consists", ". rel consists of", "rel consists of an n", "consists of an n terminal", "of an n terminal nuclear", "an n terminal nuclear factor", "n terminal nuclear factor containing", "terminal nuclear factor containing domain", "factor containing domain rel", "containing domain rel 68", "rel 68 and an", "68 and an inhibitory", "and an inhibitory c terminal", "an inhibitory c terminal domain", "c terminal domain rel", "terminal domain rel 49", "rel 49 responsible for", "49 responsible for anchoring", "responsible for anchoring rel in", "for anchoring rel in the", "anchoring rel in the cytoplasm.", "in the cytoplasm. rel", "the cytoplasm. rel is", "cytoplasm. rel is then", "rel is then cleaved by", "is then cleaved by the", "then cleaved by the caspase", "by the caspase dredd", "caspase dredd releasing", "dredd releasing the n", "releasing the n terminal domain", "the n terminal domain rel", "n terminal domain rel 68.", "domain rel 68. this", "rel 68. this translocates", "68. this translocates to", "this translocates to the nucleus", "translocates to the nucleus where", "to the nucleus where it", "the nucleus where it is", "nucleus where it is able", "where it is able to", "it is able to activate", "is able to activate transcription", "able to activate transcription of", "to activate transcription of genes", "activate transcription of genes encoding", "transcription of genes encoding antimicrobial", "of genes encoding antimicrobial peptides.

in", "genes encoding antimicrobial peptides.

in addition", "encoding antimicrobial peptides.

in addition to", "antimicrobial peptides.

in addition to being", "peptides.

in addition to being a", "addition to being a key", "to being a key component", "being a key component of", "a key component of the", "key component of the imd", "the imd pathway tak1", "imd pathway tak1 kinase", "pathway tak1 kinase is", "tak1 kinase is involved in", "kinase is involved in triggering", "is involved in triggering a", "involved in triggering a jnk", "in triggering a jnk kinase", "triggering a jnk kinase signalling", "a jnk kinase signalling cascade", "kinase signalling cascade starting", "signalling cascade starting with", "cascade starting with the", "starting with the phosphorylation of", "with the phosphorylation of the", "the phosphorylation of the jnkk", "of the jnkk hemipterous", "hep . this binds", ". this binds to", "this binds to a scaffolding", "binds to a scaffolding protein", "a scaffolding protein connector", "scaffolding protein connector of", "protein connector of kinase", "connector of kinase to ap", "of kinase to ap 1", "to ap 1 cka", "cka bringing into", "bringing into close proximity the", "into close proximity the jnk", "close proximity the jnk protein", "the jnk protein basket", "protein basket bsk", "basket bsk which", "bsk which is phosphorylated", "which is phosphorylated by hep.", "phosphorylated by hep. cka", "by hep. cka is", "hep. cka is also", "cka is also phosphorylated which", "is also phosphorylated which results", "also phosphorylated which results in", "phosphorylated which results in the", "which results in the dissociation", "results in the dissociation of", "in the dissociation of bsk", "the dissociation of bsk which", "dissociation of bsk which translocates", "of bsk which translocates to", "bsk which translocates to the", "which translocates to the nucleus.", "to the nucleus. here", "the nucleus. here it", "nucleus. here it binds", "here it binds with a", "it binds with a nuclear", "binds with a nuclear residing", "with a nuclear residing cka", "a nuclear residing cka molecule", "nuclear residing cka molecule which", "residing cka molecule which additionally", "cka molecule which additionally recruits", "molecule which additionally recruits the", "which additionally recruits the ap", "additionally recruits the ap 1", "recruits the ap 1 transcription", "the ap 1 transcription factor", "ap 1 transcription factor consisting", "1 transcription factor consisting of", "transcription factor consisting of the", "factor consisting of the c", "consisting of the c jun", "of the c jun orthologue", "c jun orthologue jra", "orthologue jra and", "jra and the c", "and the c fos orthologue", "c fos orthologue kayak", "orthologue kayak kay", "kay . bsk may", ". bsk may phosphorylate", "bsk may phosphorylate both jra", "may phosphorylate both jra and", "phosphorylate both jra and kay", "both jra and kay which", "jra and kay which dissociate", "and kay which dissociate from", "kay which dissociate from cka", "which dissociate from cka and", "dissociate from cka and activate", "from cka and activate transcription", "cka and activate transcription of", "and activate transcription of genes", "activate transcription of genes involved", "transcription of genes involved in", "of genes involved in the", "genes involved in the early", "involved in the early immune", "in the early immune response", "the early immune response thought", "early immune response thought to", "immune response thought to be", "response thought to be involved", "thought to be involved in", "to be involved in wound", "be involved in wound repair", "involved in wound repair and", "in wound repair and stress", "wound repair and stress mechanisms.", "and stress mechanisms. additionally", "mechanisms. additionally the", "additionally the gene responsible", "the gene responsible for encoding", "gene responsible for encoding the", "responsible for encoding the phosphatase", "for encoding the phosphatase puckered", "the phosphatase puckered puc", "puckered puc is", "puc is activated which", "is activated which is responsible", "activated which is responsible for", "which is responsible for dephosphorylating", "is responsible for dephosphorylating bsk", "for dephosphorylating bsk an", "dephosphorylating bsk an example", "bsk an example of", "an example of a negative", "example of a negative regulatory", "of a negative regulatory loop.

the", "a negative regulatory loop.

the imd", "negative regulatory loop.

the imd pathway", "regulatory loop.

the imd pathway mediates", "loop.

the imd pathway mediates the", "imd pathway mediates the immune", "pathway mediates the immune response", "mediates the immune response against", "the immune response against gram", "immune response against gram negative", "response against gram negative bacteria", "against gram negative bacteria infection.", "negative bacteria infection. during", "bacteria infection. during immune", "infection. during immune challenge", "during immune challenge the", "immune challenge the jnk", "challenge the jnk pathway", "the jnk pathway is activated", "jnk pathway is activated prior", "pathway is activated prior to", "is activated prior to the", "activated prior to the activation", "prior to the activation of", "to the activation of the", "the activation of the imd", "activation of the imd pathway.", "the imd pathway. this", "imd pathway. this early", "pathway. this early immune", "this early immune response does", "early immune response does not", "immune response does not require", "response does not require rel", "does not require rel activity", "require rel activity in", "rel activity in fact", "in fact it has", "fact it has been", "it has been proposed that", "has been proposed that the", "been proposed that the main", "proposed that the main target", "that the main target of", "the main target of the", "main target of the jnk", "target of the jnk pathway", "of the jnk pathway activation", "jnk pathway activation the", "pathway activation the ap", "activation the ap 1", "1 transcription factor inhibits", "transcription factor inhibits the", "factor inhibits the activation", "inhibits the activation of rel", "the activation of rel dependent", "activation of rel dependent genes.", "rel dependent genes. however", "genes. however once", "however once rel is", "once rel is activated the", "rel is activated the early", "is activated the early response", "activated the early response is", "the early response is terminated", "early response is terminated and", "response is terminated and a", "is terminated and a sustained", "terminated and a sustained immune", "and a sustained immune response", "a sustained immune response of", "sustained immune response of the", "immune response of the imd", "response of the imd pathway", "of the imd pathway is", "the imd pathway is active.

in", "imd pathway is active.

in addition", "pathway is active.

in addition to", "is active.

in addition to these", "active.

in addition to these core", "addition to these core components", "these core components many", "core components many new", "components many new gene", "many new gene products have", "new gene products have been", "gene products have been linked", "products have been linked to", "have been linked to the", "been linked to the imd", "linked to the imd pathway", "to the imd pathway but", "the imd pathway but their", "imd pathway but their function", "pathway but their function have", "but their function have not", "their function have not been", "function have not been fully", "have not been fully established:

", "been fully established:

amidase", "fully established:

amidase pgrps:", "established:

