D J Anderson

Summary

Affiliation: Abbott Laboratories
Country: USA

Publications

  1. ncbi request reprint (L)-Phenylglycine, but not necessarily other alpha2delta subunit voltage-gated calcium channel ligands, attenuates neuropathic pain in rats
    James J Lynch
    Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA
    Pain 125:136-42. 2006
  2. ncbi request reprint Synthesis and structure-activity relationship studies of 3,6-diazabicyclo[3.2.0]heptanes as novel alpha4beta2 nicotinic acetylcholine receptor selective agonists
    Jianguo Ji
    Neuroscience Research, R47W, AP9A 1, Abbott, Abbott Park, Illinois 60064, USA
    J Med Chem 50:5493-508. 2007
  3. ncbi request reprint [3H]A-585539 [(1S,4S)-2,2-dimethyl-5-(6-phenylpyridazin-3-yl)-5-aza-2-azoniabicyclo[2.2.1]heptane], a novel high-affinity alpha7 neuronal nicotinic receptor agonist: radioligand binding characterization to rat and human brain
    David J Anderson
    Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064 6125, USA
    J Pharmacol Exp Ther 324:179-87. 2008
  4. ncbi request reprint Assessment of nicotinic acetylcholine receptor-mediated release of [(3)H]-norepinephrine from rat brain slices using a new 96-well format assay
    D J Anderson
    Neurological and Urological Diseases Research, Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, IL 60064 6125, USA
    Neuropharmacology 39:2663-72. 2000
  5. doi request reprint Stimulation of dopamine release by nicotinic acetylcholine receptor ligands in rat brain slices correlates with the profile of high, but not low, sensitivity alpha4beta2 subunit combination
    David J Anderson
    Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA
    Biochem Pharmacol 78:844-51. 2009
  6. ncbi request reprint Identification and initial structure-activity relationships of (R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594), a potent, orally active, non-opiate analgesic agent acting via neuronal nicotinic acetylcholine receptors
    M W Holladay
    Neurological and Urological Diseases Research D 47W, Abbott Laboratory, Abbott Park, Illinois 60064 3500, USA
    J Med Chem 41:407-12. 1998
  7. ncbi request reprint The identification of novel structural compound classes exhibiting high affinity for neuronal nicotinic acetylcholine receptors and analgesic efficacy in preclinical models of pain
    M D Meyer
    Neurological and Urological Diseases Research, Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, IL 60064 6125, USA
    Eur J Pharmacol 393:171-7. 2000
  8. ncbi request reprint Functional characterization of the novel neuronal nicotinic acetylcholine receptor ligand GTS-21 in vitro and in vivo
    C A Briggs
    Abbott Laboratories, Abbott Park, Illinois 60064, USA
    Pharmacol Biochem Behav 57:231-41. 1997
  9. ncbi request reprint Synthesis and structure-activity relationships of 5-substituted pyridine analogues of 3
    N H Lin
    Neurological and Urological Diseases Research, D 47W, Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, IL 60064 3500, USA
    Bioorg Med Chem Lett 11:631-3. 2001
  10. pmc alpha7 nicotinic acetylcholine receptor agonist properties of tilorone and related tricyclic analogues
    C A Briggs
    Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA
    Br J Pharmacol 153:1054-61. 2008

Collaborators

Detail Information

Publications46

  1. ncbi request reprint (L)-Phenylglycine, but not necessarily other alpha2delta subunit voltage-gated calcium channel ligands, attenuates neuropathic pain in rats
    James J Lynch
    Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA
    Pain 125:136-42. 2006
    ..These results suggest that additional mechanisms, besides alpha2delta interactions, may contribute to the effects of compounds like gabapentin, pregabalin and (L)-phenylglycine in neuropathic pain...
