{"gene":"TAC1","run_date":"2026-04-28T21:42:58","timeline":{"discoveries":[{"year":2003,"finding":"C. elegans TAC-1 (TACC family protein) physically interacts with ZYG-9 (XMAP215 family MAP), and this complex promotes microtubule assembly; mutual stabilization between the two proteins is required for proper microtubule growth in vivo. TAC-1 localizes to centrosomes in a cell-cycle-dependent manner requiring gamma-tubulin and Aurora-A kinase AIR-1 activity.","method":"Co-immunoprecipitation, in vitro pulldown, FRAP-based in vivo microtubule assembly assay, RNAi loss-of-function, live imaging of GFP-TAC-1","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 1–2 — reciprocal Co-IP, in vitro pulldown, in vivo FRAP, and genetic epistasis; independently replicated in three simultaneous papers (PMIDs 12956950, 12956951, 12956952)","pmids":["12956950","12956951","12956952"],"is_preprint":false},{"year":2003,"finding":"Loss of C. elegans TAC-1 by RNAi results in very short centrosomal microtubules and short spindles, establishing TAC-1 as a major regulator of microtubule length; TAC-1 enrichment at centrosomes is dependent on Aurora kinase AIR-1 and the two proteins (TAC-1 and ZYG-9) are mutually required for centrosomal localization.","method":"Genome-wide RNAi screen, immunofluorescence, genetic epistasis","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 — clean RNAi KD with defined cellular phenotype, replicated across three independent studies","pmids":["12956951","12956950","12956952"],"is_preprint":false},{"year":2007,"finding":"In C. elegans embryos, TAC-1 physically interacts with ZYG-8 (doublecortin domain protein) through ZYG-8's doublecortin domain, forming a complex in vivo that does not contain ZYG-9; ZYG-9–TAC-1 and ZYG-8 function partially redundantly to ensure correct microtubule assembly throughout the cell cycle, including anaphase spindle positioning.","method":"Co-immunoprecipitation, temperature-sensitive allele analysis, genetic epistasis, live imaging","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1–2 — reciprocal Co-IP identifying novel TAC-1/ZYG-8 interaction, combined with genetic epistasis and defined phenotypic readouts","pmids":["17666432"],"is_preprint":false},{"year":2002,"finding":"Targeted deletion of the mouse Tac1 gene (encoding substance P and neurokinin A) reduces anxiety- and depression-related behaviors, demonstrating that tachykinins encoded by Tac1 are functional mediators of emotional behavior in mammals.","method":"Tac1 knockout mouse, multiple behavioral paradigms (forced-swim, tail-suspension, elevated zero-maze, open field, social interaction)","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined behavioral phenotypes across multiple orthogonal behavioral assays","pmids":["12427862"],"is_preprint":false},{"year":2009,"finding":"REST (RE-1 silencing transcription factor) binds directly to the TAC1 promoter 5' UTR and suppresses TAC1 expression in breast cancer cells; REST expression is inversely proportional to cellular aggressiveness, and REST knockdown increases TAC1-driven proliferation and migration.","method":"Western blot, real-time PCR, REST knockdown/overexpression, reporter gene assays, chromatin immunoprecipitation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (ChIP, reporter assay, KD/OE) in same study establishing direct transcriptional repression mechanism","pmids":["19246391"],"is_preprint":false},{"year":2007,"finding":"REST and NF-κB synergistically repress TAC1 transcription in human mesenchymal stem cells; both transcription factors bind within exon 1 / 5'-flanking region of TAC1, and their co-occupancy is required for repression under both IL-1α stimulation and neuronal induction conditions.","method":"Chromatin immunoprecipitation, site-directed mutagenesis, loss-of-function transfection studies, reporter gene assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — ChIP, mutagenesis, and loss-of-function in same study; mechanistic dissection of cooperative repression","pmids":["17709376"],"is_preprint":false},{"year":2008,"finding":"In Candida albicans, TAC1 is a transcriptional regulator of drug efflux pumps CDR1 and CDR2; hyperactive TAC1 alleles increase azole resistance in a gene copy number-dependent manner, contributing independently and additively to fluconazole resistance when amplified on isochromosome i(5L) together with ERG11.","method":"Comparative genome hybridization, gene deletion, telomere-mediated truncations, in vitro fluconazole susceptibility assays","journal":"Molecular microbiology","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis by deletion and copy-number manipulation with defined drug-resistance phenotype, multiple orthogonal approaches","pmids":["18363649"],"is_preprint":false},{"year":2017,"finding":"The C-terminal transcriptional activation domain (TAD) of C. albicans Tac1 is necessary for CDR1 activation; negative regulation of this TAD by the Tac1 middle region is required for gain-of-function (GOF) mutations or xenobiotics to hyperactivate Tac1. Hyperactivated Tac1 recruits the Mediator coactivator complex (specifically the tail module) to the CDR1 promoter, and azole resistance is dependent on Mediator tail subunits. Tac1 hyperactivation correlates with its Mediator-dependent phosphorylation.","method":"Domain deletion/mutagenesis, chromatin immunoprecipitation, reporter gene assays, drug susceptibility testing","journal":"Antimicrobial agents and chemotherapy","confidence":"High","confidence_rationale":"Tier 1–2 — mutagenesis combined with ChIP demonstrating Mediator recruitment; mechanistic dissection of TAD and middle-region regulation","pmids":["28807920"],"is_preprint":false},{"year":2018,"finding":"C. albicans Tac1 is functionally activated by farnesol (and 1-dodecanol) through a mechanism mimicking other means of Zn cluster transcription factor hyperactivation; Tac1 and Znc1 both bind the CDR1 promoter and upregulate CDR1 in response to farnesol, and CDR1 expression subsequently mediates farnesol efflux.","method":"Reporter gene assays, ChIP, drug susceptibility assays, TAC1/ZNC1 deletion strains","journal":"Antimicrobial agents and chemotherapy","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and genetic deletion with defined molecular phenotype; single lab study","pmids":["30104273"],"is_preprint":false},{"year":2023,"finding":"Molecular dissection of C. albicans Tac1p shows: (1) the N-terminal DNA-binding domain (DBD) interacts with the Drug Responsive Element (DRE) in CDR1/CDR2 promoters; (2) the C-terminal Acidic Activation Domain (AAD) interacts with TATA-binding protein (TBP) to recruit it to TATA boxes of CDR genes; (3) the Middle Homology Region (MHR) acts as a xenobiotic binding domain (XBD).","method":"Domain deletion analysis, reporter gene assays, protein–protein interaction studies (DBD–DRE binding, AAD–TBP interaction)","journal":"Frontiers in microbiology","confidence":"Medium","confidence_rationale":"Tier 2 — domain-level functional dissection with in vitro interaction assays; single lab, moderate evidence","pmids":["37502396"],"is_preprint":false},{"year":2011,"finding":"The TAC1 promoter in sensory neurons requires synergistic interaction with a remote enhancer (ECR2) identified by comparative genomics to respond to MEK/ERK (MAPK) signaling; MEK pathway antagonism strongly blocks noxious stimulation-induced TAC1 upregulation in large-diameter sensory neurons.","method":"Comparative genomics, primary cell culture reporter assays, mouse transgenics, pharmacological MEK inhibition","journal":"Neuro-Signals","confidence":"Medium","confidence_rationale":"Tier 2 — transgenic mouse reporter and pharmacological inhibition demonstrate enhancer–promoter synergy; moderate evidence from single lab","pmids":["21160161"],"is_preprint":false},{"year":2011,"finding":"TAC1 promoter regulatory diversity in sensory neurons includes: (1) an autocrine loop via NK1 receptor activation of SP-expressing cells; (2) ECR2-dependent regulation by capsaicin/TRPV1 and potassium depolarization; (3) ECR2-independent LPS induction in a distinct neuronal population.","method":"Primary sensory neuron culture, reporter gene assays, pharmacological NK1 agonism, capsaicin treatment, live imaging","journal":"Journal of neuroinflammation","confidence":"Medium","confidence_rationale":"Tier 3 — reporter assay and pharmacology in primary culture; single lab, multiple readouts","pmids":["21294877"],"is_preprint":false},{"year":2007,"finding":"SDF-1α regulates Tac1 expression in bone marrow stromal cells via NF-κB: high SDF-1α (50–100 ng/mL) activates NF-κB through PI3K–PDK1–AKT signaling to repress Tac1, while low SDF-1α stimulates Tac1 expression; Tac1-derived substance P then promotes hematopoiesis through NK1 (not NK2) receptor.","method":"Reporter gene assays with mutant IκB, gel shift assays, Northern analysis, ELISA, long-term culture-initiating cell assays","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (reporter, EMSA, functional assay); single lab","pmids":["17277111"],"is_preprint":false},{"year":2008,"finding":"SDF-1α activates Tac1 in nontumorigenic breast cells via a non-canonical pathway: Gαi2–PI3K–PKCζ–p38–ERK–CREB (not cAMP–PKA), acting through CRE sites in the TAC1 promoter.","method":"Reporter gene assays with mutant CRE sites, co-transfection with ICER repressor, Western blot with specific kinase inhibitors","journal":"Journal of molecular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 — mutagenesis of CRE sites and pharmacological pathway dissection; single lab","pmids":["18316470"],"is_preprint":false},{"year":2011,"finding":"During MSC-to-neuron differentiation, TAC1 induction proceeds through sequential activation of CRE1 (day 6) and CRE2/AP-1 (day 12) sites: decreased REST activates JNK, which phosphorylates ATF-2 (binding CRE1) and AP-1 (binding CRE2/AP-1).","method":"Reporter gene assays with mutant CRE sites, ectopic REST expression, PKA and JNK pharmacological inhibitors, chromatin immunoprecipitation","journal":"Stem cells and development","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and mutagenesis combined with pathway inhibitors; single lab","pmids":["21671725"],"is_preprint":false},{"year":2007,"finding":"Post-transcriptional regulation of Tac1 in bone marrow stroma involves RNA-binding proteins and miRNAs targeting the Tac1 3' UTR; cytokines (SCF, IL-11, TGF-β1) differentially regulate these interactions, with TGF-β1 promoting rapid RNA-binding protein association and cytokine-induced miRNA downregulation modulating Tac1 stability.","method":"RNA gel shift assays, miRNA binding assays with Tac1 3' UTR, cytokine stimulation","journal":"Brain, behavior, and immunity","confidence":"Low","confidence_rationale":"Tier 3 — single lab, single method (RNA shift) for protein binding; miRNA evidence is descriptive","pmids":["18061399"],"is_preprint":false},{"year":2013,"finding":"MeCP2 binds directly to the TAC1 promoter in HEK cells, and this binding is sensitive to valproic acid (antiepileptic) treatment, identifying TAC1 as a direct MeCP2 target gene.","method":"Chromatin immunoprecipitation in HEK cells, Sequenom EpiTYPER methylation validation, pharmacological VPA treatment","journal":"Journal of neurodevelopmental disorders","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP demonstrating direct protein–DNA interaction; single lab, moderate evidence","pmids":["23759142"],"is_preprint":false},{"year":2018,"finding":"Tac1-expressing neurons in the lateral/ventrolateral periaqueductal gray (l/vlPAG) facilitate itch-scratching cycles via descending regulation; their activation is necessary and sufficient for itch-induced scratching, and the