Benjamin T Kile

Summary

Affiliation: The Walter and Eliza Hall Institute of Medical Research
Country: Australia

Publications

  1. pmc Mutation discovery in mice by whole exome sequencing
    Heather Fairfield
    The Jackson Laboratory, 600 Main St, Bar Harbor, ME 04609, USA
    Genome Biol 12:R86. 2011
  2. pmc Mutations in the cofilin partner Aip1/Wdr1 cause autoinflammatory disease and macrothrombocytopenia
    Benjamin T Kile
    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
    Blood 110:2371-80. 2007
  3. pmc Functional analysis of Asb-1 using genetic modification in mice
    B T Kile
    The Walter and Eliza Hall Institute of Medical Research and the Cooperative Research Centre for Cellular Growth Factors, Royal Melbourne Hospital, Victoria 3050, Australia
    Mol Cell Biol 21:6189-97. 2001
  4. ncbi request reprint Negative regulators of cytokine signaling
    B T Kile
    Division of Cancer and Hematology, The Walter and Eliza Hall Institute for Medical Research and The Cooperative Research Centre for Cellular Growth Factors, Royal Melbourne Hospital, Victoria, Australia
    Int J Hematol 73:292-8. 2001
  5. ncbi request reprint Cloning and characterization of the genes encoding the ankyrin repeat and SOCS box-containing proteins Asb-1, Asb-2, Asb-3 and Asb-4
    B T Kile
    The Walter and Eliza Hall Institute for Medical Research and The Cooperative Research Centre for Cellular Growth Factors, Post Office, Royal Melbourne Hospital, Melbourne, Victoria 3050, Australia
    Gene 258:31-41. 2000
  6. doi request reprint The role of the intrinsic apoptosis pathway in platelet life and death
    B T Kile
    Molecular Medicine Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
    J Thromb Haemost 7:214-7. 2009
  7. ncbi request reprint The art and design of genetic screens: mouse
    Benjamin T Kile
    Division of Cancer and Hematology, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville 3050, Victoria, Australia
    Nat Rev Genet 6:557-67. 2005
  8. doi request reprint Mcl-1 and Bcl-x(L) coordinately regulate megakaryocyte survival
    Marlyse A Debrincat
    Cancer and Hematology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
    Blood 119:5850-8. 2012
  9. doi request reprint Caspase-9 mediates the apoptotic death of megakaryocytes and platelets, but is dispensable for their generation and function
    Michael J White
    Cancer and Hematology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
    Blood 119:4283-90. 2012
  10. pmc Dual requirement for the ETS transcription factors Fli-1 and Erg in hematopoietic stem cells and the megakaryocyte lineage
    Elizabeth A Kruse
    Divisions of Molecular Medicine and Cancer and Haematology, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville 3052, Australia
    Proc Natl Acad Sci U S A 106:13814-9. 2009

Detail Information

Publications52

  1. pmc Mutation discovery in mice by whole exome sequencing
    Heather Fairfield
    The Jackson Laboratory, 600 Main St, Bar Harbor, ME 04609, USA
    Genome Biol 12:R86. 2011
    ..We found strong candidate mutations for the majority of mutant exomes sequenced, including new models of orofacial clefting, urogenital dysmorphology, kyphosis and autoimmune hepatitis...
  2. pmc Mutations in the cofilin partner Aip1/Wdr1 cause autoinflammatory disease and macrothrombocytopenia
    Benjamin T Kile
    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
    Blood 110:2371-80. 2007
    ..These studies establish an essential requirement for Wdr1 in megakaryocytes and neutrophils, indicating that cofilin-mediated actin dynamics are critically important to the development and function of both cell types...
  3. pmc Functional analysis of Asb-1 using genetic modification in mice
    B T Kile
    The Walter and Eliza Hall Institute of Medical Research and the Cooperative Research Centre for Cellular Growth Factors, Royal Melbourne Hospital, Victoria 3050, Australia
    Mol Cell Biol 21:6189-97. 2001
    ..In contrast, the widespread overexpression of Asb-1 in the mouse has no apparent deleterious effects...
  4. ncbi request reprint Negative regulators of cytokine signaling
    B T Kile
    Division of Cancer and Hematology, The Walter and Eliza Hall Institute for Medical Research and The Cooperative Research Centre for Cellular Growth Factors, Royal Melbourne Hospital, Victoria, Australia
    Int J Hematol 73:292-8. 2001
    ....