amidase pgrps: recently", "amidase pgrps: recently it", "pgrps: recently it has", "recently it has been", "it has been shown that", "has been shown that the", "been shown that the imd", "shown that the imd pathway", "the imd pathway is down", "imd pathway is down regulated", "pathway is down regulated by", "is down regulated by the", "down regulated by the amidase", "regulated by the amidase pgrps", "the amidase pgrps pgrp", "amidase pgrps pgrp lb", "pgrps pgrp lb and", "pgrp lb and pgrp sc1.", "and pgrp sc1. they", "pgrp sc1. they exert", "sc1. they exert their", "they exert their action extracellularly", "exert their action extracellularly by", "their action extracellularly by scavenging", "action extracellularly by scavenging peptidoglycan", "extracellularly by scavenging peptidoglycan into", "by scavenging peptidoglycan into non", "scavenging peptidoglycan into non immune", "peptidoglycan into non immune stimulatory", "into non immune stimulatory fragments.
", "immune stimulatory fragments.
pgrp", "stimulatory fragments.
pgrp le:", "fragments.
pgrp le: pgrp", "pgrp le: pgrp le participates", "le: pgrp le participates with", "pgrp le participates with pgrp", "le participates with pgrp lc", "participates with pgrp lc in", "with pgrp lc in the", "pgrp lc in the sensing", "lc in the sensing of", "in the sensing of dap", "the sensing of dap pgn", "sensing of dap pgn and", "of dap pgn and may", "dap pgn and may play", "pgn and may play a", "and may play a role", "may play a role in", "play a role in the", "a role in the sensing", "role in the sensing of", "in the sensing of monomeric", "the sensing of monomeric pgn", "sensing of monomeric pgn in", "of monomeric pgn in the", "monomeric pgn in the cytosol.
", "in the cytosol.
pgrp", "the cytosol.
pgrp lf:", "cytosol.
pgrp lf: pgrp", "pgrp lf: pgrp lf appears", "lf: pgrp lf appears to", "pgrp lf appears to block", "lf appears to block pgrp", "appears to block pgrp lc", "to block pgrp lc mediated", "block pgrp lc mediated activation", "pgrp lc mediated activation of", "lc mediated activation of the", "mediated activation of the imd/jnk", "activation of the imd/jnk pathway", "of the imd/jnk pathway possibly", "the imd/jnk pathway possibly by", "imd/jnk pathway possibly by interaction", "pathway possibly by interaction with", "possibly by interaction with pgrp", "by interaction with pgrp lc", "interaction with pgrp lc at", "with pgrp lc at the", "pgrp lc at the plasma", "lc at the plasma membrane", "the plasma membrane or by", "plasma membrane or by sequestering", "membrane or by sequestering pgn", "or by sequestering pgn away", "by sequestering pgn away from", "sequestering pgn away from pgrp", "pgn away from pgrp lc", "from pgrp lc maillet", "pgrp lc maillet et", "lc maillet et al.", "maillet et al. 2008", "et al. 2008 .
", "2008 .
negative regulators", ".
negative regulators of", "negative regulators of the imd", "regulators of the imd pathway:", "of the imd pathway: caspar", "imd pathway: caspar plenty", "pathway: caspar plenty of", "caspar plenty of sh3s", "plenty of sh3s posh", "of sh3s posh .
", "posh .
scf complex", ".
scf complex components", "scf complex components may be", "complex components may be involved", "components may be involved in", "may be involved in the", "be involved in the processing", "involved in the processing of", "in the processing of rel:", "the processing of rel: skpa", "of rel: skpa cullin1", "skpa cullin1 lin19", "lin19 and slimb", "slmb khush et", "khush et al. 2002", "et al. 2002 .
", "2002 .
components of", ".
components of the", "components of the ubiquitin e3", "of the ubiquitin e3 ligase", "the ubiquitin e3 ligase complex:", "ubiquitin e3 ligase complex: bendless", "ligase complex: bendless ben", "bendless ben and", "and uev1a zhou et", "uev1a zhou et al.", "zhou et al. 2005", "et al. 2005 .
", "2005 .
jnk: the", ".
jnk: the imd", "jnk: the imd pathway can", "the imd pathway can activate", "imd pathway can activate the", "pathway can activate the jnk", "can activate the jnk pathway", "the jnk pathway through", "jnk pathway through the", "pathway through the jnkk", "the jnkk hemipterous hep", "hep at the", "at the level of tak1", "level of tak1 boutros", "of tak1 boutros et", "tak1 boutros et al.", "al. 2002 silverman", "2002 silverman et al.", "et al. 2003 .
", "2003 .
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"spz dimer binding leads", "dimer binding leads to toll", "leads to toll tl", "toll tl receptor", "tl receptor homodimerisation and" ] }, { "record_id": "GLY_000690_1_403", "filename": "fruitfly_protein_pathways_reactome", "fieldtype": "id", "phraselist": [ "gly_000690", "dme", "432626", "r dme", "dme 432626", "r dme 432626" ] }, { "record_id": "GLY_000690_1_403", "filename": "fruitfly_protein_pathways_reactome", "fieldtype": "text", "phraselist": [ "circadian clock", "clock pathway", "circadian clock pathway", "the drosophila", "drosophila molecular", "molecular circadian", "clock consists", "consists of", "of two", "two main", "main interlocked", "interlocked sets", "sets of", "of transcription/translation", "transcription/translation feedback", "feedback loops.", "these both", "both contain", "contain protein", "protein and", "and mrna", "mrna components", "components that", "that cycle", "cycle in", "in abundance", "abundance and", "and subcellular", "subcellular localisation", "localisation with", "with a", "a near", "near 24", "24 hour", "hour period.", "within the", "the core", "core components", "components of", "of the", "the clock", "both loops", "loops drive", "drive rhythmic", "rhythmic transcription", "transcription in", "in the", "the opposite", "opposite phase", "phase to", "to each", "each other.

the", "other.

the pathways", "pathways shown", "shown below", "below are", "are most", "most representative", "representative of", "of those", "those occurring", "occurring in", "in key", "key clock", "clock neurons", "neurons within", "the brains", "brains of", "of adult", "adult flies", "flies kept", "kept under", "under standard", "standard 12", "12 hour", "hour light:12", "light:12 hour", "hour dark", "dark cycles", "cycles at", "at 25°", "25° c.", "differences in", "in one", "one or", "or more", "more of", "the biochemical", "biochemical steps", "steps shown", "shown here", "here and/or", "and/or reactions", "reactions not", "not shown", "here can", "can occur", "occur in", "in different", "different brain", "brain clock", "about 150", "150 total", "total cells", "cells per", "per adult", "adult brain", "and within", "the same", "same clock", "clock cells", "cells as", "as a", "a function", "function of", "of changes", "changes in", "in environmental", "environmental conditions", "such as", "as day", "day length", "length or", "or temperature.

starting", "temperature.

starting from", "from midday", "midday and", "and continuing", "continuing through", "through to", "to early", "early night", "the per/tim", "per/tim feedback", "feedback loop", "loop is", "is initiated", "initiated when", "when the", "the basic", "basic helix", "helix loop", "loop helix/pas", "per arnt", "arnt sim", "domain transcription", "transcription factors", "and cycle", "form heterodimers", "heterodimers and", "and bind", "bind e", "e box", "box regulatory", "regulatory elements", "elements to", "to activate", "activate transcription", "transcription of", "of target", "target genes", "genes per", "and pdp1.", "the levels", "levels of", "of per", "per and", "and tim", "tim mrna", "mrna transcripts", "transcripts peak", "peak early", "early in", "the night", "whereas period", "and timeless", "proteins do", "do not", "not reach", "reach peak", "peak abundance", "abundance levels", "levels until", "until mid", "mid to", "to late", "late evening.", "tim stays", "stays at", "at low", "low levels", "levels at", "at this", "this point", "point because", "because it", "it is", "is destabilised", "destabilised by", "by light.", "per is", "is phosphorylated", "phosphorylated by", "by discs", "discs overgrown", "kinase aka", "aka double", "double time", "and casein", "casein kinase", "kinase ii", "ck2 .", "without tim", "which stabilises", "stabilises it", "is targeted", "targeted for", "for degradation", "degradation by", "by the", "the 26s", "26s proteasome", "proteasome via", "via an", "an interaction", "interaction with", "with the", "the f", "f box", "box containing", "containing protein", "supernumerary limbs", "slmb .", "in addition", "is stabilised", "stabilised by", "the protein", "protein phosphatases", "phosphatases pp2a", "pp2a and", "and pp1", "pp1 while", "while tim", "tim is", "is similarly", "similarly stabilised", "by pp1", "pp1 phosphatase.", "the coordinated", "coordinated action", "action of", "of both", "both kinases", "kinases and", "and phosphatases", "during this", "this part", "part of", "the day", "keep per", "per at", "levels and", "and in", "in a", "a hypophosphorylated", "hypophosphorylated state", "as hyperphosphorylated", "hyperphosphorylated per", "is removed", "removed due", "due to", "to low", "low tim", "tim levels.

after", "levels.

after dusk", "dusk during", "during the", "the early", "transcripts reach", "peak levels.", "tim abundance", "abundance begins", "begins to", "to increase", "increase in", "the dark", "dark and", "and forms", "forms a", "a complex", "complex with", "with per.", "along with", "with pp1", "pp1 phosphatase", "stabilises per", "per despite", "despite its", "its continued", "continued phosphorylation", "phosphorylation by", "by kinases.", "a result", "result per", "per and", "and tim", "tim accumulate", "accumulate to", "to high", "high levels", "levels during", "the middle", "middle of", "the night.", "is then", "then phosphorylated", "by ck2.", "tim dissociate", "in complex", "with dco", "enters the", "the nucleus", "nucleus followed", "followed by", "by tim", "a few", "few hours", "hours later.", "once in", "nucleus per", "tim reform", "reform their", "their heterodimer", "heterodimer and", "bind to", "to the", "the clk:cyc", "clk:cyc heterodimer", "so repressing", "repressing the", "the transcription", "heterodimer is", "removed from", "from the", "the e", "e boxes", "boxes and", "and sequestered", "sequestered in", "a stable", "stable complex", "with per", "tim to", "to reinforce", "reinforce the", "transcription inhibition.", "dco bound", "bound to", "to per", "per phosphorylates", "phosphorylates clk.", "towards the", "the end", "end of", "night per", "tim proteins", "proteins are", "are at", "at their", "their peak", "peak level.

at", "level.

at dawn", "the introduction", "introduction of", "of light", "light recalibrates", "recalibrates the", "the circadian", "circadian clock.", "the blue", "blue light", "light photoreceptor", "photoreceptor cryptochrome", "experiences a", "a light", "light induced", "induced conformational", "conformational change", "change which", "which forms", "with hyperphosphorylated", "hyperphosphorylated tim", "which leads", "leads to", "to both", "both tim", "tim and", "and cry", "cry degradation", "protein jetlag", "jet .", "and clk", "hyperphosphorylated by", "by dco", "the former", "former no", "no longer", "longer protected", "protected by", "are also", "also degraded", "degraded during", "early morning.", "per levels", "levels fall", "fall to", "to their", "their lowest", "lowest level", "level around", "around midday", "clk levels", "levels remain", "remain constant", "constant since", "since hypophosphorylated", "hypophosphorylated clk", "clk is", "is generated", "generated from", "from new", "new clk", "clk protein", "protein expression", "expression or", "or dephosphorylation", "dephosphorylation of", "of hyperphosphorylated", "hyperphosphorylated clk", "clk by", "by pp2a", "pp2a protein", "protein phosphatase.", "clk then", "then forms", "a heterodimer", "heterodimer with", "with cyc", "binds to", "to e", "boxes of", "of its", "its target", "genes and", "and a", "a new", "new cycle", "cycle of", "and pdp1", "pdp1 transcription", "transcription is", "is initiated.", "there is", "is an", "an alternate", "alternate view", "view that", "that clk", "clk binds", "to cyc", "cyc then", "then clk", "phosphorylated in", "the cytosol.", "this promotes", "promotes nuclear", "nuclear entry", "entry followed", "by further", "further clk", "clk phosphorylation.", "this string", "string of", "of events", "events at", "at present", "present remain", "remain controversial", "controversial and", "and are", "are not", "not included", "included in", "the current", "current model.

there", "model.

there is", "is a", "a second", "second feedback", "the clk", "clk loop", "interlocked with", "feedback loop.", "as mentioned", "mentioned above", "at midday", "midday clk:cyc", "clk:cyc heterodimers", "heterodimers bind", "and activate", "the target", "genes vri", "vri and", "which lead", "lead to", "the production", "production of", "the proteins", "proteins vrille", "and par", "par domain", "domain protein", "protein 1", "pdp1 activates", "activates transcription", "of clk", "clk and", "and cry", "cry genes", "while vri", "vri represses", "represses it", "by competitively", "competitively binding", "binding to", "to regulatory", "regulatory sequences", "sequences called", "called vri/pdp1", "although vri", "vri mrna", "mrna accumulates", "accumulates in", "in phase", "phase with", "with per", "tim mrnas", "pdp1 accumulation", "accumulation is", "is delayed", "delayed by", "by several", "several hours.", "in contrast", "contrast to", "the delayed", "delayed accumulation", "accumulation of", "of per", "tim protein", "protein levels", "vri protein", "levels rise", "rise in", "in sync", "sync with", "with vri", "vri mrna.", "between midday", "and dusk", "vri levels", "and the", "the superior", "superior vri/pdp1", "vri/pdp1 ratio", "ratio means", "means it", "it predominantly", "predominantly binds", "the v/p", "v/p boxes", "boxes to", "to repress", "repress clk", "cry transcription.", "levels reach", "reach their", "peak during", "night after", "after dusk", "dusk coinciding", "coinciding with", "with minimal", "minimal levels", "cry mrnas.", "cry protein", "levels build", "build slowly", "slowly as", "as it", "is relatively", "relatively stable", "stable in", "the dark.

