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

Microbial biofilm studies of the environmental control and life support system water recovery test for Space Station Freedom

NASA is developing a water recovery system (WRS) for Space Station Freedom to reclaim human waste water for reuse by astronauts as hygiene or potable water. A water recovery test (WRT) currently in progress investigates the performance of a prototype of the WRS. Analysis of biofilm accumulation, the potential for microbially influenced corrosion (MIC) in the WRT, and studies of iodine disinfection of biofilm are reported. Analysis of WRT components indicated the presence of organic deposits and biofilms in selected tubing. Water samples for the WRT contained acid-producing and sulfate-reducing organisms implicated in corrosion processes. Corrosion of an aluminum alloy was accelerated in the presence of these water samples; however, stainless steel corrosion rates were not accelerated. Biofilm iodine sensitivity tests using an experimental laboratory scale recycled water system containing a microbial check valve (MCV) demonstrated that an iodine concentration of 1 to 2 mg/L was ineffective in eliminating microbial biofilm. For complete disinfection, an initial concentration of 16 mg/L was required, which was gradually reduced by the MCV over 4 to 8 hours to 1 to 2 mg/L. This treatment may be useful in controlling biofilm formation

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

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

Near Infrared Spectroscopy of Young Brown Dwarfs in Upper Scorpius

Spectroscopic follow-up is a pre-requisite for studies of the formation and early evolution of brown dwarfs. Here we present IRTF/SpeX near-infrared spectroscopy of 30 candidate members of the young Upper Scorpius association, selected from our previous survey work. All 24 high confidence members are confirmed as young very low mass objects with spectral types from M5 to L1, 15-20 of them are likely brown dwarfs. This high yield confirms that brown dwarfs in Upper Scorpius can be identified from photometry and proper motions alone, with negligible contamination from field objects (<4%). Out of the 6 candidates with lower confidence, 5 might still be young very low mass members of Upper Scorpius, according to our spectroscopy. We demonstrate that some very low mass class II objects exhibit radically different near infrared (0.6 - 2.5micron) spectra from class III objects, with strong excess emission increasing towards longer wavelengths and partially filled in features at wavelengths shorter than 1.25micron. These characteristics can obscure the contribution of the photosphere within such spectra. Therefore, we caution that near infrared derived spectral types for objects with discs may be unreliable. Furthermore, we show that the same characteristics can be seen to some extent in all class II and even a significant fraction of class III objects (~40%), indicating that some of them are still surrounded by traces of dust and gas. Based on our spectra, we select a sample of objects with spectral types of M5 to L1, whose near-infrared emission represents the photosphere only. We recommend the use of these objects as spectroscopic templates for young brown dwarfs in the future.Comment: 12 pages, 9 figures, Accepted in MNRA

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

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

The Chemical Compositions of the Type II Cepheids -- The BL Her and W Vir Variables

Abundance analyses from high-resolution optical spectra are presented for 19 Type II Cepheids in the Galactic field. The sample includes both short-period (BL Her) and long-period (W Vir) stars. This is the first extensive abundance analysis of these variables. The C, N, and O abundances with similar spreads for the BL Her and W Vir show evidence for an atmosphere contaminated with $3\alpha$-process and CN-cycling products. A notable anomaly of the BL Her stars is an overabundance of Na by a factor of about five relative to their presumed initial abundances. This overabundance is not seen in the W Vir stars. The abundance anomalies running from mild to extreme in W Vir stars but not seen in the BL Her stars are attributed to dust-gas separation that provides an atmosphere deficient in elements of high condensation temperature, notably Al, Ca, Sc, Ti, and $s$-process elements. Such anomalies have previously been seen among RV Tau stars which represent a long-period extension of the variability enjoyed by the Type II Cepheids. Comments are offered on how the contrasting abundance anomalies of BL Her and W Vir stars may be explained in terms of the stars' evolution from the blue horizontal branch.Comment: 41 pages including 11 figures and 4 tables; Accepted for publication in Ap

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

A coarse grained model of granular compaction and relaxation

We introduce a theoretical model for the compaction of granular materials by discrete vibrations which is expected to hold when the intensity of vibration is low. The dynamical unit is taken to be clusters of granules that belong to the same collective structure. We rigourously construct the model from first principles and show that numerical solutions compare favourably with a range of experimental results. This includes the logarithmic relaxation towards a statistical steady state, the effect of varying the intensity of vibration resulting in a so-called `annealing' curve, and the power spectrum of density fluctuations in the steady state itself. A mean-field version of the model is introduced which shares many features with the exact model and is open to quantitative analysi