14 research outputs found
The Structure of the Superantigen Exfoliative Toxin A Suggests a Novel Regulation as a Serine Protease â€
Coherent anti-stokes raman scattering microspectroscopic kinetic study of fast hydrogen bond formation in microfluidic devices
The kinetics of a key noncovalent, hydrogen bonding interaction was studied in situ using coherent anti-stokes Raman scattering (CARS) microspectroscopy in a microfluidic device. The association of model compounds, pyridine and hexafluoroisopropanol, was quantitatively monitored with submicrometer resolution. Lower limits for the very high formation and dissociation rate constants of the model 1:1 pyridine-hexafluoroisopropanol hydrogen bonded complex in dichloromethane-d2 were determined to be k1 > 105 M-1s-1 and k-1 > 333.3 s-1, respectively. © 2013 American Chemical Society
Coherent Anti-Stokes Raman Scattering Microspectroscopic Kinetic Study of Fast Hydrogen Bond Formation in Microfluidic Devices
The kinetics of a key noncovalent,
hydrogen bonding interaction
was studied in situ using coherent anti-stokes Raman scattering (CARS)
microspectroscopy in a microfluidic device. The association of model
compounds, pyridine and hexafluoroisopropanol, was quantitatively
monitored with submicrometer resolution. Lower limits for the very
high formation and dissociation rate constants of the model 1:1 pyridine–hexafluoroisopropanol
hydrogen bonded complex in dichloromethane-<i>d</i><sub>2</sub> were determined to be <i>k</i><sub>1</sub> >
10<sup>5</sup> M<sup>–1</sup>s<sup>–1</sup> and <i>k</i><sub>–1</sub> > 333.3 s<sup>–1</sup>,
respectively
Os desafios da alteridade: considerações sobre gênero e sexualidade entre militantes de uma ONG/Aids carioca
Two Nuclear Life Cycle-Regulated Genes Encode Interchangeable Subunits c of Mitochondrial ATP Synthase in Podospora anserina
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A common human MLKL polymorphism confers resistance to negative regulation by phosphorylation
Acknowledgements: We thank all the following people for their technical assistance; Aira Nuguid and Tina Cardamone (Phenomics Australia Histopathology and Slide Scanning Service- The University of Melbourne). WEHI Cytometry Facility, WEHI Antibody Facility, WEHI Centre for Dynamic Imaging, WEHI Bioservices, Cheree Fitzgibbon (WEHI), Jacinta Hansen (WEHI) Jingjing Vivian Tan and Yafei Zhang (ANU, The Australian Genomics Health Alliance). The generation of MlklS131P mice by CRISPR/Cas9 gene editing was performed by Andrew Kueh and Marco Herold (WEHI MAGEC laboratory) supported by the Australian Phenomics Network (APN) and the Australian Government through the National Collaborative Research Infrastructure Strategy (NCRIS) program. We thank Warren Alexander, Mary Speir, and Melanie Bahlo for the provision of important resources and expertize. We thank Michael Hildebrand and Tom Witkowski from Epilepsy Research Centre, Department of Medicine, Austin Health for assistance with Sanger sequencing. We are grateful to the National Health and Medical Research Council for fellowship (J.M.H., 1142669; A.L.S., 2002965; J.M.M., 1172929; J.S., 1107149), grant (J.M.M., 1105023; K.R.M., 1092602; J.S., 1105023; J.M.H., 2011584) and infrastructure (IRIISS 9000719); Arthritis Australia support to K.R.M; K.E.L funding by Future Fellowships from the ARC (FT19010266). We acknowledge scholarship support for S.E.G (Australian Government Research Training Program Stipend Scholarship; Wendy Dowsett Scholarship), Y.M (Melbourne Research Scholarship; AINSE PGRA Scholarship), D.F (Australian Government Research Training Program Stipend Scholarship), A.V.J (Australian Government Research Training Program Stipend Scholarship), and S.C (Walter and Eliza Hall Handman PhD Scholarship). Victorian State Government Operational Infrastructure Support Scheme.Across the globe, 2-3% of humans carry the p.Ser132Pro single nucleotide polymorphism in MLKL, the terminal effector protein of the inflammatory form of programmed cell death, necroptosis. Here we show that this substitution confers a gain in necroptotic function in human cells, with more rapid accumulation of activated MLKLS132P in biological membranes and MLKLS132P overriding pharmacological and endogenous inhibition of MLKL. In mouse cells, the equivalent Mlkl S131P mutation confers a gene dosage dependent reduction in sensitivity to TNF-induced necroptosis in both hematopoietic and non-hematopoietic cells, but enhanced sensitivity to IFN-β induced death in non-hematopoietic cells. In vivo, MlklS131P homozygosity reduces the capacity to clear Salmonella from major organs and retards recovery of hematopoietic stem cells. Thus, by dysregulating necroptosis, the S131P substitution impairs the return to homeostasis after systemic challenge. Present day carriers of the MLKL S132P polymorphism may be the key to understanding how MLKL and necroptosis modulate the progression of complex polygenic human disease
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A common human MLKL polymorphism confers resistance to negative regulation by phosphorylation.