downstream circuit involves spinal GRPR+ neurons.","method":"Chemogenetics (DREADDs), optogenetics, neural activity recording, ablation, circuit tracing","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal in vivo manipulations (activation, inhibition, ablation) with defined circuit placement and behavioral readout","pmids":["30554781"],"is_preprint":false},{"year":2017,"finding":"In male mice, Tac1 deficiency causes delayed puberty and decreased expression of Pdyn and Nos1 in mediobasal hypothalamus; kisspeptin receptor (Kiss1R) and substance P receptor (NK1R) heterodimerize, and SP tone modulates responsiveness of GnRH neurons to kisspeptin.","method":"Tac1-/- mice, electrophysiology of arcuate Kiss1 neurons, central peptide administration, receptor heterodimerization assay","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 — KO mouse with defined neuroendocrine phenotypes plus receptor heterodimerization biochemistry; single lab","pmids":["28444173"],"is_preprint":false},{"year":2020,"finding":"Tac1-expressing neurons in the nucleus accumbens (NAc) lateral shell project to ventral pallidum and regulate stress-induced anhedonia-like behavior; inhibition/activation of Tac1NAc neurons bidirectionally modulates stress susceptibility, and NK1R inhibition promotes stress susceptibility.","method":"Chemogenetics, optogenetics, circuit tracing, viral-mediated circuit manipulation, electrophysiology","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal in vivo manipulations establishing specific circuit and behavioral role","pmids":["33147466"],"is_preprint":false},{"year":2023,"finding":"Tac1 neurons in the NAc medial shell project to the lateral hypothalamic area (LH); activation of the NAcTac1→LH pathway promotes avoidance responses to aversive stimuli, and medial prefrontal cortex sends excitatory inputs to this NAc Tac1 circuit.","method":"Chemogenetics, optogenetic circuit dissection, rabies virus retrograde tracing, circuit-specific behavioral assays","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 — multiple circuit-tracing and manipulation methods; single lab","pmids":["36901777"],"is_preprint":false},{"year":2010,"finding":"In Tac1 knockout mice lacking substance P and neurokinin A, morphine is a more potent analgesic, respiratory depression by morphine is reduced, morphine-withdrawal aversion is diminished, and behavioral sensitization is lower; demonstrating that tachykinins modulate opioid pharmacology.","method":"Tac1-/- knockout mice, analgesic assays, plethysmography, naloxone-precipitated withdrawal, conditioned place preference","journal":"British journal of pharmacology","confidence":"High","confidence_rationale":"Tier 2 — clean KO with multiple defined pharmacological phenotypes across orthogonal behavioral readouts","pmids":["20590634"],"is_preprint":false},{"year":2019,"finding":"Tac1 knockout nociceptors fail to encode the duration and magnitude of mechanical stimuli and do not develop mechanical sensitization after injury; Tac1-/- mice show reduced paw edema and weight-bearing deficits after incision, establishing tachykinins as critical modulators of primary afferent electrical excitability.","method":"In vivo electrophysiology of primary afferents in Tac1-/- mice, paw incision model, mechanical stimulation","journal":"Molecular pain","confidence":"High","confidence_rationale":"Tier 2 — direct electrophysiological recording from identified nociceptors in KO animals with clean phenotype","pmids":["31012376"],"is_preprint":false},{"year":2024,"finding":"CRISPR-Cas9-engineered gain-of-function mutations in C. parapsilosis CpTAC1 (G650E substitution) activate CpCDR1, CpCDR1B, and CpCDR1C, causing an 8-fold increase in fluconazole MIC; correction of the mutation reduces MIC 16-fold, establishing CpTAC1 as a direct activator of CDR efflux pumps in C. parapsilosis.","method":"CRISPR-Cas9 precise genome editing, RNA sequencing, RT-qPCR, broth microdilution susceptibility testing","journal":"Clinical microbiology and infection","confidence":"High","confidence_rationale":"Tier 1–2 — precise bidirectional genome editing (introduction and correction of mutation) with transcriptome-level confirmation","pmids":["37666448"],"is_preprint":false},{"year":2010,"finding":"TAC1 is identified as a long-day signal gene in sheep pituitary pars tuberalis (PT); it is strongly activated by long photoperiod in the PT and its encoded peptides (substance P and neurokinin A) act as prolactin secretagogues (tuberalin candidates) on primary pituitary cells.","method":"Microarray, in situ hybridization, primary pituitary cell prolactin secretion assay","journal":"Current biology : CB","confidence":"Medium","confidence_rationale":"Tier 2 — in situ hybridization plus direct functional assay on primary cells; single study","pmids":["20434341"],"is_preprint":false}],"current_model":"Human/mammalian TAC1 encodes the tachykinin neuropeptides substance P and neurokinin A, which are transcriptionally regulated by REST/NF-κB cooperative repression and MEK/ERK-dependent enhancer–promoter synergy, post-transcriptionally regulated by RNA-binding proteins and miRNAs; in Candida albicans, TAC1 encodes a Zn-cluster transcription factor whose N-terminal DBD binds Drug Responsive Elements in CDR1/CDR2 promoters and whose C-terminal activation domain recruits TBP and the Mediator tail module to drive azole resistance, with gain-of-function mutations relieving middle-region inhibition to hyperactivate this pathway; in C. elegans the TACC ortholog TAC-1 physically complexes with the XMAP215-family protein ZYG-9 and separately with ZYG-8 to promote centrosomal microtubule growth in an Aurora-A-dependent manner; and in mammalian neurons, Tac1-expressing circuits in PAG, nucleus accumbens, and amygdala mediate itch facilitation, stress-induced anhedonia, avoidance behavior, and fear memory consolidation through defined descending and limbic pathways."},"narrative":{"teleology":[{"year":2002,"claim":"Establishing that mammalian Tac1-derived tachykinins are functional mediators of emotional behavior resolved whether substance P/neurokinin A loss has measurable behavioral consequences in vivo.","evidence":"Tac1 knockout mice tested across multiple anxiety and depression behavioral paradigms","pmids":["12427862"],"confidence":"High","gaps":["Specific neural circuits mediating the behavioral phenotypes were undefined","Whether effects are due to substance P, neurokinin A, or both was not resolved"]},{"year":2003,"claim":"Identification of C. elegans TAC-1 as a TACC-family protein that physically complexes with ZYG-9 to promote centrosomal microtubule assembly established a conserved TACC–XMAP215 paradigm for microtubule growth regulation.","evidence":"Reciprocal co-immunoprecipitation, in vitro pulldown, FRAP-based microtubule assembly, RNAi, and live GFP imaging across three independent studies","pmids":["12956950","12956951","12956952"],"confidence":"High","gaps":["Structural basis of TAC-1–ZYG-9 interaction was not determined","Whether TAC-1 has microtubule-stabilizing activity independent of ZYG-9 was unclear"]},{"year":2007,"claim":"Discovery of REST and NF-κB cooperative repression of TAC1 transcription revealed how this neuropeptide gene is silenced in non-neuronal cells and modulated during inflammation.","evidence":"ChIP, site-directed mutagenesis, and loss-of-function transfection in human mesenchymal stem cells and breast cancer cells","pmids":["17709376","19246391"],"confidence":"High","gaps":["Whether REST–NF-κB co-occupancy is universal across all TAC1-expressing lineages was not tested","Chromatin remodeling events downstream of REST binding were not characterized"]},{"year":2007,"claim":"TAC-1 was shown to form a separate complex with doublecortin-family protein ZYG-8, partially redundant with the ZYG-9–TAC-1 complex, broadening TAC-1's role beyond a single microtubule assembly pathway.","evidence":"Co-immunoprecipitation showing TAC-1–ZYG-8 complex is ZYG-9-independent; genetic epistasis with temperature-sensitive alleles in C. elegans embryos","pmids":["17666432"],"confidence":"High","gaps":["Whether ZYG-8 and ZYG-9 compete for the same TAC-1 binding surface was not determined","Relative contribution of each complex during different cell-cycle stages was not quantified"]},{"year":2007,"claim":"Demonstrating SDF-1α dose-dependent regulation of Tac1 via NF-κB in bone marrow stroma, with substance P promoting hematopoiesis through NK1R, linked Tac1 to the hematopoietic niche.","evidence":"Reporter assays with mutant IκB, EMSA, ELISA, and long-term culture-initiating cell assays in bone marrow stromal cells","pmids":["17277111"],"confidence":"Medium","gaps":["In vivo relevance of SP-mediated hematopoiesis was not tested in Tac1 KO bone marrow","Post-transcriptional regulation details were incomplete"]},{"year":2008,"claim":"Identification of Candida albicans TAC1 as a Zn-cluster transcription factor driving CDR1/CDR2-mediated azole resistance, with gene-dose-dependent effects on fluconazole MIC, established the molecular basis of clinical drug resistance.","evidence":"Gene deletion, copy-number manipulation via telomere-mediated truncation, and fluconazole susceptibility assays","pmids":["18363649"],"confidence":"High","gaps":["The direct xenobiotic-sensing mechanism was not identified","Whether TAC1 amplification is the sole driver of isochromosome 5L–mediated resistance was unclear"]},{"year":2010,"claim":"Tac1 knockout mice showed enhanced morphine analgesia with reduced respiratory depression and withdrawal aversion, establishing tachykinins as modulators of opioid pharmacology.","evidence":"Tac1−/− mice assessed by analgesic assays, plethysmography, withdrawal, and conditioned place preference","pmids":["20590634"],"confidence":"High","gaps":["Which tachykinin (SP vs NKA) and which receptor mediate each opioid-modulating effect was not dissected","Central vs peripheral contributions were not separated"]},{"year":2011,"claim":"Discovery that TAC1 induction in sensory neurons requires MEK/ERK-dependent synergy between the promoter and a distal enhancer (ECR2) explained how noxious stimulation selectively activates TAC1 in specific neuronal populations.","evidence":"Comparative genomics, primary neuron reporter assays, mouse transgenics, and MEK pharmacological inhibition","pmids":["21160161","21294877"],"confidence":"Medium","gaps":["Identity of the transcription factors binding ECR2 was not fully resolved","In vivo contribution of ECR2 to pain phenotypes was not tested"]},{"year":2011,"claim":"Sequential CRE1 then CRE2/AP-1 site activation during MSC-to-neuron differentiation, driven by REST relief and JNK signaling, defined the temporal program of TAC1 induction during neurogenesis.","evidence":"Reporter assays with CRE site mutations, REST overexpression, JNK/PKA inhibitors, and ChIP during MSC differentiation","pmids":["21671725"],"confidence":"Medium","gaps":["Whether this temporal program operates in vivo neurogenesis was not confirmed","Epigenetic changes at the TAC1 locus during differentiation were not mapped"]},{"year":2017,"claim":"Mechanistic dissection of C. albicans Tac1 showed that gain-of-function mutations or xenobiotics relieve middle-region autoinhibition of the C-terminal activation domain, enabling Mediator tail module recruitment to CDR1, directly linking Tac1 domain architecture to drug resistance.","evidence":"Domain deletion/mutagenesis, ChIP showing Mediator recruitment, reporter assays, and drug susceptibility testing","pmids":["28807920"],"confidence":"High","gaps":["Structural basis of middle-region autoinhibition was not resolved","The specific xenobiotic-binding site within the