Installing the "magic methyl" - C-H methylation in synthesis

The selective and efficient C-H methylation of sp2 and sp3 carbon centres has become a powerful transformation in the synthetic toolbox. Due to the potential for profound changes to physicochemical properties attributed to the installation of a "Magic Methyl" group at a strategic site in a lead compound, such techniques have become highly desirable in modern drug discovery and synthesis programmes. This review will cover the diverse techniques that have been employed to enable the selective installation of the C-Me bond in a wide range of chemical structures, from simple building blocks to complex drug-like architectures

Dual catalytic enantioselective desymmetrization of allene-tethered cyclohexanones

The construction of enantioenriched azabicyclo[3.3.1]nonan-6-one heterocycles via an enantioselective desymmetrization of allene-linked cyclohexanones, enabled through a dual catalytic system, that provides synchronous activation of the cyclohexanone with a chiral prolinamide and the allene with a copper(I) co-catalyst to deliver the stereodefined bicyclic core, is described. Successful application to oxygen analogues was also achieved, thereby providing a new enantioselective synthetic entry to architecturally complex bicyclic ethereal frameworks. The mechanistic pathway and the origin of enantio- and diastereoselectivities has been uncovered using density functional theory (DFT) calculations

Valuing Governance

Book Summary: As has been abundantly documented in the popular and academic press, the humanities are facing challenging times marked by national debate regarding the importance of the humanities in higher education, program and budget cuts, and an ever-decreasing number of tenure-track jobs. In addition, the humanities face quite literally a quantification of their value as the Academy adopts a more corporate mindset. This volume provides advice to professionals in the humanities on how to forge a useful, compelling, and productive career. The book’s 13 chapters address professional approaches to developing and maintaining an active research agenda, fomenting the ideals of the teacher-scholar model, managing the service demands within and outside the college or university, and navigating institutional politics. The collection offers practical and theoretical approaches to higher education, personal anecdotes, intelligent advice, and interviews with colleagues in the humanities. Specific themes addressed include the transition from graduate student to humanities professional, diverging from prescribed paths, the humanities professor as creative writer, moving from secondary to post-secondary education, humanities in an international, market-based context, and participation in governance structures. [From the publisher] Chapter Summary: This essay focuses on providing insight and practical advice on how committed participation in the governance process offers many positives at any stage of the academic ladder. Drawing upon a practical, theoretical, and anecdotal approach, this article reflects on four areas that are enhanced by participation in governance: 1) visibility; 2) knowledge of the institution and its culture; 3) establishing meaningful friendships campus-wide; and 4) governance as a resource of invaluable advice

RNA:DNA hybrids are a novel molecular pattern sensed by TLR9.

The sensing of nucleic acids by receptors of the innate immune system is a key component of antimicrobial immunity. RNA:DNA hybrids, as essential intracellular replication intermediates generated during infection, could therefore represent a class of previously uncharacterised pathogen-associated molecular patterns sensed by pattern recognition receptors. Here we establish that RNA:DNA hybrids containing viral-derived sequences efficiently induce pro-inflammatory cytokine and antiviral type I interferon production in dendritic cells. We demonstrate that MyD88-dependent signalling is essential for this cytokine response and identify TLR9 as a specific sensor of RNA:DNA hybrids. Hybrids therefore represent a novel molecular pattern sensed by the innate immune system and so could play an important role in host response to viruses and the pathogenesis of autoimmune disease

Setting the pace: the 2011 Australasian Podiatry Council conference

The 2011 Australasian Podiatry Council conference was held from April 26 to 29 in Melbourne, Victoria, Australia. This commentary provides a brief overview of the conference, including the speakers and topic areas covered, selected original research highlights, and award winning presentations

Induction of Eosinophil Apoptosis by the Cyclin-Dependent Kinase Inhibitor AT7519 Promotes the Resolution of Eosinophil-Dominant Allergic Inflammation

