Research Topics
Genomes and Genes | Wayne I LencerSummaryAffiliation: Harvard University Country: USA Publications
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Publications
Raft trafficking of AB5 subunit bacterial toxinsWayne I Lencer
GI Cell Biology, Enders 720, Children s Hospital Boston, the Harvard Digestive Diseases Center, and the Department of Pediatrics, Harvard Medical School, 300 Longwood Ave, Boston, MA 02115, USA
Biochim Biophys Acta 1746:314-21. 2005..The way certain lipids and proteins are clustered in the plane of the membrane to form lipid rafts likely explains how the glycolipids can function as sorting motifs for the toxins...
To translocate or not: that is the problemWayne I Lencer
Department of Medicine, Children s Hospital Boston, Harvard Medical School, MA 02115, USA
Cell Host Microbe 10:179-80. 2011..In this issue, Sun et al. (2011) show that BoNT binding to one of its cell surface receptors renders it susceptible to pH-dependent conformational changes required for translocation and cellular toxicity...- Diarrhea-associated HIV-1 APIs potentiate muscarinic activation of Cl- secretion by T84 cells via prolongation of cytosolic Ca2+ signalingPaul A Rufo
GI Cell Biology, Combined Program in Pediatric Gastroenterology and Nutrition, Children s Hospital, 300 Longwood Ave, Boston, MA 02115, USA
Am J Physiol Cell Physiol 286:C998-C1008. 2004..These data show that APIs modulate Ca(2+) signaling in secretory epithelial cells and identify a novel target for treatment of clinically important API side effects... - Dependence of antibody-mediated presentation of antigen on FcRnShuo Wang Qiao
Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
Proc Natl Acad Sci U S A 105:9337-42. 2008.... - Gangliosides that associate with lipid rafts mediate transport of cholera and related toxins from the plasma membrane to endoplasmic reticulmYukako Fujinaga
GI Cell Biology, Children s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
Mol Biol Cell 14:4783-93. 2003..Our results explain why LTIIb does not cause disease in humans and suggest that gangliosides with high affinity for lipid rafts may provide a general vehicle for the transport of toxins to the ER... - Ca2+-dependent calmodulin binding to FcRn affects immunoglobulin G transport in the transcytotic pathwayBonny L Dickinson
The Research Institute for Children, Children s Hospital, Department of Pediatrics, New Orleans, LA 70118, USA
Mol Biol Cell 19:414-23. 2008..These results suggest a novel mechanism for regulation of IgG transport by calmodulin-dependent sorting of FcRn and its cargo away from a degradative pathway and into a bidirectional transcytotic route... - Neonatal Fc receptor for IgG (FcRn) regulates cross-presentation of IgG immune complexes by CD8-CD11b+ dendritic cellsKristi Baker
Division of Gastroenterology, Brigham and Women s Hospital, Boston, MA 02115, USA
Proc Natl Acad Sci U S A 108:9927-32. 2011..Given the centrality of FcRn in controlling cross-presentation, these studies lay the foundation for a unique means to therapeutically manipulate CD8(+) T-cell responses... - Bidirectional transepithelial IgG transport by a strongly polarized basolateral membrane Fcgamma-receptorSteven M Claypool
Harvard Medical School, Program in Immunology, Brigham and Women s Hospital, Boston, Massachusetts 02115, USA
Mol Biol Cell 15:1746-59. 2004..Thus, the strong cell surface polarity displayed by hFcRn results from dominant basolateral sorting by motifs in the cytoplasmic tail that nonetheless allows for a cycle of bidirectional transcytosis... - Intoxication of zebrafish and mammalian cells by cholera toxin depends on the flotillin/reggie proteins but not Derlin-1 or -2David E Saslowsky
Division of Gastroenterology, Children s Hospital, Boston, Massachusetts, USA
J Clin Invest 120:4399-4409. 2010..These results revise current models for CT intoxication and implicate protein scaffolding of lipid rafts in the endo-somal sorting of the toxin-GM1 complex... - Human neonatal Fc receptor mediates transport of IgG into luminal secretions for delivery of antigens to mucosal dendritic cellsMasaru Yoshida
Gastroenterology Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA
Immunity 20:769-83. 2004..These results explain how IgG is secreted onto mucosal surfaces and scavenges luminal antigens for recognition by the immune system... - Attenuated endocytosis and toxicity of a mutant cholera toxin with decreased ability to cluster ganglioside GM1 moleculesAnne A Wolf
GI Cell Biology, Enders 720, Children s Hospital Boston, 300 Longwood Ave, Boston, MA 02115, USA
Infect Immun 76:1476-84. 2008.... - Selective translocation of the Bordetella pertussis adenylate cyclase toxin across the basolateral membranes of polarized epithelial cellsJoshua C Eby
Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA
J Biol Chem 285:10662-70. 2010..Thus, elements of the basolateral membrane render epithelial cells highly sensitive to the entry of ACT in the absence of a specific receptor for toxin binding... 