  5. ncbi request reprint Cloning and characterization of the genes encoding the ankyrin repeat and SOCS box-containing proteins Asb-1, Asb-2, Asb-3 and Asb-4
    B T Kile
    The Walter and Eliza Hall Institute for Medical Research and The Cooperative Research Centre for Cellular Growth Factors, Post Office, Royal Melbourne Hospital, Melbourne, Victoria 3050, Australia
    Gene 258:31-41. 2000
    ..We report here the cloning, characterization, mapping and expression analysis of four members of the ankyrin repeat and SOCS box-containing (Asb) protein family...
  6. doi request reprint The role of the intrinsic apoptosis pathway in platelet life and death
    B T Kile
    Molecular Medicine Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
    J Thromb Haemost 7:214-7. 2009
    ..This review examines the role of the intrinsic apoptosis pathway, regulated by the Bcl-2 family of proteins, in platelet biology...
  7. ncbi request reprint The art and design of genetic screens: mouse
    Benjamin T Kile
    Division of Cancer and Hematology, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville 3050, Victoria, Australia
    Nat Rev Genet 6:557-67. 2005
    ....
  8. doi request reprint Mcl-1 and Bcl-x(L) coordinately regulate megakaryocyte survival
    Marlyse A Debrincat
    Cancer and Hematology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
    Blood 119:5850-8. 2012
    ..Our studies indicate that the combination of Bcl-x(L) and Mcl-1 is essential for the viability of the megakaryocyte lineage...
  9. doi request reprint Caspase-9 mediates the apoptotic death of megakaryocytes and platelets, but is dispensable for their generation and function
    Michael J White
    Cancer and Hematology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
    Blood 119:4283-90. 2012
    ..These studies demonstrate that the apoptotic caspase cascade is required for the efficient death of megakaryocytes and platelets, but is dispensable for their generation and function...
  10. pmc Dual requirement for the ETS transcription factors Fli-1 and Erg in hematopoietic stem cells and the megakaryocyte lineage
    Elizabeth A Kruse
    Divisions of Molecular Medicine and Cancer and Haematology, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville 3052, Australia
    Proc Natl Acad Sci U S A 106:13814-9. 2009
    ..These results illustrate an indispensable requirement for both Fli-1 and Erg in normal HSC and megakaryocyte homeostasis, and suggest these transcription factors may coregulate common target genes...
  11. doi request reprint Reduced lymphocyte longevity and homeostatic proliferation in lamin B receptor-deficient mice results in profound and progressive lymphopenia
    Anne M Verhagen
    Walter and Eliza Hall Institute, Parkville, Victoria 3052, Australia
    J Immunol 188:122-34. 2012
    ..In summary, this study demonstrates that LBR deficiency affects not only nuclear architecture but also proliferation, cell viability, and gene expression of hematopoietic cells...
  12. doi request reprint Erg is required for self-renewal of hematopoietic stem cells during stress hematopoiesis in mice
    Ashley P Ng
    Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
    Blood 118:2454-61. 2011
    ..Thus, Erg is a critical regulator of adult HSCs, essential for maintaining self-renewal at times of high HSC cycling...
  13. pmc Point mutation in the gene encoding p300 suppresses thrombocytopenia in Mpl-/- mice
    Maria Kauppi
    Cancer and Haematology, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
    Blood 112:3148-53. 2008
    ....
  14. pmc Critical roles for c-Myb in lymphoid priming and early B-cell development
    Kylie T Greig
    The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
    Blood 115:2796-805. 2010
    ..These data show that c-Myb plays a critical role in the regulatory pathways governing lymphoid specification and early B-cell differentiation...
  15. pmc Proapoptotic Bak and Bax guard against fatal systemic and organ-specific autoimmune disease
    Kylie D Mason
    The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia
    Proc Natl Acad Sci U S A 110:2599-604. 2013
    ..This suggests that direct activators of the intrinsic apoptotic pathway, such as BH3 mimetics, may be useful for treatment of diverse autoimmune diseases...
  16. pmc Hematopoietic overexpression of the transcription factor Erg induces lymphoid and erythro-megakaryocytic leukemia
    Catherine L Carmichael
    Cancer and Hematology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Vic, Australia
    Proc Natl Acad Sci U S A 109:15437-42. 2012
    ..Thus, in mice, Erg overexpression induces the development of not only lymphoid leukemia but also erythro-megakaryocytic leukemia...
