Drug-like analogues of the parasitic worm-derived immunomodulator ES-62 are therapeutic in the MRL/Lpr model of systemic lupus erythematosus

Introduction ES-62, a phosphorylcholine (PC)-containing immunomodulator secreted by the parasitic worm Acanthocheilonema viteae, protects against nephritis in the MRL/Lpr mouse model of systemic lupus erythematosus (SLE). However, ES-62 is not suitable for development as a therapy and thus we have designed drug-like small molecule analogues (SMAs) based around its active PC-moiety. To provide proof of concept that ES-62-based SMAs exhibit therapeutic potential in SLE, we have investigated the capacity of two SMAs to protect against nephritis when administered to MRL/Lpr mice after onset of kidney damage. Methods SMAs 11a and 12b were evaluated for their ability to suppress antinuclear antibody (ANA) generation and consequent kidney pathology in MRL/Lpr mice when administered after the onset of proteinuria. Results SMAs 11a and 12b suppressed development of ANA and proteinuria. Protection reflected downregulation of MyD88 expression by kidney cells and this was associated with reduced production of IL-6, a cytokine that exhibits promise as a therapeutic target for this condition. Conclusions SMAs 11a and 12b provide proof of principle that synthetic compounds based on the safe immunomodulatory mechanisms of parasitic worms can exhibit therapeutic potential as a novel class of drugs for SLE, a disease for which current therapies remain inadequate

Statistical modeling of competitive threshold collision-induced dissociation

Journal ArticleCollision-induced dissociation of (R1OH)Li+(R2OH) with xenon is studied using guided ion beam mass spectrometry. R1OH and R2OH include the following molecules: water, methanol, ethanol, 1-propanol, 2-propanol, and 1-butanol. In all cases, the primary products formed correspond to endothermic loss of one of the neutral alcohols, with minor products that include those formed by ligand exchange and loss of both ligands

Turtle Blood Cell Morphology

Blood cells from Pseudemys elegans, P. troostii, Emys blandingii, and Chrysemys bellii bellii were studied. Smears were stained with Wright\u27s stain and washed with citrate buffer and double distilled water. The RBC were typical. White cells, in order of frequency of occurrence, were large acidophil granulocytcs or eosinophils, 26-41%; small acidophils, 22-26%; neutrophil granulocytes, 19-32%; lymphocytcs, 11-22%; and monocytes, 0.3%. Thrombocytes were not measured or counted. Data on cell sizes are given for P. elegans

A molecular perspective on the limits of life: Enzymes under pressure

From a purely operational standpoint, the existence of microbes that can grow under extreme conditions, or "extremophiles", leads to the question of how the molecules making up these microbes can maintain both their structure and function. While microbes that live under extremes of temperature have been heavily studied, those that live under extremes of pressure have been neglected, in part due to the difficulty of collecting samples and performing experiments under the ambient conditions of the microbe. However, thermodynamic arguments imply that the effects of pressure might lead to different organismal solutions than from the effects of temperature. Observationally, some of these solutions might be in the condensed matter properties of the intracellular milieu in addition to genetic modifications of the macromolecules or repair mechanisms for the macromolecules. Here, the effects of pressure on enzymes, which are proteins essential for the growth and reproduction of an organism, and some adaptations against these effects are reviewed and amplified by the results from molecular dynamics simulations. The aim is to provide biological background for soft matter studies of these systems under pressure.Comment: 16 pages, 8 figure