Immune and non-immune functions of the (not so) neonatal Fc receptor, FcRnKristi Baker
Division of Gastroenterology, Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
Semin Immunopathol 31:223-36. 2009..A greater understanding of FcRn's pleiotropic roles is thus imperative for a variety of therapeutic purposes...- Role of p97 AAA-ATPase in the retrotranslocation of the cholera toxin A1 chain, a non-ubiquitinated substrateMichael Kothe
GI Cell Biology, Children s Hospital Boston, the Harvard Digestive Diseases Center, Harvard Medical School, Massachusetts 02115, USA
J Biol Chem 280:28127-32. 2005..These results suggest that p97 does not provide the primary driving force for extracting the A1 chain from the endoplasmic reticulum, a finding that is consistent with a requirement for polyubiquitination in p97 function... - An FcRn-dependent role for anti-flagellin immunoglobulin G in pathogenesis of colitis in miceKanna Kobayashi
Gastroenterology Division, Department of Medicine, Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
Gastroenterology 137:1746-56.e1. 2009.... - Lipid sorting by ceramide structure from plasma membrane to ER for the cholera toxin receptor ganglioside GM1Daniel J F Chinnapen
Division of Gastroenterology, Boston Children s Hospital, Harvard Medical School, Boston, MA 02115, USA
Dev Cell 23:573-86. 2012..The results implicate a protein-dependent mechanism of lipid sorting by ceramide structure and provide a molecular explanation for the diversity and specificity of retrograde trafficking by CT in host cells... - Retrograde transport of cholera toxin from the plasma membrane to the endoplasmic reticulum requires the trans-Golgi network but not the Golgi apparatus in Exo2-treated cellsYan Feng
Department of Cell Biology, Institute of Chemistry and Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA
EMBO Rep 5:596-601. 2004..We propose that even in the absence of Exo2 the glycolipid pathway that carries the toxin from plasma membrane into the ER bypasses the Golgi apparatus entirely... - The recycling and transcytotic pathways for IgG transport by FcRn are distinct and display an inherent polaritySalit Tzaban
Children s Hospital, Gastroenterology Division, Harvard Digestive Diseases Center, Harvard Medical School, Boston, MA 02115, USA
J Cell Biol 185:673-84. 2009.... - N-terminal extension of the cholera toxin A1-chain causes rapid degradation after retrotranslocation from endoplasmic reticulum to cytosolNaomi L B Wernick
Gastrointestinal Cell Biology Laboratory, Children s Hospital, and Harvard Medical School, Boston, Massachusetts 02115, USA
J Biol Chem 285:6145-52. 2010..Thus, retrotranslocation and refolding of the wild-type A1-chain must proceed in a way that protects these Lys residues from attack by E3 ligases... - Neonatal Fc receptor: from immunity to therapeuticsTimothy T Kuo
Division of Gastroenterology, Department of Medicine, Brigham and Women s Hospital, Harvard Medical School, 75 Francis St, Boston, MA 02115, USA
J Clin Immunol 30:777-89. 2010..Here, we aim to summarize the basic understanding of FcRn biology, its functions in various organs, and the therapeutic design of antibody- and albumin-based therapeutics in light of their interactions with FcRn... - Neonatal Fc receptor for IgG regulates mucosal immune responses to luminal bacteriaMasaru Yoshida
Department of Medicine, Brigham and Women s Hospital, and Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, MA 02115, USA
J Clin Invest 116:2142-2151. 2006.... - A biochemical method for tracking cholera toxin transport from plasma membrane to Golgi and endoplasmic reticulumHeidi E De Luca
Gastrointestinal Cell Biology, Children's Hospital Boston, Harvard Medical School, Boston, MA, USA
