Rita J Valentino

Summary

Affiliation: University of Pennsylvania
Country: USA

Publications

  1. pmc Sex-specific cell signaling: the corticotropin-releasing factor receptor model
    Rita J Valentino
    The Children s Hospital of Philadelphia, Philadelphia, PA 19104, USA
    Trends Pharmacol Sci 34:437-44. 2013
  2. pmc Sex-biased stress signaling: the corticotropin-releasing factor receptor as a model
    Rita J Valentino
    The Children s Hospital of Philadelphia, Philadelphia, PA 19104, USA
    Mol Pharmacol 83:737-45. 2013
  3. pmc Corticotropin-releasing factor in the dorsal raphe nucleus: Linking stress coping and addiction
    Rita J Valentino
    The Children s Hospital of Philadelphia, Philadelphia, PA 19104, USA
    Brain Res 1314:29-37. 2010
  4. pmc Molecular and cellular sex differences at the intersection of stress and arousal
    Rita J Valentino
    Department of Anesthesiology and Critical Care Medicine, The Children s Hospital of Philadelphia, Philadelphia, PA 19104, USA
    Neuropharmacology 62:13-20. 2012
  5. pmc Individual differences in reactivity to social stress predict susceptibility and resilience to a depressive phenotype: role of corticotropin-releasing factor
    Susan K Wood
    The Children s Hospital of Philadelphia, Abramson Research Center, 3615 Civic Center Boulevard, Philadelphia, Pennsylvania 19104, USA
    Endocrinology 151:1795-805. 2010
  6. pmc Stress-induced redistribution of corticotropin-releasing factor receptor subtypes in the dorsal raphe nucleus
    Maria Waselus
    Department of Neurosurgery, Thomas Jefferson University, Farber Institute for Neurosciences, Philadelphia, Pennsylvania 19107, USA
    Biol Psychiatry 66:76-83. 2009
  7. pmc Stress-induced intracellular trafficking of corticotropin-releasing factor receptors in rat locus coeruleus neurons
    Beverly A S Reyes
    Department of Neurosurgery, Farber Institute for Neurosciences, Thomas Jefferson University, 900 Walnut Street, Suite 400, Philadelphia, Pennsylvania 19107, USA
    Endocrinology 149:122-30. 2008
  8. ncbi request reprint Selective activation of corticotropin-releasing factor-2 receptors on neurochemically identified neurons in the rat dorsal raphe nucleus reveals dual actions
    Luise Pernar
    The Children s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA
    J Neurosci 24:1305-11. 2004
  9. pmc Cellular adaptations of dorsal raphe serotonin neurons associated with the development of active coping in response to social stress
    Susan K Wood
    Department of Anesthesia and Critical Care Medicine, Division of Stress Neurobiology, The Children s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
    Biol Psychiatry 73:1087-94. 2013
  10. ncbi request reprint The role of noradrenergic tone in the dorsal raphe nucleus of the mouse in the acute behavioral effects of antidepressant drugs
    Anita J Bechtholt
    Department of Pharmacology, University of Pennsylvania, Philadelphia, PA 19104, USA
    Eur Neuropsychopharmacol 17:215-26. 2007

Collaborators

Detail Information

Publications48

  1. pmc Sex-specific cell signaling: the corticotropin-releasing factor receptor model
    Rita J Valentino
    The Children s Hospital of Philadelphia, Philadelphia, PA 19104, USA
    Trends Pharmacol Sci 34:437-44. 2013
    ....
  2. pmc Sex-biased stress signaling: the corticotropin-releasing factor receptor as a model
    Rita J Valentino
    The Children s Hospital of Philadelphia, Philadelphia, PA 19104, USA
    Mol Pharmacol 83:737-45. 2013
    ..The possibility that analogous sex differences may occur with other G-protein-coupled receptors underscores the impact of this effect and is discussed...
  3. pmc Corticotropin-releasing factor in the dorsal raphe nucleus: Linking stress coping and addiction
    Rita J Valentino
    The Children s Hospital of Philadelphia, Philadelphia, PA 19104, USA
    Brain Res 1314:29-37. 2010
    ..Finally, work on CRF regulation of the DRN-5-HT system is integrated with literature on the role of 5-HT-dopamine interactions in addiction...