pdp1", "dark.

pdp1 levels", "peak between", "between mid", "late night.", "levels decline", "decline during", "this time", "time due", "to tim:per", "tim:per influenced", "influenced repression", "repression of", "of vri", "vri transcription.", "the decreasing", "decreasing ratio", "ratio of", "of vri/pdp1", "vri/pdp1 levels", "levels favours", "favours binding", "binding of", "of pdp1", "pdp1 to", "boxes resulting", "resulting in", "in activation", "activation of", "pdp1 protein", "levels start", "start to", "to decline", "the late", "late night", "night and", "are low", "low by", "despite this", "pdp1 continues", "continues to", "activate clk", "cry transcription", "transcription until", "until midday", "midday when", "when vri", "levels are", "are sufficient", "after the", "the next", "next cycle", "of clk:cyc", "clk:cyc mediated", "mediated transcription", "to take", "take over", "over the", "the binding", "and repress", "repress transcription.

recently", "clk:cyc transcription", "of some", "some new", "new target", "and their", "their associated", "associated feedback", "feedback loops", "loops have", "have come", "come to", "to light", "light such", "as the", "the cwo", "cwo gene", "gene and", "and its", "its protein", "protein product", "product clockwork", "clockwork orange", "cwo .", "is confusion", "confusion as", "as to", "to whether", "whether cwo", "which binds", "pdp1 activates", "activates or", "or represses", "represses their", "their transcription.", "there are", "are likely", "likely to", "to be", "be many", "many more", "of these", "these secondary", "secondary transcription", "transcription loops", "loops connected", "connected to", "core clock", "clock mechanism", "mechanism to", "to add", "add yet", "yet more", "more modes", "modes of", "of regulation.", "the drosophila molecular", "drosophila molecular circadian", "molecular circadian clock", "circadian clock consists", "clock consists of", "consists of two", "of two main", "two main interlocked", "main interlocked sets", "interlocked sets of", "sets of transcription/translation", "of transcription/translation feedback", "transcription/translation feedback loops.", "loops. these", "these both contain", "both contain protein", "contain protein and", "protein and mrna", "and mrna components", "mrna components that", "components that cycle", "that cycle in", "cycle in abundance", "in abundance and", "abundance and subcellular", "and subcellular localisation", "subcellular localisation with", "localisation with a", "with a near", "a near 24", "near 24 hour", "24 hour period.", "period. within", "within the core", "the core components", "core components of", "components of the", "of the clock", "the clock pathway", "pathway both", "both loops drive", "loops drive rhythmic", "drive rhythmic transcription", "rhythmic transcription in", "transcription in the", "in the opposite", "the opposite phase", "opposite phase to", "phase to each", "to each other.

the", "each other.

the pathways", "other.

the pathways shown", "pathways shown below", "shown below are", "below are most", "are most representative", "most representative of", "representative of those", "of those occurring", "those occurring in", "occurring in key", "in key clock", "key clock neurons", "clock neurons within", "neurons within the", "within the brains", "the brains of", "brains of adult", "of adult flies", "adult flies kept", "flies kept under", "kept under standard", "under standard 12", "standard 12 hour", "12 hour light:12", "hour light:12 hour", "light:12 hour dark", "hour dark cycles", "dark cycles at", "cycles at 25°", "at 25° c.", "c. differences", "differences in one", "in one or", "one or more", "or more of", "more of the", "of the biochemical", "the biochemical steps", "biochemical steps shown", "steps shown here", "shown here and/or", "here and/or reactions", "and/or reactions not", "reactions not shown", "not shown here", "shown here can", "here can occur", "can occur in", "occur in different", "in different brain", "different brain clock", "brain clock neurons", "neurons about", "about 150 total", "150 total cells", "total cells per", "cells per adult", "per adult brain", "brain and", "and within the", "within the same", "the same clock", "same clock cells", "clock cells as", "cells as a", "as a function", "a function of", "function of changes", "of changes in", "changes in environmental", "in environmental conditions", "conditions such", "such as day", "as day length", "day length or", "length or temperature.

starting", "or temperature.

starting from", "temperature.

starting from midday", "from midday and", "midday and continuing", "and continuing through", "continuing through to", "through to early", "to early night", "night the", "the per/tim feedback", "per/tim feedback loop", "feedback loop is", "loop is initiated", "is initiated when", "initiated when the", "when the basic", "the basic helix", "basic helix loop", "helix loop helix/pas", "helix/pas per", "per arnt sim", "sim domain", "domain transcription factors", "factors clock", "clock clk", "clk and", "cycle cyc", "form heterodimers and", "heterodimers and bind", "and bind e", "bind e box", "e box regulatory", "box regulatory elements", "regulatory elements to", "elements to activate", "to activate transcription", "activate transcription of", "transcription of target", "of target genes", "target genes per", "per tim", "tim vri", "pdp1. the", "the levels of", "levels of per", "of per and", "per and tim", "and tim mrna", "tim mrna transcripts", "mrna transcripts peak", "transcripts peak early", "peak early in", "early in the", "in the night", "night whereas", "period per", "timeless tim", "proteins do not", "do not reach", "not reach peak", "reach peak abundance", "peak abundance levels", "abundance levels until", "levels until mid", "until mid to", "mid to late", "to late evening.", "evening. tim", "tim stays at", "stays at low", "at low levels", "low levels at", "levels at this", "at this point", "this point because", "point because it", "because it is", "it is destabilised", "is destabilised by", "destabilised by light.", "light. per", "per is phosphorylated", "is phosphorylated by", "phosphorylated by discs", "by discs overgrown", "overgrown dco", "dco kinase", "kinase aka double", "aka double time", "time dbt", "dbt and", "and casein kinase", "casein kinase ii", "ii ck2", ". without", "tim which", "which stabilises it", "it per", "per is targeted", "is targeted for", "targeted for degradation", "for degradation by", "degradation by the", "by the 26s", "the 26s proteasome", "26s proteasome via", "proteasome via an", "via an interaction", "an interaction with", "interaction with the", "with the f", "the f box", "f box containing", "box containing protein", "protein supernumerary", "limbs slmb", ". in", "addition per", "per is stabilised", "is stabilised by", "stabilised by the", "by the protein", "the protein phosphatases", "protein phosphatases pp2a", "phosphatases pp2a and", "pp2a and pp1", "and pp1 while", "pp1 while tim", "while tim is", "tim is similarly", "is similarly stabilised", "similarly stabilised by", "stabilised by pp1", "by pp1 phosphatase.", "phosphatase. the", "the coordinated action", "coordinated action of", "action of both", "of both kinases", "both kinases and", "kinases and phosphatases", "phosphatases during", "during this part", "this part of", "part of the", "of the day", "day keep", "keep per at", "per at low", "low levels and", "levels and in", "and in a", "in a hypophosphorylated", "a hypophosphorylated state", "state as", "as hyperphosphorylated per", "hyperphosphorylated per is", "per is removed", "is removed due", "removed due to", "due to low", "to low tim", "low tim levels.

after", "tim levels.

after dusk", "levels.

after dusk during", "dusk during the", "during the early", "the early night", "night per", "mrna transcripts reach", "transcripts reach peak", "reach peak levels.", "levels. tim", "tim abundance begins", "abundance begins to", "begins to increase", "to increase in", "increase in the", "in the dark", "the dark and", "dark and forms", "and forms a", "forms a complex", "a complex with", "complex with per.", "per. this", "this along", "along with pp1", "with pp1 phosphatase", "phosphatase stabilises", "stabilises per despite", "per despite its", "despite its continued", "its continued phosphorylation", "continued phosphorylation by", "phosphorylation by kinases.", "kinases. as", "as a result", "a result per", "result per and", "per and tim", "and tim accumulate", "tim accumulate to", "accumulate to high", "to high levels", "high levels during", "levels during the", "during the middle", "the middle of", "middle of the", "of the night.", "night. tim", "tim is then", "is then phosphorylated", "then phosphorylated by", "phosphorylated by ck2.", "ck2. per", "and tim dissociate", "dissociate per", "per in", "in complex with", "complex with dco", "dco enters", "enters the nucleus", "the nucleus followed", "nucleus followed by", "followed by tim", "tim a", "a few hours", "few hours later.", "later. once", "once in the", "in the nucleus", "the nucleus per", "nucleus per and", "and tim reform", "tim reform their", "reform their heterodimer", "their heterodimer and", "heterodimer and bind", "and bind to", "bind to the", "to the clk:cyc", "the clk:cyc heterodimer", "heterodimer so", "so repressing the", "repressing the transcription", "the transcription of", "transcription of per", "clk:cyc heterodimer is", "heterodimer is removed", "is removed from", "removed from the", "from the e", "the e boxes", "e boxes and", "boxes and sequestered", "and sequestered in", "sequestered in a", "in a stable", "a stable complex", "stable complex with", "complex with per", "with per and", "and tim to", "tim to reinforce", "to reinforce the", "reinforce the transcription", "the transcription inhibition.", "inhibition. in", "addition dco", "dco bound to", "bound to per", "to per phosphorylates", "per phosphorylates clk.", "clk. towards", "towards the end", "the end of", "end of the", "of the night", "the night per", "night per and", "and tim proteins", "tim proteins are", "proteins are at", "are at their", "at their peak", "their peak level.

at", "peak level.