  17. doi request reprint Bcl-xL-inhibitory BH3 mimetics can induce a transient thrombocytopathy that undermines the hemostatic function of platelets
    Simone M Schoenwaelder
    Australian Centre for Blood Diseases, Monash University, Melbourne, Australia
    Blood 118:1663-74. 2011
    ..Overall, these studies demonstrate that Bcl-x(L)-inhibitory BH3 mimetics not only induce thrombocytopenia but also a transient thrombocytopathy that can undermine the hemostatic function of platelets...
  18. pmc Megakaryocytes possess a functional intrinsic apoptosis pathway that must be restrained to survive and produce platelets
    Emma C Josefsson
    Molecular Medicine Division, Cancer and Hematology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia
    J Exp Med 208:2017-31. 2011
    ..Thus, megakaryocytes do not activate the intrinsic pathway to generate platelets; rather, the opposite is true: they must restrain it to survive and progress safely through proplatelet formation and platelet shedding...
  19. pmc Thrombocytopenia and erythrocytosis in mice with a mutation in the gene encoding the hemoglobin β minor chain
    Maria Kauppi
    Cancer and Haematology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Australia
    Proc Natl Acad Sci U S A 109:576-81. 2012
    ..The Plt12 mouse is a model of high O(2)-affinity hemoglobinopathy and provides insights into hematopoiesis under conditions of chronic hypoxia...
  20. doi request reprint An ENU-induced mouse mutant of SHIP1 reveals a critical role of the stem cell isoform for suppression of macrophage activation
    Nhu Y N Nguyen
    Rotary Bone Marrow Research Laboratories, Royal Melbourne Hospital, Victoria 3050, Australia
    Blood 117:5362-71. 2011
    ..Our results suggest that s-SHIP synergizes with SHIP1 for suppression of macrophage activation, thus providing the first evidence for a role of s-SHIP in adult hematopoiesis...
  21. doi request reprint Trisomy of Erg is required for myeloproliferation in a mouse model of Down syndrome
    Ashley P Ng
    Cancer and Haematology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
    Blood 115:3966-9. 2010
    ....
  22. pmc A model for studying the hemostatic consumption or destruction of platelets
    Mark R Dowling
    Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
    PLoS ONE 8:e57783. 2013
    ....
  23. ncbi request reprint Ankyrin repeat and suppressors of cytokine signaling box protein asb-9 targets creatine kinase B for degradation
    Marlyse A Debrincat
    Division of Cancer and Haematology, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia
    J Biol Chem 282:4728-37. 2007
    ..The targeting of CKB for degradation by Asb-9 was primarily SOCS box-dependent and suggests that Asb-9 acts as a specific ubiquitin ligase regulating levels of this evolutionarily conserved enzyme...
  24. pmc Transposon mutagenesis reveals cooperation of ETS family transcription factors with signaling pathways in erythro-megakaryocytic leukemia
    Jian Zhong Tang
    The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia
    Proc Natl Acad Sci U S A 110:6091-6. 2013
    ....
  25. doi request reprint ENU mutagenesis identifies the first mouse mutants reproducing human β-thalassemia at the genomic level
    Fiona C Brown
    Australian Centre for Blood Diseases, Monash University, Melbourne, VIC 3004, Australia
    Blood Cells Mol Dis 50:86-92. 2013
    ..The RBC13 and RBC14 lines are the first β-thalassemia mouse models that reproduce human β-thalassemia at the genomic level, and as such highlight the power of ENU mutagenesis screens in generating mouse models of human disease...
  26. doi request reprint The transcription factor Erg is essential for definitive hematopoiesis and the function of adult hematopoietic stem cells
    Stephen J Loughran
    Division of Molecular Medicine, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3050, Australia
    Nat Immunol 9:810-9. 2008
    ..We show that Erg is required for definitive hematopoiesis, adult hematopoietic stem cell function and the maintenance of normal peripheral blood platelet numbers...
  27. doi request reprint A kinase-dead allele of Lyn attenuates autoimmune disease normally associated with Lyn deficiency
    Anne M Verhagen
    Signal Transduction Laboratory, St Vincent s Institute, Fitzroy, Victoria, Australia
    J Immunol 182:2020-9. 2009
    ..Furthermore, our results provide evidence for an additional role for Lyn kinase, distinct from its catalytic activity, in regulating intracellular signaling pathways...
  28. pmc A mouse model of harlequin ichthyosis delineates a key role for Abca12 in lipid homeostasis
    Ian Smyth
    Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Australia
    PLoS Genet 4:e1000192. 2008
    ..Furthermore, we identify Abca12 as a mediator of Abca1-regulated cellular cholesterol efflux, a finding that may have significant implications for other diseases of lipid metabolism and homeostasis, including atherosclerosis...