  4. pmc Molecular and cellular sex differences at the intersection of stress and arousal
    Rita J Valentino
    Department of Anesthesiology and Critical Care Medicine, The Children s Hospital of Philadelphia, Philadelphia, PA 19104, USA
    Neuropharmacology 62:13-20. 2012
    ..The clinical and therapeutic considerations arising from this perspective are discussed. This article is part of a Special Issue entitled 'Anxiety and Depression'...
  5. pmc Individual differences in reactivity to social stress predict susceptibility and resilience to a depressive phenotype: role of corticotropin-releasing factor
    Susan K Wood
    The Children s Hospital of Philadelphia, Abramson Research Center, 3615 Civic Center Boulevard, Philadelphia, Pennsylvania 19104, USA
    Endocrinology 151:1795-805. 2010
    ..Together, these data suggest that inherent differences in stress reactivity, perhaps as a result of differences in CRF regulation, may predict long-term consequences of social stress and vulnerability to depressive-like symptoms...
  6. pmc Stress-induced redistribution of corticotropin-releasing factor receptor subtypes in the dorsal raphe nucleus
    Maria Waselus
    Department of Neurosurgery, Thomas Jefferson University, Farber Institute for Neurosciences, Philadelphia, Pennsylvania 19107, USA
    Biol Psychiatry 66:76-83. 2009
    ..CRF(1) and CRF(2) receptor subtypes have opposing effects on this system that are associated with active versus passive coping strategies, respectively...
  7. pmc Stress-induced intracellular trafficking of corticotropin-releasing factor receptors in rat locus coeruleus neurons
    Beverly A S Reyes
    Department of Neurosurgery, Farber Institute for Neurosciences, Thomas Jefferson University, 900 Walnut Street, Suite 400, Philadelphia, Pennsylvania 19107, USA
    Endocrinology 149:122-30. 2008
    ....
  8. ncbi request reprint Selective activation of corticotropin-releasing factor-2 receptors on neurochemically identified neurons in the rat dorsal raphe nucleus reveals dual actions
    Luise Pernar
    The Children s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA
    J Neurosci 24:1305-11. 2004
    ..Importantly, the tone of the DR-5-HT system can be regulated in a dynamic manner through CRF-R2 activation, being either decreased or increased depending on the level of endogenous or exogenous ligand...
  9. pmc Cellular adaptations of dorsal raphe serotonin neurons associated with the development of active coping in response to social stress
    Susan K Wood
    Department of Anesthesia and Critical Care Medicine, Division of Stress Neurobiology, The Children s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
    Biol Psychiatry 73:1087-94. 2013
    ..We used a rat social stress model that shows individual differences in coping strategies to determine whether differences in CRF-5-HT interactions underlie individual differences in the vulnerability to social stress...
  10. ncbi request reprint The role of noradrenergic tone in the dorsal raphe nucleus of the mouse in the acute behavioral effects of antidepressant drugs
    Anita J Bechtholt
    Department of Pharmacology, University of Pennsylvania, Philadelphia, PA 19104, USA
    Eur Neuropsychopharmacol 17:215-26. 2007
    ....
  11. ncbi request reprint Hypothalamic projections to locus coeruleus neurons in rat brain
    Beverly A S Reyes
    Department of Neurosurgery, Farber Institute for Neurosciences, Thomas Jefferson University, 900 Walnut Street, Suite 400, Philadelphia, PA 19107, USA
    Eur J Neurosci 22:93-106. 2005
    ..Moreover, PVN neurons that use CRF as a neurohormone are distinct from those that use CRF as a neuromodulator to impact on the LC...
  12. pmc Differential blockade of CRF-evoked behaviors by depletion of norepinephrine and serotonin in rats
    Owen Howard
    Department of Psychiatry, University of Pennsylvania, 125 South 31st Street, Philadelphia, PA 19104, USA
    Psychopharmacology (Berl) 199:569-82. 2008
    ..Central administration of corticotropin-releasing factor (CRF) elicits a specific pattern of behavioral responses resembling a stress-like state and is anxiogenic in rodent models of anxiety...