at dawn", "dawn the", "the introduction of", "introduction of light", "of light recalibrates", "light recalibrates the", "recalibrates the circadian", "the circadian clock.", "clock. the", "the blue light", "blue light photoreceptor", "light photoreceptor cryptochrome", "cryptochrome cry", "cry experiences", "experiences a light", "a light induced", "light induced conformational", "induced conformational change", "conformational change which", "change which forms", "which forms a", "complex with hyperphosphorylated", "with hyperphosphorylated tim", "which leads to", "leads to both", "to both tim", "both tim and", "tim and cry", "and cry degradation", "cry degradation by", "containing protein jetlag", "jetlag jet", ". per", "per and clk", "clk hyperphosphorylated", "hyperphosphorylated by dco", "dco the", "the former no", "former no longer", "no longer protected", "longer protected by", "protected by tim", "tim are", "are also degraded", "also degraded during", "degraded during the", "the early morning.", "morning. per", "per levels fall", "levels fall to", "fall to their", "to their lowest", "their lowest level", "lowest level around", "level around midday", "midday however", "however clk", "clk levels remain", "levels remain constant", "remain constant since", "constant since hypophosphorylated", "since hypophosphorylated clk", "hypophosphorylated clk is", "clk is generated", "is generated from", "generated from new", "from new clk", "new clk protein", "clk protein expression", "protein expression or", "expression or dephosphorylation", "or dephosphorylation of", "dephosphorylation of hyperphosphorylated", "of hyperphosphorylated clk", "hyperphosphorylated clk by", "clk by pp2a", "by pp2a protein", "pp2a protein phosphatase.", "phosphatase. hypophosphorylated", "hypophosphorylated clk then", "clk then forms", "then forms a", "forms a heterodimer", "a heterodimer with", "heterodimer with cyc", "cyc binds", "binds to e", "to e boxes", "e boxes of", "boxes of its", "of its target", "its target genes", "target genes and", "genes and a", "and a new", "a new cycle", "new cycle of", "cycle of per", "and pdp1 transcription", "pdp1 transcription is", "transcription is initiated.", "initiated. there", "there is an", "is an alternate", "an alternate view", "alternate view that", "view that clk", "that clk binds", "clk binds to", "binds to cyc", "to cyc then", "cyc then clk", "then clk is", "clk is phosphorylated", "is phosphorylated in", "phosphorylated in the", "in the cytosol.", "cytosol. this", "this promotes nuclear", "promotes nuclear entry", "nuclear entry followed", "entry followed by", "followed by further", "by further clk", "further clk phosphorylation.", "phosphorylation. however", "however this", "this string of", "string of events", "of events at", "events at present", "at present remain", "present remain controversial", "remain controversial and", "controversial and are", "and are not", "are not included", "not included in", "included in the", "in the current", "the current model.

there", "current model.

there is", "model.

there is a", "is a second", "a second feedback", "second feedback loop", "loop the", "the clk loop", "loop interlocked", "interlocked with the", "with the per/tim", "per/tim feedback loop.", "loop. as", "as mentioned above", "above at", "at midday clk:cyc", "midday clk:cyc heterodimers", "clk:cyc heterodimers bind", "heterodimers bind to", "to the e", "boxes and activate", "and activate transcription", "transcription of the", "of the target", "the target genes", "target genes vri", "genes vri and", "vri and pdp1", "pdp1 which", "which lead to", "lead to the", "to the production", "the production of", "production of the", "of the proteins", "the proteins vrille", "vrille vri", "vri and", "and par domain", "par domain protein", "domain protein 1", "1 pdp1", "pdp1 respectively.", "respectively. pdp1", "pdp1 activates transcription", "activates transcription of", "transcription of clk", "of clk and", "clk and cry", "and cry genes", "genes while", "while vri represses", "vri represses it", "it by", "by competitively binding", "competitively binding to", "binding to regulatory", "to regulatory sequences", "regulatory sequences called", "sequences called vri/pdp1", "vri/pdp1 v/p", "v/p boxes.", "boxes. although", "although vri mrna", "vri mrna accumulates", "mrna accumulates in", "accumulates in phase", "in phase with", "phase with per", "with per and", "and tim mrnas", "mrnas pdp1", "pdp1 accumulation is", "accumulation is delayed", "is delayed by", "delayed by several", "by several hours.", "hours. in", "in contrast to", "contrast to the", "to the delayed", "the delayed accumulation", "delayed accumulation of", "accumulation of per", "of per and", "and tim protein", "tim protein levels", "levels vri", "vri protein levels", "protein levels rise", "levels rise in", "rise in sync", "in sync with", "sync with vri", "with vri mrna.", "mrna. between", "between midday and", "midday and dusk", "dusk vri", "vri levels rise", "rise and", "and the superior", "the superior vri/pdp1", "superior vri/pdp1 ratio", "vri/pdp1 ratio means", "ratio means it", "means it predominantly", "it predominantly binds", "predominantly binds to", "binds to the", "to the v/p", "the v/p boxes", "v/p boxes to", "boxes to repress", "to repress clk", "repress clk and", "and cry transcription.", "transcription. vri", "vri levels reach", "levels reach their", "reach their peak", "their peak during", "peak during the", "early night after", "night after dusk", "after dusk coinciding", "dusk coinciding with", "coinciding with minimal", "with minimal levels", "minimal levels of", "levels of clk", "and cry mrnas.", "mrnas. however", "however cry", "cry protein levels", "protein levels build", "levels build slowly", "build slowly as", "slowly as it", "as it is", "it is relatively", "is relatively stable", "relatively stable in", "stable in the", "in the dark.

pdp1", "the dark.

pdp1 levels", "dark.

pdp1 levels reach", "their peak between", "peak between mid", "between mid to", "to late night.", "night. vri", "vri levels decline", "levels decline during", "decline during this", "during this time", "this time due", "time due to", "due to tim:per", "to tim:per influenced", "tim:per influenced repression", "influenced repression of", "repression of vri", "of vri transcription.", "transcription. the", "the decreasing ratio", "decreasing ratio of", "ratio of vri/pdp1", "of vri/pdp1 levels", "vri/pdp1 levels favours", "levels favours binding", "favours binding of", "binding of pdp1", "of pdp1 to", "pdp1 to the", "v/p boxes resulting", "boxes resulting in", "resulting in activation", "in activation of", "activation of clk", "transcription. pdp1", "pdp1 protein levels", "protein levels start", "levels start to", "start to decline", "to decline during", "decline during the", "during the late", "the late night", "late night and", "night and are", "and are low", "are low by", "low by the", "by the early", "morning. however", "however despite", "this pdp1", "pdp1 continues to", "continues to activate", "to activate clk", "activate clk and", "and cry transcription", "cry transcription until", "transcription until midday", "until midday when", "midday when vri", "when vri protein", "protein levels are", "levels are sufficient", "sufficient after", "after the next", "the next cycle", "next cycle of", "cycle of clk:cyc", "of clk:cyc mediated", "clk:cyc mediated transcription", "transcription to", "to take over", "take over the", "over the binding", "the binding of", "binding of the", "of the v/p", "v/p boxes and", "boxes and repress", "and repress transcription.

recently", "transcription.

recently clk:cyc", "clk:cyc transcription of", "transcription of some", "of some new", "some new target", "new target genes", "genes and their", "and their associated", "their associated feedback", "associated feedback loops", "feedback loops have", "loops have come", "have come to", "come to light", "to light such", "light such as", "such as the", "as the cwo", "the cwo gene", "cwo gene and", "gene and its", "and its protein", "its protein product", "protein product clockwork", "product clockwork orange", "orange cwo", ". however", "however there", "there is confusion", "is confusion as", "confusion as to", "as to whether", "to whether cwo", "cwo which", "which binds to", "boxes of per", "and pdp1 activates", "pdp1 activates or", "activates or represses", "or represses their", "represses their transcription.", "transcription. there", "there are likely", "are likely to", "likely to be", "to be many", "be many more", "many more of", "more of these", "of these secondary", "these secondary transcription", "secondary transcription loops", "transcription loops connected", "loops connected to", "connected to the", "to the core", "the core clock", "core clock mechanism", "clock mechanism to", "mechanism to add", "to add yet", "add yet more", "yet more modes", "more modes of", "modes of regulation.", "the drosophila molecular circadian", "drosophila molecular circadian clock", "molecular circadian clock consists", "circadian clock consists of", "clock consists of two", "consists of two main", "of two main interlocked", "two main interlocked sets", "main interlocked sets of", "interlocked sets of transcription/translation", "sets of transcription/translation feedback", "of transcription/translation feedback loops.", "feedback loops. these", "loops. these both", "these both contain protein", "both contain protein and", "contain protein and mrna", "protein and mrna components", "and mrna components that", "mrna components that cycle", "components that cycle in", "that cycle in abundance", "cycle in abundance and", "in abundance and subcellular", "abundance and subcellular localisation", "and subcellular localisation with", "subcellular localisation with a", "localisation with a near", "with a near 24", "a near 24 hour", "near 24 hour period.", "hour period. within", "period. within the", "within the core components", "the core components of", "core components of the", "components of the clock", "of the clock pathway", "clock pathway both", "pathway both loops", "both loops drive rhythmic", "loops drive rhythmic transcription", "drive rhythmic transcription in", "rhythmic transcription in the", "transcription in the opposite", "in the opposite phase", "the opposite phase to", "opposite phase to each", "phase to each other.

the", "to each other.

the pathways", "each other.

the pathways shown", "other.

the pathways shown below", "pathways shown below are", "shown below are most", "below are most representative", "are most representative of", "most representative of those", "representative of those occurring", "of those occurring in", "those occurring in key", "occurring in key clock", "in key clock neurons", "key clock neurons within", "clock neurons within the", "neurons within the brains", "within the brains of", "the brains of adult", "brains of adult flies", "of adult flies kept", "adult flies kept under", "flies kept under standard", "kept under standard 12", "under standard 12 hour", "standard 12 hour light:12", "12 hour light:12 hour", "hour light:12 hour dark", "light:12 hour dark cycles", "hour dark cycles at", "dark cycles at 25°", "cycles at 25° c.", "25° c. differences", "c. differences in", "differences in one or", "in one or more", "one or more of", "or more of the", "more of the biochemical", "of the biochemical steps", "the biochemical steps shown", "biochemical steps shown here", "steps shown here and/or", "shown here and/or reactions", "here and/or reactions not", "and/or reactions not shown", "reactions not shown here", "not shown here can", "shown here can occur", "here can occur in", "can occur in different", "occur in different brain", "in different brain clock", "different brain clock neurons", "clock neurons about", "neurons about 150", "about 150 total cells", "150 total cells per", "total cells per adult", "cells per adult brain", "adult brain and", "brain and within", "and within the same", "within the same clock", "the same clock cells", "same clock cells as", "clock cells as a", "cells as a function", "as a function of", "a function of changes", "function of changes in", "of changes in environmental", "changes in environmental conditions", "environmental conditions such", "conditions such as", "such as day length", "as day length or", "day length or temperature.

starting", "length or temperature.