  2. ncbi request reprint Synthesis and structure-activity relationship studies of 3,6-diazabicyclo[3.2.0]heptanes as novel alpha4beta2 nicotinic acetylcholine receptor selective agonists
    Jianguo Ji
    Neuroscience Research, R47W, AP9A 1, Abbott, Abbott Park, Illinois 60064, USA
    J Med Chem 50:5493-508. 2007
    ..The SAR studies of these novel ligands led to the discovery of several compounds with interesting in vitro pharmacological profiles...
  3. ncbi request reprint [3H]A-585539 [(1S,4S)-2,2-dimethyl-5-(6-phenylpyridazin-3-yl)-5-aza-2-azoniabicyclo[2.2.1]heptane], a novel high-affinity alpha7 neuronal nicotinic receptor agonist: radioligand binding characterization to rat and human brain
    David J Anderson
    Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064 6125, USA
    J Pharmacol Exp Ther 324:179-87. 2008
    ....
  4. ncbi request reprint Assessment of nicotinic acetylcholine receptor-mediated release of [(3)H]-norepinephrine from rat brain slices using a new 96-well format assay
    D J Anderson
    Neurological and Urological Diseases Research, Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, IL 60064 6125, USA
    Neuropharmacology 39:2663-72. 2000
    ..In contrast, DHbetaE antagonism of [(3)H]-dopamine release from striatal slices using a similar methodology was competitive...
  5. doi request reprint Stimulation of dopamine release by nicotinic acetylcholine receptor ligands in rat brain slices correlates with the profile of high, but not low, sensitivity alpha4beta2 subunit combination
    David J Anderson
    Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA
    Biochem Pharmacol 78:844-51. 2009
    ..In summary, this study provides support for HS alpha4beta2* nAChR involvement in neurotransmitter release...
  6. ncbi request reprint Identification and initial structure-activity relationships of (R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594), a potent, orally active, non-opiate analgesic agent acting via neuronal nicotinic acetylcholine receptors
    M W Holladay
    Neurological and Urological Diseases Research D 47W, Abbott Laboratory, Abbott Park, Illinois 60064 3500, USA
    J Med Chem 41:407-12. 1998
    ..Structure-activity studies of analogues related to 4 and 5 suggest that the N-unsubstituted azetidine moiety and the 2-chloro substituent on the pyridine ring are important contributors to potent analgesic activity...
  7. ncbi request reprint The identification of novel structural compound classes exhibiting high affinity for neuronal nicotinic acetylcholine receptors and analgesic efficacy in preclinical models of pain
    M D Meyer
    Neurological and Urological Diseases Research, Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, IL 60064 6125, USA
    Eur J Pharmacol 393:171-7. 2000
    ....
  8. ncbi request reprint Functional characterization of the novel neuronal nicotinic acetylcholine receptor ligand GTS-21 in vitro and in vivo
    C A Briggs
    Abbott Laboratories, Abbott Park, Illinois 60064, USA
    Pharmacol Biochem Behav 57:231-41. 1997
    ..Neither was it active in the elevated plus maze anxiety model (0.19-6.2 micromol/kg.IP) in normal mice. However, GTS-21 did improve learning performance of monkeys in the delayed matching-to-sample task (32-130 nmol/kg.i.m.)...
  9. ncbi request reprint Synthesis and structure-activity relationships of 5-substituted pyridine analogues of 3
    N H Lin
    Neurological and Urological Diseases Research, D 47W, Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, IL 60064 3500, USA
    Bioorg Med Chem Lett 11:631-3. 2001
    ..055 to 0.69 nM compared to a Ki value of 0.15 nM for compound 1. Assessment of functional activity at subtypes of neuronal nicotinic acetylcholine receptors led to identify several agonists and antagonists...
  10. pmc alpha7 nicotinic acetylcholine receptor agonist properties of tilorone and related tricyclic analogues
    C A Briggs
    Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA
    Br J Pharmacol 153:1054-61. 2008
    ..Alternatively, the present study identifies tilorone as a novel alpha7-selective agonist and characterizes analogues developed from this lead...
