Zdenek Zidek

Summary

Affiliation: Academy of Sciences of the Czech Republic
Country: Czech Republic

Publications

  1. pmc Current status and challenges of cytokine pharmacology
    Z Zidek
    Department of Pharmacology, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, v v i, Videnska 1083, 142 20 Prague 4, Czech Republic
    Br J Pharmacol 157:342-61. 2009
  2. ncbi request reprint Effects of sesquiterpene, flavonoid and coumarin types of compounds from Artemisia annua L. on production of mediators of angiogenesis
    Xiaoxin X Zhu
    Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Nanxiaojie 16, Dongzhimen Nei Avenue, Beijing 100700, China
    Pharmacol Rep 65:410-20. 2013
  3. doi request reprint Microfiltration method of removal of bacterial contaminants and their monitoring by nitric oxide and Limulus assays
    Zdenek Zidek
    Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Videnska 1083, 14220 Prague 4, Czech Republic
    Nitric Oxide 28:1-7. 2013
  4. ncbi request reprint Antiretroviral agent (R)-9-(2-phosphonomethoxypropyl)adenine stimulates cytokine and nitric oxide production
    Z Zidek
    Institute of Pharmacology, Academy of Sciences of the Czech Republic, Prague
    Eur J Pharmacol 331:245-52. 1997
  5. ncbi request reprint Involvement of adenosine A1 receptors in upregulation of nitric oxide by acyclic nucleotide analogues
    Zdenek Zidek
    Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Videnska 1083, 142 20 Prague 4, Czech Republic
    Eur J Pharmacol 501:79-86. 2004
  6. doi request reprint Intrinsic nitric oxide-stimulatory activity of lipoteichoic acids from different Gram-positive bacteria
    Zdenek Zidek
    Institute of Experimental Medicine, Department of Pharmacology, Videnska 1083, 142 20 Prague 4, Czech Republic
    Nitric Oxide 23:300-10. 2010
  7. ncbi request reprint In vivo effects of antiviral acyclic nucleoside phosphonate 9-[2-(phosphonomethoxy)ethyl]adenine (adefovir) on cytochrome P450 system of rat liver microsomes
    Zdenek Zidek
    Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague
    J Biomed Sci 13:295-301. 2006
  8. ncbi request reprint Cytotoxicity of pivoxil esters of antiviral acyclic nucleoside phosphonates: adefovir dipivoxil versus adefovir
    Zdenek Zidek
    Institute of Experimental Medicine, Academy of Sciences, Videnska 1083, Prague, Czech Republic
    Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 149:315-9. 2005
  9. doi request reprint Decisive role of lipopolysaccharide in activating nitric oxide and cytokine production by the probiotic Escherichia coli strain Nissle 1917
    Z Zidek
    Institute of Experimental Medicine, v v i, Academy of Sciences of the Czech Republic, 142 20, Prague 4, Czech Republic
    Folia Microbiol (Praha) 55:181-9. 2010
  10. ncbi request reprint Cytostatic activity of antiviral acyclic nucleoside phosphonates in rodent lymphocytes
    Zdenek Zidek
    Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, 142 20 Prague, Czech Republic
    Toxicol Appl Pharmacol 192:246-53. 2003

Collaborators

Detail Information

Publications44

  1. pmc Current status and challenges of cytokine pharmacology
    Z Zidek
    Department of Pharmacology, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, v v i, Videnska 1083, 142 20 Prague 4, Czech Republic
    Br J Pharmacol 157:342-61. 2009
    ..The aim of the review is to encourage more intensive studies in these fields of cytokine pharmacology. It also outlines major areas of searching promising candidates for immunotherapeutic interventions...
  2. ncbi request reprint Effects of sesquiterpene, flavonoid and coumarin types of compounds from Artemisia annua L. on production of mediators of angiogenesis
    Xiaoxin X Zhu
    Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Nanxiaojie 16, Dongzhimen Nei Avenue, Beijing 100700, China
    Pharmacol Rep 65:410-20. 2013
    ..annua on the immune-activated production of major mediators of angiogenesis playing a crucial role in growth of tumors and formation of metastasis...