starting from", "or temperature.

starting from midday", "temperature.

starting from midday and", "from midday and continuing", "midday and continuing through", "and continuing through to", "continuing through to early", "through to early night", "early night the", "night the per/tim", "the per/tim feedback loop", "per/tim feedback loop is", "feedback loop is initiated", "loop is initiated when", "is initiated when the", "initiated when the basic", "when the basic helix", "the basic helix loop", "basic helix loop helix/pas", "loop helix/pas per", "helix/pas per arnt", "arnt sim domain", "sim domain transcription", "transcription factors clock", "clk and cycle", "and cycle cyc", "cyc form", "form heterodimers and bind", "heterodimers and bind e", "and bind e box", "bind e box regulatory", "e box regulatory elements", "box regulatory elements to", "regulatory elements to activate", "elements to activate transcription", "to activate transcription of", "activate transcription of target", "transcription of target genes", "of target genes per", "genes per tim", "vri and pdp1.", "and pdp1. the", "pdp1. the levels", "the levels of per", "levels of per and", "of per and tim", "per and tim mrna", "and tim mrna transcripts", "tim mrna transcripts peak", "mrna transcripts peak early", "transcripts peak early in", "peak early in the", "early in the night", "the night whereas", "night whereas period", "whereas period per", "per and timeless", "and timeless tim", "tim proteins do", "proteins do not reach", "do not reach peak", "not reach peak abundance", "reach peak abundance levels", "peak abundance levels until", "abundance levels until mid", "levels until mid to", "until mid to late", "mid to late evening.", "late evening. tim", "evening. tim stays", "tim stays at low", "stays at low levels", "at low levels at", "low levels at this", "levels at this point", "at this point because", "this point because it", "point because it is", "because it is destabilised", "it is destabilised by", "is destabilised by light.", "by light. per", "light. per is", "per is phosphorylated by", "is phosphorylated by discs", "phosphorylated by discs overgrown", "discs overgrown dco", "dco kinase aka", "kinase aka double time", "double time dbt", "dbt and casein", "and casein kinase ii", "kinase ii ck2", "ii ck2 .", "ck2 . without", ". without tim", "without tim which", "tim which stabilises", "stabilises it per", "it per is", "per is targeted for", "is targeted for degradation", "targeted for degradation by", "for degradation by the", "degradation by the 26s", "by the 26s proteasome", "the 26s proteasome via", "26s proteasome via an", "proteasome via an interaction", "via an interaction with", "an interaction with the", "interaction with the f", "with the f box", "the f box containing", "f box containing protein", "containing protein supernumerary", "protein supernumerary limbs", "supernumerary limbs slmb", "limbs slmb .", "slmb . in", ". in addition", "in addition per", "addition per is", "per is stabilised by", "is stabilised by the", "stabilised by the protein", "by the protein phosphatases", "the protein phosphatases pp2a", "protein phosphatases pp2a and", "phosphatases pp2a and pp1", "pp2a and pp1 while", "and pp1 while tim", "pp1 while tim is", "while tim is similarly", "tim is similarly stabilised", "is similarly stabilised by", "similarly stabilised by pp1", "stabilised by pp1 phosphatase.", "pp1 phosphatase. the", "phosphatase. the coordinated", "the coordinated action of", "coordinated action of both", "action of both kinases", "of both kinases and", "both kinases and phosphatases", "and phosphatases during", "phosphatases during this", "during this part of", "this part of the", "part of the day", "the day keep", "day keep per", "keep per at low", "per at low levels", "at low levels and", "low levels and in", "levels and in a", "and in a hypophosphorylated", "in a hypophosphorylated state", "hypophosphorylated state as", "state as hyperphosphorylated", "as hyperphosphorylated per is", "hyperphosphorylated per is removed", "per is removed due", "is removed due to", "removed due to low", "due to low tim", "to low tim levels.

after", "low tim levels.

after dusk", "tim levels.

after dusk during", "levels.

after dusk during the", "dusk during the early", "during the early night", "early night per", "night per and", "tim mrna transcripts reach", "mrna transcripts reach peak", "transcripts reach peak levels.", "peak levels. tim", "levels. tim abundance", "tim abundance begins to", "abundance begins to increase", "begins to increase in", "to increase in the", "increase in the dark", "in the dark and", "the dark and forms", "dark and forms a", "and forms a complex", "forms a complex with", "a complex with per.", "with per. this", "this along with", "along with pp1 phosphatase", "pp1 phosphatase stabilises", "phosphatase stabilises per", "stabilises per despite its", "per despite its continued", "despite its continued phosphorylation", "its continued phosphorylation by", "continued phosphorylation by kinases.", "by kinases. as", "kinases. as a", "as a result per", "a result per and", "result per and tim", "per and tim accumulate", "and tim accumulate to", "tim accumulate to high", "accumulate to high levels", "to high levels during", "high levels during the", "levels during the middle", "during the middle of", "the middle of the", "middle of the night.", "the night. tim", "night. tim is", "tim is then phosphorylated", "is then phosphorylated by", "then phosphorylated by ck2.", "by ck2. per", "ck2. per and", "per and tim dissociate", "tim dissociate per", "per in complex", "in complex with dco", "with dco enters", "dco enters the", "enters the nucleus followed", "the nucleus followed by", "nucleus followed by tim", "by tim a", "tim a few", "a few hours later.", "hours later. once", "later. once in", "once in the nucleus", "in the nucleus per", "the nucleus per and", "nucleus per and tim", "per and tim reform", "and tim reform their", "tim reform their heterodimer", "reform their heterodimer and", "their heterodimer and bind", "heterodimer and bind to", "and bind to the", "bind to the clk:cyc", "to the clk:cyc heterodimer", "clk:cyc heterodimer so", "heterodimer so repressing", "so repressing the transcription", "repressing the transcription of", "the transcription of per", "of per tim", "pdp1. the clk:cyc", "the clk:cyc heterodimer is", "clk:cyc heterodimer is removed", "heterodimer is removed from", "is removed from the", "removed from the e", "from the e boxes", "the e boxes and", "e boxes and sequestered", "boxes and sequestered in", "and sequestered in a", "sequestered in a stable", "in a stable complex", "a stable complex with", "stable complex with per", "complex with per and", "with per and tim", "per and tim to", "and tim to reinforce", "tim to reinforce the", "to reinforce the transcription", "reinforce the transcription inhibition.", "transcription inhibition. in", "inhibition. in addition", "in addition dco", "addition dco bound", "dco bound to per", "bound to per phosphorylates", "to per phosphorylates clk.", "phosphorylates clk. towards", "clk. towards the", "towards the end of", "the end of the", "end of the night", "of the night per", "the night per and", "night per and tim", "per and tim proteins", "and tim proteins are", "tim proteins are at", "proteins are at their", "are at their peak", "at their peak level.

at", "their peak level.

at dawn", "level.

at dawn the", "dawn the introduction", "the introduction of light", "introduction of light recalibrates", "of light recalibrates the", "light recalibrates the circadian", "recalibrates the circadian clock.", "circadian clock. the", "clock. the blue", "the blue light photoreceptor", "blue light photoreceptor cryptochrome", "photoreceptor cryptochrome cry", "cry experiences a", "experiences a light induced", "a light induced conformational", "light induced conformational change", "induced conformational change which", "conformational change which forms", "change which forms a", "which forms a complex", "a complex with hyperphosphorylated", "complex with hyperphosphorylated tim", "hyperphosphorylated tim which", "tim which leads", "which leads to both", "leads to both tim", "to both tim and", "both tim and cry", "tim and cry degradation", "and cry degradation by", "cry degradation by the", "box containing protein jetlag", "protein jetlag jet", "jetlag jet .", "jet . per", ". per and", "and clk hyperphosphorylated", "clk hyperphosphorylated by", "by dco the", "dco the former", "the former no longer", "former no longer protected", "no longer protected by", "longer protected by tim", "by tim are", "tim are also", "are also degraded during", "also degraded during the", "degraded during the early", "during the early morning.", "early morning. per", "morning. per levels", "per levels fall to", "levels fall to their", "fall to their lowest", "to their lowest level", "their lowest level around", "lowest level around midday", "around midday however", "however clk levels", "clk levels remain constant", "levels remain constant since", "remain constant since hypophosphorylated", "constant since hypophosphorylated clk", "since hypophosphorylated clk is", "hypophosphorylated clk is generated", "clk is generated from", "is generated from new", "generated from new clk", "from new clk protein", "new clk protein expression", "clk protein expression or", "protein expression or dephosphorylation", "expression or dephosphorylation of", "or dephosphorylation of hyperphosphorylated", "dephosphorylation of hyperphosphorylated clk", "of hyperphosphorylated clk by", "hyperphosphorylated clk by pp2a", "clk by pp2a protein", "by pp2a protein phosphatase.", "protein phosphatase. hypophosphorylated", "phosphatase. hypophosphorylated clk", "hypophosphorylated clk then forms", "clk then forms a", "then forms a heterodimer", "forms a heterodimer with", "a heterodimer with cyc", "with cyc binds", "cyc binds to", "binds to e boxes", "to e boxes of", "e boxes of its", "boxes of its target", "of its target genes", "its target genes and", "target genes and a", "genes and a new", "and a new cycle", "a new cycle of", "new cycle of per", "and pdp1 transcription is", "pdp1 transcription is initiated.", "is initiated. there", "initiated. there is", "there is an alternate", "is an alternate view", "an alternate view that", "alternate view that clk", "view that clk binds", "that clk binds to", "clk binds to cyc", "binds to cyc then", "to cyc then clk", "cyc then clk is", "then clk is phosphorylated", "clk is phosphorylated in", "is phosphorylated in the", "phosphorylated in the cytosol.", "the cytosol. this", "cytosol. this promotes", "this promotes nuclear entry", "promotes nuclear entry followed", "nuclear entry followed by", "entry followed by further", "followed by further clk", "by further clk phosphorylation.", "clk phosphorylation. however", "however this string", "this string of events", "string of events at", "of events at present", "events at present remain", "at present remain controversial", "present remain controversial and", "remain controversial and are", "controversial and are not", "and are not included", "are not included in", "not included in the", "included in the current", "in the current model.

there", "the current model.

there is", "current model.

there is a", "model.