Methods Mol Biol 341:127-39. 2006..This provides a biochemical readout for toxin entry into the trans Golgi (by 35S-sulfation) and ER (by N-glycosylation). In this chapter, we describe the methods we developed to study this trafficking pathway... - Distribution of the IgG Fc receptor, FcRn, in the human fetal intestineUzma Shah
Mucosal Immunology Laboratory, Combined Program in Pediatric Gastroenterology and Nutrition, Massachusetts General Hospital, Charlestown, Massachusetts 02129 4404, USA
Pediatr Res 53:295-301. 2003.... - Ceramide activates JNK to inhibit a cAMP-gated K+ conductance and Cl- secretion in intestinal epitheliaDavid E Saslowsky
GI Cell Biology, Children s Hospital, and the Harvard Digestive Diseases Center, Boston, MA 02115, USA
FASEB J 23:259-70. 2009..These results define a novel lipid-mediated pathway for regulation of salt and water homeostasis at mucosal surfaces... - Cholera toxin toxicity does not require functional Arf6- and dynamin-dependent endocytic pathwaysRamiro H Massol
Department of Cell Biology, Harvard Medical School and The Center for Blood Research for Biomedical Research, Boston, Massachusetts 02115, USA
Mol Biol Cell 15:3631-41. 2004..These results are consistent with the existence of an additional retrograde pathway used by CT to reach the ER... - The intracellular voyage of cholera toxin: going retroWayne I Lencer
GI Cell Biology, Children s Hospital and the Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA
Trends Biochem Sci 28:639-45. 2003..Upon entering the cytosol, the A1-chain rapidly refolds, avoids the proteasome and induces toxicity... - The immunologic functions of the neonatal Fc receptor for IgGTimo Rath
Division of Gastroenterology, Department of Medicine, Brigham and Women s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA
J Clin Immunol 33:S9-17. 2013..The increasing appreciation for FcRn in both homeostatic and pathological conditions is generating an intense interest in the potential for therapeutic modulation of FcRn binding to IgG and albumin... - Rafting with cholera toxin: endocytosis and trafficking from plasma membrane to ERDaniel J F Chinnapen
GI Cell Biology, Children s Hospital, Boston, MA 21115, USA
FEMS Microbiol Lett 266:129-37. 2007..GM1 is the vehicle that carries CT from PM to ER. Thus, the toxin pathway from PM to ER is a lipid-based sorting pathway, which is potentially meditated by the determinants of the GM1 ganglioside structure itself... - Retrograde transport of cholera toxin into the ER of host cellsWayne I Lencer
GI Cell Biology, Children s Hospital Boston, Harvard Digestive Diseases Center, Department of Pediatrics Harvard Medical School, Boston, MA 02115, USA
Int J Med Microbiol 293:491-4. 2004..Here we discuss recent studies on the mechanism of transport from plasma membrane to the ER and on the reactions that unfold and retrotranslocate a portion of the toxin to the cytosol where toxicity is induced... - Uncoupling of the cholera toxin-G(M1) ganglioside receptor complex from endocytosis, retrograde Golgi trafficking, and downstream signal transduction by depletion of membrane cholesterolAnne A Wolf
Gastrointestinal Cell Biology, Department of Pediatrics, Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
J Biol Chem 277:16249-56. 2002..Taken together these data imply that cholesterol may function to couple the CT-G(M1) complex with raft domains and with other membrane components of the lipid raft required for CT entry into the cell... - TorsinA participates in endoplasmic reticulum-associated degradationFlavia C Nery
1 Neuroscience Center, Department of Neurology, and Center for Molecular Imaging Research, Department of Radiology, Massachusetts General Hospital and Program in Neuroscience, Harvard Medical School, Boston, Massachusetts 02114, USA 2
Nat Commun 2:393. 2011..Therefore, compromised ERAD function in the cells of DYT1 patients may increase sensitivity to endoplasmic reticulum stress with consequent alterations in neuronal function contributing to the disease state... - The heavy chain of neonatal Fc receptor for IgG is sequestered in endoplasmic reticulum by forming oligomers in the absence of beta2-microglobulin associationXiaoping Zhu
