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

Ribo-seQC: comprehensive analysis of cytoplasmic and organellar ribosome profiling data

Summary: Ribosome profiling enables genome-wide analysis of translation with unprecedented resolution. We present Ribo-seQC, a versatile tool for the comprehensive analysis of Ribo-seq data, providing in-depth insights on data quality and translational profiles for cytoplasmic and organelle ribosomes. Ribo-seQC automatically generates platform-independent HTML reports, offering a detailed and easy-to-share basis for collaborative Ribo-seq projects. Availability: Ribo-seQC is available at https://github.com/ohlerlab/RiboseQC and submitted to Bioconductor. Contact: uwe.ohler{at}mdc-berlin.d

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

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

Diffuse Gas and LMXBs in the Chandra Observation of the S0 Galaxy NGC 1553

We have spatially and spectrally resolved the sources of X-ray emission from the X-ray faint S0 galaxy NGC 1553 using an observation from the Chandra X-ray Observatory. The majority (70%) of the emission in the 0.3 - 10.0 keV band is diffuse, and the remaining 30% is resolved into 49 discrete sources. Most of the discrete sources associated with the galaxy appear to be low mass X-ray binaries (LMXBs). The luminosity function of the LMXB sources is well-fit by a broken power-law with a break luminosity comparable to the Eddington luminosity for a 1.4 solar mass neutron star. It is likely that those sources with luminosities above the break are accreting black holes and those below are mostly neutron stars in binary systems. Spectra were extracted for the total emission, diffuse emission, and sum of the resolved sources; the spectral fits for all require a model including both a soft and hard component. The diffuse emission is predominately soft while the emission from the sources is mostly hard. Approximately 24% of the diffuse emission arises from unresolved LMXBs, with the remainder resulting from thermal emission from hot gas. There is a very bright source at the projected position of the nucleus of the galaxy. The spectrum and luminosity derived from this central source are consistent with it being an AGN; the galaxy also is a weak radio source. Finally, the diffuse emission exhibits significant substructure with an intriguing spiral feature passing through the center of the galaxy. The X-ray spectrum and surface brightness of the spiral feature are consistent with adiabatic or shock compression of ambient gas, but not with cooling. This feature may be due to compression of the hot interstellar gas by radio lobes or jets associated with the AGN.Comment: 23 pages using emulateapj.sty; ApJ, in press; revised version includes correction to error in the L_X,src/L_B ratio as well as other revision

Linearized gravity and gauge conditions

In this paper we consider the field equations for linearized gravity and other integer spin fields on the Kerr spacetime, and more generally on spacetimes of Petrov type D. We give a derivation, using the GHP formalism, of decoupled field equations for the linearized Weyl scalars for all spin weights and identify the gauge source functions occuring in these. For the spin weight 0 Weyl scalar, imposing a generalized harmonic coordinate gauge yields a generalization of the Regge-Wheeler equation. Specializing to the Schwarzschild case, we derive the gauge invariant Regge-Wheeler and Zerilli equation directly from the equation for the spin 0 scalar.Comment: 24 pages, corresponds to published versio

Follow-up of blood-pressure lowering and glucose control in type 2 diabetes.

BACKGROUND In the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) factorial trial, the combination of perindopril and indapamide reduced mortality among patients with type 2 diabetes, but intensive glucose control, targeting a glycated hemoglobin level of less than 6.5%, did not. We now report results of the 6-year post-trial follow-up. METHODS We invited surviving participants, who had previously been assigned to perindopril–indapamide or placebo and to intensive or standard glucose control (with the glucose-control comparison extending for an additional 6 months), to participate in a post-trial follow-up evaluation. The primary end points were death from any cause and major macrovascular events. RESULTS The baseline characteristics were similar among the 11,140 patients who originally underwent randomization and the 8494 patients who participated in the post-trial follow-up for a median of 5.9 years (blood-pressure–lowering comparison) or 5.4 years (glucose-control comparison). Between-group differences in blood pressure and glycated hemoglobin levels during the trial were no longer evident by the first post-trial visit. The reductions in the risk of death from any cause and of death from cardiovascular causes that had been observed in the group receiving active blood-pressure–lowering treatment during the trial were attenuated but significant at the end of the post-trial follow-up; the hazard ratios were 0.91 (95% confidence interval [CI], 0.84 to 0.99; P=0.03) and 0.88 (95% CI, 0.77 to 0.99; P=0.04), respectively. No differences were observed during follow-up in the risk of death from any cause or major macrovascular events between the intensive-glucose-control group and the standard-glucose-control group; the hazard ratios were 1.00 (95% CI, 0.92 to 1.08) and 1.00 (95% CI, 0.92 to 1.08), respectively. CONCLUSIONS The benefits with respect to mortality that had been observed among patients originally assigned to blood-pressure–lowering therapy were attenuated but still evident at the end of follow-up. There was no evidence that intensive glucose control during the trial led to long-term benefits with respect to mortality or macrovascular events

