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

Forecasting the Jordanian stock index: modelling asymmetric volatility and distribution effects within a GARCH framework

The modelling of market returns can be especially problematical in emerging and frontier financial markets given the propensity of their returns to exhibit significant non-normality and volatility asymmetries. This paper attempts to identify which representations within the GARCH family of models can most efficiently deal with these issues. A number of different distributions (normal, Student t, GED and skewed Student) and different volatility of returns asymmetry representations (EGARCH and GJR- -GARCH) are examined. Our data set consists of daily Jordanian stock market returns over the period January 2000 – November 2014. Using both the Superior Predicative Ability (SPA) and Model Confidence Set (MCS) testing frameworks it is found that using GJR-GARCH with a skewed Student distribution most accurately and efficiently forecasts Jordanian market movements. Our findings are consistent with similar research undertaken in respect to developed markets.</p

Observations of chemical differentiation in clumpy molecular clouds

We have extensively mapped a sample of dense molecular clouds (L1512, TMC-1C, L1262, Per 7, L1389, L1251E) in lines of HC3N, CH3OH, SO and C^{18}O. We demonstrate that a high degree of chemical differentiation is present in all of the observed clouds. We analyse the molecular maps for each cloud, demonstrating a systematic chemical differentiation across the sample, which we relate to the evolutionary state of the cloud. We relate our observations to the cloud physical, kinematical and evolutionary properties, and also compare them to the predictions of simple chemical models. The implications of this work for understanding the origin of the clumpy structures and chemical differentiation observed in dense clouds are discussed.Comment: 20 pages, 7 figures. Higher quality figures appear in the published journal articl

Protective effect of small molecule analogues of the Acanthocheilonema viteae secreted product ES-62 on oxazolone-induced ear inflammation

ES-62 is the major secreted protein of the rodent filarial nematode Acanthocheilonema viteae. The molecule contains covalently attached phosphorylcholine (PC) residues, which confer anti-inflammatory properties on ES-62, underpinning the idea that drugs based on this active moiety may have therapeutic potential in human diseases associated with aberrant inflammation. Here we demonstrate that two synthetic small molecule analogues (SMAs) of ES-62 termed SMA 11a and SMA 12b are protective in the oxazolone-induced acute allergic contact dermatitis mouse model of skin inflammation, as measured by a significant reduction in ear inflammation following their administration before oxazolone sensitisation and before oxazolone challenge. Furthermore, it was found that when tested, 12b was effective at reducing ear swelling even when first administered before challenge. Histological analysis of the ears showed elevated cellular infiltration and collagen deposition in oxazolone-treated mice both of which were reduced by treatment with the two SMAs. Likewise, the oxazolone-induced increase in IFNγ mRNA in the ears was reduced but no effect on other cytokines investigated was observed. Finally, no influence on the mast cell populations in the ear was observed

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

The influence of South African mineral water on reduction of risk of calcium oxalate kidney stone formation

No Abstract

Coarse-grained simulation of transmembrane peptides in the gel phase

We use Dissipative Particle Dynamics simulations, combined with parallel tempering and umbrella sampling, to investigate the potential of mean force between model transmembrane peptides in the various phases of a lipid bilayer, including the low-temperature gel phase. The observed oscillations in the effective interaction between peptides are consistent with the different structures of the surrounding lipid phases

Crustal structure of the Arabian Plate: New constraints from the analysis of teleseismic receiver functions

An edited version of this paper was published by Elsevier Science. Copyright 2005, Elsevier Science. See also: http://dx.doi.org/10.1016/j.epsl.2004.12.020; http://atlas.geo.cornell.edu/SaudiArabia/publications/Al-Damegh%202005.htmReceiver functions for numerous teleseismic earthquakes recorded at 23 broadband and mid-band stations in Saudi Arabia and Jordan were analyzed to map crustal thickness within and around the Arabian plate. We used spectral division as well as time domain deconvolution to compute the individual receiver functions and receiver function stacks. The receiver functions were then stacked using the slant stacking approach to estimate Moho depths and Vp/Vs for each station. The errors in the slant stacking were estimated using a bootstrap re-sampling technique. We also employed a grid search waveform modeling technique to estimate the crustal velocity structure for seven stations. A jackknife re-sampling approach was used to estimate errors in the grid search results for three stations. In addition to our results, we have also included published receiver function results from two temporary networks in the Arabian shield and Oman as well as three permanent GSN stations in the region. The average crustal thickness of the late Proterozoic Arabian shield is 39 km. The crust thins to about 23 km along the Red Sea coast and to about 25 km along the margin of the Gulf of Aqaba. In the northern part of the Arabian platform, the crust varies from 33 to 37 km thick. However, the crust is thicker (41?53 km) in the southeastern part of the platform. There is a dramatic change in crustal thickness between the topographic escarpment of the Arabian shield and the shorelines of the Red Sea. We compared our results in the Arabian shield to nine other Proterozoic and Archean shields that include reasonably well determined Moho depths, mostly based on receiver functions. The average crustal thickness for all shields is 39 km, while the average for Proterozoic shields is 40 km, and the average for Archean shields is 38 km. We found the crustal thickness of Proterozoic shields to vary between 33 and 44 km, while Archean shields vary between 32 and 47 km. Overall, we do not observe a significant difference between Proterozoic and Archean crustal thickness. We observed a dramatic change in crustal thickness along the Red Sea margin that occurs over a very short distance. We projected our results over a cross-section extending from the Red Sea ridge to the shield escarpment and contrasted it with a typical Atlantic margin. The transition from oceanic to continental crust of the Red Sea margin occurs over a distance of about 250 km, while the transition along a typical portion of the western Atlantic margin occurs at a distance of about 450 km. This important new observation highlights the abruptness of the breakup of Arabia. We argue that a preexisting zone of weakness coupled with anomalously hot upper mantle could have initiated and expedited the breakup

Kinetics of early stages in dissolution process of lamellar surfactant phases process

The dissolution process of concentrated surfactant solutions in various solvents is important in everyday use of surfactant-based products and in the manufacturing process of chemical formulations containing surfactants [1]. The main goal of this study is to investigate the kinetics of the early stages of the surfactant dissolution process. Dissipative particle dynamics (DPD) simulations were used to achieve this goal. Initially, simulations to equilibrium state were undertaken to find a phase diagram for different surfactant lengths. Lamellar phases at 80 vol% of surfactant were then dissolved in a box of water. The surfactant molecule used in this study is represented as a block of (–C3H6–); type A, tail beads connected to a block of EO2 (type B) beads and an OSO3_ head bead type C bead.The dissolution process was tracked by visual analysis and local concentration analysis. By examining the surfactant dissolution process mechanism, it is clear that this process is a two-stage process, consisting of a transformation part dependent on the probability of an initial micelle forming and then a diffusing part of the micelles through the water. A zonal model was used to validate this hypothesis and it was found that as the chain length increased, both the rate of the transformation and the diffusion parts of the process become slow down. It was also seen that the diffusion parameter of the micelles increased with increasing concentration.<br/

Biomarker discovery and redundancy reduction towards classification using a multi-factorial MALDI-TOF MS T2DM mouse model dataset

Diabetes like many diseases and biological processes is not mono-causal. On the one hand multifactorial studies with complex experimental design are required for its comprehensive analysis. On the other hand, the data from these studies often include a substantial amount of redundancy such as proteins that are typically represented by a multitude of peptides. Coping simultaneously with both complexities (experimental and technological) makes data analysis a challenge for Bioinformatics