  3. doi request reprint Microfiltration method of removal of bacterial contaminants and their monitoring by nitric oxide and Limulus assays
    Zdenek Zidek
    Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Videnska 1083, 14220 Prague 4, Czech Republic
    Nitric Oxide 28:1-7. 2013
    ..All types of the filters (3kDa to 100kDa) are equally effective. It is suggested that the microfiltration procedure may be considered as a preferable, general and easy method of sample decontamination...
  4. ncbi request reprint Antiretroviral agent (R)-9-(2-phosphonomethoxypropyl)adenine stimulates cytokine and nitric oxide production
    Z Zidek
    Institute of Pharmacology, Academy of Sciences of the Czech Republic, Prague
    Eur J Pharmacol 331:245-52. 1997
    ..The novel findings on the immunomodulatory potential of acyclic nucleotide analogs are discussed in the context of their possible implication in antiviral therapeutic efficacy...
  5. ncbi request reprint Involvement of adenosine A1 receptors in upregulation of nitric oxide by acyclic nucleotide analogues
    Zdenek Zidek
    Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Videnska 1083, 142 20 Prague 4, Czech Republic
    Eur J Pharmacol 501:79-86. 2004
    ....
  6. doi request reprint Intrinsic nitric oxide-stimulatory activity of lipoteichoic acids from different Gram-positive bacteria
    Zdenek Zidek
    Institute of Experimental Medicine, Department of Pharmacology, Videnska 1083, 142 20 Prague 4, Czech Republic
    Nitric Oxide 23:300-10. 2010
    ..The results prove the intrinsic immunostimulatory properties of LTAs of Gram-positive bacteria. The positive response of LTA in the LAL assay results from its capacity to bind to LAL. In addition, LTA binds with high affinity to PMX...
  7. ncbi request reprint In vivo effects of antiviral acyclic nucleoside phosphonate 9-[2-(phosphonomethoxy)ethyl]adenine (adefovir) on cytochrome P450 system of rat liver microsomes
    Zdenek Zidek
    Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague
    J Biomed Sci 13:295-301. 2006
    ..It may be concluded that repeated systemic administration of higher doses of PMEA results in a partial degradation of rat CYP protein to inactive P420...
  8. ncbi request reprint Cytotoxicity of pivoxil esters of antiviral acyclic nucleoside phosphonates: adefovir dipivoxil versus adefovir
    Zdenek Zidek
    Institute of Experimental Medicine, Academy of Sciences, Videnska 1083, Prague, Czech Republic
    Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 149:315-9. 2005
    ..The present data are consistent with the view that pivoxil prodrug of PMEA, bis-POM-PMEA possesses enhanced but also broader spectrum of biological effects than the parent compound...
  9. doi request reprint Decisive role of lipopolysaccharide in activating nitric oxide and cytokine production by the probiotic Escherichia coli strain Nissle 1917
    Z Zidek
    Institute of Experimental Medicine, v v i, Academy of Sciences of the Czech Republic, 142 20, Prague 4, Czech Republic
    Folia Microbiol (Praha) 55:181-9. 2010
    ..It is suggested that the immunostimulatory activity of LPS is modulated by EcN-derived factor(s), the nature of which remains to be identified...
  10. ncbi request reprint Cytostatic activity of antiviral acyclic nucleoside phosphonates in rodent lymphocytes
    Zdenek Zidek
    Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, 142 20 Prague, Czech Republic
    Toxicol Appl Pharmacol 192:246-53. 2003
    ..036 microM). The N(6)-substituted derivatives of (S)-PMPA are virtually devoid of cytostatic activity. No tight correlation between the cytostatic and reported antiviral effects could be detected...