  11. ncbi request reprint Structural aspects of high affinity ligands for the alpha 4 beta 2 neuronal nicotinic receptor
    M J Dart
    Department of Structural Biology, Abbott Laboratories, Abbott Park, IL 60064, USA
    Pharm Acta Helv 74:115-23. 2000
    ..A preliminary pharmacophore model is proposed in which a reasonable superposition of the putative pharmacophoric elements of the diverse array of high affinity ligands for the alpha 4 beta 2 nAChR reported herein may be accommodated...
  12. pmc Pharmacology of alpha7 nicotinic acetylcholine receptor mediated extracellular signal-regulated kinase signalling in PC12 cells
    R el Kouhen
    Neuroscience Research, Abbott Laboratories, Department R47W, Abbott Park, IL 60064 6125, USA E mail
    Br J Pharmacol 156:638-48. 2009
    ..In this study, we investigated activation and modulation of alpha7 nAChR-mediated phosphorylation of extracellular signal-regulated kinases (ERK1/2) in PC12 cells, using selective agonists and positive allosteric modulators...
  13. ncbi request reprint 2-Aryl-2-hydroxyethylamine substituted 4-oxo-4,7-dihydrothieno[2,3-b]pyridines as broad-spectrum inhibitors of human herpesvirus polymerases
    Mark E Schnute
    Global Research and Development, Pfizer Inc, 700 Chesterfield Parkway West, St Louis, MO 63017, USA
    Bioorg Med Chem Lett 17:3349-53. 2007
    ..These compounds demonstrate broad-spectrum inhibition of the herpesvirus polymerases HCMV, HSV-1, EBV, and VZV with high specificity compared to human DNA polymerases...
  14. ncbi request reprint A steroid-conjugated contrast agent for magnetic resonance imaging of cell signaling
    Jiyoun Lee
    Department of Chemistry, Northwestern University, Evanston, Illinois 60201, USA
    J Am Chem Soc 127:13164-6. 2005
    ..By combining a transcriptional system and a noninvasive imaging technology, such as MRI, it would be a powerful tool to research the cell signaling pathway in vivo...
  15. ncbi request reprint Structure-activity relationships of alpha-amino acid ligands for the alpha2delta subunit of voltage-gated calcium channels
    Kathleen H Mortell
    Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA
    Bioorg Med Chem Lett 16:1138-41. 2006
    ..Potent analogs were identified. Their activity in an in vivo pain assay is described...
  16. ncbi request reprint Structure-activity studies and analgesic efficacy of N-(3-pyridinyl)-bridged bicyclic diamines, exceptionally potent agonists at nicotinic acetylcholine receptors
    William H Bunnelle
    Neuroscience Research, Abbott Laboratories, Department R47W, Building AP9A, Abbott Park, Illinois 60064 6117, USA
    J Med Chem 50:3627-44. 2007
    ....
  17. ncbi request reprint A-85380: a pharmacological probe for the preclinical and clinical investigation of the alphabeta neuronal nicotinic acetylcholine receptor
    Lynne E Rueter
    Abbott Laboratories, Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Park, IL, USA
    CNS Drug Rev 12:100-12. 2006
    ..Although not developed as a therapeutic agent, A-85380 has proven to be an important component in the development of novel nAChR ligands for the treatment of pain and other disorders...
  18. ncbi request reprint Antisense knockdown of the rat alpha7 nicotinic acetylcholine receptor produces spatial memory impairment
    Peter Curzon
    Neuroscience Research, Abbott Laboratories GPRD, Abbott Park, IL 60064 6115, United States
    Neurosci Lett 410:15-9. 2006
    ....
  19. ncbi request reprint Synthesis and structure-activity relationships of 3,8-diazabicyclo[4.2.0]octane ligands, potent nicotinic acetylcholine receptor agonists
    Jennifer M Frost
    Neuroscience Research, Abbott Laboratories, Abbott Park, IL 60064, USA
    J Med Chem 49:7843-53. 2006
    ..e., 24, 25, 28, 30, 32, and 47) exhibit equivalent or greater affinity for the halpha4beta2 receptor relative to epibatidine, and like epibatidine, many exhibit robust analgesic efficacy in the rat formalin model of persistent pain...