Eosinophils not only defend the body against parasitic infection but are also involved in pathological inflammatory allergic diseases such as asthma, allergic rhinitis and contact dermatitis. Clearance of apoptotic eosinophils by macrophages is a key process responsible for driving the resolution of eosinophilic inflammation and can be defective in allergic diseases. However, enhanced resolution of eosinophilic inflammation by deliberate induction of eosinophil apoptosis using pharmacological agents has not been previously demonstrated. Here we investigated the effect of a novel cyclin-dependent kinase inhibitor drug, AT7519, on human and mouse eosinophil apoptosis and examined whether it could enhance the resolution of a murine model of eosinophil-dominant inflammation in vivo.Eosinophils from blood of healthy donors were treated with AT7519 and apoptosis assessed morphologically and by flow-cytometric detection of annexin-V/propidium iodide staining. AT7519 induced eosinophil apoptosis in a concentration dependent manner. Therapeutic administration of AT7519 in eosinophil-dominant allergic inflammation was investigated using an established ovalbumin-sensitised mouse model of allergic pleurisy. Following ovalbumin challenge AT7519 was administered systemically at the peak of pleural inflammation and inflammatory cell infiltrate, apoptosis and evidence of macrophage phagocytosis of apoptotic eosinophils assessed at appropriate time points. Administration of AT7519 dramatically enhanced the resolution of allergic pleurisy via direct induction of eosinophil apoptosis without detriment to macrophage clearance of these cells. This enhanced resolution of inflammation was shown to be caspase-dependent as the effects of AT7519 were reduced by treatment with a broad spectrum caspase inhibitor (z-vad-fmk).Our data show that AT7519 induces human eosinophil apoptosis and enhances the resolution of a murine model of allergic pleurisy by inducing caspase-dependent eosinophil apoptosis and enhancing macrophage ingestion of apoptotic eosinophils. These findings demonstrate the utility of cyclin-dependent kinase inhibitors such as AT7519 as potential therapeutic agents for the treatment of eosinophil dominant allergic disorders

Development of anisotropic structure in the Earth's lower mantle by solid-state convection

Seismological observations reveal highly anisotropic patches at the bottom of the Earth's lower mantle, whereas the bulk of the mantle has been observed to be largely isotropic(1-4). These patches have been interpreted to correspond to areas where subduction has taken place in the past or to areas where mantle plumes are upwelling, but the underlying cause for the anisotropy is unknown-both shape-preferred orientation of elastically heterogenous materials(5) and lattice-preferred orientation of a homogeneous material(6-8) have been proposed. Both of these mechanisms imply that large-strain deformation occurs within the anisotropic regions, but the geodynamic implications of the mechanisms differ. Shape-preferred orientation would imply the presence of large elastic (and hence chemical) heterogeneity whereas lattice-preferred orientation requires deformation at high stresses. Here we show, on the basis of numerical modelling incorporating mineral physics of elasticity and development of lattice-preferred orientation, that slab deformation in the deep lower mantle can account for the presence of strong anisotropy in the circum-Pacific region. In this model-where development of the mineral fabric (the alignment of mineral grains) is caused solely by solid-state deformation of chemically homogeneous mantle material-anisotropy is caused by large-strain deformation at high stresses, due to the collision of subducted slabs with the core-mantle boundary.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62804/1/416310a.pd

Dental management considerations for the patient with an acquired coagulopathy. Part 1: Coagulopathies from systemic disease

Current teaching suggests that many patients are at risk for prolonged bleeding during and following invasive dental procedures, due to an acquired coagulopathy from systemic disease and/or from medications. However, treatment standards for these patients often are the result of long-standing dogma with little or no scientific basis. The medical history is critical for the identification of patients potentially at risk for prolonged bleeding from dental treatment. Some time-honoured laboratory tests have little or no use in community dental practice. Loss of functioning hepatic, renal, or bone marrow tissue predisposes to acquired coagulopathies through different mechanisms, but the relationship to oral haemostasis is poorly understood. Given the lack of established, science-based standards, proper dental management requires an understanding of certain principles of pathophysiology for these medical conditions and a few standard laboratory tests. Making changes in anticoagulant drug regimens are often unwarranted and/or expensive, and can put patients at far greater risk for morbidity and mortality than the unlikely outcome of postoperative bleeding. It should be recognised that prolonged bleeding is a rare event following invasive dental procedures, and therefore the vast majority of patients with suspected acquired coagulopathies are best managed in the community practice setting

Multiple volcanic episodes of flood basalts caused by thermochemical mantle plumes

The hypothesis that a single mushroom-like mantle plume head can generate a large igneous province within a few million years has been widely accepted(1). The Siberian Traps at the Permian Triassic boundary(2) and the Deccan Traps at the Cretaceous Tertiary boundary(3) were probably erupted within one million years. These large eruptions have been linked to mass extinctions. But recent geochronological data(4-11) reveal more than one pulse of major eruptions with diverse magma flux within several flood basalts extending over tens of million years. This observation indicates that the processes leading to large igneous provinces are more complicated than the purely thermal, single-stage plume model suggests. Here we present numerical experiments to demonstrate that the entrainment of a dense eclogite-derived material at the base of the mantle by thermal plumes can develop secondary instabilities due to the interaction between thermal and compositional buoyancy forces. The characteristic timescales of the development of the secondary instabilities and the variation of the plume strength are compatible with the observations. Such a process may contribute to multiple episodes of large igneous provinces.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62705/1/nature03697.pd