  11. ncbi request reprint Immunobiological activity of N-[2-(phosphonomethoxy)alkyl] derivatives of N6-substituted adenines, and 2,6-diaminopurines
    Zdenek Zidek
    Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Videnska 1083, 142 20 Prague 4, Czech Republic
    Eur J Pharmacol 475:149-59. 2003
    ..They exhibit immunostimulatory effects at concentrations as low as 1 to 5 microM. It is suggested that these compounds might be prospective candidates for antiviral therapeutic exploitation...
  12. ncbi request reprint Inhibition of murine macrophage nitric oxide synthase expression by a pivoxil prodrug of antiviral acyclic nucleotide analogue 9-(2-phosphonomethoxyethyl)adenine
    Z Zidek
    Institute of Pharmacology, Academy of Sciences of the Czech Republic, Prague
    Biochem Pharmacol 54:855-61. 1997
    ..Suppressed transcription of mRNA for inducible NO synthase (EC 1.14.13.39) resulting in decreased synthesis of NO synthase protein was found. Parent compound PMEA was virtually ineffective...
  13. ncbi request reprint Erratic behavior of nitric oxide within the immune system: illustrative review of conflicting data and their immunopharmacological aspects
    Z Zidek
    Institute of Pharmacology, Academy of Sciences of the Czech Republic, Prague
    Int J Immunopharmacol 20:319-43. 1998
    ..Hopefully, this approach could improve the predictability of the clinical outcomes of NO manipulation...
  14. ncbi request reprint Chemokines, nitric oxide and antiarthritic effects of 9-(2-phosphonomethoxyethyl)adenine (Adefovir)
    Z Zidek
    Institute of Pharmacology, Academy of Sciences of the Czech Republic, Prague
    Eur J Pharmacol 376:91-100. 1999
    ..Possible mechanisms for the anti-RANTES activity of PMEA remains to be firmly established...
  15. ncbi request reprint Genetic variation in in-vitro cytokine-induced production of nitric oxide by murine peritoneal macrophages
    Z Zidek
    Institute of Pharmacology, Academy of Sciences of the Czech Republic, Prague
    Pharmacogenetics 10:493-501. 2000
    ..Possible implications of the findings for various fields of NO biomedical research are discussed...
  16. ncbi request reprint Macrophage activation by antiviral acyclic nucleoside phosphonates in dependence on priming immune stimuli
    Z Zidek
    Institute of Pharmacology, Academy of Sciences of the Czech Republic, Videnska 1083, 14220 4, Prague, Czech Republic
    Int J Immunopharmacol 22:1121-9. 2000
    ..It can be concluded that the expression of immunomodulatory properties of ANPs depends on the immune state of cells and its activation by distinct priming signals...
  17. ncbi request reprint Role of cytokines in the modulation of nitric oxide production by cyclic AMP
    Z Zidek
    Laboratory of Molecular Immunopharmacology, Institute of Pharmacology, Academy of Sciences, Videnska 1083, 14220 Prague, Czech Republic
    Eur Cytokine Netw 12:22-32. 2001
    ..The cytokine ratio may be influenced by dynamically developing multiple down- and up-regulatory feedback circuits among cytokines, NO, and cAMP...
  18. pmc Activation by 9-(R)-[2-(phosphonomethoxy)propyl]adenine of chemokine (RANTES, macrophage inflammatory protein 1alpha) and cytokine (tumor necrosis factor alpha, interleukin-10 [IL-10], IL-1beta) production
    Z Zidek
    Institute of Pharmacology, Academy of Sciences of the Czech Republic, Prague, Czech Republic
    Antimicrob Agents Chemother 45:3381-6. 2001
    ..The findings contribute to a more complex understanding of mechanisms of antiviral effectiveness of PMPA and support the view that this drug could become a promising candidate for therapeutic exploitation in anti-HIV preventive medicine...
  19. ncbi request reprint Secretion of antiretroviral chemokines by human cells cultured with acyclic nucleoside phosphonates
    Zdenek Zidek
    Institute of Experimental Medicine, Department of Pharmacology, Academy of Sciences of the Czech Republic, Prague 4, Czech Republic
    Eur J Pharmacol 574:77-84. 2007
    ..It may be suggested that acyclic nucleoside phosphonates represent a new generation of antivirotics with combined antimetabolic and therapeutically prospective immunostimulatory properties...