  13. ncbi request reprint Sexually dimorphic responses of the brain norepinephrine system to stress and corticotropin-releasing factor
    Andre L Curtis
    Department of Pediatrics, The Children s Hospital of Philadelphia, Philadelphia, PA 19104, USA
    Neuropsychopharmacology 31:544-54. 2006
    ..These sex differences in the CRF regulation of the LC-NE system translate to a differential response to stress and may play a role in the increased vulnerability of females to stress-related psychiatric disorders...
  14. ncbi request reprint Convergent responses of Barrington's nucleus neurons to pelvic visceral stimuli in the rat: a juxtacellular labelling study
    Marie Laure Rouzade-Dominguez
    The Children s Hospital of Philadelphia, 34th and Civic Center Blvd, 402 Abramson Pediatric Research Center, Philadelphia, PA 19104, USA
    Eur J Neurosci 18:3325-34. 2003
    ..Dysfunctions in this circuit may underlie the coexistence of colon and bladder symptoms observed in functional bowel disorders...
  15. pmc Social stress engages opioid regulation of locus coeruleus norepinephrine neurons and induces a state of cellular and physical opiate dependence
    Nayla N Chaijale
    Division of Stress Neurobiology, Department of Anesthesiology, Abramson Research Center, The Children s Hospital of Philadelphia, Philadelphia, PA 19104, USA
    Neuropsychopharmacology 38:1833-43. 2013
    ..These cellular effects may predispose individuals with a history of repeated social stress to substance abuse behaviors...
  16. pmc A corticotropin-releasing factor receptor antagonist improves urodynamic dysfunction produced by social stress or partial bladder outlet obstruction in male rats
    Susan K Wood
    The Children s Hospital of Philadelphia, Philadelphia, PA 19104, USA
    Am J Physiol Regul Integr Comp Physiol 304:R940-50. 2013
    ..These findings implicate a role for Barrington's nucleus CRF in stress- and pBOO-induced urodynamic changes and suggest that CRF₁ antagonists may be useful therapeutic agents for the treatment of urinary dysfunction...
  17. pmc Presynaptic inhibition of diverse afferents to the locus ceruleus by kappa-opiate receptors: a novel mechanism for regulating the central norepinephrine system
    Arati Kreibich
    The Children s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA
    J Neurosci 28:6516-25. 2008
    ..The results implicate kappa-ORs as a novel target for alleviating symptoms of opiate withdrawal, stress-related disorders, or disorders characterized by abnormal sensory responses, such as autism...
  18. ncbi request reprint Agonist-induced internalization of corticotropin-releasing factor receptors in noradrenergic neurons of the rat locus coeruleus
    Beverly A S Reyes
    Department of Neurosurgery, Farber Institute for Neurosciences, Thomas Jefferson University, 900 Walnut Street, Suite 400, Philadelphia, PA 19107, USA
    Eur J Neurosci 23:2991-8. 2006
    ..This process may be a pivotal target by which stressors or pharmacological agents regulate the sensitivity of the LC-NE system to CRF and subsequent stressors...
  19. pmc Overexpression of corticotropin-releasing factor in Barrington's nucleus neurons by adeno-associated viral transduction: effects on bladder function and behavior
    Kile McFadden
    The Children s Hospital of Philadelphia, Philadelphia, PA 19104, USA
    Eur J Neurosci 36:3356-64. 2012
    ..The findings support an inhibitory influence of CRF in Barrington's nucleus regulation of the bladder and an excitatory influence on the brain norepinephrine system that translates to behavioral activation...
  20. ncbi request reprint Differential projections of dorsal raphe nucleus neurons to the lateral septum and striatum
    Maria Waselus
    Department of Neurosurgery, Thomas Jefferson University, Farber Institute for Neurosciences, 900 Walnut Street, Philadelphia, PA 19107, USA
    J Chem Neuroanat 31:233-42. 2006
    ..Taken together with previous microdialysis studies, these results support the existence of distinct DRN-5-HT-forebrain projections that are differentially regulated by stress...