middle homology region was not identified"]},{"year":2018,"claim":"Identification of Tac1-expressing PAG neurons as necessary and sufficient for itch-scratch facilitation via descending spinal GRPR+ circuits placed Tac1 within a defined sensory-modulatory circuit.","evidence":"Chemogenetics, optogenetics, neural recording, ablation, and circuit tracing in mice","pmids":["30554781"],"confidence":"High","gaps":["Whether substance P itself or co-released transmitters mediate the descending itch signal was not resolved","Role of neurokinin A in this circuit was not tested"]},{"year":2019,"claim":"Demonstrating that Tac1 knockout nociceptors fail to encode mechanical stimulus intensity and do not develop post-injury sensitization established tachykinins as modulators of primary afferent excitability, not just central neuromodulators.","evidence":"In vivo electrophysiology of primary afferents in Tac1−/− mice with paw incision model","pmids":["31012376"],"confidence":"High","gaps":["Mechanism by which tachykinins modulate ion channel activity in nociceptors was not identified","Whether this reflects autocrine signaling was not determined"]},{"year":2020,"claim":"Tac1-expressing NAc lateral shell neurons were shown to bidirectionally regulate stress-induced anhedonia via projections to ventral pallidum, establishing a limbic circuit role for Tac1 in mood regulation.","evidence":"Chemogenetics, optogenetics, circuit tracing, electrophysiology in stressed vs resilient mice","pmids":["33147466"],"confidence":"High","gaps":["Whether SP or NKA mediates the anti-anhedonic effect was not resolved","Upstream inputs activating NAc Tac1 neurons during stress were not mapped"]},{"year":2023,"claim":"Domain-level dissection of C. albicans Tac1 confirmed the N-terminal DBD binds DREs and the C-terminal AAD directly recruits TBP, completing a minimal model for Tac1-driven transcriptional activation of CDR genes.","evidence":"Domain deletion analysis, reporter assays, and protein–protein interaction studies","pmids":["37502396"],"confidence":"Medium","gaps":["No structural data for any Tac1 domain exists","Whether AAD–TBP interaction is sufficient without Mediator was not tested"]},{"year":2024,"claim":"CRISPR-engineered gain-of-function TAC1 mutations in C. parapsilosis recapitulated azole resistance, confirming conservation of the TAC1-CDR resistance mechanism beyond C. albicans.","evidence":"Bidirectional CRISPR-Cas9 editing, RNA-seq, and broth microdilution MIC testing in C. parapsilosis","pmids":["37666448"],"confidence":"High","gaps":["Domain architecture and activation mechanism in C. parapsilosis Tac1 have not been dissected","Whether Mediator recruitment is conserved in this species is unknown"]},{"year":null,"claim":"Major open questions include the structural basis of Tac1 autoinhibition and xenobiotic sensing in Candida, the specific tachykinin peptide (SP vs NKA) responsible for individual circuit-level behavioral phenotypes in mammals, and the mechanism by which tachykinins modulate primary afferent excitability.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal or cryo-EM structure of any Tac1 domain","SP vs NKA contribution not separated in most neural circuit studies","Autocrine vs paracrine tachykinin signaling at nociceptors not resolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[3,17,19,21,22,24]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[6,7,8,9,23]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[3,17,19,24]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[6,7,9]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[3,17,19,20,22]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[12,13,18]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[4,5,7,9,14]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[6,7,23]}],"complexes":["ZYG-9–TAC-1 complex","ZYG-8–TAC-1 complex"],"partners":["ZYG-9","ZYG-8","REST","RELA","TACR1","MED15","TBP","MECP2"],"other_free_text":[]},"mechanistic_narrative":"Mammalian TAC1 encodes the precursor of the tachykinin neuropeptides substance P and neurokinin A, which function as critical modulators of nociception, emotional behavior, neuroendocrine signaling, and itch processing through defined neural circuits. Tac1 knockout mice exhibit reduced anxiety- and depression-related behaviors [PMID:12427862], altered opioid pharmacology [PMID:20590634], failure of nociceptor mechanical encoding and sensitization [PMID:31012376], and delayed male puberty due to impaired kisspeptin–GnRH signaling [PMID:28444173]; Tac1-expressing neurons in the periaqueductal gray, nucleus accumbens, and amygdala drive itch facilitation, stress-induced anhedonia, and avoidance behavior through projection-specific circuits [PMID:30554781, PMID:33147466, PMID:36901777]. TAC1 transcription is repressed by REST and NF-κB acting cooperatively at the promoter [PMID:17709376, PMID:19246391] and is induced through MEK/ERK-dependent enhancer–promoter synergy and sequential CRE/AP-1 site activation during neuronal differentiation [PMID:21160161, PMID:21671725]. In Candida albicans, the unrelated Zn-cluster transcription factor Tac1 drives azole resistance by binding Drug Responsive Elements in CDR1/CDR2 promoters via its N-terminal DNA-binding domain and recruiting TBP and the Mediator tail module through its C-terminal activation domain, with gain-of-function mutations relieving middle-region autoinhibition [PMID:28807920, PMID:37502396, PMID:18363649]."},"prefetch_data":{"uniprot":{"accession":"P20366","full_name":"Protachykinin-1","aliases":["PPT"],"length_aa":129,"mass_kda":15.0,"function":"Tachykinins are active peptides which excite neurons, evoke behavioral responses, are potent vasodilators and secretagogues, and contract (directly or indirectly) many smooth muscles Is a ligand for TACR1, and triggers G protein-coupled receptor signaling via activation of phosphatidylinositol hydrolysis by phospholipase C. Substance P binding to TACR1 also triggers signaling via activation of adenylate cyclase activity which results in increased intracellular levels of cyclic AMP (cAMP) (By similarity). Is also a TACR3 agonist with low receptor affinity (PubMed:37391393). Basic secretagogue neuropeptide released from the terminals of specific sensory nerves (PubMed:30686732). Acts as a ligand for MRGPRX2 receptor in mast cells, initiating a signaling that mediates neurogenic inflammation and pain (PubMed:30686732, PubMed:34789875). Neurogenic inflammation includes mast cell activation, recruitment of immune cells and release of inflammatory mediators, such as cytokines and chemokines (By similarity). The inflammatory response can then activate or sensitize nociceptors, promoting pain (By similarity) Is a ligand for TACR2, and triggers G protein-coupled receptor signaling via activation of G(q) and phosphatidylinositol hydrolysis by phospholipase C (PubMed:35882833). Binding to TACR2 also triggers signaling via activation of adenylate cyclase activity which results in increased intracellular levels of cyclic AMP (cAMP)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P20366/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TAC1","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TAC1","total_profiled":1310},"omim":[{"mim_id":"611599","title":"MICRO RNA 206; MIR206","url":"https://www.omim.org/entry/611599"},{"mim_id":"610175","title":"MICRO RNA 130A; MIR130A","url":"https://www.omim.org/entry/610175"},{"mim_id":"604255","title":"LADYBIRD HOMEOBOX 1; LBX1","url":"https://www.omim.org/entry/604255"},{"mim_id":"300005","title":"METHYL-CpG-BINDING PROTEIN 2; MECP2","url":"https://www.omim.org/entry/300005"},{"mim_id":"162332","title":"TACHYKININ RECEPTOR 3; TACR3","url":"https://www.omim.org/entry/162332"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":223.0}],"url":"https://www.proteinatlas.org/search/TAC1"},"hgnc":{"alias_symbol":["NPK"],"prev_symbol":["TAC2","NKNA"]},"alphafold":{"accession":"P20366","domains":[{"cath_id":"-","chopping":"2-57","consensus_level":"high","plddt":72.3271,"start":2,"end":57}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P20366","model_url":"https://alphafold.ebi.ac.uk/files/AF-P20366-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P20366-F1-predicted_aligned_error_v6.png","plddt_mean":66.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TAC1","jax_strain_url":"https://www.jax.org/strain/search?query=TAC1"},"sequence":{"accession":"P20366","fasta_url":"https://rest.uniprot.org/uniprotkb/P20366.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P20366/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P20366"}},"corpus_meta":[{"pmid":"18363649","id":"PMC_18363649","title":"An isochromosome confers drug resistance in vivo by amplification of two genes, ERG11 and TAC1.","date":"2008","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/18363649","citation_count":267,"is_preprint":false},{"pmid":"17908158","id":"PMC_17908158","title":"TAC1, a major quantitative trait locus controlling tiller angle in rice.","date":"2007","source":"The Plant journal : for cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/17908158","citation_count":229,"is_preprint":false},{"pmid":"29775595","id":"PMC_29775595","title":"The Neuropeptide Tac2 Controls a Distributed Brain State Induced by Chronic Social Isolation Stress.","date":"2018","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/29775595","citation_count":209,"is_preprint":false},{"pmid":"12956950","id":"PMC_12956950","title":"TAC-1 and ZYG-9 form a complex that promotes microtubule assembly in C. elegans embryos.","date":"2003","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/12956950","citation_count":124,"is_preprint":false},{"pmid":"25046442","id":"PMC_25046442","title":"Impact of long-term N, P, K, and NPK fertilization on the composition and potential functions of the bacterial community in grassland soil.","date":"2014","source":"FEMS microbiology ecology","url":"https://pubmed.ncbi.nlm.nih.gov/25046442","citation_count":110,"is_preprint":false},{"pmid":"12427862","id":"PMC_12427862","title":"Diminished anxiety- and depression-related behaviors in mice with selective deletion of the Tac1 gene.","date":"2002","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/12427862","citation_count":109,"is_preprint":false},{"pmid":"30554781","id":"PMC_30554781","title":"Tac1-Expressing Neurons in the Periaqueductal Gray Facilitate the Itch-Scratching Cycle via Descending Regulation.","date":"2018","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/30554781","citation_count":109,"is_preprint":false},{"pmid":"28905629","id":"PMC_28905629","title":"Nanoparticle and Ionic Zn Promote Nutrient Loading of Sorghum Grain under Low NPK Fertilization.","date":"2017","source":"Journal of agricultural and food chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/28905629","citation_count":99,"is_preprint":false},{"pmid":"12956951","id":"PMC_12956951","title":"TAC-1, a regulator of microtubule length in the C. elegans embryo.","date":"2003","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/12956951","citation_count":96,"is_preprint":false},{"pmid":"27814357","id":"PMC_27814357","title":"A Novel Tiller Angle Gene, TAC3, together with TAC1 and D2 Largely Determine the Natural Variation of Tiller Angle in Rice Cultivars.","date":"2016","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27814357","citation_count":94,"is_preprint":false},{"pmid":"21687735","id":"PMC_21687735","title":"Cloning and characterization of a putative TAC1 ortholog associated with leaf angle in maize (Zea mays L.).","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21687735","citation_count":91,"is_preprint":false},{"pmid":"12956952","id":"PMC_12956952","title":"Caenorhabditis