  20. ncbi request reprint Purine P1 receptor-dependent immunostimulatory effects of antiviral acyclic analogues of adenine and 2,6-diaminopurine
    Eva Kmoníčková
    Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague
    Eur J Pharmacol 530:179-87. 2006
    ..The suppression is due to decreased transcription of cytokine mRNA. It may be suggested that acyclic nucleoside phosphonates are nonspecific ligands for purine P(1) receptors...
  21. ncbi request reprint Nucleotide analogues with immunobiological properties: 9-[2-Hydroxy-3-(phosphonomethoxy)propyl]-adenine (HPMPA), -2,6-diaminopurine (HPMPDAP), and their N6-substituted derivatives
    Petr Potmesil
    Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Centre for New Antivirals and Antineoplastics, Videnska 1083, 142 20 Prague 4, Czech Republic
    Eur J Pharmacol 540:191-9. 2006
    ..The immunomodulatory effects were found to be at least in part dependent on P1 purinoreceptors, and mediated by transcriptional factor nuclear factor-kappaB...
  22. ncbi request reprint Nitric oxide production in mouse and rat macrophages: a rapid and efficient assay for screening of drugs immunostimulatory effects in human cells
    Eva Kmoníčková
    Institute of Experimental Medicine, Department of Pharmacology, Academy of Sciences, v v i, Videnska 1083, 142 20 Prague 4, Czech Republic
    Nitric Oxide 17:160-9. 2007
    ....
  23. ncbi request reprint Synthesis of guanidino analogues of PMPDAP and their immunobiological activity
    Michal Cesnek
    Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v v i, Flemingovo nam 2, 166 10 Praha 6, Czech Republic
    Bioorg Med Chem 16:965-80. 2008
    ..The most active compounds are 27 and 54. None of the compounds tested exhibited any significant cytostatic effect or antiviral effect...
  24. doi request reprint Inhibitor of sarco-endoplasmic reticulum Ca2+-ATPase thapsigargin stimulates production of nitric oxide and secretion of interferon-gamma
    Eva Kmoníčková
    Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Department of Pharmacology, v v i, Videnska 1083, 142 20 Prague 4, Czech Republic
    Eur J Pharmacol 588:85-92. 2008
    ..In summary, the original findings demonstrate immunostimulatory potential of thapsigargin and warrant more detailed preclinical studies...
  25. ncbi request reprint Stimulation of nitric oxide, cytokine and prostaglandin production by low-molecular weight fractions of probiotic Lactobacillus casei lysate
    Eva Kmoníčková
    Institute of Experimental Medicine, Academy of Sciences of the Czech Republic
    Neuro Endocrinol Lett 33:166-72. 2012
    ..The aim of the study was the analysis of immunobiological properties of bacterial lysates and characterization of chemical constituents participating on this mode of action...
  26. doi request reprint Hepatoprotective effect of curcumin in lipopolysaccharide/-galactosamine model of liver injury in rats: relationship to HO-1/CO antioxidant system
    Dalibor Cerný
    Institute of Pharmacology, Charles University in Prague, Czech Republic
    Fitoterapia 82:786-91. 2011
    ..4-fold, p=0.001), but reduced NOS-2 (4.1-fold, p=0.01) expressions. In conclusion, the tuning of CO/NO pathways is important in shedding light on curcumin's cytoprotective effects in this model...
  27. ncbi request reprint Modulator of intracellular Ca(2+), thapsigargin, interferes with in vitro secretion of cytokines and nitric oxide
    Eva Kmoníčková
    Institute of Experimental Medicine, Academy of Sciences, Prague, Czech Republic
    Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 149:321-4. 2005
    ..On the other hand, production of NO which was marginally activated by low concentration of LPS was upregulated by TG...
