2,448 research outputs found

    A quantitative empirical directing group scale for selectivity in iridium-catalysed hydrogen isotope exchange reactions

    Get PDF
    A palette of commonly used directing groups, including various pharmaceutically relevant nitrogen-containing heterocycles, are quantitatively ranked based on the results of intermolecular hydrogen isotope exchange competition reactions using two iridium complexes: [Ir(COD)(IMes)(PPh3)][BArF24] and [IrCl(COD)(IMes)]. The directing group power scales that have been constructed from these data reveal a wide range of reactivity covering four orders of magnitude. Intramolecular competition experiments have demonstrated that the obtained reactivity scale provides accurate predictions of regioselectivity within molecules with multiple competing directing groups. This work contributes to our understanding and control of regioselectivity in metal-catalysed C-H activation reactions

    Quantitative prediction of selectivity in iridium-catalysed hydrogen isotope exchange reactions

    Get PDF
    A pallette of commonly used directing groups, including various pharmaceutically relevant nitrogen-containing heterocycles, are quantitatively ranked based on the results of intermolecular hydrogen isotope exchange competition reactions using two iridium complexes: [Ir(COD)(IMes)(PPh3)][BArF24] and [IrCl(COD)(IMes)]. The directing group power scales that have been constructred from these data reveal a wide range of reactivity covering four orders of magnitude. Intramolecular competition experiments have demonstrated that the obtained reactivity scale provides accurate predictions of regioselectivity within molecules with multiple competing directing groups. This work contributes to our understanding and control of regioselectivity in metal-catalysed C-H activation reactions

    Emergence of the Shackleton Range from beneath the Antarctic Ice Sheet due to glacial erosion

    Get PDF
    This paper explores the long-term evolution of a subglacial fjord landscape in the Shackleton Range, Antarctica. We propose that prolonged ice-sheet erosion across a passive continental margin caused troughs to deepen and lower the surrounding ice-sheet surface, leaving adjacent mountains exposed. Geomorphological evidence suggests a change in the direction of regional ice flow accompanied emergence. Simple calculations suggest that isostatic compensation caused by the deepening of bounding ice-stream troughs lowered the ice-sheet surface relative to the mountains by ~800m. Use of multiple cosmogenic isotopes on bedrock and erratics (26Al, 10Be, 21Ne) provides evidence that overriding of the massif and the deepening of the adjacent troughs occurred earlier than the Quaternary. Perhaps this occurred in the mid-Miocene, as elsewhere in East Antarctica in the McMurdo Dry Valleys and the Lambert basin. The implication is that glacial erosion instigates feedback that can change ice-sheet thickness, extent, and direction of flow. Indeed, as the subglacial troughs evolve over millions of years, they increase topographic relief; and this changes the dynamics of the ice sheet. © 2013 Elsevier B.V

    Fractional boundary value problems: Analysis and numerical methods

    Get PDF
    This is the author's PDF of an article published in Fractional calculus and applied analysis 2011. The original publication is available at www.springerlink.comThis journal article discusses nonlinear boundary value problems.Fundacao para a Ciencia e Tecnologi

    Taking Gene Therapy into the Clinic

    Get PDF
    Gene therapy represents a promising novel treatment strategy for colorectal cancer. Preclinical data has been encouraging and several clinical trials are underway. Many phase 1 trials have proven the safety of the reagents but have yet to demonstrate significant therapeutic benefit. Ongoing efforts are being made to improve the efficiency of gene delivery and accuracy of gene targeting with the aim of enhancing antitumor potency. It is envisaged that gene therapy will be used in combination with other therapies including surgery, chemotherapy, and radiotherapy to facilitate the improvements in cancer treatments in the future