there is a second", "is a second feedback", "a second feedback loop", "feedback loop the", "loop the clk", "clk loop interlocked", "loop interlocked with", "interlocked with the per/tim", "with the per/tim feedback", "the per/tim feedback loop.", "feedback loop. as", "loop. as mentioned", "mentioned above at", "above at midday", "at midday clk:cyc heterodimers", "midday clk:cyc heterodimers bind", "clk:cyc heterodimers bind to", "heterodimers bind to the", "bind to the e", "to the e boxes", "e boxes and activate", "boxes and activate transcription", "and activate transcription of", "activate transcription of the", "transcription of the target", "of the target genes", "the target genes vri", "target genes vri and", "genes vri and pdp1", "and pdp1 which", "pdp1 which lead", "which lead to the", "lead to the production", "to the production of", "the production of the", "production of the proteins", "of the proteins vrille", "proteins vrille vri", "vri and par", "and par domain protein", "par domain protein 1", "protein 1 pdp1", "respectively. pdp1 activates", "pdp1 activates transcription of", "activates transcription of clk", "transcription of clk and", "of clk and cry", "clk and cry genes", "cry genes while", "genes while vri", "while vri represses it", "represses it by", "it by competitively", "by competitively binding to", "competitively binding to regulatory", "binding to regulatory sequences", "to regulatory sequences called", "regulatory sequences called vri/pdp1", "called vri/pdp1 v/p", "boxes. although vri", "although vri mrna accumulates", "vri mrna accumulates in", "mrna accumulates in phase", "accumulates in phase with", "in phase with per", "phase with per and", "with per and tim", "per and tim mrnas", "tim mrnas pdp1", "mrnas pdp1 accumulation", "pdp1 accumulation is delayed", "accumulation is delayed by", "is delayed by several", "delayed by several hours.", "several hours. in", "hours. in contrast", "in contrast to the", "contrast to the delayed", "to the delayed accumulation", "the delayed accumulation of", "delayed accumulation of per", "accumulation of per and", "of per and tim", "per and tim protein", "and tim protein levels", "protein levels vri", "levels vri protein", "vri protein levels rise", "protein levels rise in", "levels rise in sync", "rise in sync with", "in sync with vri", "sync with vri mrna.", "vri mrna. between", "mrna. between midday", "between midday and dusk", "and dusk vri", "dusk vri levels", "levels rise and", "rise and the", "and the superior vri/pdp1", "the superior vri/pdp1 ratio", "superior vri/pdp1 ratio means", "vri/pdp1 ratio means it", "ratio means it predominantly", "means it predominantly binds", "it predominantly binds to", "predominantly binds to the", "binds to the v/p", "to the v/p boxes", "the v/p boxes to", "v/p boxes to repress", "boxes to repress clk", "to repress clk and", "repress clk and cry", "clk and cry transcription.", "cry transcription. vri", "transcription. vri levels", "vri levels reach their", "levels reach their peak", "reach their peak during", "their peak during the", "peak during the early", "the early night after", "early night after dusk", "night after dusk coinciding", "after dusk coinciding with", "dusk coinciding with minimal", "coinciding with minimal levels", "with minimal levels of", "minimal levels of clk", "levels of clk and", "clk and cry mrnas.", "cry mrnas. however", "however cry protein", "cry protein levels build", "protein levels build slowly", "levels build slowly as", "build slowly as it", "slowly as it is", "as it is relatively", "it is relatively stable", "is relatively stable in", "relatively stable in the", "stable in the dark.

pdp1", "in the dark.

pdp1 levels", "the dark.

pdp1 levels reach", "dark.

pdp1 levels reach their", "reach their peak between", "their peak between mid", "peak between mid to", "between mid to late", "mid to late night.", "late night. vri", "night. vri levels", "vri levels decline during", "levels decline during this", "decline during this time", "during this time due", "this time due to", "time due to tim:per", "due to tim:per influenced", "to tim:per influenced repression", "tim:per influenced repression of", "influenced repression of vri", "repression of vri transcription.", "vri transcription. the", "transcription. the decreasing", "the decreasing ratio of", "decreasing ratio of vri/pdp1", "ratio of vri/pdp1 levels", "of vri/pdp1 levels favours", "vri/pdp1 levels favours binding", "levels favours binding of", "favours binding of pdp1", "binding of pdp1 to", "of pdp1 to the", "pdp1 to the v/p", "the v/p boxes resulting", "v/p boxes resulting in", "boxes resulting in activation", "resulting in activation of", "in activation of clk", "activation of clk and", "cry transcription. pdp1", "transcription. pdp1 protein", "pdp1 protein levels start", "protein levels start to", "levels start to decline", "start to decline during", "to decline during the", "decline during the late", "during the late night", "the late night and", "late night and are", "night and are low", "and are low by", "are low by the", "low by the early", "by the early morning.", "early morning. however", "however despite this", "despite this pdp1", "this pdp1 continues", "pdp1 continues to activate", "continues to activate clk", "to activate clk and", "activate clk and cry", "clk and cry transcription", "and cry transcription until", "cry transcription until midday", "transcription until midday when", "until midday when vri", "midday when vri protein", "when vri protein levels", "vri protein levels are", "protein levels are sufficient", "are sufficient after", "sufficient after the", "after the next cycle", "the next cycle of", "next cycle of clk:cyc", "cycle of clk:cyc mediated", "of clk:cyc mediated transcription", "mediated transcription to", "transcription to take", "to take over the", "take over the binding", "over the binding of", "the binding of the", "binding of the v/p", "of the v/p boxes", "the v/p boxes and", "v/p boxes and repress", "boxes and repress transcription.

recently", "repress transcription.

recently clk:cyc", "transcription.

recently clk:cyc transcription", "clk:cyc transcription of some", "transcription of some new", "of some new target", "some new target genes", "new target genes and", "target genes and their", "genes and their associated", "and their associated feedback", "their associated feedback loops", "associated feedback loops have", "feedback loops have come", "loops have come to", "have come to light", "come to light such", "to light such as", "light such as the", "such as the cwo", "as the cwo gene", "the cwo gene and", "cwo gene and its", "gene and its protein", "and its protein product", "its protein product clockwork", "protein product clockwork orange", "clockwork orange cwo", "orange cwo .", "cwo . however", "however there is", "there is confusion as", "is confusion as to", "confusion as to whether", "as to whether cwo", "whether cwo which", "cwo which binds", "which binds to the", "binds to the e", "the e boxes of", "e boxes of per", "and pdp1 activates or", "pdp1 activates or represses", "activates or represses their", "or represses their transcription.", "their transcription. there", "transcription. there are", "there are likely to", "are likely to be", "likely to be many", "to be many more", "be many more of", "many more of these", "more of these secondary", "of these secondary transcription", "these secondary transcription loops", "secondary transcription loops connected", "transcription loops connected to", "loops connected to the", "connected to the core", "to the core clock", "the core clock mechanism", "core clock mechanism to", "clock mechanism to add", "mechanism to add yet", "to add yet more", "add yet more modes", "yet more modes of", "more modes of regulation.", "the drosophila molecular circadian clock", "drosophila molecular circadian clock consists", "molecular circadian clock consists of", "circadian clock consists of two", "clock consists of two main", "consists of two main interlocked", "of two main interlocked sets", "two main interlocked sets of", "main interlocked sets of transcription/translation", "interlocked sets of transcription/translation feedback", "sets of transcription/translation feedback loops.", "transcription/translation feedback loops. these", "feedback loops. these both", "loops. these both contain", "these both contain protein and", "both contain protein and mrna", "contain protein and mrna components", "protein and mrna components that", "and mrna components that cycle", "mrna components that cycle in", "components that cycle in abundance", "that cycle in abundance and", "cycle in abundance and subcellular", "in abundance and subcellular localisation", "abundance and subcellular localisation with", "and subcellular localisation with a", "subcellular localisation with a near", "localisation with a near 24", "with a near 24 hour", "a near 24 hour period.", "24 hour period. within", "hour period. within the", "period. within the core", "within the core components of", "the core components of the", "core components of the clock", "components of the clock pathway", "the clock pathway both", "clock pathway both loops", "pathway both loops drive", "both loops drive rhythmic transcription", "loops drive rhythmic transcription in", "drive rhythmic transcription in the", "rhythmic transcription in the opposite", "transcription in the opposite phase", "in the opposite phase to", "the opposite phase to each", "opposite phase to each other.

the", "phase to each other.

the pathways", "to each other.

the pathways shown", "each other.

the pathways shown below", "other.

the pathways shown below are", "pathways shown below are most", "shown below are most representative", "below are most representative of", "are most representative of those", "most representative of those occurring", "representative of those occurring in", "of those occurring in key", "those occurring in key clock", "occurring in key clock neurons", "in key clock neurons within", "key clock neurons within the", "clock neurons within the brains", "neurons within the brains of", "within the brains of adult", "the brains of adult flies", "brains of adult flies kept", "of adult flies kept under", "adult flies kept under standard", "flies kept under standard 12", "kept under standard 12 hour", "under standard 12 hour light:12", "standard 12 hour light:12 hour", "12 hour light:12 hour dark", "hour light:12 hour dark cycles", "light:12 hour dark cycles at", "hour dark cycles at 25°", "dark cycles at 25° c.", "at 25° c. differences", "25° c. differences in", "c. differences in one", "differences in one or more", "in one or more of", "one or more of the", "or more of the biochemical", "more of the biochemical steps", "of the biochemical steps shown", "the biochemical steps shown here", "biochemical steps shown here and/or", "steps shown here and/or reactions", "shown here and/or reactions not", "here and/or reactions not shown", "and/or reactions not shown here", "reactions not shown here can", "not shown here can occur", "shown here can occur in", "here can occur in different", "can occur in different brain", "occur in different brain clock", "in different brain clock neurons", "brain clock neurons about", "clock neurons about 150", "neurons about 150 total", "about 150 total cells per", "150 total cells per adult", "total cells per adult brain", "per adult brain and", "adult brain and within", "brain and within the", "and within the same clock", "within the same clock cells", "the same clock cells as", "same clock cells as a", "clock cells as a function", "cells as a function of", "as a function of changes", "a function of changes in", "function of changes in environmental", "of changes in environmental conditions", "in environmental conditions such", "environmental conditions such as", "conditions such as day", "such as day length or", "as day length or temperature.

starting", "day length or temperature.

starting from", "length or temperature.

starting from midday", "or temperature.

starting from midday and", "temperature.