  28. doi request reprint Differential effects of acyclic nucleoside phosphonates on nitric oxide and cytokines in rat hepatocytes and macrophages
    Petra Kostecká
    Institute of Experimental Medicine, Academy of Sciences, Videnska 1083, 14220 Prague 4, Czech Republic
    Int Immunopharmacol 12:342-9. 2012
    ..The potential of hepatocytes to synthesize cytokines can contribute to better understanding of liver immune function and can serve for pharmacological intervention in liver diseases...
  29. ncbi request reprint Effects of Lactobacillus casei on the expression and the activity of cytochromes P450 and on the CYP mRNA level in the intestine and the liver of male rats
    Zuzana Matuskova
    Department of Pharmacology, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic
    Neuro Endocrinol Lett 32:8-14. 2011
    ..The aim of the study was to find whether probiotic Lactobacillus casei influences the expression or the activity of cytochromes P450 (CYP) and whether it has an influence on the level of CYP mRNA in male rats...
  30. ncbi request reprint Synthesis and immunobiological activity of base substituted 2-amino-3-(purin-9-yl)propanoic acid derivatives
    Petra Doláková
    Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic
    Bioorg Med Chem 13:2349-54. 2005
    ..Most of these compounds also augmented NO biosynthesis triggered primarily by IFN-gamma...
  31. doi request reprint Resveratrol attenuates lipopolysaccharide-induced hepatitis in D-galactosamine sensitized rats: role of nitric oxide synthase 2 and heme oxygenase-1
    Hassan Farghali
    Institute of Pharmacology, 1st Faculty of Medicine, Charles University, Prague, Albertov 4, 128 00 Prague 2, Czech Republic
    Nitric Oxide 21:216-25. 2009
    ....
  32. ncbi request reprint Synthesis of 9-alkyl and 9-heteroalkyl substituted 2-amino-6-guanidinopurines and their influence on the NO-production in macrophages
    Michal Cesnek
    Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo nam 2, 166 10 Praha 6, Czech Republic
    Bioorg Med Chem 13:2917-26. 2005
    ..The activity of the thus prepared compounds on murine macrophages was examined. Compounds 4a, 4b, and 4d inhibit the LPS+IFN-gamma-induced NO production in murine macrophages while compound 4h stimulates this production...
  33. doi request reprint Sesquiterpene lactone trilobolide activates production of interferon-γ and nitric oxide
    Eva Kmoníčková
    Department of Pharmacology, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, vvi, Prague, Czech Republic
    Fitoterapia 81:1213-9. 2010
    ..BAPTA-AM, a chelator of the intracellular calcium, remained without any effect on the secretion of IFN-γ triggered by TB. These results demonstrate that TB is a potent immunostimulatory agent...
  34. ncbi request reprint Influence of probiotics on rat liver biotransformation enzymes
    Zuzana Matuskova
    Department of Pharmacology, Palacky University, Olomouc, Czech Republic
    Neuro Endocrinol Lett 30:41-5. 2009
    ..The aim of the study was to find, whether probiotic Escherichia coli Nissle 1917 O6:K5:H1 (EcN) influence the amount and activity of cytochromes P450 (CYP) in rat liver...
  35. doi request reprint Lack of interference of common phytoecdysteroids with production of nitric oxide by immune-activated mammalian macrophages
    Juraj Harmatha
    Institute of Organic Chemistry and Biochemistry, Academy of Sciences, Laboratory of Natural Products, v v i, Flemingovo nam 2, 166 10 Prague 6, Czech Republic
    Steroids 73:466-71. 2008
    ..However, the tested ecdysteroids did not interfere with the immunobiological activity of the immunocompetent cells. Our results thus differ from the so far reported information...
  36. ncbi request reprint Effects of probiotic Escherichia coli Nissle 1917 on expression of cytochromes P450 along the gastrointestinal tract of male rats
    Zuzana Matuskova
    Department of Pharmacology, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic
    Neuro Endocrinol Lett 31:46-50. 2010
    ..The aim of the study was to find whether probiotic Escherichia coli Nissle 1917 O6:K5:H1 (EcN) influences the expression of cytochromes P450 (CYP) in the rat intestine...