    Neuromyelitis optica pathogenesis and aquaporin 4

    Get PDF
    Neuromyelitis optica (NMO) is a severe, debilitating human disease that predominantly features immunopathology in the optic nerves and the spinal cord. An IgG1 autoantibody (NMO-IgG) that binds aquaporin 4 (AQP4) has been identified in the sera of a significant number of NMO patients, as well as in patients with two related neurologic conditions, bilateral optic neuritis (ON), and longitudinal extensive transverse myelitis (LETM), that are generally considered to lie within the NMO spectrum of diseases. NMO-IgG is not the only autoantibody found in NMO patient sera, but the correlation of pathology in central nervous system (CNS) with tissues that normally express high levels of AQP4 suggests NMO-IgG might be pathogenic. If this is the case, it is important to identify and understand the mechanism(s) whereby an immune response is induced against AQP4. This review focuses on open questions about the "events" that need to be understood to determine if AQP4 and NMO-IgG are involved in the pathogenesis of NMO. These questions include: 1) How might AQP4-specific T and B cells be primed by either CNS AQP4 or peripheral pools of AQP4? 2) Do the different AQP4-expressing tissues and perhaps the membrane structural organization of AQP4 influence NMO-IgG binding efficacy and thus pathogenesis? 3) Does prior infection, genetic predisposition, or underlying immune dysregulation contribute to a confluence of events which lead to NMO in select individuals? A small animal model of NMO is essential to demonstrate whether AQP4 is indeed the incipient autoantigen capable of inducing NMO-IgG formation and NMO. If the NMO model is consistent with the human disease, it can be used to examine how changes in AQP4 expression and blood-brain barrier (BBB) integrity, both of which can be regulated by CNS inflammation, contribute to inductive events for anti-AQP4-specific immune response. In this review, we identify reagents and experimental questions that need to be developed and addressed to enhance our understanding of the pathogenesis of NMO. Finally, dysregulation of tolerance associated with autoimmune disease appears to have a role in NMO. Animal models would allow manipulation of hormone levels, B cell growth factors, and other elements known to increase the penetrance of autoimmune disease. Thus an AQP4 animal model would provide a means to manipulate events which are now associated with NMO and thus demonstrate what set of events or multiplicity of events can push the anti-AQP4 response to be pathogenic

    Neuromyelitis Optica Pathogenesis and Aquaporin 4

    Get PDF
    Neuromyelitis optica (NMO) is a severe, debilitating human disease that predominantly features immunopathology in the optic nerves and the spinal cord. An IgG1 autoantibody (NMO-IgG) that binds aquaporin 4 (AQP4) has been identified in the sera of a significant number of NMO patients, as well as in patients with two related neurologic conditions, bilateral optic neuritis (ON), and longitudinal extensive transverse myelitis (LETM), that are generally considered to lie within the NMO spectrum of diseases. NMO-IgG is not the only autoantibody found in NMO patient sera, but the correlation of pathology in central nervous system (CNS) with tissues that normally express high levels of AQP4 suggests NMO-IgG might be pathogenic. If this is the case, it is important to identify and understand the mechanism(s) whereby an immune response is induced against AQP4. This review focuses on open questions about the events that need to be understood to determine if AQP4 and NMO-IgG are involved in the pathogenesis of NMO. These questions include: 1) How might AQP4-specific T and B cells be primed by either CNS AQP4 or peripheral pools of AQP4? 2) Do the different AQP4-expressing tissues and perhaps the membrane structural organization of AQP4 influence NMO-IgG binding efficacy and thus pathogenesis? 3) Does prior infection, genetic predisposition, or underlying immune dysregulation contribute to a confluence of events which lead to NMO in select individuals? A small animal model of NMO is essential to demonstrate whether AQP4 is indeed the incipient autoantigen capable of inducing NMO-IgG formation and NMO. If the NMO model is consistent with the human disease, it can be used to examine how changes in AQP4 expression and blood-brain barrier (BBB) integrity, both of which can be regulated by CNS inflammation, contribute to inductive events for anti-AQP4-specific immune response. In this review, we identify reagents and experimental questions that need to be developed and addressed to enhance our understanding of the pathogenesis of NMO. Finally, dysregulation of tolerance associated with autoimmune disease appears to have a role in NMO. Animal models would allow manipulation of hormone levels, B cell growth factors, and other elements known to increase the penetrance of autoimmune disease. Thus an AQP4 animal model would provide a means to manipulate events which are now associated with NMO and thus demonstrate what set of events or multiplicity of events can push the anti-AQP4 response to be pathogenic

    Efficient methods for enol phosphate synthesis using carbon-centred magnesium bases

    Get PDF
    Efficient conversion of ketones into kinetic enol phosphates under mild and accessible conditions has been realised using the developed methods with di-tert-butylmagnesium and bismesitylmagnesium. Optimisation of the quench protocol resulted in high yields of enol phosphates from a range of cyclohexanones and aryl methyl ketones, with tolerance of a range of additional functional units
    • …
    corecore