Gastroenterology Division, Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
Biochem J 367:703-14. 2002..The beta(2)m association with FcRn HC is critical for correct folding of FcRn and exiting the ER for routing to endosomes and the cell surface... - Receptor-mediated immunoglobulin G transport across mucosal barriers in adult life: functional expression of FcRn in the mammalian lungGerburg M Spiekermann
The Combined Program in Pediatric Gastroenterology and Nutrition, Children's Hospital, Boston, MA 02115, USA
J Exp Med 196:303-10. 2002..These data show that mucosal surfaces that express FcRn reabsorb IgG and explain a mechanism by which IgG may act in immune surveillance to retrieve lumenal antigens for processing in the lamina propria or systemically... - A passionate kiss, then run: exocytosis and recycling of IgG by FcRnWayne I Lencer
GI Cell Biology, Division of Pediatric Gastroenterology and Nutrition, Children s Hospital, Boston, MA 02115, USA
Trends Cell Biol 15:5-9. 2005..Similar to the process seen for neurotransmitter release at synaptic junctions, other vesicles fuse only partially, releasing FcRn-IgG complexes to mix into the plasma membrane in cycles of 3-4s over prolonged periods of time... - Cross-presentation of IgG-containing immune complexesKristi Baker
Division of Gastroenterology, Department of Medicine, Brigham and Women s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA
Cell Mol Life Sci 70:1319-34. 2013.... - The Cdc42 inhibitor secramine B prevents cAMP-induced K+ conductance in intestinal epithelial cellsHenry E Pelish
Department of Cell Biology and The CBR Institute for Biomedical Research, Harvard Medical School, Boston, Massachusetts, USA
Biochem Pharmacol 71:1720-6. 2006..These results suggest that Rho GTPases may be involved in the regulation of the chloride secretory response and identify secramine B an inhibitor of cAMP-dependent K+ conductance in intestinal epithelial cells... - Conversion of apical plasma membrane sphingomyelin to ceramide attenuates the intoxication of host cells by cholera toxinDavid E Saslowsky
Children s Hospital, Harvard Digestive Diseases Center, Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA
Cell Microbiol 10:67-80. 2008..This result suggests that the cause for toxin resistance occurs at steps required for retro-translocation of the CT A1-chain to the cytosol... - How the controller is controlled - neonatal Fc receptor expression and immunoglobulin G homeostasisShuo-Wang Qiao
Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
Immunology 120:145-7. 2007 - Insights on the trafficking and retro-translocation of glycosphingolipid-binding bacterial toxinsJin A Cho
Division of Gastroenterology and Nutrition, Department of Medicine, Children s Hospital Boston, Boston MA, USA Department of Pediatrics, Harvard Medical School, Boston, MA, USA
Front Cell Infect Microbiol 2:51. 2012..We also discuss several new studies that address the mechanisms of toxin unfolding in the ER and the mechanisms of CT A1-chain retro-translocation to the cytosol... - Cholera toxin: an intracellular journey into the cytosol by way of the endoplasmic reticulumNaomi L B Wernick
GI Cell Biology, Children s Hospital and Harvard Medical School, Boston, MA, USA
Toxins (Basel) 2:310-25. 2010..Here, we review the mechanisms of toxin trafficking by GM1 and retro-translocation of the A1-chain to the cytosol... - Functional reconstitution of human FcRn in Madin-Darby canine kidney cells requires co-expressed human beta 2-microglobulinSteven M Claypool
Harvard Medical School, Program in Immunology, Gastroenterogy Division, Brigham and Women s Hospital, Boston, Massachusetts 02115, USA