  21. ncbi request reprint Circuitry underlying regulation of the serotonergic system by swim stress
    Michelle Roche
    The Children s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA
    J Neurosci 23:970-7. 2003
    ..This circuitry may underlie some of the acute behavioral responses to swim stress as well as the neuronal plasticity involved in long-term behavioral changes produced by this stress...
  22. pmc Impact of overactive bladder on the brain: central sequelae of a visceral pathology
    Elizabeth Rickenbacher
    Departments of Anesthesiology and Critical Care Medicine and Surgery, Children s Hospital of Philadelphia, Philadelphia, PA 19104, USA
    Proc Natl Acad Sci U S A 105:10589-94. 2008
    ..The results further imply that pharmacological manipulation of central NE function may alleviate central sequelae of these visceral disorders...
  23. pmc Depressive and cardiovascular disease comorbidity in a rat model of social stress: a putative role for corticotropin-releasing factor
    Susan K Wood
    Department of Anesthesiology and Critical Care Medicine, The Children s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
    Psychopharmacology (Berl) 222:325-36. 2012
    ..Depression is associated with medical comorbidities, particularly cardiovascular disease. However, mechanisms linking depression and cardiovascular disease remain unclear...
  24. pmc Predator stress engages corticotropin-releasing factor and opioid systems to alter the operating mode of locus coeruleus norepinephrine neurons
    Andre L Curtis
    Department of Anesthesiology and Critical Care Medicine, The Children s Hospital of Philadelphia, Philadelphia, PA 19104, United States
    Neuropharmacology 62:1737-45. 2012
    ..Changes in the balance of CRF:opioid regulation of the LC could have consequences for stress vulnerability...
  25. ncbi request reprint Overlapping and distinct brain regions associated with the anxiolytic effects of chlordiazepoxide and chronic fluoxetine
    Anita J Bechtholt
    Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104 3403, USA
    Neuropsychopharmacology 33:2117-30. 2008
    ..These findings identified brain regions where the effects of chronic antidepressants and benzodiazepines may converge to produce anxiolytic activity, as well as distinct sites of action for the two classes of drugs...
  26. pmc Antidepressant-like effects of kappa-opioid receptor antagonists in Wistar Kyoto rats
    Gregory V Carr
    Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104, USA
    Neuropsychopharmacology 35:752-63. 2010
    ..These results support the use of the WKY rat as a model of affective disorders potentially involving KOR overactivity and provide more evidence that KOR antagonists could potentially be used as novel antidepressants...
  27. ncbi request reprint Impact of state of arousal and stress neuropeptides on urodynamic function in freely moving rats
    Darcie A Kiddoo
    Department of Surgery, The Children s Hospital of Philadelphia, 402C Abramson Bldg, Osler Cr, Philadelphia, PA 19104, USA
    Am J Physiol Regul Integr Comp Physiol 290:R1697-706. 2006
    ..In addition, the results provide evidence for an inhibitory influence of CRF in the spinal pathway on micturition. Targeting the CRF system in the spinal cord may provide a novel approach for treating urinary disorders...
  28. ncbi request reprint Ultrastructural evidence for a role of gamma-aminobutyric acid in mediating the effects of corticotropin-releasing factor on the rat dorsal raphe serotonin system
    Maria Waselus
    Department of Neurosurgery, Thomas Jefferson University, Farber Institute for Neurosciences, Philadelphia, Pennsylvania 19107, USA
    J Comp Neurol 482:155-65. 2005
    ....
  29. ncbi request reprint Chronic morphine sensitizes the brain norepinephrine system to corticotropin-releasing factor and stress
    Guang Ping Xu
    Department of Pediatrics, The Children s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA
    J Neurosci 24:8193-7. 2004
    ..g., hyperarousal, attentional dysfunction), and this may contribute to the maintenance of opiate-seeking behavior...