elegans TAC-1 and ZYG-9 form a complex that is essential for long astral and spindle microtubules.","date":"2003","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/12956952","citation_count":88,"is_preprint":false},{"pmid":"24976214","id":"PMC_24976214","title":"A role for Tac2, NkB, and Nk3 receptor in normal and dysregulated fear memory consolidation.","date":"2014","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/24976214","citation_count":83,"is_preprint":false},{"pmid":"24243794","id":"PMC_24243794","title":"Distinct roles of Candida albicans drug resistance transcription factors TAC1, MRR1, and UPC2 in virulence.","date":"2013","source":"Eukaryotic cell","url":"https://pubmed.ncbi.nlm.nih.gov/24243794","citation_count":70,"is_preprint":false},{"pmid":"20434341","id":"PMC_20434341","title":"Identification of Eya3 and TAC1 as long-day signals in the sheep pituitary.","date":"2010","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/20434341","citation_count":69,"is_preprint":false},{"pmid":"24486589","id":"PMC_24486589","title":"Functional identification of cancer-specific methylation of CDO1, HOXA9, and TAC1 for the diagnosis of lung cancer.","date":"2014","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/24486589","citation_count":68,"is_preprint":false},{"pmid":"22893725","id":"PMC_22893725","title":"Increased neurokinin B (Tac2) expression in the mouse arcuate nucleus is an early marker of pubertal onset with differential sensitivity to sex steroid-negative feedback than Kiss1.","date":"2012","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/22893725","citation_count":68,"is_preprint":false},{"pmid":"32060036","id":"PMC_32060036","title":"Mapping of Sensory Nerve Subsets within the Vagal Ganglia and the Brainstem Using Reporter Mice for Pirt, TRPV1, 5-HT3, and Tac1 Expression.","date":"2020","source":"eNeuro","url":"https://pubmed.ncbi.nlm.nih.gov/32060036","citation_count":67,"is_preprint":false},{"pmid":"34311410","id":"PMC_34311410","title":"Heterotrophic nitrification and aerobic denitrification by a novel Acinetobacter sp. TAC-1 at low temperature and high ammonia nitrogen.","date":"2021","source":"Bioresource technology","url":"https://pubmed.ncbi.nlm.nih.gov/34311410","citation_count":64,"is_preprint":false},{"pmid":"19246391","id":"PMC_19246391","title":"RE-1-silencing transcription factor shows tumor-suppressor functions and negatively regulates the oncogenic TAC1 in breast cancer cells.","date":"2009","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/19246391","citation_count":61,"is_preprint":false},{"pmid":"32999383","id":"PMC_32999383","title":"Different organic manure sources and NPK fertilizer on soil chemical properties, growth, yield and quality of okra.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/32999383","citation_count":54,"is_preprint":false},{"pmid":"21980509","id":"PMC_21980509","title":"The transcription factor Ndt80 does not contribute to Mrr1-, Tac1-, and Upc2-mediated fluconazole resistance in Candida albicans.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21980509","citation_count":49,"is_preprint":false},{"pmid":"28807920","id":"PMC_28807920","title":"Mediator Tail Module Is Required for Tac1-Activated CDR1 Expression and Azole Resistance in Candida albicans.","date":"2017","source":"Antimicrobial agents and chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/28807920","citation_count":47,"is_preprint":false},{"pmid":"32269265","id":"PMC_32269265","title":"Opposing influences of TAC1 and LAZY1 on Lateral Shoot Orientation in Arabidopsis.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/32269265","citation_count":42,"is_preprint":false},{"pmid":"31812023","id":"PMC_31812023","title":"Optimization of NPK fertilization combined with phytoremediation of cadmium contaminated soil by orthogonal experiment.","date":"2019","source":"Ecotoxicology and environmental safety","url":"https://pubmed.ncbi.nlm.nih.gov/31812023","citation_count":42,"is_preprint":false},{"pmid":"24051054","id":"PMC_24051054","title":"Deciphering azole resistance mechanisms with a focus on transcription factor-encoding genes TAC1, MRR1 and UPC2 in a set of fluconazole-resistant clinical isolates of Candida albicans.","date":"2013","source":"International journal of antimicrobial agents","url":"https://pubmed.ncbi.nlm.nih.gov/24051054","citation_count":41,"is_preprint":false},{"pmid":"33941789","id":"PMC_33941789","title":"Sex differences in fear memory consolidation via Tac2 signaling in mice.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/33941789","citation_count":37,"is_preprint":false},{"pmid":"27238620","id":"PMC_27238620","title":"Amygdala-Dependent Molecular Mechanisms of the Tac2 Pathway in Fear Learning.","date":"2016","source":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/27238620","citation_count":36,"is_preprint":false},{"pmid":"22272772","id":"PMC_22272772","title":"Genetic marking and characterization of Tac2-expressing neurons in the central and peripheral nervous system.","date":"2012","source":"Molecular brain","url":"https://pubmed.ncbi.nlm.nih.gov/22272772","citation_count":35,"is_preprint":false},{"pmid":"29736251","id":"PMC_29736251","title":"Alteration of TAC1 expression in Prunus species leads to pleiotropic shoot phenotypes.","date":"2018","source":"Horticulture research","url":"https://pubmed.ncbi.nlm.nih.gov/29736251","citation_count":35,"is_preprint":false},{"pmid":"23089365","id":"PMC_23089365","title":"Molecular evolution of the TAC1 gene from rice (Oryza sativa L.).","date":"2012","source":"Journal of genetics and genomics = Yi chuan xue bao","url":"https://pubmed.ncbi.nlm.nih.gov/23089365","citation_count":35,"is_preprint":false},{"pmid":"26862996","id":"PMC_26862996","title":"ERα in Tac2 Neurons Regulates Puberty Onset in Female Mice.","date":"2016","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/26862996","citation_count":34,"is_preprint":false},{"pmid":"17709376","id":"PMC_17709376","title":"Synergy between the RE-1 silencer of transcription and NFkappaB in the repression of the neurotransmitter gene TAC1 in human mesenchymal stem cells.","date":"2007","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17709376","citation_count":34,"is_preprint":false},{"pmid":"19070410","id":"PMC_19070410","title":"Evaluation of physiological, growth and yield responses of a tropical oil crop (Brassica campestris L. var. Kranti) under ambient ozone pollution at varying NPK levels.","date":"2008","source":"Environmental pollution (Barking, Essex : 1987)","url":"https://pubmed.ncbi.nlm.nih.gov/19070410","citation_count":34,"is_preprint":false},{"pmid":"17666432","id":"PMC_17666432","title":"ZYG-9, TAC-1 and ZYG-8 together ensure correct microtubule function throughout the cell cycle of C. elegans embryos.","date":"2007","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/17666432","citation_count":30,"is_preprint":false},{"pmid":"28444173","id":"PMC_28444173","title":"Tac1 Signaling Is Required for Sexual Maturation and Responsiveness of GnRH Neurons to Kisspeptin in the Male Mouse.","date":"2017","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/28444173","citation_count":29,"is_preprint":false},{"pmid":"23499760","id":"PMC_23499760","title":"Role of Pituitary Adenylate-Cyclase Activating Polypeptide and Tac1 gene derived tachykinins in sensory, motor and vascular functions under normal and neuropathic conditions.","date":"2013","source":"Peptides","url":"https://pubmed.ncbi.nlm.nih.gov/23499760","citation_count":28,"is_preprint":false},{"pmid":"30759553","id":"PMC_30759553","title":"Effect of foliar application of NPK nanoparticle fertilization on yield and genotoxicity in wheat (Triticum aestivum L.).","date":"2018","source":"The Science of the total environment","url":"https://pubmed.ncbi.nlm.nih.gov/30759553","citation_count":26,"is_preprint":false},{"pmid":"21294877","id":"PMC_21294877","title":"Evidence for regulatory diversity and auto-regulation at the TAC1 locus in sensory neurones.","date":"2011","source":"Journal of neuroinflammation","url":"https://pubmed.ncbi.nlm.nih.gov/21294877","citation_count":24,"is_preprint":false},{"pmid":"33147466","id":"PMC_33147466","title":"Nucleus Accumbens Tac1-Expressing Neurons Mediate Stress-Induced Anhedonia-like Behavior in Mice.","date":"2020","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/33147466","citation_count":23,"is_preprint":false},{"pmid":"29576999","id":"PMC_29576999","title":"The effect of chitosan-PMAA-NPK nanofertilizer on Pisum sativum plants.","date":"2018","source":"3 Biotech","url":"https://pubmed.ncbi.nlm.nih.gov/29576999","citation_count":23,"is_preprint":false},{"pmid":"30104273","id":"PMC_30104273","title":"Candida albicans Zn Cluster Transcription Factors Tac1 and Znc1 Are Activated by Farnesol To Upregulate a Transcriptional Program Including the Multidrug Efflux Pump CDR1.","date":"2018","source":"Antimicrobial agents and chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/30104273","citation_count":22,"is_preprint":false},{"pmid":"17277111","id":"PMC_17277111","title":"Stromal derived growth factor-1alpha: another mediator in neural-emerging immune system through Tac1 expression in bone marrow stromal cells.","date":"2007","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/17277111","citation_count":22,"is_preprint":false},{"pmid":"29478144","id":"PMC_29478144","title":"Integration of transcriptomic and cytoarchitectonic data implicates a role for MAOA and TAC1 in the limbic-cortical network.","date":"2018","source":"Brain structure & function","url":"https://pubmed.ncbi.nlm.nih.gov/29478144","citation_count":21,"is_preprint":false},{"pmid":"37666448","id":"PMC_37666448","title":"Mutations in TAC1 and ERG11 are major drivers of triazole antifungal resistance in clinical isolates of Candida parapsilosis.","date":"2023","source":"Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases","url":"https://pubmed.ncbi.nlm.nih.gov/37666448","citation_count":21,"is_preprint":false},{"pmid":"24735328","id":"PMC_24735328","title":"Electrophysiology of arcuate neurokinin B neurons in female Tac2-EGFP transgenic mice.","date":"2014","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/24735328","citation_count":20,"is_preprint":false},{"pmid":"25659412","id":"PMC_25659412","title":"Chronic oestradiol reduces the dendritic spine density of KNDy (kisspeptin/neurokinin B/dynorphin) neurones in the arcuate nucleus of ovariectomised Tac2-enhanced green fluorescent protein transgenic mice.","date":"2015","source":"Journal of neuroendocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/25659412","citation_count":20,"is_preprint":false},{"pmid":"21160161","id":"PMC_21160161","title":"Long-range regulatory synergy is required to allow control of the TAC1 locus by MEK/ERK signalling in sensory neurones.","date":"2010","source":"Neuro-Signals","url":"https://pubmed.ncbi.nlm.nih.gov/21160161","citation_count":20,"is_preprint":false},{"pmid":"31012376","id":"PMC_31012376","title":"Tachykinins modulate nociceptive responsiveness and sensitization: In vivo electrical characterization of primary sensory neurons in tachykinin knockout (Tac1 KO) mice.","date":"2019","source":"Molecular pain","url":"https://pubmed.ncbi.nlm.nih.gov/31012376","citation_count":20,"is_preprint":false},{"pmid":"30485833","id":"PMC_30485833","title":"LOC134466 methylation promotes oncogenesis of endometrial carcinoma through LOC134466/hsa-miR-196a-5p/TAC1 axis.","date":"2018","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/30485833","citation_count":19,"is_preprint":false},{"pmid":"29682090","id":"PMC_29682090","title":"The neuropeptide genes SST, TAC1, HCRT, NPY, and GAL are powerful epigenetic biomarkers in head and neck cancer: a site-specific analysis.","date":"2018","source":"Clinical epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/29682090","citation_count":19,"is_preprint":false},{"pmid":"38624217","id":"PMC_38624217","title":"Precise genome editing underlines the distinct contributions of mutations in ERG11, ERG3, MRR1, and TAC1 genes to antifungal resistance in Candida parapsilosis.","date":"2024","source":"Antimicrobial agents and chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/38624217","citation_count":18,"is_preprint":false},{"pmid":"31466523","id":"PMC_31466523","title":"Tac2-N acts as a novel oncogene and promotes tumor metastasis via activation of NF-κB signaling in lung cancer.","date":"2019","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/31466523","citation_count":17,"is_preprint":false},{"pmid":"36901777","id":"PMC_36901777","title":"A Nucleus Accumbens Tac1 Neural Circuit Regulates Avoidance Responses to Aversive Stimuli.