  20. ncbi request reprint Broad-spectrum efficacy across cognitive domains by alpha7 nicotinic acetylcholine receptor agonism correlates with activation of ERK1/2 and CREB phosphorylation pathways
    Robert S Bitner
    Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064, USA
    J Neurosci 27:10578-87. 2007
    ....
  21. doi request reprint Analysis of gene expression profiles in rat hippocampus following treatment with nicotine and an alpha7 nAChR selective agonist
    Jeffrey F Waring
    Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA
    Neurosci Res 60:266-74. 2008
    ..Overall, our results identify gene expression changes that may contribute to further defining the roles of nAChR activation in cognitive function...
  22. ncbi request reprint A-366833: a novel nicotinonitrile-substituted 3,6-diazabicyclo[3.2.0]-heptane alpha4beta2 nicotinic acetylcholine receptor selective agonist: Synthesis, analgesic efficacy and tolerability profile in animal models
    Jianguo Ji
    Neuroscience Research, Department R47W, Bldg AP9A, Global Pharmaceutical Research and Development, Abbott, Abbott Park, IL 60064, USA
    Biochem Pharmacol 74:1253-62. 2007
    ..These studies indicate that compounds like A-366833 with improved agonist selectivity at alpha4beta2 vs. alpha3beta4 nAChR can elicit a broad spectrum of analgesic efficacy without concurrent adverse effects...
  23. ncbi request reprint ABT-089: pharmacological properties of a neuronal nicotinic acetylcholine receptor agonist for the potential treatment of cognitive disorders
    Lynne E Rueter
    Abbott Laboratories, Neuroscience Research, R4N5, AP9A, 100 Abbott Park Rd, Abbott Park, IL 60064 6115, USA
    CNS Drug Rev 10:167-82. 2004
    ..Together these data suggest that ABT-089 is a NNR modulator with the potential for treating cognitive disorders with markedly limited adverse cardiovascular and gastrointestinal side effects...
  24. ncbi request reprint 6-Chloropyridazin-3-yl derivatives active as nicotinic agents: synthesis, binding, and modeling studies
    Lucio Toma
    Dipartimento di Chimica Organica, Universita di Pavia, Via Taramelli 10, 27100 Pavia, Italy
    J Med Chem 45:4011-7. 2002
    ..Thus, this SAR study gives support to the hypothesis that these longer distances are still compatible with affinity for alpha4beta2 receptors in the nanomolar range...
  25. doi request reprint Preclinical characterization of A-582941: a novel alpha7 neuronal nicotinic receptor agonist with broad spectrum cognition-enhancing properties
    Karin R Tietje
    Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064, USA
    CNS Neurosci Ther 14:65-82. 2008
    ....
  26. ncbi request reprint Conformationally constrained nicotines: polycyclic, bridged, and spiro-annulated analogues as novel ligands for the nicotinic acetylcholine receptor
    Thomas Ullrich
    Institute of Applied Synthetic Chemistry, Vienna University of Technology, Getreidemarkt 9 E163, A 1060 Vienna, Austria
    J Med Chem 45:4047-54. 2002
    ....
  27. ncbi request reprint Synthesis and biological evaluation of pyridine-modified analogues of 3-(2-aminoethoxy)pyridine as novel nicotinic receptor ligands
    Nan horng Lin
    Neurological and Urological Diseases Research, D 47W, Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, IL 60064 3500, USA
    Bioorg Med Chem Lett 12:3321-4. 2002
    ..The substituted analogues exhibited K(i) values ranging from 0.076 to 319 nM compared to a K(i) value of 26 nM for compound 1. Among the compounds tested, 5'-vinyl-6'-chloro substituted 1 was the most potent...