starting from midday and continuing", "from midday and continuing through", "midday and continuing through to", "and continuing through to early", "continuing through to early night", "to early night the", "early night the per/tim", "night the per/tim feedback", "the per/tim feedback loop is", "per/tim feedback loop is initiated", "feedback loop is initiated when", "loop is initiated when the", "is initiated when the basic", "initiated when the basic helix", "when the basic helix loop", "the basic helix loop helix/pas", "helix loop helix/pas per", "loop helix/pas per arnt", "helix/pas per arnt sim", "per arnt sim domain", "arnt sim domain transcription", "sim domain transcription factors", "domain transcription factors clock", "factors clock clk", "clock clk and", "cyc form heterodimers", "form heterodimers and bind e", "heterodimers and bind e box", "and bind e box regulatory", "bind e box regulatory elements", "e box regulatory elements to", "box regulatory elements to activate", "regulatory elements to activate transcription", "elements to activate transcription of", "to activate transcription of target", "activate transcription of target genes", "transcription of target genes per", "target genes per tim", "per tim vri", "tim vri and", "and pdp1. the levels", "pdp1. the levels of", "the levels of per and", "levels of per and tim", "of per and tim mrna", "per and tim mrna transcripts", "and tim mrna transcripts peak", "tim mrna transcripts peak early", "mrna transcripts peak early in", "transcripts peak early in the", "peak early in the night", "in the night whereas", "the night whereas period", "period per and", "timeless tim proteins", "tim proteins do not", "proteins do not reach peak", "do not reach peak abundance", "not reach peak abundance levels", "reach peak abundance levels until", "peak abundance levels until mid", "abundance levels until mid to", "levels until mid to late", "until mid to late evening.", "to late evening. tim", "late evening. tim stays", "evening. tim stays at", "tim stays at low levels", "stays at low levels at", "at low levels at this", "low levels at this point", "levels at this point because", "at this point because it", "this point because it is", "point because it is destabilised", "because it is destabilised by", "it is destabilised by light.", "destabilised by light. per", "by light. per is", "light. per is phosphorylated", "per is phosphorylated by discs", "is phosphorylated by discs overgrown", "by discs overgrown dco", "overgrown dco kinase", "dco kinase aka double", "aka double time dbt", "time dbt and", "dbt and casein kinase", "casein kinase ii ck2", "kinase ii ck2 .", "ck2 . without tim", "without tim which stabilises", "tim which stabilises it", "which stabilises it per", "stabilises it per is", "it per is targeted", "per is targeted for degradation", "is targeted for degradation by", "targeted for degradation by the", "for degradation by the 26s", "degradation by the 26s proteasome", "by the 26s proteasome via", "the 26s proteasome via an", "26s proteasome via an interaction", "proteasome via an interaction with", "via an interaction with the", "an interaction with the f", "interaction with the f box", "with the f box containing", "the f box containing protein", "box containing protein supernumerary", "containing protein supernumerary limbs", "supernumerary limbs slmb .", "slmb . in addition", "in addition per is", "addition per is stabilised", "per is stabilised by the", "is stabilised by the protein", "stabilised by the protein phosphatases", "by the protein phosphatases pp2a", "the protein phosphatases pp2a and", "protein phosphatases pp2a and pp1", "phosphatases pp2a and pp1 while", "pp2a and pp1 while tim", "and pp1 while tim is", "pp1 while tim is similarly", "while tim is similarly stabilised", "tim is similarly stabilised by", "is similarly stabilised by pp1", "similarly stabilised by pp1 phosphatase.", "by pp1 phosphatase. the", "pp1 phosphatase. the coordinated", "phosphatase. the coordinated action", "the coordinated action of both", "coordinated action of both kinases", "action of both kinases and", "of both kinases and phosphatases", "kinases and phosphatases during", "and phosphatases during this", "phosphatases during this part", "during this part of the", "this part of the day", "of the day keep", "the day keep per", "day keep per at", "keep per at low levels", "per at low levels and", "at low levels and in", "low levels and in a", "levels and in a hypophosphorylated", "and in a hypophosphorylated state", "a hypophosphorylated state as", "hypophosphorylated state as hyperphosphorylated", "state as hyperphosphorylated per", "as hyperphosphorylated per is removed", "hyperphosphorylated per is removed due", "per is removed due to", "is removed due to low", "removed due to low tim", "due to low tim levels.

after", "to low tim levels.

after dusk", "low tim levels.

after dusk during", "tim levels.

after dusk during the", "levels.

after dusk during the early", "dusk during the early night", "the early night per", "early night per and", "night per and tim", "and tim mrna transcripts reach", "tim mrna transcripts reach peak", "mrna transcripts reach peak levels.", "reach peak levels. tim", "peak levels. tim abundance", "levels. tim abundance begins", "tim abundance begins to increase", "abundance begins to increase in", "begins to increase in the", "to increase in the dark", "increase in the dark and", "in the dark and forms", "the dark and forms a", "dark and forms a complex", "and forms a complex with", "forms a complex with per.", "complex with per. this", "per. this along", "this along with pp1", "with pp1 phosphatase stabilises", "pp1 phosphatase stabilises per", "phosphatase stabilises per despite", "stabilises per despite its continued", "per despite its continued phosphorylation", "despite its continued phosphorylation by", "its continued phosphorylation by kinases.", "phosphorylation by kinases. as", "by kinases. as a", "kinases. as a result", "as a result per and", "a result per and tim", "result per and tim accumulate", "per and tim accumulate to", "and tim accumulate to high", "tim accumulate to high levels", "accumulate to high levels during", "to high levels during the", "high levels during the middle", "levels during the middle of", "during the middle of the", "the middle of the night.", "of the night. tim", "the night. tim is", "night. tim is then", "tim is then phosphorylated by", "is then phosphorylated by ck2.", "phosphorylated by ck2. per", "by ck2. per and", "ck2. per and tim", "and tim dissociate per", "dissociate per in", "per in complex with", "complex with dco enters", "with dco enters the", "dco enters the nucleus", "enters the nucleus followed by", "the nucleus followed by tim", "followed by tim a", "by tim a few", "tim a few hours", "few hours later. once", "hours later. once in", "later. once in the", "once in the nucleus per", "in the nucleus per and", "the nucleus per and tim", "nucleus per and tim reform", "per and tim reform their", "and tim reform their heterodimer", "tim reform their heterodimer and", "reform their heterodimer and bind", "their heterodimer and bind to", "heterodimer and bind to the", "and bind to the clk:cyc", "bind to the clk:cyc heterodimer", "the clk:cyc heterodimer so", "clk:cyc heterodimer so repressing", "heterodimer so repressing the", "so repressing the transcription of", "repressing the transcription of per", "transcription of per tim", "and pdp1. the clk:cyc", "pdp1. the clk:cyc heterodimer", "the clk:cyc heterodimer is removed", "clk:cyc heterodimer is removed from", "heterodimer is removed from the", "is removed from the e", "removed from the e boxes", "from the e boxes and", "the e boxes and sequestered", "e boxes and sequestered in", "boxes and sequestered in a", "and sequestered in a stable", "sequestered in a stable complex", "in a stable complex with", "a stable complex with per", "stable complex with per and", "complex with per and tim", "with per and tim to", "per and tim to reinforce", "and tim to reinforce the", "tim to reinforce the transcription", "to reinforce the transcription inhibition.", "the transcription inhibition. in", "transcription inhibition. in addition", "in addition dco bound", "addition dco bound to", "dco bound to per phosphorylates", "bound to per phosphorylates clk.", "per phosphorylates clk. towards", "phosphorylates clk. towards the", "clk. towards the end", "towards the end of the", "the end of the night", "end of the night per", "of the night per and", "the night per and tim", "night per and tim proteins", "per and tim proteins are", "and tim proteins are at", "tim proteins are at their", "proteins are at their peak", "are at their peak level.

at", "at their peak level.

at dawn", "peak level.

at dawn the", "level.

at dawn the introduction", "dawn the introduction of", "the introduction of light recalibrates", "introduction of light recalibrates the", "of light recalibrates the circadian", "light recalibrates the circadian clock.", "the circadian clock. the", "circadian clock. the blue", "clock. the blue light", "the blue light photoreceptor cryptochrome", "light photoreceptor cryptochrome cry", "cryptochrome cry experiences", "cry experiences a light", "experiences a light induced conformational", "a light induced conformational change", "light induced conformational change which", "induced conformational change which forms", "conformational change which forms a", "change which forms a complex", "which forms a complex with", "forms a complex with hyperphosphorylated", "a complex with hyperphosphorylated tim", "with hyperphosphorylated tim which", "hyperphosphorylated tim which leads", "tim which leads to", "which leads to both tim", "leads to both tim and", "to both tim and cry", "both tim and cry degradation", "tim and cry degradation by", "and cry degradation by the", "cry degradation by the 26s", "f box containing protein jetlag", "containing protein jetlag jet", "protein jetlag jet .", "jet . per and", ". per and clk", "per and clk hyperphosphorylated", "and clk hyperphosphorylated by", "clk hyperphosphorylated by dco", "hyperphosphorylated by dco the", "by dco the former", "dco the former no", "the former no longer protected", "former no longer protected by", "no longer protected by tim", "protected by tim are", "by tim are also", "tim are also degraded", "are also degraded during the", "also degraded during the early", "degraded during the early morning.", "the early morning. per", "early morning. per levels", "morning. per levels fall", "per levels fall to their", "levels fall to their lowest", "fall to their lowest level", "to their lowest level around", "their lowest level around midday", "level around midday however", "midday however clk", "however clk levels remain", "clk levels remain constant since", "levels remain constant since hypophosphorylated", "remain constant since hypophosphorylated clk", "constant since hypophosphorylated clk is", "since hypophosphorylated clk is generated", "hypophosphorylated clk is generated from", "clk is generated from new", "is generated from new clk", "generated from new clk protein", "from new clk protein expression", "new clk protein expression or", "clk protein expression or dephosphorylation", "protein expression or dephosphorylation of", "expression or dephosphorylation of hyperphosphorylated", "or dephosphorylation of hyperphosphorylated clk", "dephosphorylation of hyperphosphorylated clk by", "of hyperphosphorylated clk by pp2a", "hyperphosphorylated clk by pp2a protein", "clk by pp2a protein phosphatase.", "pp2a protein phosphatase. hypophosphorylated", "protein phosphatase. hypophosphorylated clk", "phosphatase. hypophosphorylated clk then", "hypophosphorylated clk then forms a", "clk then forms a heterodimer", "then forms a heterodimer with", "forms a heterodimer with cyc", "heterodimer with cyc binds", "with cyc binds to", "cyc binds to e", "binds to e boxes of", "to e boxes of its", "e boxes of its target", "boxes of its target genes", "of its target genes and", "its target genes and a", "target genes and a new", "genes and a new cycle", "and a new cycle of", "a new cycle of per", "cycle of per tim", "vri and pdp1 transcription", "and pdp1 transcription is initiated.", "transcription is initiated. there", "is initiated. there is", "initiated. there is an", "there is an alternate view", "is an alternate view that", "an alternate view that clk", "alternate view that clk binds", "view that clk binds to", "that clk binds to cyc", "clk binds to cyc then", "binds to cyc then clk", "to cyc then clk is", "cyc then clk is phosphorylated", "then clk is phosphorylated in", "clk is phosphorylated in the", "is phosphorylated in the cytosol.", "in the cytosol. this", "the cytosol. this promotes", "cytosol. this promotes nuclear", "this promotes nuclear entry followed", "promotes nuclear entry followed by", "nuclear entry followed by further", "entry followed by further clk", "followed by further clk phosphorylation.", "further clk phosphorylation. however", "phosphorylation. however this", "however this string of", "this string of events at", "string of events at present", "of events at present remain", "events at present remain controversial", "at present remain controversial and", "present remain controversial and are", "remain controversial and are not", "controversial and are not included", "and are not included in", "are not included in the", "not included in the current", "included in the current model.