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36901777","citation_count":15,"is_preprint":false},{"pmid":"30682802","id":"PMC_30682802","title":"Co-Application of Milk Tea Waste and NPK Fertilizers to Improve Sandy Soil Biochemical Properties and Wheat Growth.","date":"2019","source":"Molecules (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/30682802","citation_count":14,"is_preprint":false},{"pmid":"17409218","id":"PMC_17409218","title":"Nuclear factor-kappaB accounts for the repressor effects of high stromal cell-derived factor-1alpha levels on Tac1 expression in nontumorigenic breast cells.","date":"2007","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/17409218","citation_count":14,"is_preprint":false},{"pmid":"21671725","id":"PMC_21671725","title":"Developmental regulation of TAC1 in peptidergic-induced human mesenchymal stem cells: implication for spinal cord injury in zebrafish.","date":"2011","source":"Stem cells and development","url":"https://pubmed.ncbi.nlm.nih.gov/21671725","citation_count":14,"is_preprint":false},{"pmid":"37368599","id":"PMC_37368599","title":"Triazine Herbicide and NPK Fertilizer Exposure: Accumulation of Heavy Metals and Rare Earth Elements, Effects on Cuticle Melanization, and Immunocompetence in the Model Species Tenebrio molitor.","date":"2023","source":"Toxics","url":"https://pubmed.ncbi.nlm.nih.gov/37368599","citation_count":14,"is_preprint":false},{"pmid":"15620584","id":"PMC_15620584","title":"Amelioration of Indian urban air pollution phytotoxicity in Beta vulgaris L. by modifying NPK nutrients.","date":"2005","source":"Environmental pollution (Barking, Essex : 1987)","url":"https://pubmed.ncbi.nlm.nih.gov/15620584","citation_count":13,"is_preprint":false},{"pmid":"33461013","id":"PMC_33461013","title":"Transforming wet blue leather and potato peel into an eco-friendly bio-organic NPK fertilizer for intensifying crop productivity and retrieving value-added recyclable chromium salts.","date":"2021","source":"Journal of hazardous materials","url":"https://pubmed.ncbi.nlm.nih.gov/33461013","citation_count":13,"is_preprint":false},{"pmid":"22868114","id":"PMC_22868114","title":"Nutritional and antioxidant profiles of pumpkin (Cucurbita pepo Linn.) immature and mature fruits as influenced by NPK fertilizer.","date":"2012","source":"Food chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22868114","citation_count":13,"is_preprint":false},{"pmid":"35729637","id":"PMC_35729637","title":"Hyperandrogenism induces proportional changes in the expression of Kiss-1, Tac2, and DynA in hypothalamic KNDy neurons.","date":"2022","source":"Reproductive biology and endocrinology : RB&E","url":"https://pubmed.ncbi.nlm.nih.gov/35729637","citation_count":12,"is_preprint":false},{"pmid":"35178132","id":"PMC_35178132","title":"The Neuropeptide-Related HERC5/TAC1 Interactions May Be Associated with the Dysregulation of lncRNA GAS5 Expression in Gestational Diabetes Mellitus Exosomes.","date":"2022","source":"Disease markers","url":"https://pubmed.ncbi.nlm.nih.gov/35178132","citation_count":12,"is_preprint":false},{"pmid":"17376622","id":"PMC_17376622","title":"Tachykinin 1 (TAC1) gene SNPs and haplotypes with autism: a case-control study.","date":"2007","source":"Brain & development","url":"https://pubmed.ncbi.nlm.nih.gov/17376622","citation_count":11,"is_preprint":false},{"pmid":"20590634","id":"PMC_20590634","title":"Increased morphine analgesia and reduced side effects in mice lacking the tac1 gene.","date":"2010","source":"British journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/20590634","citation_count":11,"is_preprint":false},{"pmid":"15729363","id":"PMC_15729363","title":"Haplotype analysis of the preprotachykinin-1 (TAC1) gene in multiple sclerosis.","date":"2005","source":"Genes and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/15729363","citation_count":11,"is_preprint":false},{"pmid":"23759142","id":"PMC_23759142","title":"Comparative DNA methylation among females with neurodevelopmental disorders and seizures identifies TAC1 as a MeCP2 target gene.","date":"2013","source":"Journal of neurodevelopmental disorders","url":"https://pubmed.ncbi.nlm.nih.gov/23759142","citation_count":11,"is_preprint":false},{"pmid":"15207300","id":"PMC_15207300","title":"Comparative effectiveness of cattle manure, poultry manure, phosphocompost and fertilizer-NPK on three cropping systems in vertisols of semi-arid tropics. II. Dry matter yield, nodulation, chlorophyll content and enzyme activity.","date":"2004","source":"Bioresource technology","url":"https://pubmed.ncbi.nlm.nih.gov/15207300","citation_count":11,"is_preprint":false},{"pmid":"33867115","id":"PMC_33867115","title":"A Second Wave for the Neurokinin Tac2 Pathway in Brain Research.","date":"2021","source":"Biological psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/33867115","citation_count":10,"is_preprint":false},{"pmid":"36169896","id":"PMC_36169896","title":"Expression pattern of drug-resistance genes ERG11 and TAC1 in Candida albicans Clinical isolates.","date":"2022","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/36169896","citation_count":9,"is_preprint":false},{"pmid":"31210930","id":"PMC_31210930","title":"Effects of NPK and biochar fertilized soil on the proximate composition and mineral evaluation of maize flour.","date":"2018","source":"Food science & nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/31210930","citation_count":9,"is_preprint":false},{"pmid":"18061399","id":"PMC_18061399","title":"Tac1 regulation by RNA-binding protein and miRNA in bone marrow stroma: Implication for hematopoietic activity.","date":"2007","source":"Brain, behavior, and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/18061399","citation_count":9,"is_preprint":false},{"pmid":"17175032","id":"PMC_17175032","title":"The neuropeptide genes TAC1, TAC3, TAC4, VIP and PACAP(ADCYAP1), and susceptibility to multiple sclerosis.","date":"2006","source":"Journal of neuroimmunology","url":"https://pubmed.ncbi.nlm.nih.gov/17175032","citation_count":8,"is_preprint":false},{"pmid":"35371119","id":"PMC_35371119","title":"Influence of Nutrient (NPK) Factors on Growth, and Pharmacodynamic Component Biosynthesis of Atractylodes chinensis: An Insight on Acetyl-CoA Carboxylase (ACC), 3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMGR), and Farnesyl Pyrophosphate Synthase (FPPS) Signaling Responses.","date":"2022","source":"Frontiers in plant science","url":"https://pubmed.ncbi.nlm.nih.gov/35371119","citation_count":8,"is_preprint":false},{"pmid":"18316470","id":"PMC_18316470","title":"Stromal-derived factor-1alpha induces a non-canonical pathway to activate the endocrine-linked Tac1 gene in non-tumorigenic breast cells.","date":"2008","source":"Journal of molecular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/18316470","citation_count":8,"is_preprint":false},{"pmid":"28775376","id":"PMC_28775376","title":"Altered circadian feeding behavior and improvement of metabolic syndrome in obese Tac1-deficient mice.","date":"2017","source":"International journal of obesity (2005)","url":"https://pubmed.ncbi.nlm.nih.gov/28775376","citation_count":8,"is_preprint":false},{"pmid":"32194717","id":"PMC_32194717","title":"Analysis of the methylation of CpG islands in the CDO1, TAC1 and CHFR genes in pancreatic ductal cancer.","date":"2020","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/32194717","citation_count":8,"is_preprint":false},{"pmid":"20033737","id":"PMC_20033737","title":"Can NPK fertilizers enhance seedling growth and mycorrhizal status of Tuber melanosporum-inoculated Quercus ilex seedlings?","date":"2009","source":"Mycorrhiza","url":"https://pubmed.ncbi.nlm.nih.gov/20033737","citation_count":8,"is_preprint":false},{"pmid":"32989391","id":"PMC_32989391","title":"Tac2-N serves an oncogenic role and promotes drug resistance in human gastric cancer cells.","date":"2020","source":"Experimental and therapeutic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32989391","citation_count":7,"is_preprint":false},{"pmid":"29485996","id":"PMC_29485996","title":"Characterization of knockin mice at the Rosa26, Tac1 and Plekhg1 loci generated by homologous recombination in oocytes.","date":"2018","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/29485996","citation_count":7,"is_preprint":false},{"pmid":"36989993","id":"PMC_36989993","title":"Comparative transcriptome analyses under individual and combined nutrient starvations provide insights into N/P/K interactions in rice.","date":"2023","source":"Plant physiology and biochemistry : PPB","url":"https://pubmed.ncbi.nlm.nih.gov/36989993","citation_count":7,"is_preprint":false},{"pmid":"37765463","id":"PMC_37765463","title":"Beyond NPK: Mineral Nutrient-Mediated Modulation in Orchestrating Flowering Time.","date":"2023","source":"Plants (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/37765463","citation_count":6,"is_preprint":false},{"pmid":"30769143","id":"PMC_30769143","title":"Exploring the involvement of Tac2 in the mouse hippocampal stress response through gene networking.","date":"2019","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/30769143","citation_count":6,"is_preprint":false},{"pmid":"17521418","id":"PMC_17521418","title":"Reduced expression of TAC1, PENK and SOCS2 in Hcrtr-2 mutated narcoleptic dog brain.","date":"2007","source":"BMC neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/17521418","citation_count":6,"is_preprint":false},{"pmid":"23065762","id":"PMC_23065762","title":"Hypoxic ventilatory response in Tac1-/- neonatal mice following exposure to opioids.","date":"2012","source":"Journal of applied physiology (Bethesda, Md. : 1985)","url":"https://pubmed.ncbi.nlm.nih.gov/23065762","citation_count":6,"is_preprint":false},{"pmid":"36617784","id":"PMC_36617784","title":"Identification of TAC1 Associated with Alzheimer's Disease Using a Robust Rank Aggregation Approach.","date":"2023","source":"Journal of Alzheimer's disease : JAD","url":"https://pubmed.ncbi.nlm.nih.gov/36617784","citation_count":5,"is_preprint":false},{"pmid":"26072188","id":"PMC_26072188","title":"Liquid chromatography-electrospray linear ion trap mass spectrometry analysis of targeted neuropeptides in Tac1(-/-) mouse spinal cords reveals significant lower concentration of opioid peptides.","date":"2015","source":"Neuropeptides","url":"https://pubmed.ncbi.nlm.nih.gov/26072188","citation_count":5,"is_preprint":false},{"pmid":"34840225","id":"PMC_34840225","title":"Tac2-N Promotes Glioma Proliferation and Indicates Poor Clinical Outcomes.","date":"2021","source":"The Tohoku journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34840225","citation_count":4,"is_preprint":false},{"pmid":"29721500","id":"PMC_29721500","title":"Antioxidant Enzyme Activities and Secondary Metabolite Profiling of Oil Palm Seedlings Treated with Combination of NPK Fertilizers Infected with Ganoderma boninense.","date":"2018","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/29721500","citation_count":4,"is_preprint":false},{"pmid":"38164144","id":"PMC_38164144","title":"The plasticity of neuropeptide Y-Y1 receptor system on Tac2 neurons contributes to mechanical hyperknesis during chronic itch.","date":"2024","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/38164144","citation_count":4,"is_preprint":false},{"pmid":"37502396","id":"PMC_37502396","title":"Molecular dissection studies of TAC1, a transcription activator of Candida drug resistance genes of the human pathogenic fungus Candida albicans.","date":"2023","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/37502396","citation_count":4,"is_preprint":false},{"pmid":"38770776","id":"PMC_38770776","title":"The TAC1 Gene in Candida albicans: Structure, Function, and Role in Azole Resistance: A Mini-Review.","date":"2024","source":"Microbial drug resistance (Larchmont, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/38770776","citation_count":3,"is_preprint":false},{"pmid":"32850109","id":"PMC_32850109","title":"The additive effect of biochar amendment and simulated nitrogen deposition stimulates the plant height, photosynthesis and accumulation of NPK in pecan (Carya illinoinensis) seedlings.","date":"2020","source":"AoB PLANTS","url":"https://pubmed.ncbi.nlm.nih.gov/32850109","citation_count":3,"is_preprint":false},{"pmid":"38227710","id":"PMC_38227710","title":"Genetic variants in the TAC1 transcriptional regulatory region affect on trainability and excitability levels in Belgian Malinois dogs.","date":"2024","source":"Veterinary medicine and science","url":"https://pubmed.ncbi.nlm.nih.gov/38227710","citation_count":3,"is_preprint":false},{"pmid":"25746346","id":"PMC_25746346","title":"Acute phase cytokines, TAC1, and toll-like receptor4 mRNA expression and health associated with group size in veal calves.","date":"2015","source":"Veterinary immunology and immunopathology","url":"https://pubmed.ncbi.nlm.nih.gov/25746346","citation_count":3,"is_preprint":false},{"pmid":"20217335","id":"PMC_20217335","title":"Acute morphine effects on respiratory activity in mice with target deletion of the tachykinin 1 gene (Tac1-/-).","date":"2010","source":"Advances in experimental medicine and biology","url":"https://pubmed.ncbi.nlm.nih.gov/20217335","citation_count":3,"is_preprint":false},{"pmid":"40052456","id":"PMC_40052456","title":"Precise tiller angle control by manipulating TAC1 expression in rice.","date":"2025","source":"Journal of integrative plant biology","url":"https://pubmed.ncbi.nlm.nih.gov/40052456","citation_count":2,"is_preprint":false},{"pmid":"39109723","id":"PMC_39109723","title":"NPK fertilization modulates enzyme activity and mitigates the impacts of salinity on West Indian cherry.","date":"2024","source":"Brazilian journal of biology = Revista brasleira de biologia","url":"https://pubmed.ncbi.nlm.nih.gov/39109723","citation_count":2,"is_preprint":false},{"pmid":"38085356","id":"PMC_38085356","title":"Different contributions of PROG1 and TAC1 to the angular kinematics of the main culm and tillers of wild rice (Oryza rufipogon).","date":"2023","source":"Planta","url":"https://pubmed.ncbi.nlm.nih.gov/38085356","citation_count":2,"is_preprint":false},{"pmid":"37360226","id":"PMC_37360226","title":"Nutritional Quality and Popability of Popcorn (Zea mays L. var. everta) in Response to Compost and NPK 20-7-3 Application under Dryland Condition of South Africa.","date":"2023","source":"International journal of food science","url":"https://pubmed.ncbi.nlm.nih.gov/37360226","citation_count":2,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51859,"output_tokens":5932,"usd":0.122278},"stage2":{"model":"claude-opus-4-6","input_tokens":9629,"output_tokens":3762,"usd":0.213292},"total_usd":0.33557,"stage1_batch_id":"msgbatch_01RPbVc9PDH9zQmYK5Hs6srm","stage2_batch_id":"msgbatch_01JVbVLzeKN2yVrsGp3zC8aM","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"C. elegans TAC-1 (TACC family protein) physically interacts with ZYG-9 (XMAP215 family MAP), and this complex promotes microtubule assembly; mutual stabilization between the two proteins is required for proper microtubule growth in vivo. TAC-1 localizes to centrosomes in a cell-cycle-dependent manner requiring gamma-tubulin and Aurora-A kinase AIR-1 activity.\",\n      \"method\": \"Co-immunoprecipitation, in vitro pulldown, FRAP-based in vivo microtubule assembly assay, RNAi loss-of-function, live imaging of GFP-TAC-1\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — reciprocal Co-IP, in vitro pulldown, in vivo FRAP, and genetic epistasis; independently replicated in three simultaneous papers (PMIDs 12956950, 12956951, 12956952)\",\n      \"pmids\": [\"12956950\", \"12956951\", \"12956952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Loss of C. elegans TAC-1 by RNAi results in very short centrosomal microtubules and short spindles, establishing TAC-1 as a major regulator of microtubule length; TAC-1 enrichment at centrosomes is dependent on Aurora kinase AIR-1 and the two proteins (TAC-1 and ZYG-9) are mutually required for centrosomal localization.\",\n      \"method\": \"Genome-wide RNAi screen, immunofluorescence, genetic epistasis\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean RNAi KD with defined cellular phenotype, replicated across three independent studies\",\n      \"pmids\": [\"12956951\", \"12956950\", \"12956952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"In C. elegans embryos, TAC-1 physically interacts with ZYG-8 (doublecortin domain protein) through ZYG-8's doublecortin domain, forming a complex in vivo that does not contain ZYG-9; ZYG-9–TAC-1 and ZYG-8 function partially redundantly to ensure correct microtubule assembly throughout the cell cycle, including anaphase spindle positioning.\",\n      \"method\": \"Co-immunoprecipitation, temperature-sensitive allele analysis, genetic epistasis, live imaging\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — reciprocal Co-IP identifying novel TAC-1/ZYG-8 interaction, combined with genetic epistasis and defined phenotypic readouts\",\n      \"pmids\": [\"17666432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Targeted deletion of the mouse Tac1 gene (encoding substance P and neurokinin A) reduces anxiety- and depression-related behaviors, demonstrating that tachykinins encoded by Tac1 are functional mediators of emotional behavior in mammals.\",\n      \"method\": \"Tac1 knockout mouse, multiple behavioral paradigms (forced-swim, tail-suspension, elevated zero-maze, open field, social interaction)\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined behavioral phenotypes across multiple orthogonal behavioral assays\",\n      \"pmids\": [\"12427862\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"REST (RE-1 silencing transcription factor) binds directly to the TAC1 promoter 5' UTR and suppresses TAC1 expression in breast cancer cells; REST expression is inversely proportional to cellular aggressiveness, and REST knockdown increases TAC1-driven proliferation and migration.\",\n      \"method\": \"Western blot, real-time PCR, REST knockdown/overexpression, reporter gene assays, chromatin immunoprecipitation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (ChIP, reporter assay, KD/OE) in same study establishing direct transcriptional repression mechanism\",\n      \"pmids\": [\"19246391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"REST and NF-κB synergistically repress TAC1 transcription in human mesenchymal stem cells; both transcription factors bind within exon 1 / 5'-flanking region of TAC1, and their co-occupancy is required for repression under both IL-1α stimulation and neuronal induction conditions.\",\n      \"method\": \"Chromatin immunoprecipitation, site-directed mutagenesis, loss-of-function transfection studies, reporter gene assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — ChIP, mutagenesis, and loss-of-function in same study; mechanistic dissection of cooperative repression\",\n      \"pmids\": [\"17709376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"In Candida albicans, TAC1 is a transcriptional regulator of drug efflux pumps CDR1 and CDR2; hyperactive TAC1 alleles increase azole resistance in a gene copy number-dependent manner, contributing independently and additively to fluconazole resistance when amplified on isochromosome i(5L) together with ERG11.\",\n      \"method\": \"Comparative genome hybridization, gene deletion, telomere-mediated truncations, in vitro fluconazole susceptibility assays\",\n      \"journal\": \"Molecular microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis by deletion and copy-number manipulation with defined drug-resistance phenotype, multiple orthogonal approaches\",\n      \"pmids\": [\"18363649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The C-terminal transcriptional activation domain (TAD) of C. albicans Tac1 is necessary for CDR1 activation; negative regulation of this TAD by the Tac1 middle region is required for gain-of-function (GOF) mutations or xenobiotics to hyperactivate Tac1. Hyperactivated Tac1 recruits the Mediator coactivator complex (specifically the tail module) to the CDR1 promoter, and azole resistance is dependent on Mediator tail subunits. Tac1 hyperactivation correlates with its Mediator-dependent phosphorylation.\",\n      \"method\": \"Domain deletion/mutagenesis, chromatin immunoprecipitation, reporter gene assays, drug susceptibility testing\",\n      \"journal\": \"Antimicrobial agents and chemotherapy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — mutagenesis combined with ChIP demonstrating Mediator recruitment; mechanistic dissection of TAD and middle-region regulation\",\n      \"pmids\": [\"28807920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"C. albicans Tac1 is functionally activated by farnesol (and 1-dodecanol) through a mechanism mimicking other means of Zn cluster transcription factor hyperactivation; Tac1 and Znc1 both bind the CDR1 promoter and upregulate CDR1 in response to farnesol, and CDR1 expression subsequently mediates farnesol efflux.\",\n      \"method\": \"Reporter gene assays, ChIP, drug susceptibility assays, TAC1/ZNC1 deletion strains\",\n      \"journal\": \"Antimicrobial agents and chemotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and genetic deletion with defined molecular phenotype; single lab study\",\n      \"pmids\": [\"30104273\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Molecular dissection of C. albicans Tac1p shows: (1) the N-terminal DNA-binding domain (DBD) interacts with the Drug Responsive Element (DRE) in CDR1/CDR2 promoters; (2) the C-terminal Acidic Activation Domain (AAD) interacts with TATA-binding protein (TBP) to recruit it to TATA boxes of CDR genes; (3) the Middle Homology Region (MHR) acts as a xenobiotic binding domain (XBD).\",\n      \"method\": \"Domain deletion analysis, reporter gene assays, protein–protein interaction studies (DBD–DRE binding, AAD–TBP interaction)\",\n      \"journal\": \"Frontiers in microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain-level functional dissection with in vitro interaction assays; single lab, moderate evidence\",\n      \"pmids\": [\"37502396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The TAC1 promoter in sensory neurons requires synergistic interaction with a remote enhancer (ECR2) identified by comparative genomics to respond to MEK/ERK (MAPK) signaling; MEK pathway antagonism strongly blocks noxious stimulation-induced TAC1 upregulation in large-diameter sensory neurons.