  30. ncbi request reprint Substance P Acts through local circuits within the rat dorsal raphe nucleus to alter serotonergic neuronal activity
    Rita J Valentino
    The Children s Hospital of Philadelphia, Abramson Pediatric Research Center, Philadelphia, Pennsylvania 19104, USA
    J Neurosci 23:7155-9. 2003
    ..Interactions between NK1 and 5-HT1A receptors within DR neural networks may contribute to the mechanism of action of novel antidepressants acting at NK1 receptors...
  31. ncbi request reprint A neurochemically distinct dorsal raphe-limbic circuit with a potential role in affective disorders
    Kathryn G Commons
    The Children s Hospital of Philadelphia, Abramson Pediatric Research Center, Philadelphia, PA 19104, USA
    Neuropsychopharmacology 28:206-15. 2003
    ..This circuit may be relevant for understanding the mechanism of action of novel psychotherapeutic agents that act through NK1 or CRF receptors...
  32. pmc Sexual dimorphism in locus coeruleus dendritic morphology: a structural basis for sex differences in emotional arousal
    Debra A Bangasser
    Department of Anesthesiology and Critical Care Medicine, Division Stress Neurobiology, The Children s Hospital of Philadelphia, Philadelphia, PA 19104, United States
    Physiol Behav 103:342-51. 2011
    ..This may be a structural basis for heightened arousal in females, an effect which may, in part, account for the sex bias in incidence of stress-related psychiatric disorders...
  33. pmc Identifying genes in monoamine nuclei that may determine stress vulnerability and depressive behavior in Wistar-Kyoto rats
    Kimberly A Pearson
    Department of Pediatrics, The Children s Hospital of Philadelphia, Philadelphia, PA 19104 4399, USA
    Neuropsychopharmacology 31:2449-61. 2006
    ..The specific genes revealed by the present analysis as being differentially expressed in WKY rats may contribute to their unique behavioral profile and suggest targets that confer susceptibility to stress-related psychiatric disorders...
  34. pmc Manganese-enhanced magnetic resonance imaging (MEMRI) reveals brain circuitry involved in responding to an acute novel stress in rats with a history of repeated social stress
    Debra A Bangasser
    Department of Anesthesiology and Critical Care Medicine, Children s Hospital of Philadelphia, Philadelphia, PA 19104, United States Department of Psychology and Neuroscience Program, Temple University, Philadelphia, PA 19122, United States Electronic address
    Physiol Behav 122:228-36. 2013
    ..Finally, these data underscore the utility of ex vivo MEMRI to identify and distinguish circuits engaged in behavioral responses...
  35. pmc Social stress-induced bladder dysfunction: potential role of corticotropin-releasing factor
    Susan K Wood
    Department of Anesthesiology and Critical Care Medicine, The Children s Hospital of Philadelphia, Philadelphia, PA 19104, USA
    Am J Physiol Regul Integr Comp Physiol 296:R1671-8. 2009
    ..This mechanism may underlie dysfunctional voiding in children and/or contribute to the development of stress-induced bladder disorders in adulthood...
  36. ncbi request reprint Corticotropin-releasing factor promotes growth of brain norepinephrine neuronal processes through Rho GTPase regulators of the actin cytoskeleton in rat
    Jerome D Swinny
    Department of Pediatrics, 402C Abramson Bldg, Children s Hospital of Philadelphia, Philadelphia, PA 19104, USA
    Eur J Neurosci 24:2481-90. 2006
    ..By regulating the extension of processes into pericoerulear regions where limbic afferents terminate, these peptides may determine the degree to which the LC-NE system is influenced by limbic structures that mediate emotional expression...
  37. ncbi request reprint Inducible cAMP early repressor regulates corticosterone suppression after tricyclic antidepressant treatment
    Alana C Conti
    Department of Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    J Neurosci 24:1967-75. 2004
    ....
  38. ncbi request reprint Evidence for corticotropin-releasing factor regulation of serotonin in the lateral septum during acute swim stress: adaptation produced by repeated swimming
    Michelle L Price
    David Mahoney Institute Neurological Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA
    Psychopharmacology (Berl) 162:406-14. 2002
    ..Corticotropin-releasing factor (CRF) administered into the dorsal raphe nucleus (DRN) also decreases 5-HT release in the lateral septum, suggesting that CRF may mediate the effects of swim stress...