  37. ncbi request reprint Experimental approaches to studies on drug metabolism and drug interactions in man: interaction of acyclic nucleoside phosphonates with human liver cytochromes P450 and flavin-containing monooxygenase 3
    Jaroslav Matal
    Department of Pharmacology, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic
    Neuro Endocrinol Lett 27:27-30. 2006
    ..To determine a possible influence of acyclic nucleoside phosphonates on FMO3 and CYP activity at molecular level in vitro...
  38. doi request reprint Effects of resveratrol pretreatment on tert-butylhydroperoxide induced hepatocyte toxicity in immobilized perifused hepatocytes: involvement of inducible nitric oxide synthase and hemoxygenase-1
    Dalibor Cerný
    Institute of Pharmacology, 1st Faculty of Medicine, Charles University, Albertov 4, 128 00 Prague 2, Czech Republic
    Nitric Oxide 20:1-8. 2009
    ..It may be concluded that resveratrol and sylimarin ameliorative effects on tBH hepatocyte toxicity are comparable; involve NOS-2 and HO-1 expression and should be re-evaluated in various in vitro and in vivo experimental conditions...
  39. ncbi request reprint Acyclic nucleoside phosphonate antivirals activate gene expression of monocyte chemotactic protein 1 and 3
    Petr Potmesil
    Institute of Experimental Medicine, Department of Immunopharmacology, Academy of Sciences of the Czech Republic, Centre for New Antivirals and Antineoplastics, Prague 4, Czech Republic
    J Biomed Sci 14:59-66. 2007
    ..Enhancement of monocyte chemotactic protein expression was found to be mediated by transcriptional factor nuclear factor-kappaB (NF-kappaB)...
  40. ncbi request reprint Activation of macrophages by gliadin fragments: isolation and characterization of active peptide
    Ludmila Tuckova
    Institute of Microbiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic
    J Leukoc Biol 71:625-31. 2002
    ..In contrast, C-terminally shortened peptides had a lower ability to stimulate macrophages than the native form...
  41. ncbi request reprint Modulation of spontaneous and lipopolysaccharide-induced nitric oxide production and apoptosis by d-galactosamine in rat hepatocyte culture: the significance of combinations of different methods
    Nikolina Kutinova Canova
    Institute of Pharmacology, 1st Faculty of Medicine, Charles University in Prague, Czech Republic
    Toxicol Mech Methods 18:63-74. 2008
    ....
  42. doi request reprint Trilobolide and related sesquiterpene lactones from Laser trilobum possessing immunobiological properties
    Juraj Harmatha
    Institute of Organic Chemistry and Biochemistry, Academy of Sciences, vvi, Prague, Czech Republic
    Fitoterapia 89:157-66. 2013
    ..On the contrary, the other L. trilobum and Laserpitium siler constituents are only very mild activators, or even inhibitors of the cytokine and nitric oxide production. ..
  43. doi request reprint The role of gut microbiota (commensal bacteria) and the mucosal barrier in the pathogenesis of inflammatory and autoimmune diseases and cancer: contribution of germ-free and gnotobiotic animal models of human diseases
    Helena Tlaskalova-Hogenova
    Institute of Microbiology, Academy of Sciences of the Czech Republic, v v i, Prague, Czech Republic
    Cell Mol Immunol 8:110-20. 2011
    ..g., probiotics and prebiotics) whose administration may aid in disease prevention and treatment...
  44. pmc Immunobiological properties of selected natural and chemically modified phenylpropanoids
    Juraj Harmatha
    Institute of Organic Chemistry and Biochemistry, Academy of Sciences, v v i, Flemingovo nam 2, CZ 166 10 Prague, Czech Republic
    Interdiscip Toxicol 4:5-10. 2011
    ....