\",\n      \"method\": \"Comparative genomics, primary cell culture reporter assays, mouse transgenics, pharmacological MEK inhibition\",\n      \"journal\": \"Neuro-Signals\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — transgenic mouse reporter and pharmacological inhibition demonstrate enhancer–promoter synergy; moderate evidence from single lab\",\n      \"pmids\": [\"21160161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TAC1 promoter regulatory diversity in sensory neurons includes: (1) an autocrine loop via NK1 receptor activation of SP-expressing cells; (2) ECR2-dependent regulation by capsaicin/TRPV1 and potassium depolarization; (3) ECR2-independent LPS induction in a distinct neuronal population.\",\n      \"method\": \"Primary sensory neuron culture, reporter gene assays, pharmacological NK1 agonism, capsaicin treatment, live imaging\",\n      \"journal\": \"Journal of neuroinflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — reporter assay and pharmacology in primary culture; single lab, multiple readouts\",\n      \"pmids\": [\"21294877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"SDF-1α regulates Tac1 expression in bone marrow stromal cells via NF-κB: high SDF-1α (50–100 ng/mL) activates NF-κB through PI3K–PDK1–AKT signaling to repress Tac1, while low SDF-1α stimulates Tac1 expression; Tac1-derived substance P then promotes hematopoiesis through NK1 (not NK2) receptor.\",\n      \"method\": \"Reporter gene assays with mutant IκB, gel shift assays, Northern analysis, ELISA, long-term culture-initiating cell assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (reporter, EMSA, functional assay); single lab\",\n      \"pmids\": [\"17277111\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SDF-1α activates Tac1 in nontumorigenic breast cells via a non-canonical pathway: Gαi2–PI3K–PKCζ–p38–ERK–CREB (not cAMP–PKA), acting through CRE sites in the TAC1 promoter.\",\n      \"method\": \"Reporter gene assays with mutant CRE sites, co-transfection with ICER repressor, Western blot with specific kinase inhibitors\",\n      \"journal\": \"Journal of molecular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mutagenesis of CRE sites and pharmacological pathway dissection; single lab\",\n      \"pmids\": [\"18316470\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"During MSC-to-neuron differentiation, TAC1 induction proceeds through sequential activation of CRE1 (day 6) and CRE2/AP-1 (day 12) sites: decreased REST activates JNK, which phosphorylates ATF-2 (binding CRE1) and AP-1 (binding CRE2/AP-1).\",\n      \"method\": \"Reporter gene assays with mutant CRE sites, ectopic REST expression, PKA and JNK pharmacological inhibitors, chromatin immunoprecipitation\",\n      \"journal\": \"Stem cells and development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and mutagenesis combined with pathway inhibitors; single lab\",\n      \"pmids\": [\"21671725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Post-transcriptional regulation of Tac1 in bone marrow stroma involves RNA-binding proteins and miRNAs targeting the Tac1 3' UTR; cytokines (SCF, IL-11, TGF-β1) differentially regulate these interactions, with TGF-β1 promoting rapid RNA-binding protein association and cytokine-induced miRNA downregulation modulating Tac1 stability.\",\n      \"method\": \"RNA gel shift assays, miRNA binding assays with Tac1 3' UTR, cytokine stimulation\",\n      \"journal\": \"Brain, behavior, and immunity\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, single method (RNA shift) for protein binding; miRNA evidence is descriptive\",\n      \"pmids\": [\"18061399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"MeCP2 binds directly to the TAC1 promoter in HEK cells, and this binding is sensitive to valproic acid (antiepileptic) treatment, identifying TAC1 as a direct MeCP2 target gene.\",\n      \"method\": \"Chromatin immunoprecipitation in HEK cells, Sequenom EpiTYPER methylation validation, pharmacological VPA treatment\",\n      \"journal\": \"Journal of neurodevelopmental disorders\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP demonstrating direct protein–DNA interaction; single lab, moderate evidence\",\n      \"pmids\": [\"23759142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Tac1-expressing neurons in the lateral/ventrolateral periaqueductal gray (l/vlPAG) facilitate itch-scratching cycles via descending regulation; their activation is necessary and sufficient for itch-induced scratching, and the downstream circuit involves spinal GRPR+ neurons.\",\n      \"method\": \"Chemogenetics (DREADDs), optogenetics, neural activity recording, ablation, circuit tracing\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal in vivo manipulations (activation, inhibition, ablation) with defined circuit placement and behavioral readout\",\n      \"pmids\": [\"30554781\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In male mice, Tac1 deficiency causes delayed puberty and decreased expression of Pdyn and Nos1 in mediobasal hypothalamus; kisspeptin receptor (Kiss1R) and substance P receptor (NK1R) heterodimerize, and SP tone modulates responsiveness of GnRH neurons to kisspeptin.\",\n      \"method\": \"Tac1-/- mice, electrophysiology of arcuate Kiss1 neurons, central peptide administration, receptor heterodimerization assay\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with defined neuroendocrine phenotypes plus receptor heterodimerization biochemistry; single lab\",\n      \"pmids\": [\"28444173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Tac1-expressing neurons in the nucleus accumbens (NAc) lateral shell project to ventral pallidum and regulate stress-induced anhedonia-like behavior; inhibition/activation of Tac1NAc neurons bidirectionally modulates stress susceptibility, and NK1R inhibition promotes stress susceptibility.\",\n      \"method\": \"Chemogenetics, optogenetics, circuit tracing, viral-mediated circuit manipulation, electrophysiology\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal in vivo manipulations establishing specific circuit and behavioral role\",\n      \"pmids\": [\"33147466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Tac1 neurons in the NAc medial shell project to the lateral hypothalamic area (LH); activation of the NAcTac1→LH pathway promotes avoidance responses to aversive stimuli, and medial prefrontal cortex sends excitatory inputs to this NAc Tac1 circuit.\",\n      \"method\": \"Chemogenetics, optogenetic circuit dissection, rabies virus retrograde tracing, circuit-specific behavioral assays\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple circuit-tracing and manipulation methods; single lab\",\n      \"pmids\": [\"36901777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In Tac1 knockout mice lacking substance P and neurokinin A, morphine is a more potent analgesic, respiratory depression by morphine is reduced, morphine-withdrawal aversion is diminished, and behavioral sensitization is lower; demonstrating that tachykinins modulate opioid pharmacology.\",\n      \"method\": \"Tac1-/- knockout mice, analgesic assays, plethysmography, naloxone-precipitated withdrawal, conditioned place preference\",\n      \"journal\": \"British journal of pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with multiple defined pharmacological phenotypes across orthogonal behavioral readouts\",\n      \"pmids\": [\"20590634\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Tac1 knockout nociceptors fail to encode the duration and magnitude of mechanical stimuli and do not develop mechanical sensitization after injury; Tac1-/- mice show reduced paw edema and weight-bearing deficits after incision, establishing tachykinins as critical modulators of primary afferent electrical excitability.\",\n      \"method\": \"In vivo electrophysiology of primary afferents in Tac1-/- mice, paw incision model, mechanical stimulation\",\n      \"journal\": \"Molecular pain\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct electrophysiological recording from identified nociceptors in KO animals with clean phenotype\",\n      \"pmids\": [\"31012376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CRISPR-Cas9-engineered gain-of-function mutations in C. parapsilosis CpTAC1 (G650E substitution) activate CpCDR1, CpCDR1B, and CpCDR1C, causing an 8-fold increase in fluconazole MIC; correction of the mutation reduces MIC 16-fold, establishing CpTAC1 as a direct activator of CDR efflux pumps in C. parapsilosis.\",\n      \"method\": \"CRISPR-Cas9 precise genome editing, RNA sequencing, RT-qPCR, broth microdilution susceptibility testing\",\n      \"journal\": \"Clinical microbiology and infection\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — precise bidirectional genome editing (introduction and correction of mutation) with transcriptome-level confirmation\",\n      \"pmids\": [\"37666448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TAC1 is identified as a long-day signal gene in sheep pituitary pars tuberalis (PT); it is strongly activated by long photoperiod in the PT and its encoded peptides (substance P and neurokinin A) act as prolactin secretagogues (tuberalin candidates) on primary pituitary cells.\",\n      \"method\": \"Microarray, in situ hybridization, primary pituitary cell prolactin secretion assay\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in situ hybridization plus direct functional assay on primary cells; single study\",\n      \"pmids\": [\"20434341\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Human/mammalian TAC1 encodes the tachykinin neuropeptides substance P and neurokinin A, which are transcriptionally regulated by REST/NF-κB cooperative repression and MEK/ERK-dependent enhancer–promoter synergy, post-transcriptionally regulated by RNA-binding proteins and miRNAs; in Candida albicans, TAC1 encodes a Zn-cluster transcription factor whose N-terminal DBD binds Drug Responsive Elements in CDR1/CDR2 promoters and whose C-terminal activation domain recruits TBP and the Mediator tail module to drive azole resistance, with gain-of-function mutations relieving middle-region inhibition to hyperactivate this pathway; in C. elegans the TACC ortholog TAC-1 physically complexes with the XMAP215-family protein ZYG-9 and separately with ZYG-8 to promote centrosomal microtubule growth in an Aurora-A-dependent manner; and in mammalian neurons, Tac1-expressing circuits in PAG, nucleus accumbens, and amygdala mediate itch facilitation, stress-induced anhedonia, avoidance behavior, and fear memory consolidation through defined descending and limbic pathways.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"Mammalian TAC1 encodes the precursor of the tachykinin neuropeptides substance P and neurokinin A, which function as critical modulators of nociception, emotional behavior, neuroendocrine signaling, and itch processing through defined neural circuits. Tac1 knockout mice exhibit reduced anxiety- and depression-related behaviors [PMID:12427862], altered opioid pharmacology [PMID:20590634], failure of nociceptor mechanical encoding and sensitization [PMID:31012376], and delayed male puberty due to impaired kisspeptin–GnRH signaling [PMID:28444173]; Tac1-expressing neurons in the periaqueductal gray, nucleus accumbens, and amygdala drive itch facilitation, stress-induced anhedonia, and avoidance behavior through projection-specific circuits [PMID:30554781, PMID:33147466, PMID:36901777]. TAC1 transcription is repressed by REST and NF-κB acting cooperatively at the promoter [PMID:17709376, PMID:19246391] and is induced through MEK/ERK-dependent enhancer–promoter synergy and sequential CRE/AP-1 site activation during neuronal differentiation [PMID:21160161, PMID:21671725]. In Candida albicans, the unrelated Zn-cluster transcription factor Tac1 drives azole resistance by binding Drug Responsive Elements in CDR1/CDR2 promoters via its N-terminal DNA-binding domain and recruiting TBP and the Mediator tail module through its C-terminal activation domain, with gain-of-function mutations relieving middle-region autoinhibition [PMID:28807920, PMID:37502396, PMID:18363649].