  39. pmc Convergent regulation of locus coeruleus activity as an adaptive response to stress
    Rita J Valentino
    The Children s Hospital of Philadelphia, 402C Abramson Building, Osler Cr, Philadelphia, PA 19104, United States
    Eur J Pharmacol 583:194-203. 2008
    ..This review focuses specifically on the locus coeruleus because it is the major source of norepinephrine to the forebrain and has been implicated in behavioral and cognitive aspects of stress responses...
  40. ncbi request reprint Assessing substrates underlying the behavioral effects of antidepressants using the modified rat forced swimming test
    John F Cryan
    Department of Psychiatry and Pharmacology, University of Pennsylvania, 538A Clinical Research Building, 415 Curie Boulevard, Philadelphia, PA 19104, USA
    Neurosci Biobehav Rev 29:547-69. 2005
    ..Finally, a physiological model of performance in the rat FST has been proposed involving the regulation of 5-HT transmission by corticotropin releasing factor (CRF)...
  41. pmc Corticotropin-releasing factor in the norepinephrine nucleus, locus coeruleus, facilitates behavioral flexibility
    Kevin Snyder
    The University of Pennsylvania, Philadelphia, PA, USA
    Neuropsychopharmacology 37:520-30. 2012
    ....
  42. pmc Sex differences in molecular and cellular substrates of stress
    Debra A Bangasser
    Department of Anesthesiology and Critical Care Medicine, The Children s Hospital of Philadelphia, Philadelphia, PA 19104, USA
    Cell Mol Neurobiol 32:709-23. 2012
    ..The implications of these sex differences for the treatment of stress-related psychiatric disorders also will be discussed...
  43. pmc Chronic stress exacerbates tau pathology, neurodegeneration, and cognitive performance through a corticotropin-releasing factor receptor-dependent mechanism in a transgenic mouse model of tauopathy
    Jenna C Carroll
    Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, School of Medicine and Institute on Aging, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    J Neurosci 31:14436-49. 2011
    ..These studies also implicate CRF in AD pathophysiology and suggest that pharmacological manipulation of this neuropeptide may be a potential therapeutic strategy for AD...
  44. ncbi request reprint Cellular basis for the effects of substance P in the periaqueductal gray and dorsal raphe nucleus
    Kathryn G Commons
    Children s Hospital of Philadelphia, Joseph Stokes Research Institute, 402 Abramson Research Center, Philadelphia, Pennsylvania 19104, USA
    J Comp Neurol 447:82-97. 2002
    ..This circuitry could contribute to, as well as coordinate, effects of SP on pain perception and mood...
  45. pmc Ventral tegmental afferents in stress-induced reinstatement: the role of cAMP response element-binding protein
    Lisa A Briand
    Department of Pharmacology, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
    J Neurosci 30:16149-59. 2010
    ....
  46. pmc The bladder-brain connection: putative role of corticotropin-releasing factor
    Rita J Valentino
    Department of Anesthesia and Critical Care Medicine, The Children s Hospital of Philadelphia, Civic Center Boulevard, Philadelphia, PA 19104, USA
    Nat Rev Urol 8:19-28. 2011
    ..The stress-related neuropeptide, corticotropin-releasing factor, which is prominent in Barrington's nucleus neurons, is a potential mediator of these effects...
  47. ncbi request reprint Central representation of bladder and colon revealed by dual transsynaptic tracing in the rat: substrates for pelvic visceral coordination
    Marie Laure Rouzade-Dominguez
    The Children s Hospital of Philadelphia, 34th and Civic Center Blvd, 402 Abramson Pediatric Research Center, Philadelphia, PA 19104, USA
    Eur J Neurosci 18:3311-24. 2003
    ..These anatomical substrates may underlie the central coordination of bladder and colon function and play a role in disorders characterized by a coexistence of bladder and colonic symptoms...
  48. pmc Repeated neonatal handling with maternal separation permanently alters hippocampal GABAA receptors and behavioral stress responses
    Fu Chun Hsu
    The Children s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA 19104, USA
    Proc Natl Acad Sci U S A 100:12213-8. 2003
    ....