Research Topics
| T HardenSummaryAffiliation: University of North Carolina Country: USA Publications
Research Grants
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Detail Information
Publications
Purification and G protein subunit regulation of a phospholipase C-beta from Xenopus laevis oocytesT M Filtz
Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA
J Biol Chem 271:31121-6. 1996....- Regulation of phospholipase C isozymes by ras superfamily GTPasesT Kendall Harden
Departments of Pharmacology, Biochemistry and Biophysics, and Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
Annu Rev Pharmacol Toxicol 46:355-79. 2006.... - A fusion protein of the human P2Y(1) receptor and NTPDase1 exhibits functional activities of the native receptor and ectoenzyme and reduced signaling responses to endogenously released nucleotidesClaudia Alvarado-Castillo
Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA
Mol Pharmacol 62:521-8. 2002..Although marked elevation of inositol phosphate levels occurred with wild-type P2Y(1) receptor expression, levels in cells expressing the fusion protein were not different from those in wild-type CHO-K1 cells... - Phospholipase C isozymes as effectors of Ras superfamily GTPasesT Kendall Harden
Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
J Lipid Res 50:S243-8. 2009..High resolution three-dimensional structures of phospholipase C isozymes also are beginning to shed light on their mechanism of activation... - Signalling and pharmacological properties of the P2Y receptorT K Harden
Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
Acta Physiol (Oxf) 199:149-60. 2010..This receptor historically was thought to be activated selectively by UDP-glucose and other UDP-sugars. However, UDP is also a very potent agonist of this receptor, and may prove to be one of its most important cognate activators... - Application of RGS box proteins to evaluate G-protein selectivity in receptor-promoted signalingMelinda D Hains
Department of Pharmacology, The University of North Carolina School of Medicine, Chapel Hill 27599, USA
Methods Enzymol 389:71-88. 2004.... - Quantification of isozyme-specific activation of phospholipase C-beta2 by Rac GTPases and phospholipase C-epsilon by Rho GTPases in an intact cell assay systemDavid M Bourdon
Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, USA
Methods Enzymol 406:489-99. 2006.... - Regulation of P2Y1 receptor-mediated signaling by the ectonucleoside triphosphate diphosphohydrolase isozymes NTPDase1 and NTPDase2Claudia Alvarado-Castillo
Department of Pharmacology, University of North Carolina School of Medicine, CB 7365, Chapel Hill, NC 27599 7365, USA
Mol Pharmacol 67:114-22. 2005.... - RGS6, RGS7, RGS9, and RGS11 stimulate GTPase activity of Gi family G-proteins with differential selectivity and maximal activityShelley B Hooks
Department of Pharmacology, University of North Carolina, Chapel Hill 27599, USA
J Biol Chem 278:10087-93. 2003..Therefore, R7 family RGS proteins are G(i) family-selective GAPs with potentially important differences in activities... - Kinetic scaffolding mediated by a phospholipase C-beta and Gq signaling complexGary L Waldo
Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
Science 330:974-80. 2010..Mutations within this domain dramatically delay signal termination in vitro and in vivo. Consequently, this work suggests a dynamic catch-and-release mechanism used to sharpen spatiotemporal signals mediated by diverse sensory inputs... - [32P]2-iodo-N6-methyl-(N)-methanocarba-2'-deoxyadenosine-3',5'-bisphosphate ([32P]MRS2500), a novel radioligand for quantification of native P2Y1 receptorsDayle Houston
Department of Pharmacology, University of North Carolina School of Medicine, CB 7365 Chapel Hill, NC 27599, USA
Br J Pharmacol 147:459-67. 2006..Taken together, these data illustrate the synthesis and characterization of a novel P2Y1 receptor radioligand and its utility for examining P2Y1 receptor expression in native mammalian tissues... - PLC-epsilon: a shared effector protein in Ras-, Rho-, and G alpha beta gamma-mediated signalingMichele R Wing
Department of Pharmacology University of North Carolina School of Medicine Chapel Hill, NC 27599, USA
Mol Interv 3:273-80. 2003..Thus, PLC-epsilon is a multifunctional nexus protein that senses and mediates crosstalk between heterotrimeric and small GTPase signaling pathways... - Regulation of PLCbeta isoforms by RacJason T Snyder
Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, USA