It\u27s about the patients: Practical antibiotic stewardship in outpatient settings in the United States

Antibiotic-resistant pathogens cause over 35,000 preventable deaths in the United States every year, and multiple strategies could decrease morbidity and mortality. As antibiotic stewardship requirements are being deployed for the outpatient setting, community providers are facing systematic challenges in implementing stewardship programs. Given that the vast majority of antibiotics are prescribed in the outpatient setting, there are endless opportunities to make a smart and informed choice when prescribing and to move the needle on antibiotic stewardship. Antibiotic stewardship in the community, or smart prescribing as we suggest, should factor in antibiotic efficacy, safety, local resistance rates, and overall cost, in addition to patient-specific factors and disease presentation, to arrive at an appropriate therapy. Here, we discuss some of the challenges, such as patient/parent pressure to prescribe, lack of data or resources for implementation, and a disconnect between guidelines and real-world practice, among others. We have assembled an easy-to-use best practice guide for providers in the outpatient setting who lack the time or resources to develop a plan or consult lengthy guidelines. We provide specific suggestions for antibiotic prescribing that align real-world clinical practice with best practices for antibiotic stewardship for two of the most common bacterial infections seen in the outpatient setting: community-acquired pneumonia and skin and soft-tissue infection. In addition, we discuss many ways that community providers, payors, and regulatory bodies can make antibiotic stewardship easier to implement and more streamlined in the outpatient setting

Axial Vector JPC=1++J^{PC}=1^{++} Charmonium and Bottomonium Hybrid Mass Predictions with QCD Sum-Rules

Axial vector $(J^{PC}=1^{++})$ charmonium and bottomonium hybrid masses are determined via QCD Laplace sum-rules. Previous sum-rule studies in this channel did not incorporate the dimension-six gluon condensate, which has been shown to be important for $1^{--}$ and $0^{-+}$ heavy quark hybrids. An updated analysis of axial vector charmonium and bottomonium hybrids is presented, including the effects of the dimension-six gluon condensate. The axial vector charmonium and bottomonium hybrid masses are predicted to be 5.13 GeV and 11.32 GeV, respectively. We discuss the implications of this result for the charmonium-like XYZ states and the charmonium hybrid multiplet structure observed in recent lattice calculations.Comment: 10 pages, 7 figures. Updated to match published versio

Towards an Understanding of the Mid-Infrared Surface Brightness of Normal Galaxies

We report a mid-infrared color and surface brightness analysis of IC 10, NGC 1313, and NGC 6946, three of the nearby galaxies studied under the Infrared Space Observatory Key Project on Normal Galaxies. Images with < 9 arcsecond (170 pc) resolution of these nearly face-on, late-type galaxies were obtained using the LW2 (6.75 mu) and LW3 (15 mu) ISOCAM filters. Though their global I_nu(6.75 mu)/I_nu(15 mu) flux ratios are similar and typical of normal galaxies, they show distinct trends of this color ratio with mid-infrared surface brightness. We find that I_nu(6.75 mu)/I_nu(15 mu) ~< 1 only occurs for regions of intense heating activity where the continuum rises at 15 micron and where PAH destruction can play an important role. The shape of the color-surface brightness trend also appears to depend, to the second-order, on the hardness of the ionizing radiation. We discuss these findings in the context of a two-component model for the phases of the interstellar medium and suggest that star formation intensity is largely responsible for the mid-infrared surface brightness and colors within normal galaxies, whereas differences in dust column density are the primary drivers of variations in the mid-infrared surface brightness between the disks of normal galaxies.Comment: 19 pages, 6 figures, uses AAS LaTeX; to appear in the November Astronomical Journa