  28. ncbi request reprint Differential regulation of nicotinic receptor-mediated neurotransmitter release following chronic (-)-nicotine administration
    Iris Jacobs
    Abbott Laboratories, Department 47W, Abbott Park Building AP 9A, Abbott Park, IL 60064 6125, USA
    Neuropharmacology 43:847-56. 2002
    ..These results support findings from earlier studies comparing the pharmacology of nAChR-evoked striatal versus cortical [(3)H]-DA release...
  29. pmc Applying a targeted label-free approach using LC-MS AMT tags to evaluate changes in protein phosphorylation following phosphatase inhibition
    Feng Yang
    Biological Sciences Division, Pacific Northwest National Laboratory, P O Box 999, Richland, Washington 99352, USA
    J Proteome Res 6:4489-97. 2007
    ..These data can be used to define underlying signaling pathways and events regulated by the PPP family of S/T phosphatases...
  30. pmc Perinatal androgens and adult behavior vary with nestling social system in siblicidal boobies
    Martina S Müller
    Department of Biology, Wake Forest University, Winston Salem, North Carolina, United States of America
    PLoS ONE 3:e2460. 2008
    ..Both Nazca booby chicks facultatively upregulate testosterone (T) during fights, motivating the prediction that baseline androgen levels differ between obligately siblicidal and other species...
  31. pmc Identification of positionally distinct astrocyte subtypes whose identities are specified by a homeodomain code
    Christian Hochstim
    Division of Biology 216 76, Howard Hughes Medical Institute, California Institute of Technology, Pasadena, CA 91125, USA
    Cell 133:510-22. 2008
    ....
  32. doi request reprint The auditory midbrain implant: effects of electrode location
    Hubert H Lim
    Otorhinolaryngology Department, Hannover Medical University, Carl Neuberg Strasse1, Gebaeude K5, Ebene 1, Raum 4010, Hannover 30625, Germany
    Hear Res 242:74-85. 2008
    ..e., those designed for cochlear implants) can restore sufficient speech perception...
  33. pmc A common genetic target for environmental and heritable influences on aggressiveness in Drosophila
    Liming Wang
    Division of Biology 216 76 and Engineering and Applied Sciences 136 93 and Howard Hughes Medical Institute, California Institute of Technology, Pasadena, CA 91125, USA
    Proc Natl Acad Sci U S A 105:5657-63. 2008
    ..Cyp6a20 is expressed in a subset of nonneuronal support cells associated with pheromone-sensing olfactory sensilla, suggesting that social experience may influence aggressiveness by regulating pheromone sensitivity...
  34. ncbi request reprint Light activation of an innate olfactory avoidance response in Drosophila
    Greg S B Suh
    Division of Biology 216 76 and Howard Hughes Medical Institute, California Institute of Technology, Pasadena, California 91125, USA
    Curr Biol 17:905-8. 2007
    ..Thus, avoidance behavior appears hardwired into the olfactory circuitry that detects CO2 in Drosophila...
  35. ncbi request reprint Selective electrical silencing of mammalian neurons in vitro by the use of invertebrate ligand-gated chloride channels
    Eric M Slimko
    Computation and Neural Systems Program and Division of Biology, California Institute of Technology, Pasadena, California 91125, USA
    J Neurosci 22:7373-9. 2002
    ..These experiments demonstrate the feasibility of using invertebrate ligand-activated Cl- channels as an approach to modulate excitability...
  36. ncbi request reprint SOX10 maintains multipotency and inhibits neuronal differentiation of neural crest stem cells
    Jaesang Kim
    Howard Hughes Medical Institute, Division of Biology 216 76, California Institute of Technology, Pasadena, California 91125, USA
    Neuron 38:17-31. 2003
    ....