Methods Enzymol 406:272-80. 2006..The experimental format described is also readily adaptable toward characterizing guanine nucleotide-dependent binding events of both small and heterotrimeric G proteins with various classes of GTPase regulatory proteins... - Molecular cloning and characterization of PLC-eta2Yixing Zhou
Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
Biochem J 391:667-76. 2005..Co-expression of PLC-eta2 with Gbeta1gamma2 dimers of heterotrimeric G-proteins resulted in marked stimulation of inositol lipid hydrolysis. Thus PLC-eta2 may in part function downstream of G-protein-coupled receptors... - Direct activation of phospholipase C-epsilon by RhoMichele R Wing
Department of Pharmacology, The Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA
J Biol Chem 278:41253-8. 2003.... - Induction of novel agonist selectivity for the ADP-activated P2Y1 receptor versus the ADP-activated P2Y12 and P2Y13 receptors by conformational constraint of an ADP analogMariya Chhatriwala
University of North Carolina, School of Medicine, Department of Pharmacology, CB #7365, Chapel Hill, NC 27599-7365, USA
J Pharmacol Exp Ther 311:1038-43. 2004.... - The pleckstrin homology domain of phospholipase C-beta2 as an effector site for RacJason T Snyder
Department of Pharmacology, The University of North Carolina, Chapel Hill, North Carolina 27599, USA
J Biol Chem 278:21099-104. 2003..Together, these findings present a quantitative evaluation of the direct interactions between Rac GTPases and PLC-beta isozymes and define a novel role for the PH domain of PLC-beta2 as a putative effector site for Rac GTPases... - DLC-1 suppresses non-small cell lung cancer growth and invasion by RhoGAP-dependent and independent mechanismsKevin D Healy
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, NC 27599 7295, USA
Mol Carcinog 47:326-37. 2008..Combined, these studies provide information on the mechanism of DLC-1 function and regulation, and further support the role of DLC-1 tumor suppression in NSCLC... - Dual activation of phospholipase C-epsilon by Rho and Ras GTPasesJason P Seifert
Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA
J Biol Chem 283:29690-8. 2008..These results indicate that PLC-epsilon can be directly and concomitantly activated by both RhoA and individual Ras GTPases resulting in diverse upstream control of signaling cascades downstream of PLC-epsilon... - Quantification of Gi-mediated inhibition of adenylyl cyclase activity reveals that UDP is a potent agonist of the human P2Y14 receptorRhonda L Carter
Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC, USA
Mol Pharmacol 76:1341-8. 2009..We conclude that UDP is an important cognate agonist of the human P2Y14 receptor... - RhoA activates purified phospholipase C-epsilon by a guanine nucleotide-dependent mechanismJason P Seifert
Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA
J Biol Chem 279:47992-7. 2004..These results indicate that PLC-epsilon is a direct downstream effector for RhoA and that RhoA-dependent activation of PLC-epsilon depends on a unique insert within the catalytic core of the phospholipase... - Development of selective high affinity antagonists, agonists, and radioligands for the P2Y1 receptorDayle Houston
Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
Comb Chem High Throughput Screen 11:410-9. 2008..A similar rational approach is being applied to develop selective ligands for other subtypes of P2Y receptors... - Galpha12/13- and rho-dependent activation of phospholipase C-epsilon by lysophosphatidic acid and thrombin receptorsMelinda D Hains
Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7365, USA
Mol Pharmacol 69:2068-75. 2006..These studies illustrate that specific LPA and thrombin receptors promote inositol lipid signaling via activation of Galpha(12/13) and Rho... - General and versatile autoinhibition of PLC isozymesStephanie N Hicks
Department of Pharmacology, The University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
Mol Cell 31:383-94. 2008..Similar regulation occurs in other PLC members, and a general mechanism of interfacial activation at membranes is presented that provides a unifying framework for PLC activation by diverse stimuli... - A unique fold of phospholipase C-beta mediates dimerization and interaction with G alpha qAlex U Singer
Department of Pharmacology, The University of North Carolina at Chapel Hill, North Carolina 27599, USA