J Biol Chem 277:28038-50. 2002..These results show that human FcRn travels to the cell surface via the normal secretory pathway and that the appropriate expression and function of human FcRn in MDCK cells depends upon the co-expression of human beta(2)m... - Role of ubiquitination in retro-translocation of cholera toxin and escape of cytosolic degradationChiara Rodighiero
GI Cell Biology, Children s Hospital and Harvard Medical School, Boston, MA 02115, USA
EMBO Rep 3:1222-7. 2002.... - The zebrafish dag1 mutant: a novel genetic model for dystroglycanopathiesVandana Gupta
Genomics Program and Division of Genetics, The Manton Center for Orphan Disease Research, Children s Hospital Boston, Boston, MA 02115, USA
Hum Mol Genet 20:1712-25. 2011.... - Claudin-8 expression in Madin-Darby canine kidney cells augments the paracellular barrier to cation permeationAlan S L Yu
Department of Medicine, University of Southern California Keck School of Medicine, Los Angeles, California 90033, USA
J Biol Chem 278:17350-9. 2003..Our findings suggest that claudin-8 plays an important role in the paracellular cation barrier of the distal renal tubule... - Paneth cell cryptdins act in vitro as apical paracrine regulators of the innate inflammatory responsePatricia W Lin
Gastrointestinal Cell Biology Department, Combined Program in Pediatric Gastroenterology and Nutrition, Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA
J Biol Chem 279:19902-7. 2004..These results show that selective cryptdins may amplify their roles in innate immunity by acting as novel paracrine agonists to coordinate an inflammatory response with the antimicrobial secretions of Paneth cells... - Patching a leaky intestineWayne I Lencer
Department of Medicine, Children's Hospital Boston and Harvard Medical School, Boston, USA
N Engl J Med 359:526-8. 2008 - Signal transduction by bacterial proteinsWayne I Lencer
Children's Hospital, Boston, Massachusetts, USA
J Pediatr Gastroenterol Nutr 40:S33-4. 2005 - Derlin-1 facilitates the retro-translocation of cholera toxinKaleena M Bernardi
Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Mol Biol Cell 19:877-84. 2008..CTB may play a role in this process by targeting the holotoxin to Derlin-1, enabling the Derlin-1-bound PDI to unfold the A1 subunit and prepare it for transport... - Protein disulfide isomerase-like proteins play opposing roles during retrotranslocationMichele L Forster
Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
J Cell Biol 173:853-9. 2006..Thus, our data identify PDI family proteins that play opposing roles in ER quality control and establish an assay to further delineate the mechanism of CT retrotranslocation... - Trafficking of cholera toxin-ganglioside GM1 complex into Golgi and induction of toxicity depend on actin cytoskeletonKamran Badizadegan
Department of Pathology, Massachusetts General Hospital, Boston 02114, USA
Am J Physiol Cell Physiol 287:C1453-62. 2004.... - The HA proteins of botulinum toxin disrupt intestinal epithelial intercellular junctions to increase toxin absorptionTakuhiro Matsumura
Laboratory for Infection Cell Biology, International Research Center for Infectious Diseases, Research Institute for Microbial Diseases, Osaka University, 3 1 Yamada oka, Suita, Osaka 565 0871, Japan
Cell Microbiol 10:355-64. 2008..These studies show that the 16S BoNT complex is a multifunctional protein assembly equipped with the machinery to efficiently breach the intestinal barrier and act systemically on peripheral nerves... - Pulmonary delivery of an erythropoietin Fc fusion protein in non-human primates through an immunoglobulin transport pathwayAlan J Bitonti
Syntonix Pharmaceuticals, Incorporated, Waltham, MA 02451, USA
Proc Natl Acad Sci U S A 101:9763-8. 2004..c. in humans. These studies show that FcRn can be harnessed to noninvasively deliver bioactive proteins into the systemic circulation in therapeutic quantities... - Cryptdin 3 forms anion selective channels in cytoplasmic membranes of human embryonic kidney cellsGang Yue