  37. ncbi request reprint Neural correlates of competing fear behaviors evoked by an innately aversive stimulus
    Raymond Mongeau
    Division of Biology, California Institute of Technology, Pasadena, California 91125, USA
    J Neurosci 23:3855-68. 2003
    ..These complementary patterns of c-fos induction, taken together with known connections between these structures, suggest ways in which the brain may mediate the balance between these opponent defensive behaviors...
  38. ncbi request reprint Diel changes in plasma melatonin and corticosterone concentrations in tropical Nazca boobies (Sula granti) in relation to moon phase and age
    Elisa M Tarlow
    Department of Animal Biology, 505 S Goodwin Ave, University of Illinois at Urbana Champaign, IL 61820, USA
    Gen Comp Endocrinol 133:297-304. 2003
    ..First, melatonin rhythms can be directly affected by the light intensity associated with full moon. Second, prey availability may change foraging patterns and can therefore indirectly alter corticosterone secretion in Nazca boobies...
  39. ncbi request reprint A single population of olfactory sensory neurons mediates an innate avoidance behaviour in Drosophila
    Greg S B Suh
    Howard Hughes Medical Institute, California Institute of Technology, Pasadena, California 91125, USA
    Nature 431:854-9. 2004
    ..These data demonstrate that the activation of a single population of sensory neurons innervating one glomerulus is responsible for an innate avoidance behaviour in Drosophila...
  40. pmc Improved proteome coverage by using high efficiency cysteinyl peptide enrichment: the human mammary epithelial cell proteome
    Tao Liu
    Biological Sciences Division and Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, WA 99352, USA
    Proteomics 5:1263-73. 2005
    ..These results demonstrate that the use of the CPE approach provides improved efficiency in comprehensive proteome-wide analyses of highly complex mammalian biological systems...
  41. ncbi request reprint Lhx6 delineates a pathway mediating innate reproductive behaviors from the amygdala to the hypothalamus
    Gloria B Choi
    Division of Biology 216 76, California Institute of Technology, Pasadena, California 91125, USA
    Neuron 46:647-60. 2005
    ..Our data therefore identify a potential neural substrate for integrating the influences of conflicting behavioral cues and a transcription factor family that may contribute to the development of this substrate...
  42. ncbi request reprint Isolation of arterial-specific genes by subtractive hybridization reveals molecular heterogeneity among arterial endothelial cells
    Donghun Shin
    Division of Biology 216 76, California Institute of Technology, Pasadena, California 91125, USA
    Dev Dyn 233:1589-604. 2005
    ..Taken together, these data reveal unanticipated temporal and spatial heterogeneity among arterial endothelial cells of various tissues and organs, raising new questions regarding the functional significance of this diversity...
  43. ncbi request reprint Contributions of marginal offspring to reproductive success of Nazca booby (Sula granti) parents: tests of multiple hypotheses
    Courtney A Humphries
    Department of Biology, Wake Forest University, Winston Salem, NC 27109, USA
    Oecologia 147:379-90. 2006
    ....
  44. ncbi request reprint Auditory cortical responses to electrical stimulation of the inferior colliculus: implications for an auditory midbrain implant
    Hubert H Lim
    Kresge Hearing Research Institute, Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109 2122, USA
    J Neurophysiol 96:975-88. 2006
    ..Overall, this study provides the foundation for future AMI research and development...
  45. ncbi request reprint Reversible silencing of neuronal excitability in behaving mice by a genetically targeted, ivermectin-gated Cl- channel
    Walter Lerchner
    Division of Biology 216 76, California Institute of Technology, Pasadena, CA 91125, USA
    Neuron 54:35-49. 2007
    ..The two-subunit GluCl/IVM system permits "intersectional" strategies designed to increase the cellular specificity of silencing in transgenic animals...
  46. ncbi request reprint Cardiovascular ephrinB2 function is essential for embryonic angiogenesis
    Sebastian S Gerety
    Division of Biology 216 76, California Institute of Technology, Pasadena, CA 91125, USA
    Development 129:1397-410. 2002
    ....