Nat Struct Biol 9:32-6. 2002..Effector dimerization, as highlighted by PLC-betas, provides a viable mechanism for regulating signaling cascades linked to heterotrimeric G proteins... - Purification and functional reconstitution of the human P2Y12 receptorErik T Bodor
Department of Pharmacology, University of North Carolina Chapel Hill, Chapel Hill, NC 27599-7365, USA
Mol Pharmacol 64:1210-6. 2003.... - Structure of Galpha(i1) bound to a GDP-selective peptide provides insight into guanine nucleotide exchangeChristopher A Johnston
Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Structure 13:1069-80. 2005..Our results cast light onto a potential mechanism by which Galpha subunits adopt a conformation suitable for nucleotide exchange... - Quantitation of the P2Y(1) receptor with a high affinity radiolabeled antagonistGary L Waldo
Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA
Mol Pharmacol 62:1249-57. 2002..Taken together, these results indicate that [(3)H]MRS2279 is the first broadly applicable antagonist radioligand for a P2Y receptor... - Gi-dependent cell signaling responses of the human P2Y14 receptor in model cell systemsIngrid P Fricks
Department of Pharmacology, University of North Carolina, School of Medicine, Chapel Hill, NC 27599, USA
J Pharmacol Exp Ther 330:162-8. 2009..This work also identifies two stable P2Y(14)-R-expressing cell lines and differentiated HL-60 cells as model systems for the study of P2Y(14)-R-dependent signal transduction... - Crystal structure of Rac1 bound to its effector phospholipase C-beta2Mark R Jezyk
Department of Biochemistry and Biophysics The University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA
Nat Struct Mol Biol 13:1135-40. 2006.... - Aberrant receptor internalization and enhanced FRS2-dependent signaling contribute to the transforming activity of the fibroblast growth factor receptor 2 IIIb C3 isoformJiyoung Y Cha
Lineberger Comprehensive Cancer Center, Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina 27599 7295, USA
J Biol Chem 284:6227-40. 2009..Our data support a dual mechanism where deletion of the 770YXXL773 motif promotes FGFR2 IIIb C3 transforming activity by causing aberrant receptor recycling and stability and persistent FRS2-dependent signaling... - Direct activation of purified phospholipase C epsilon by RhoA studied in reconstituted phospholipid vesiclesJason P Seifert
Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, USA
Methods Enzymol 406:260-71. 2006..The capacity of GTPgammaS-bound RhoA to stimulate the phospholipase activity of PLC-epsilon is assessed by reconstitution of the RhoA in mixed-detergent phospholipid micelles containing PtdIns(4,5)P2 substrate... - Mechanisms of release of nucleotides and integration of their action as P2X- and P2Y-receptor activating moleculesEduardo R Lazarowski
Department of Pharmacology, University of North Carolina School of Medicine, CB#7365, Chapel Hill, NC 27599, USA
Mol Pharmacol 64:785-95. 2003 - UDP is a competitive antagonist at the human P2Y14 receptorIngrid P Fricks
Department of Pharmacology, University of North Carolina, CB 7365 Mary Ellen Jones Bldg, Chapel Hill, NC 27599 7365, USA
J Pharmacol Exp Ther 325:588-94. 2008..35 muM) at the rat P2Y(14)-R. These results identify the first competitive antagonist of the P2Y(14)-R and demonstrate pharmacological differences between receptor orthologs... - Agonist versus antagonist action of ATP at the P2Y4 receptor is determined by the second extracellular loopChristopher L Herold
Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina 27599 7365, USA
J Biol Chem 279:11456-64. 2004..Taken together, these results suggest that the second extracellular loop and the NH(2) terminus form a functional motif that plays a key role in determining whether ATP functions as an agonist or antagonist at mammalian P2Y(4) receptors... - Polarized expression of human P2Y receptors in epithelial cells from kidney, lung, and colonSamuel C Wolff
Department of Pharmacology, The University of North Carolina-Chapel Hill, 1027 Mary Ellen Jones Bldg, CB# 7365, Chapel Hill, NC 27599, USA
Am J Physiol Cell Physiol 288:C624-32. 2005..These experiments highlight the highly polarized expression of P2Y receptors in epithelial cells... - Agonist binding and Gq-stimulating activities of the purified human P2Y1 receptorGary L Waldo
Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599 7365, USA
Mol Pharmacol 65:426-36. 2004..These results illustrate that the binding and signaling properties of the human P2Y1-R can be studied with purified proteins under conditions that circumvent the complications that occur in vivo... - Purification and in vitro functional analysis of R7 subfamily RGS proteins in complex with Gbeta5Shelley B Hooks