Acknowledgements: We thank all the following people for their technical assistance; Aira Nuguid and Tina Cardamone (Phenomics Australia Histopathology and Slide Scanning Service- The University of Melbourne). WEHI Cytometry Facility, WEHI Antibody Facility, WEHI Centre for Dynamic Imaging, WEHI Bioservices, Cheree Fitzgibbon (WEHI), Jacinta Hansen (WEHI) Jingjing Vivian Tan and Yafei Zhang (ANU, The Australian Genomics Health Alliance). The generation of MlklS131P mice by CRISPR/Cas9 gene editing was performed by Andrew Kueh and Marco Herold (WEHI MAGEC laboratory) supported by the Australian Phenomics Network (APN) and the Australian Government through the National Collaborative Research Infrastructure Strategy (NCRIS) program. We thank Warren Alexander, Mary Speir, and Melanie Bahlo for the provision of important resources and expertize. We thank Michael Hildebrand and Tom Witkowski from Epilepsy Research Centre, Department of Medicine, Austin Health for assistance with Sanger sequencing. We are grateful to the National Health and Medical Research Council for fellowship (J.M.H., 1142669; A.L.S., 2002965; J.M.M., 1172929; J.S., 1107149), grant (J.M.M., 1105023; K.R.M., 1092602; J.S., 1105023; J.M.H., 2011584) and infrastructure (IRIISS 9000719); Arthritis Australia support to K.R.M; K.E.L funding by Future Fellowships from the ARC (FT19010266). We acknowledge scholarship support for S.E.G (Australian Government Research Training Program Stipend Scholarship; Wendy Dowsett Scholarship), Y.M (Melbourne Research Scholarship; AINSE PGRA Scholarship), D.F (Australian Government Research Training Program Stipend Scholarship), A.V.J (Australian Government Research Training Program Stipend Scholarship), and S.C (Walter and Eliza Hall Handman PhD Scholarship). Victorian State Government Operational Infrastructure Support Scheme.Across the globe, 2-3% of humans carry the p.Ser132Pro single nucleotide polymorphism in MLKL, the terminal effector protein of the inflammatory form of programmed cell death, necroptosis. Here we show that this substitution confers a gain in necroptotic function in human cells, with more rapid accumulation of activated MLKLS132P in biological membranes and MLKLS132P overriding pharmacological and endogenous inhibition of MLKL. In mouse cells, the equivalent Mlkl S131P mutation confers a gene dosage dependent reduction in sensitivity to TNF-induced necroptosis in both hematopoietic and non-hematopoietic cells, but enhanced sensitivity to IFN-β induced death in non-hematopoietic cells. In vivo, MlklS131P homozygosity reduces the capacity to clear Salmonella from major organs and retards recovery of hematopoietic stem cells. Thus, by dysregulating necroptosis, the S131P substitution impairs the return to homeostasis after systemic challenge. Present day carriers of the MLKL S132P polymorphism may be the key to understanding how MLKL and necroptosis modulate the progression of complex polygenic human disease
A common human MLKL polymorphism confers resistance to negative regulation by phosphorylation
Abstract Across the globe, 2-3% of humans carry the p.Ser132Pro single nucleotide polymorphism in MLKL, the terminal effector protein of the inflammatory form of programmed cell death, necroptosis. Here we show that this substitution confers a gain in necroptotic function in human cells, with more rapid accumulation of activated MLKLS132P in biological membranes and MLKLS132P overriding pharmacological and endogenous inhibition of MLKL. In mouse cells, the equivalent Mlkl S131P mutation confers a gene dosage dependent reduction in sensitivity to TNF-induced necroptosis in both hematopoietic and non-hematopoietic cells, but enhanced sensitivity to IFN-β induced death in non-hematopoietic cells. In vivo, Mlkl S131P homozygosity reduces the capacity to clear Salmonella from major organs and retards recovery of hematopoietic stem cells. Thus, by dysregulating necroptosis, the S131P substitution impairs the return to homeostasis after systemic challenge. Present day carriers of the MLKL S132P polymorphism may be the key to understanding how MLKL and necroptosis modulate the progression of complex polygenic human disease