  29. pmc Mutational inhibition of c-Myb or p300 ameliorates treatment-induced thrombocytopenia
    Douglas J Hilton
    Molecular Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
    Blood 113:5599-604. 2009
    ..The data suggest potential utility of c-Myb/p300 as a target for therapeutic intervention in thrombocytopenia of diverse origins...
  30. doi request reprint Platelet senescence is regulated by an internal timer, not damage inflicted by hits
    Mark R Dowling
    Immunology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
    Blood 116:1776-8. 2010
    ..Thus, at steady state, platelet senescence is probably the product of internal processes rather than external hits...
  31. pmc Agm1/Pgm3-mediated sugar nucleotide synthesis is essential for hematopoiesis and development
    Kylie T Greig
    Division of Molecular Medicine, The Walter and Eliza Hall Institute of Medical Research, Victoria, Australia
    Mol Cell Biol 27:5849-59. 2007
    ....
  32. ncbi request reprint Programmed anuclear cell death delimits platelet life span
    Kylie D Mason
    Molecular Genetics of Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3050, Australia
    Cell 128:1173-86. 2007
    ....
  33. pmc ERG dependence distinguishes developmental control of hematopoietic stem cell maintenance from hematopoietic specification
    Samir Taoudi
    Molecular Medicine Division, The Walter and Eliza Institute of Medical Research, Melbourne, Parkville, Victoria 3052, Australia
    Genes Dev 25:251-62. 2011
    ..We show that, from the fetal period, ERG acts as a direct upstream regulator of Gata2 and Runx1 gene activity. Without ERG, physiological HSC maintenance fails, leading to the rapid exhaustion of definitive hematopoiesis...
  34. ncbi request reprint The suppressors of cytokine signalling (SOCS)
    B T Kile
    Division of Cancer and Hematology, The Walter and Eliza Hall Institute for Medical Research and The Cooperative Research Centre for Cellular Growth Factors, Royal Melbourne Hospital, Victoria, Australia
    Cell Mol Life Sci 58:1627-35. 2001
    ..Indispensable roles for members of this family have been identified in the regulation of interferon gamma, growth hormone and erythropoietin, and the absence of SOCS-1 or SOCS-3 is lethal in mice...
  35. doi request reprint NLRP1 inflammasome activation induces pyroptosis of hematopoietic progenitor cells
    Seth L Masters
    The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia
    Immunity 37:1009-23. 2012
    ..Conversely, NLRP1-deficient mice showed enhanced recovery from chemotherapy and LCMV infection, demonstrating that NLRP1 acts as a cellular sentinel to alert Caspase-1 to hematopoietic and infectious stress...
  36. ncbi request reprint A novel mutation in the Nfkb2 gene generates an NF-kappa B2 "super repressor"
    Elena Tucker
    St Vincent s Institute, Fitzroy, Victoria, Australia
    J Immunol 179:7514-22. 2007
    ..These findings demonstrate a key role for NF-kappaB2 in the regulation of RelA activation and suggest overlap in the function of NF-kappaB members in canonical and noncanonical pathway signaling...
  37. ncbi request reprint The SOCS box: a tale of destruction and degradation
    Benjamin T Kile
    The Walter and Eliza Hall Institute of Medical Research and the Cooperative Research Centre for Cellular Growth Factors, Parkville, Victoria, Australia
    Trends Biochem Sci 27:235-41. 2002
    ..In this way, SOCS proteins regulate protein turnover by targeting proteins for polyubiquitination and, therefore, for proteasome-mediated degradation...
  38. doi request reprint Two distinct pathways regulate platelet phosphatidylserine exposure and procoagulant function
    Simone M Schoenwaelder
    Australian Centre for Blood Diseases, Monash University, 89 Commercial Road, Melbourne, Victoria 3004, Australia
    Blood 114:663-6. 2009
    ..These studies show the existence of 2 distinct pathways regulating the procoagulant function of platelets...
  39. pmc MyD88 is a critical regulator of hematopoietic cell-mediated neuroprotection seen after stroke
    Catherine E Downes
    Department of Pharmacology, University of Melbourne, Parkville, Victoria, Australia
    PLoS ONE 8:e57948. 2013
    ..We have demonstrated that MyD88-dependent signalling in the hematopoietic cell lineage reduces infarct size following stroke and that infiltrating cells to the site of neuroinflammation are neuroprotective following stroke...