Department of Pharmacology, University of North Carolina, Chapel Hill 27599, USA
Methods Enzymol 390:163-77. 2004..The ability of the heterodimers to accelerate the intrinsic GTPase activity of Galpha subunits was assessed in steady-state GTPase assays performed on proteoliposomes consisting of phospholipids, purified G proteins, and purified GPCRs... - Activation of human phospholipase C-eta2 by GbetagammaYixing Zhou
Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA
Biochemistry 47:4410-7. 2008..Taken together, these studies illustrate that PLC-eta2 is a direct downstream effector of Gbetagamma and, therefore, of receptor-activated heterotrimeric G proteins... - Crystal structure of the multifunctional Gbeta5-RGS9 complexMatthew L Cheever
Department of Pharmacology, University of North Carolina School of Medicine, Campus Box 7365, Chapel Hill, North Carolina 27599 7365, USA
Nat Struct Mol Biol 15:155-62. 2008..This structure reveals a canonical RGS domain that is functionally integrated within a molecular complex that is poised for integration of multiple steps during G-protein activation and deactivation... - Release of cellular UDP-glucose as a potential extracellular signaling moleculeEduardo R Lazarowski
Department of Medicine, Cystic Fibrosis Center, University of North Carolina School of Medicine, Chapel Hill 27599, USA
Mol Pharmacol 63:1190-7. 2003..Because cellular UDP-glucose is concentrated in the lumen of the endoplasmic reticulum, we speculate that UDP-glucose release may occur as a result of vesicle transport during trafficking of glycoproteins to the plasma membrane... - C(8) substituted 1-azabicyclo[3.3.1]non-3-enes and C(8) substituted 1-azabicyclo[3.3.1]nonan-4-ones: novel muscarinic receptor antagonistsMyoung Goo Kim
Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7360, USA
J Med Chem 46:2216-26. 2003..Compound 3 serves as a novel lead compound for further drug development... - Requirement of Cys399 for processing of the human ecto-ATPase (NTPDase2) and its implications for determination of the activities of splice variants of the enzymeJesús Mateo
Department of Pharmacology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599 7365, USA
J Biol Chem 278:39960-8. 2003.... - 2-Substitution of adenine nucleotide analogues containing a bicyclo[3.1.0]hexane ring system locked in a northern conformation: enhanced potency as P2Y1 receptor antagonistsHak Sung Kim
Molecular Recognition Section, Laboratory of Bioorganic Chemistry, NIDDK, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892-0810, USA
J Med Chem 46:4974-87. 2003..An enzymatic method of synthesis of the 3',5'-bisphosphate from the corresponding 3'-monophosphate, suitable for the preparation of a radiophosphorylated analogue, was explored... - Antiaggregatory activity in human platelets of potent antagonists of the P2Y 1 receptorMarco Cattaneo
Hematology and Thrombosis Unit, Ospedale San Paolo, DMCO-University of Milan, Milan, Italy
Biochem Pharmacol 68:1995-2002. 2004..Thus, all three of the bisphosphate derivatives are highly selective antagonists of the platelet P2Y(1) receptor, and MRS2500 is the most potent such antagonist yet reported... - Adenine nucleotide analogues locked in a Northern methanocarba conformation: enhanced stability and potency as P2Y(1) receptor agonistsR Gnana Ravi
Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes, Digestive and Kidney Diseases/NIH, Building 8A, Room B1A-17, Bethesda, MD 20892-0810, USA
J Med Chem 45:2090-100. 2002..This suggests that new, more stable and selective nucleotide agonists may be designed on the basis of the (N)-conformation, which greatly enhanced potency at P2Y(1) receptors... - UDP acts as a growth factor for vascular smooth muscle cells by activation of P2Y(6) receptorsMingyan Hou
Division of Experimental Vascular Research, Department of Medicine, University Hospital, SE 221 85 Lund, Sweden
Am J Physiol Heart Circ Physiol 282:H784-92. 2002..The results demonstrate that UDP stimulates mitogenesis through activation of P2Y(6) receptors and that the receptor is regulated by factors important in the development of vascular disease... - Methanocarba modification of uracil and adenine nucleotides: high potency of Northern ring conformation at P2Y1, P2Y2, P2Y4, and P2Y11 but not P2Y6 receptorsHak Sung Kim
Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-0810, USA