Center for Cell and Molecular Signaling, Emory University School of Medicine, Atlanta, Georgia 30322, USA
Am J Physiol Gastrointest Liver Physiol 282:G757-65. 2002..1, 1.6, 4.2, and 12.5 ms. These results suggest that cryptdin 3 forms anion-selective channels on the cytoplasmic membrane of HEK cells and that the kinetics of one such channel are affected by its interaction with other such channels... - Research agenda for pediatric gastroenterology, hepatology and nutrition: secretion and diarrhea. Report of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition for the Children's Digestive Health and Nutrition FoundationWayne I Lencer
Children's Digestive Health and Nutrition Foundation, PO Box 6, Flourtown, PA 19031, USA
J Pediatr Gastroenterol Nutr 35:S246-9. 2002 - Myosin light chain phosphorylation regulates barrier function by remodeling tight junction structureLe Shen
Department of Pathology, The University of Chicago, 5841 South Maryland Avenue, MC 1089, Chicago, IL 60637, USA
J Cell Sci 119:2095-106. 2006..We conclude that myosin light chain phosphorylation alone is sufficient to induce tight junction regulation and provide new insights into the molecular mechanisms that mediate this regulation... - Calnexin and ERp57 facilitate the assembly of the neonatal Fc receptor for IgG with beta 2-microglobulin in the endoplasmic reticulumXiaoping Zhu
Laboratory of Immunology, Virginia Maryland Regional College of Veterinary Medicine, University of Maryland, 8075 Greenmead Drive, College Park, MD 20742, USA
J Immunol 175:967-76. 2005..220 (tapasin-deficient) and 721.174 (TAP-deficient) cells transfected with FcRn. These findings show the importance of chaperones in FcRn assembly...
Research Grants
- TRAINING IN PEDIATRIC GASTROENTEROLOGY AND NUTRITIONWayne Lencer; Fiscal Year: 2007..Integration of training with the candidates' future goals in academic medicine, a strong focus on original research, and strong mentoring in science and career development are essential features of the program. ..
- FcRn-dependent sorting of IgG and IgG-opsinized antigens by epithelial cellsWayne Lencer; Fiscal Year: 2009..Here, we study how an intestinal receptor for transporting immunoglobulin G (the most dominant form of antibodies in humans) dictates the outcome of this interaction. ..
- FcRn-dependent sorting of IgG and IgG-opsinized antigens by epithelial cellsWayne Lencer; Fiscal Year: 2010..Here, we study how an intestinal receptor for transporting immunoglobulin G (the most dominant form of antibodies in humans) dictates the outcome of this interaction. ..
- Intestinal Disease - enterocyte toxin interactionWayne Lencer; Fiscal Year: 2007..Such diseases are global in distribution and include acute infectious diarrheas as well as those that result from abnormal interactions with the intestinal microflora, such as IBD. ..
- Intestinal Disease - enterocyte toxin interactionWayne Lencer; Fiscal Year: 2010..Such diseases are global in distribution and include acute infectious diarrheas as well as those that result from abnormal interactions with the intestinal microflora, such as IBD. ..
- Intestinal Disease: Enterocyte/Toxin InteractionWayne Lencer; Fiscal Year: 2005..abstract_text> ..
- INTESTINAL DISEASE--ENTEROCYTE TOXIN INTERACTIONWayne Lencer; Fiscal Year: 2000..Such information may enhance the development of novel strategies for oral immunization and tissue specific drug delivery for use in a variety of intestinal diseases. ..
- CRYPTDIN EFFECTS ON CRYPT EPITHELIAWayne Lencer; Fiscal Year: 2004....
- Genetic Analysis for Cell Invasion by Bacterial ToxinsWayne Lencer; Fiscal Year: 2004..The project has direct relevance to the fields of cell biology, microbial pathogenesis, and biodefense, and it has clinical application. ..