there", "in the current model.

there is", "the current model.

there is a", "current model.

there is a second", "model.

there is a second feedback", "is a second feedback loop", "second feedback loop the", "feedback loop the clk", "loop the clk loop", "the clk loop interlocked", "clk loop interlocked with", "loop interlocked with the", "interlocked with the per/tim feedback", "with the per/tim feedback loop.", "per/tim feedback loop. as", "feedback loop. as mentioned", "loop. as mentioned above", "as mentioned above at", "mentioned above at midday", "above at midday clk:cyc", "at midday clk:cyc heterodimers bind", "midday clk:cyc heterodimers bind to", "clk:cyc heterodimers bind to the", "heterodimers bind to the e", "bind to the e boxes", "to the e boxes and", "the e boxes and activate", "e boxes and activate transcription", "boxes and activate transcription of", "and activate transcription of the", "activate transcription of the target", "transcription of the target genes", "of the target genes vri", "the target genes vri and", "target genes vri and pdp1", "vri and pdp1 which", "and pdp1 which lead", "pdp1 which lead to", "which lead to the production", "lead to the production of", "to the production of the", "the production of the proteins", "production of the proteins vrille", "the proteins vrille vri", "vrille vri and", "vri and par domain", "and par domain protein 1", "domain protein 1 pdp1", "1 pdp1 respectively.", "pdp1 respectively. pdp1", "respectively. pdp1 activates transcription", "pdp1 activates transcription of clk", "activates transcription of clk and", "transcription of clk and cry", "of clk and cry genes", "and cry genes while", "cry genes while vri", "genes while vri represses", "vri represses it by", "represses it by competitively", "it by competitively binding", "by competitively binding to regulatory", "competitively binding to regulatory sequences", "binding to regulatory sequences called", "to regulatory sequences called vri/pdp1", "sequences called vri/pdp1 v/p", "vri/pdp1 v/p boxes.", "v/p boxes. although", "boxes. although vri mrna", "although vri mrna accumulates in", "vri mrna accumulates in phase", "mrna accumulates in phase with", "accumulates in phase with per", "in phase with per and", "phase with per and tim", "with per and tim mrnas", "and tim mrnas pdp1", "tim mrnas pdp1 accumulation", "mrnas pdp1 accumulation is", "pdp1 accumulation is delayed by", "accumulation is delayed by several", "is delayed by several hours.", "by several hours. in", "several hours. in contrast", "hours. in contrast to", "in contrast to the delayed", "contrast to the delayed accumulation", "to the delayed accumulation of", "the delayed accumulation of per", "delayed accumulation of per and", "accumulation of per and tim", "of per and tim protein", "per and tim protein levels", "tim protein levels vri", "protein levels vri protein", "levels vri protein levels", "vri protein levels rise in", "protein levels rise in sync", "levels rise in sync with", "rise in sync with vri", "in sync with vri mrna.", "with vri mrna. between", "vri mrna. between midday", "mrna. between midday and", "midday and dusk vri", "and dusk vri levels", "dusk vri levels rise", "vri levels rise and", "levels rise and the", "rise and the superior", "and the superior vri/pdp1 ratio", "the superior vri/pdp1 ratio means", "superior vri/pdp1 ratio means it", "vri/pdp1 ratio means it predominantly", "ratio means it predominantly binds", "means it predominantly binds to", "it predominantly binds to the", "predominantly binds to the v/p", "binds to the v/p boxes", "to the v/p boxes to", "the v/p boxes to repress", "v/p boxes to repress clk", "boxes to repress clk and", "to repress clk and cry", "repress clk and cry transcription.", "and cry transcription. vri", "cry transcription. vri levels", "transcription. vri levels reach", "vri levels reach their peak", "levels reach their peak during", "reach their peak during the", "their peak during the early", "peak during the early night", "during the early night after", "the early night after dusk", "early night after dusk coinciding", "night after dusk coinciding with", "after dusk coinciding with minimal", "dusk coinciding with minimal levels", "coinciding with minimal levels of", "with minimal levels of clk", "minimal levels of clk and", "levels of clk and cry", "of clk and cry mrnas.", "and cry mrnas. however", "mrnas. however cry", "however cry protein levels", "cry protein levels build slowly", "protein levels build slowly as", "levels build slowly as it", "build slowly as it is", "slowly as it is relatively", "as it is relatively stable", "it is relatively stable in", "is relatively stable in the", "relatively stable in the dark.

pdp1", "stable in the dark.

pdp1 levels", "in the dark.

pdp1 levels reach", "the dark.

pdp1 levels reach their", "dark.

pdp1 levels reach their peak", "levels reach their peak between", "reach their peak between mid", "their peak between mid to", "peak between mid to late", "between mid to late night.", "to late night. vri", "late night. vri levels", "night. vri levels decline", "vri levels decline during this", "levels decline during this time", "decline during this time due", "during this time due to", "this time due to tim:per", "time due to tim:per influenced", "due to tim:per influenced repression", "to tim:per influenced repression of", "tim:per influenced repression of vri", "influenced repression of vri transcription.", "of vri transcription. the", "vri transcription. the decreasing", "transcription. the decreasing ratio", "the decreasing ratio of vri/pdp1", "decreasing ratio of vri/pdp1 levels", "ratio of vri/pdp1 levels favours", "of vri/pdp1 levels favours binding", "vri/pdp1 levels favours binding of", "levels favours binding of pdp1", "favours binding of pdp1 to", "binding of pdp1 to the", "of pdp1 to the v/p", "pdp1 to the v/p boxes", "to the v/p boxes resulting", "the v/p boxes resulting in", "v/p boxes resulting in activation", "boxes resulting in activation of", "resulting in activation of clk", "in activation of clk and", "activation of clk and cry", "of clk and cry transcription.", "and cry transcription. pdp1", "cry transcription. pdp1 protein", "transcription. pdp1 protein levels", "pdp1 protein levels start to", "protein levels start to decline", "levels start to decline during", "start to decline during the", "to decline during the late", "decline during the late night", "during the late night and", "the late night and are", "late night and are low", "night and are low by", "and are low by the", "are low by the early", "low by the early morning.", "the early morning. however", "morning. however despite", "despite this pdp1 continues", "this pdp1 continues to", "pdp1 continues to activate clk", "continues to activate clk and", "to activate clk and cry", "activate clk and cry transcription", "clk and cry transcription until", "and cry transcription until midday", "cry transcription until midday when", "transcription until midday when vri", "until midday when vri protein", "midday when vri protein levels", "when vri protein levels are", "vri protein levels are sufficient", "levels are sufficient after", "are sufficient after the", "sufficient after the next", "after the next cycle of", "the next cycle of clk:cyc", "next cycle of clk:cyc mediated", "cycle of clk:cyc mediated transcription", "clk:cyc mediated transcription to", "mediated transcription to take", "transcription to take over", "to take over the binding", "take over the binding of", "over the binding of the", "the binding of the v/p", "binding of the v/p boxes", "of the v/p boxes and", "the v/p boxes and repress", "v/p boxes and repress transcription.

recently", "and repress transcription.

recently clk:cyc", "repress transcription.

recently clk:cyc transcription", "transcription.

recently clk:cyc transcription of", "clk:cyc transcription of some new", "transcription of some new target", "of some new target genes", "some new target genes and", "new target genes and their", "target genes and their associated", "genes and their associated feedback", "and their associated feedback loops", "their associated feedback loops have", "associated feedback loops have come", "feedback loops have come to", "loops have come to light", "have come to light such", "come to light such as", "to light such as the", "light such as the cwo", "such as the cwo gene", "as the cwo gene and", "the cwo gene and its", "cwo gene and its protein", "gene and its protein product", "and its protein product clockwork", "its protein product clockwork orange", "product clockwork orange cwo", "clockwork orange cwo .", ". however there", "however there is confusion", "there is confusion as to", "is confusion as to whether", "confusion as to whether cwo", "to whether cwo which", "whether cwo which binds", "cwo which binds to", "which binds to the e", "binds to the e boxes", "to the e boxes of", "the e boxes of per", "boxes of per tim", "vri and pdp1 activates", "and pdp1 activates or represses", "pdp1 activates or represses their", "activates or represses their transcription.", "represses their transcription. there", "their transcription. there are", "transcription. there are likely", "there are likely to be", "are likely to be many", "likely to be many more", "to be many more of", "be many more of these", "many more of these secondary", "more of these secondary transcription", "of these secondary transcription loops", "these secondary transcription loops connected", "secondary transcription loops connected to", "transcription loops connected to the", "loops connected to the core", "connected to the core clock", "to the core clock mechanism", "the core clock mechanism to", "core clock mechanism to add", "clock mechanism to add yet", "mechanism to add yet more", "to add yet more modes", "add yet more modes of", "yet more modes of regulation." ] }, { "record_id": "GLY_000690_1_404", "filename": "fruitfly_protein_pathways_reactome", "fieldtype": "id", "phraselist": [ "gly_000690", "dme", "432722", "r dme", "dme 432722", "r dme 432722" ] }, { "record_id": "GLY_000690_1_404", "filename": "fruitfly_protein_pathways_reactome", "fieldtype": "text", "phraselist": [ "golgi associated", "associated vesicle", "vesicle biogenesis", "golgi associated vesicle", "associated vesicle biogenesis", "golgi associated vesicle biogenesis", "this event", "event has", "has been", "been computationally", "computationally inferred", "inferred from", "from an", "an event", "event that", "that has", "been demonstrated", "demonstrated in", "in another", "another species.

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