  40. pmc Variability of inducible expression across the hematopoietic system of tetracycline transactivator transgenic mice
    Megumi Takiguchi
    Molecular Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
    PLoS ONE 8:e54009. 2013
    ....
  41. doi request reprint Platelet life span and apoptosis
    Emma C Josefsson
    Cancer and Haematology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Vic, Australia
    Methods Mol Biol 788:59-71. 2012
    ..Here, we describe methods to determine platelet life span, enumerate young platelets, and measure hallmarks of platelet apoptosis, such as PS exposure, caspase activation, and mitochondrial dysfunction...
  42. ncbi request reprint Suppressors of cytokine signaling (SOCS): negative regulators of signal transduction
    W S Alexander
    The Walter and Eliza Hall Institute of Medical Research and the Cooperative Research Centre for Cellular Growth Factors, Royal Melbourne Hospital, Victoria, Australia
    J Leukoc Biol 66:588-92. 1999
    ..We propose that the absence of SOCS-1 in these mice prevents lymphocytes and liver cells from appropriately controlling signals from cytokines with cytotoxic side effects...
  43. doi request reprint ABCA12 regulates ABCA1-dependent cholesterol efflux from macrophages and the development of atherosclerosis
    Ying Fu
    Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia
    Cell Metab 18:225-38. 2013
    ..Thus, ABCA12 regulates the cellular cholesterol metabolism via an LXRβ-dependent posttranscriptional mechanism...
  44. pmc Thrombocytopenia and kidney disease in mice with a mutation in the C1galt1 gene
    Warren S Alexander
    The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia
    Proc Natl Acad Sci U S A 103:16442-7. 2006
    ..The disease in plt1/plt1 mice suggests that, in addition to immune-mediated effects, intrinsic C1Gal-T1 deficiency in megakaryocytes and the kidney may contribute to pathology...
  45. pmc Novel roles for erythroid Ankyrin-1 revealed through an ENU-induced null mouse mutant
    Gerhard Rank
    Rotary Bone Marrow Research Laboratory, Melbourne Health Research Directorate, Parkville, Australia
    Blood 113:3352-62. 2009
    ..These findings provide novel insights into the role of Ank-1, and define an ideal model for the study of HS and malarial resistance...
  46. doi request reprint Apoptotic processes in megakaryocytes and platelets
    Michael J White
    Molecular Medicine Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
    Semin Hematol 47:227-34. 2010
    ..This review discusses the current state of knowledge about how apoptosis and apoptotic proteins contribute to the generation and function of megakaryocytes and platelets...
  47. ncbi request reprint Probabilistic analysis of recessive mutagenesis screen strategies
    Jeremy D Silver
    Division of Molecular Medicine and the Division of Bioinformatics, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
    Mamm Genome 18:5-22. 2007
    ..This method allows researchers to contrast, for a range of experimental designs, the cost per mutation screened and to maximize the number of mutations that one can expect to screen in a given experiment...
  48. ncbi request reprint Functional genetic analysis of mouse chromosome 11
    Benjamin T Kile
    Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA
    Nature 425:81-6. 2003
    ..The mutations reveal new defects in haematopoiesis, craniofacial and cardiovascular development, and fertility...
  49. pmc The role of the ETS factor erg in zebrafish vasculogenesis
    Felix Ellett
    Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3050, Australia
    Mech Dev 126:220-9. 2009
    ....
  50. pmc Two ENU-induced alleles of Atp2b2 cause deafness in mice
    Marina R Carpinelli
    Murdoch Childrens Research Institute, Royal Children s Hospital, Parkville, Victoria, Australia
    PLoS ONE 8:e67479. 2013
    ..The Atp2b2 (Deaf13) mutation leads to a p. R561S substitution in the catalytic core. Mice homozygous for these mutations display profound hearing loss. Heterozygotes display mild to moderate, progressive hearing loss. ..
  51. ncbi request reprint Genetic mapping of mouse centromere protein (Incenp and Cenpe) genes
    K J Fowler
    The Murdoch Institute, Royal Children s Hospital, Parkville, Victoria, Australia
    Cytogenet Cell Genet 82:67-70. 1998
    ..Comparison of Cenpe and human CENPE, which maps to chromosome region 4q24-->q25, has further identified a new region of homology between the two species...
  52. ncbi request reprint Cloning, expression, and promoter structure of a mammalian inner centromere protein (INCENP)
    R Saffery
    The Murdoch Institute, Royal Children s Hospital, Flemington Road, Parkville, 3052, Victoria, Australia
    Mamm Genome 10:415-8. 1999