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Establishing that mammalian Tac1-derived tachykinins are functional mediators of emotional behavior resolved whether substance P/neurokinin A loss has measurable behavioral consequences in vivo.\",\n      \"evidence\": \"Tac1 knockout mice tested across multiple anxiety and depression behavioral paradigms\",\n      \"pmids\": [\"12427862\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific neural circuits mediating the behavioral phenotypes were undefined\", \"Whether effects are due to substance P, neurokinin A, or both was not resolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identification of C. elegans TAC-1 as a TACC-family protein that physically complexes with ZYG-9 to promote centrosomal microtubule assembly established a conserved TACC–XMAP215 paradigm for microtubule growth regulation.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, in vitro pulldown, FRAP-based microtubule assembly, RNAi, and live GFP imaging across three independent studies\",\n      \"pmids\": [\"12956950\", \"12956951\", \"12956952\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of TAC-1–ZYG-9 interaction was not determined\", \"Whether TAC-1 has microtubule-stabilizing activity independent of ZYG-9 was unclear\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Discovery of REST and NF-κB cooperative repression of TAC1 transcription revealed how this neuropeptide gene is silenced in non-neuronal cells and modulated during inflammation.\",\n      \"evidence\": \"ChIP, site-directed mutagenesis, and loss-of-function transfection in human mesenchymal stem cells and breast cancer cells\",\n      \"pmids\": [\"17709376\", \"19246391\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether REST–NF-κB co-occupancy is universal across all TAC1-expressing lineages was not tested\", \"Chromatin remodeling events downstream of REST binding were not characterized\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"TAC-1 was shown to form a separate complex with doublecortin-family protein ZYG-8, partially redundant with the ZYG-9–TAC-1 complex, broadening TAC-1's role beyond a single microtubule assembly pathway.\",\n      \"evidence\": \"Co-immunoprecipitation showing TAC-1–ZYG-8 complex is ZYG-9-independent; genetic epistasis with temperature-sensitive alleles in C. elegans embryos\",\n      \"pmids\": [\"17666432\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ZYG-8 and ZYG-9 compete for the same TAC-1 binding surface was not determined\", \"Relative contribution of each complex during different cell-cycle stages was not quantified\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrating SDF-1α dose-dependent regulation of Tac1 via NF-κB in bone marrow stroma, with substance P promoting hematopoiesis through NK1R, linked Tac1 to the hematopoietic niche.\",\n      \"evidence\": \"Reporter assays with mutant IκB, EMSA, ELISA, and long-term culture-initiating cell assays in bone marrow stromal cells\",\n      \"pmids\": [\"17277111\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance of SP-mediated hematopoiesis was not tested in Tac1 KO bone marrow\", \"Post-transcriptional regulation details were incomplete\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identification of Candida albicans TAC1 as a Zn-cluster transcription factor driving CDR1/CDR2-mediated azole resistance, with gene-dose-dependent effects on fluconazole MIC, established the molecular basis of clinical drug resistance.\",\n      \"evidence\": \"Gene deletion, copy-number manipulation via telomere-mediated truncation, and fluconazole susceptibility assays\",\n      \"pmids\": [\"18363649\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The direct xenobiotic-sensing mechanism was not identified\", \"Whether TAC1 amplification is the sole driver of isochromosome 5L–mediated resistance was unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Tac1 knockout mice showed enhanced morphine analgesia with reduced respiratory depression and withdrawal aversion, establishing tachykinins as modulators of opioid pharmacology.\",\n      \"evidence\": \"Tac1−/− mice assessed by analgesic assays, plethysmography, withdrawal, and conditioned place preference\",\n      \"pmids\": [\"20590634\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which tachykinin (SP vs NKA) and which receptor mediate each opioid-modulating effect was not dissected\", \"Central vs peripheral contributions were not separated\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Discovery that TAC1 induction in sensory neurons requires MEK/ERK-dependent synergy between the promoter and a distal enhancer (ECR2) explained how noxious stimulation selectively activates TAC1 in specific neuronal populations.\",\n      \"evidence\": \"Comparative genomics, primary neuron reporter assays, mouse transgenics, and MEK pharmacological inhibition\",\n      \"pmids\": [\"21160161\", \"21294877\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the transcription factors binding ECR2 was not fully resolved\", \"In vivo contribution of ECR2 to pain phenotypes was not tested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Sequential CRE1 then CRE2/AP-1 site activation during MSC-to-neuron differentiation, driven by REST relief and JNK signaling, defined the temporal program of TAC1 induction during neurogenesis.\",\n      \"evidence\": \"Reporter assays with CRE site mutations, REST overexpression, JNK/PKA inhibitors, and ChIP during MSC differentiation\",\n      \"pmids\": [\"21671725\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether this temporal program operates in vivo neurogenesis was not confirmed\", \"Epigenetic changes at the TAC1 locus during differentiation were not mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Mechanistic dissection of C. albicans Tac1 showed that gain-of-function mutations or xenobiotics relieve middle-region autoinhibition of the C-terminal activation domain, enabling Mediator tail module recruitment to CDR1, directly linking Tac1 domain architecture to drug resistance.\",\n      \"evidence\": \"Domain deletion/mutagenesis, ChIP showing Mediator recruitment, reporter assays, and drug susceptibility testing\",\n      \"pmids\": [\"28807920\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of middle-region autoinhibition was not resolved\", \"The specific xenobiotic-binding site within the middle homology region was not identified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identification of Tac1-expressing PAG neurons as necessary and sufficient for itch-scratch facilitation via descending spinal GRPR+ circuits placed Tac1 within a defined sensory-modulatory circuit.\",\n      \"evidence\": \"Chemogenetics, optogenetics, neural recording, ablation, and circuit tracing in mice\",\n      \"pmids\": [\"30554781\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether substance P itself or co-released transmitters mediate the descending itch signal was not resolved\", \"Role of neurokinin A in this circuit was not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrating that Tac1 knockout nociceptors fail to encode mechanical stimulus intensity and do not develop post-injury sensitization established tachykinins as modulators of primary afferent excitability, not just central neuromodulators.\",\n      \"evidence\": \"In vivo electrophysiology of primary afferents in Tac1−/− mice with paw incision model\",\n      \"pmids\": [\"31012376\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which tachykinins modulate ion channel activity in nociceptors was not identified\", \"Whether this reflects autocrine signaling was not determined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Tac1-expressing NAc lateral shell neurons were shown to bidirectionally regulate stress-induced anhedonia via projections to ventral pallidum, establishing a limbic circuit role for Tac1 in mood regulation.\",\n      \"evidence\": \"Chemogenetics, optogenetics, circuit tracing, electrophysiology in stressed vs resilient mice\",\n      \"pmids\": [\"33147466\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SP or NKA mediates the anti-anhedonic effect was not resolved\", \"Upstream inputs activating NAc Tac1 neurons during stress were not mapped\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Domain-level dissection of C. albicans Tac1 confirmed the N-terminal DBD binds DREs and the C-terminal AAD directly recruits TBP, completing a minimal model for Tac1-driven transcriptional activation of CDR genes.\",\n      \"evidence\": \"Domain deletion analysis, reporter assays, and protein–protein interaction studies\",\n      \"pmids\": [\"37502396\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural data for any Tac1 domain exists\", \"Whether AAD–TBP interaction is sufficient without Mediator was not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"CRISPR-engineered gain-of-function TAC1 mutations in C. parapsilosis recapitulated azole resistance, confirming conservation of the TAC1-CDR resistance mechanism beyond C. albicans.\",\n      \"evidence\": \"Bidirectional CRISPR-Cas9 editing, RNA-seq, and broth microdilution MIC testing in C. parapsilosis\",\n      \"pmids\": [\"37666448\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Domain architecture and activation mechanism in C. parapsilosis Tac1 have not been dissected\", \"Whether Mediator recruitment is conserved in this species is unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Major open questions include the structural basis of Tac1 autoinhibition and xenobiotic sensing in Candida, the specific tachykinin peptide (SP vs NKA) responsible for individual circuit-level behavioral phenotypes in mammals, and the mechanism by which tachykinins modulate primary afferent excitability.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal or cryo-EM structure of any Tac1 domain\", \"SP vs NKA contribution not separated in most neural circuit studies\", \"Autocrine vs paracrine tachykinin signaling at nociceptors not resolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [3, 17, 19, 21, 22, 24]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [6, 7, 8, 9, 23]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [3, 17, 19, 24]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [6, 7, 9]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [3, 17, 19, 20, 22]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [12, 13, 18]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [4, 5, 7, 9, 14]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [6, 7, 23]}\n    ],\n    \"complexes\": [\n      \"ZYG-9–TAC-1 complex\",\n      \"ZYG-8–TAC-1 complex\"\n    ],\n    \"partners\": [\n      \"ZYG-9\",\n      \"ZYG-8\",\n      \"REST\",\n      \"RELA\",\n      \"TACR1\",\n      \"MED15\",\n      \"TBP\",\n      \"MECP2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}