The parasitic worm-derived immunomodulator, ES-62 and its drug-like small molecule analogues exhibit therapeutic potential in a model of chronic asthma

Chronic asthma is associated with persistent lung inflammation and long-term remodelling of the airways that have proved refractory to conventional treatments such as steroids, despite their efficacy in controlling acute airway contraction and bronchial inflammation. As its recent dramatic increase in industrialised countries has not been mirrored in developing regions, it has been suggested that helminth infection may protect humans against developing asthma. Consistent with this, ES-62, an immunomodulator secreted by the parasitic worm Acanthocheilonema viteae, can prevent pathology associated with chronic asthma (cellular infiltration of the lungs, particularly neutrophils and mast cells, mucus hyper-production and airway thickening) in an experimental mouse model. Importantly, ES-62 can act even after airway remodelling has been established, arresting pathogenesis and ameliorating the inflammatory flares resulting from repeated exposure to allergen that are a debilitating feature of severe chronic asthma. Moreover, two chemical analogues of ES-62, 11a and 12b mimic its therapeutic actions in restoring levels of regulatory B cells and suppressing neutrophil and mast cell responses. These studies therefore provide a platform for developing ES-62-based drugs, with compounds 11a and 12b representing the first step in the development of a novel class of drugs to combat the hitherto intractable disorder of chronic asthma

Mass Predictions for Pseudoscalar JPC=0−+J^{PC}=0^{-+} Charmonium and Bottomonium Hybrids in QCD Sum-Rules

Masses of the pseudoscalar $(J^{PC}=0^{-+})$ charmonium and bottomonium hybrids are determined using QCD Laplace sum-rules. The effects of the dimension-six gluon condensate are included in our analysis and result in a stable sum-rule analysis, whereas previous studies of these states were unable to optimize mass predictions. The pseudoscalar charmonium hybrid is predicted to have a mass of approximately 3.8 GeV and the corresponding bottomonium prediction is 10.6 GeV. Calculating the full correlation function, rather than only the imaginary part, is shown to be necessary for accurate formulation of the sum-rules. The charmonium hybrid mass prediction is discussed within the context of the X Y Z resonances.Comment: 10 pages, 7 embedded figures. Analysis extended and refined in v

Exploring the Spectrum of Heavy Quarkonium Hybrids with QCD Sum Rules

QCD Laplace sum rules are used to calculate heavy quarkonium (charmonium and bottomonium) hybrid masses in several distinct $J^{PC}$ channels. Previous studies of heavy quarkonium hybrids did not include the effects of dimension-six condensates, leading to unstable sum rules and unreliable mass predictions in some channels. We have updated these sum rules to include dimension-six condensates, providing new mass predictions for the spectra of heavy quarkonium hybrids. We confirm the finding of other approaches that the negative-parity $J^{PC}=(0,1,2)^{-+},\,1^{--}$ states form the lightest hybrid supermultiplet and the positive-parity $J^{PC}=(0,1)^{+-},\,(0,1,2)^{++}$ states are members of a heavier supermultiplet. Our results disfavor a pure charmonium hybrid interpretation of the $X(3872)$, in agreement with previous work.Comment: Presented by RTK at the Theory Canada 9 Conference, held at Wilfrid Laurier University in June 2014. Submitted for the conference proceedings to be published in the Canadian Journal of Physics. 5 pages, 1 figure. Version 2: reference added, typo correcte

QCD Sum Rule Analysis of Heavy Quarkonium Hybrids

We have studied the charmonium and bottomonium hybrid states with various $J^{PC}$ quantum numbers in QCD sum rules. At leading order in $\alpha_s$, the two-point correlation functions have been calculated up to dimension six including the tri-gluon condensate and four-quark condensate. After performing the QCD sum rule analysis, we have confirmed that the dimension six condensates can stabilize the hybrid sum rules and allow the reliable mass predictions. We have updated the mass spectra of the charmonium and bottomonium hybrid states and identified that the negative-parity states with $J^{PC}=(0, 1, 2)^{-+}, 1^{--}$ form the lightest hybrid supermultiplet while the positive-parity states with $J^{PC}=(0, 1)^{+-}, (0, 1, 2)^{++}$ belong to a heavier hybrid supermultiplet.Comment: 7 pages, 1 figures. Some minor edits have been made. Presentation at the DPF 2013 Meeting of the American Physical Society Division of Particles and Fields, Santa Cruz, California, August 13-17, 201

Distribution and function of HCN channels in the apical dendritic tuft of neocortical pyramidal neurons

The apical tuft is the most remote area of the dendritic tree of neocortical pyramidal neurons. Despite its distal location, the apical dendritic tuft of layer 5 pyramidal neurons receives substantial excitatory synaptic drive and actively processes corticocortical input during behavior. The properties of the voltage-activated ion channels that regulate synaptic integration in tuft dendrites have, however, not been thoroughly investigated. Here, we use electrophysiological and optical approaches to examine the subcellular distribution and function of hyperpolarization-activated cyclic nucleotide-gated nonselective cation (HCN) channels in rat layer 5B pyramidal neurons. Outside-out patch recordings demonstrated that the amplitude and properties of ensembleHCNchannel activity were uniform in patches excised from distal apical dendritic trunk and tuft sites. Simultaneous apical dendritic tuft and trunk whole-cell current-clamp recordings revealed that the pharmacological blockade of HCN channels decreased voltage compartmentalization and enhanced the generation and spread of apical dendritic tuft and trunk regenerative activity. Furthermore, multisite two-photon glutamate uncaging demonstrated that HCN channels control the amplitude and duration of synaptically evoked regenerative activity in the distal apical dendritic tuft. In contrast, at proximal apical dendritic trunk and somatic recording sites, the blockade of HCN channels decreased excitability. Dynamicclamp experiments revealed that these compartment-specific actions of HCN channels were heavily influenced by the local and distributed impact of the high density of HCN channels in the distal apical dendritic arbor. The properties and subcellular distribution pattern of HCN channels are therefore tuned to regulate the interaction between integration compartments in layer 5B pyramidal neurons