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

Time Variability in the X-ray Nebula Powered by Pulsar B1509-58

We use new and archival Chandra and ROSAT data to study the time variability of the X-ray emission from the pulsar wind nebula (PWN) powered by PSR B1509-58 on timescales of one week to twelve years. There is variability in the size, number, and brightness of compact knots appearing within 20" of the pulsar, with at least one knot showing a possible outflow velocity of ~0.6c (assuming a distance to the source of 5.2 kpc). The transient nature of these knots may indicate that they are produced by turbulence in the flows surrounding the pulsar. A previously identified prominent jet extending 12 pc to the southeast of the pulsar increased in brightness by 30% over 9 years; apparent outflow of material along this jet is observed with a velocity of ~0.5c. However, outflow alone cannot account for the changes in the jet on such short timescales. Magnetohydrodynamic sausage or kink instabilities are feasible explanations for the jet variability with timescale of ~1.3-2 years. An arc structure, located 30"-45" north of the pulsar, shows transverse structural variations and appears to have moved inward with a velocity of ~0.03c over three years. The overall structure and brightness of the diffuse PWN exterior to this arc and excluding the jet has remained the same over the twelve year span. The photon indices of the diffuse PWN and possibly the jet steepen with increasing radius, likely indicating synchrotron cooling at X-ray energies.Comment: accepted to ApJ, 14 pages, 8 figure

Norm-dependent Random Matrix Ensembles in External Field and Supersymmetry

The class of norm-dependent Random Matrix Ensembles is studied in the presence of an external field. The probability density in those ensembles depends on the trace of the squared random matrices, but is otherwise arbitrary. An exact mapping to superspace is performed. A transformation formula is derived which gives the probability density in superspace as a single integral over the probability density in ordinary space. This is done for orthogonal, unitary and symplectic symmetry. In the case of unitary symmetry, some explicit results for the correlation functions are derived.Comment: 19 page

Spectral Statistics of Instantaneous Normal Modes in Liquids and Random Matrices

We study the statistical properties of eigenvalues of the Hessian matrix ${\cal H}$ (matrix of second derivatives of the potential energy) for a classical atomic liquid, and compare these properties with predictions for random matrix models (RMM). The eigenvalue spectra (the Instantaneous Normal Mode or INM spectra) are evaluated numerically for configurations generated by molecular dynamics simulations. We find that distribution of spacings between nearest neighbor eigenvalues, s, obeys quite well the Wigner prediction $s exp(-s^2)$, with the agreement being better for higher densities at fixed temperature. The deviations display a correlation with the number of localized eigenstates (normal modes) in the liquid; there are fewer localized states at higher densities which we quantify by calculating the participation ratios of the normal modes. We confirm this observation by calculating the spacing distribution for parts of the INM spectra with high participation ratios, obtaining greater conformity with the Wigner form. We also calculate the spectral rigidity and find a substantial dependence on the density of the liquid.Comment: To appear in Phys. Rev. E; 10 pages, 6 figure

H_2 Absorption and Fluorescence for Gamma Ray Bursts in Molecular Clouds

If a gamma ray burst with strong UV emission occurs in a molecular cloud, there will be observable consequences resulting from excitation of the surrounding H2. The UV pulse from the GRB will pump H2 into vibrationally-excited levels which produce strong absorption at wavelengths < 1650 A. As a result, both the prompt flash and later afterglow will exhibit strong absorption shortward of 1650 A, with specific spectroscopic features. Such a cutoff in the emission from GRB 980329 may already have been observed by Fruchter et al.; if so, GRB 980329 was at redshift 3.0 < z < 4.4 . BVRI photometry of GRB 990510 could also be explained by H2 absorption if GRB 990510 is at redshift 1.6 < z < 2.3. The fluorescence accompanying the UV pumping of the H2 will result in UV emission from the GRB which can extend over days or months, depending on parameters of the ambient medium and beaming of the GRB flash. The 7.5-13.6 eV fluorescent luminosity is \sim 10^{41.7} erg/s for standard estimates of the parameters of the GRB and the ambient medium. Spectroscopy can distinguish this fluorescent emission from other possible sources of transient optical emission, such as a supernova.Comment: 13 pages, including 4 figures. submitted to Ap.J.(Letters

Microwave radiometric observations near 19.35, 92 and 183 GHz of precipitation in tropical storm Cora

Observations of rain cells in the remains of a decaying tropical storm were made by Airborne Microwave Radiometers at 19.35,92 and three frequencies near 183 GHz. Extremely low brightness temperatures, as low as 140 K were noted in the 92 and 183 GHz observations. These can be accounted for by the ice often associated with raindrop formation. Further, 183 GHz observations can be interpreted in terms of the height of the ice. The brightness temperatures observed suggest the presence of precipitation sized ice as high as 9 km or more