J Med Chem 45:208-18. 2002..Our results suggest that new nucleotide agonists may be designed on the basis of the (N) conformation that favors selectivity for P2Y1, P2Y2, P2Y4, and P2Y11 receptors... - Nucleotide analogues containing 2-oxa-bicyclo[2.2.1]heptane and l-alpha-threofuranosyl ring systems: interactions with P2Y receptorsMichihiro Ohno
Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases/NIH/DHHS, Bethesda, MD 20892-0810, USA
Bioorg Med Chem 12:5619-30. 2004..9 microM) versus P2Y(4) receptors. The P2Y(1) receptor binding modes, including rotational angles, were estimated using molecular modeling and receptor docking... - Synthesis and potency of novel uracil nucleotides and derivatives as P2Y2 and P2Y6 receptor agonistsHyojin Ko
Molecular Recognition Section, Laboratory of Bioorganic Chemistry, NIDDK, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892 0810, USA
Bioorg Med Chem 16:6319-32. 2008.... - Structure-activity relationship of uridine 5'-diphosphoglucose analogues as agonists of the human P2Y14 receptorHyojin Ko
Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
J Med Chem 50:2030-9. 2007..The hexose moiety of UDPG interacts with multiple H-bonding and charged residues and provides a fertile region for agonist modification... - Molecular modeling of the human P2Y2 receptor and design of a selective agonist, 2'-amino-2'-deoxy-2-thiouridine 5'-triphosphateAndrei A Ivanov
Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
J Med Chem 50:1166-76. 2007..This detailed view of P2Y2 receptor recognition suggests mutations for model validation... - Structure-activity relationships of uridine 5'-diphosphate analogues at the human P2Y6 receptorPedro Besada
Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
J Med Chem 49:5532-43. 2006..These results provide a better understanding of molecular recognition at the P2Y6 receptor and will be helpful in designing selective and potent P2Y6 receptor ligands... - Human P2Y(6) receptor: molecular modeling leads to the rational design of a novel agonist based on a unique conformational preferenceStefano Costanzi
NIDDK, National Institutes of Health, DHHS, Bethesda, Maryland 20892 USA
J Med Chem 48:8108-11. 2005..MD results also suggested a conformational change of the second extracellular loop consequent to agonist binding... - Structure activity and molecular modeling analyses of ribose- and base-modified uridine 5'-triphosphate analogues at the human P2Y2 and P2Y4 receptorsKenneth A Jacobson
Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA
Biochem Pharmacol 71:540-9. 2006.... - P2Y1 antagonists: combining receptor-based modeling and QSAR for a quantitative prediction of the biological activity based on consensus scoringStefano Costanzi
Laboratory of Biological Modeling, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland 20892, USA
J Med Chem 50:3229-41. 2007..LIST-CM outperformed internal and external predictivity of any individual model to predict accurately the potency of 75% of the test set...
Research Grants
- REGULATION OF PHOSPHOLIPASE CT Harden; Fiscal Year: 2002..Completion of the work described in this proposal should considerably extend knowledge of the identify, specificity, and mechanism of interaction of the component proteins of the receptor-regulated inositol lipid signalling pathway. ..
- P2Y-PURINERGIC RECEPTORST Harden; Fiscal Year: 2004..abstract_text> ..
- G protein signal integration by multifunctional proteinsT Harden; Fiscal Year: 2006..abstract_text> ..
- P2Y-PURINERGIC RECEPTORST Harden; Fiscal Year: 2007....
- P2Y-PURINERGIC RECEPTORST Harden; Fiscal Year: 2009..We anticipate that furthering the basic understanding of other receptors in this group of important signaling proteins will lead to similarly important therapeutic agents. ..
- P2Y-PURINERGIC RECEPTORST Kendall Harden; Fiscal Year: 2010..We anticipate that furthering the basic understanding of other receptors in this group of important signaling proteins will lead to similarly important therapeutic agents. ..
- P2Y-PURINERGIC RECEPTORST Harden; Fiscal Year: 2000....
- MUSCARINIC RECEPTOR SUBTYPES ON CULTURED CELLST Harden; Fiscal Year: 1991..Rational therapy of a number of pathophysiological conditions, e.g. Alzheimer's disease, can ultimately benefit from this knowledge...
- P2Y-PURINERGIC RECEPTORST Harden; Fiscal Year: 1993....
- P2Y-PURINERGIC RECEPTORST Harden; Fiscal Year: 2009..We anticipate that furthering the basic understanding of other receptors in this group of important signaling proteins will lead to similarly important therapeutic agents. ..