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

Laid Off: American Workers and Employers Assess a Volatile Labor Market

This Work Trends survey shows that despite economic growth, worker concern for the economy, their job security, and the threat of terrorism is increasing; workers and employers express fear about outsourcing jobs abroad

Local molecular field theory for the treatment of electrostatics

We examine in detail the theoretical underpinnings of previous successful applications of local molecular field (LMF) theory to charged systems. LMF theory generally accounts for the averaged effects of long-ranged components of the intermolecular interactions by using an effective or restructured external field. The derivation starts from the exact Yvon-Born-Green hierarchy and shows that the approximation can be very accurate when the interactions averaged over are slowly varying at characteristic nearest-neighbor distances. Application of LMF theory to Coulomb interactions alone allows for great simplifications of the governing equations. LMF theory then reduces to a single equation for a restructured electrostatic potential that satisfies Poisson's equation defined with a smoothed charge density. Because of this charge smoothing by a Gaussian of width sigma, this equation may be solved more simply than the detailed simulation geometry might suggest. Proper choice of the smoothing length sigma plays a major role in ensuring the accuracy of this approximation. We examine the results of a basic confinement of water between corrugated wall and justify the simple LMF equation used in a previous publication. We further generalize these results to confinements that include fixed charges in order to demonstrate the broader impact of charge smoothing by sigma. The slowly-varying part of the restructured electrostatic potential will be more symmetric than the local details of confinements.Comment: To be published in J Phys-Cond Matt; small misprint corrected in Eq. (12) in V

Market Differentials for Meat Quality Improvement: Meat Standards Australia

Eating quality is one of the most important factors influencing demand for beef. Meat Standards Australia is a voluntary beef grading system aimed at improving consumer certainty about beef quality, improving overall beef quality and strengthening supply chain linkages. Since its inception in 1999/2000, substantial improvements in beef quality, as measured by the system, have been identified. An evaluation was undertaken to estimate the economic value of these improvements to the industry. It was found that MSA graded beef consistently attracted premiums above nongraded beef, with mean values of 29c/kg and 39c/kg (carcass equivalent) at the wholesale and retail levels respectively, while the food service sector received an average of 39c/kg (carcass equivalent). The total retail value of the program to date is estimated to be between $218 to 230 million and$171 million at the wholesale level (in terms of 2005 prices).Livestock Production/Industries,

Attraction Between Like-Charged Walls: Short-Ranged Simulations Using Local Molecular Field Theory

Effective attraction between like-charged walls mediated by counterions is studied using local molecular field (LMF) theory. Monte Carlo simulations of the "mimic system'' given by LMF theory, with short-ranged "Coulomb core" interactions in an effective single particle potential incorporating a mean-field average of the long-ranged Coulomb interactions, provide a direct test of the theory, and are in excellent agreement with more complex simulations of the full Coulomb system by Moreira and Netz [Eur. Phys. J. E 8, 33 (2002)]. A simple, generally-applicable criterion to determine the consistency parameter sigma_{min} needed for accurate use of the LMF theory is presented

Influence of Ageing, pH and Various Additives on Crystal Formation in Artificial Urine

In order to investigate the effect of various factors on urinary crystallization processes, a series of five experiments was carried out using an artificial urine (AU) in a rotary evaporator. The influence of ageing, pH and organic, inorganic and potential inhibitory additives formed the basis of the study. Precipitates were characterized by X-ray powder diffraction, scanning electron microscopy and energy dispersive X-ray analysis. In the ageing experiment, AU aliquots, adjusted to various pH values, were allowed to stand for several days and were not evaporated. Calcium oxalate monohydrate (COM) was formed at low pH, while whitlockite, apatite and struvite occurred at pH \u3e 7. In the second experiment, AU aliquots at various pH values, were evaporated. Similar results to those of series 1 were recorded but, in addition, calcium oxalate trihydrate (COT) precipitated in the pH range 3 to 6.5 and brushite at pH \u3e 5.5. In series 3, uric acid, creatinine and urea were included in AU aliquots (pH 5.5) which were subjected to evaporation. Uric acid promoted the formation of uric acid dihydrate; however, when present with creatinine, dihydrate formation was inhibited. Urea appeared to inhibit precipitation. In the fourth experiment, MgO, methylene blue and chondroitin sulphate A were independently included in the AU (pH 5.5). Precipitates of calcium oxalate mono-, di- and trihydrates were obtained. In the final experiment fluoride aliquots of variable concentrations were included in the AU (pH 5.5 and 6.5). COT crystals of superior quality to those observed in control solutions were obtained

Self-guided mindfulness and cognitive behavioural practices reduce anxiety in autistic adults: A pilot 8-month waitlist-controlled trial of widely available online tools

Anxiety in autism is an important treatment target because of its consequences for quality of life and wellbeing. Growing evidence suggests that Cognitive Behaviour Therapies (CBT) and Mindfulness-Based Therapies (MBT) can ameliorate anxiety in autism but cost-effective delivery remains a challenge. This pilot randomized controlled trial examined whether online CBT and MBT self-help programmes could help reduce anxiety in 54 autistic adults who were randomly allocated to either an online CBT (n=16) or MBT (n=19) programme or a waitlist control group (WL; n=19). Primary outcome measures of anxiety, secondary outcome measures of broader wellbeing, and potential process of change variables were collected at baseline, after programme completion, and then 3 and 6 months post-completion. Baseline data confirmed that intolerance of uncertainty and emotional acceptance accounted for up to 61% of self-reported anxiety across all participants. The 23 participants who were retained in the active conditions (14 MBT, 9 CBT) showed significant decreases in anxiety that were maintained over 3, and to some extent also 6 months. Overall, results suggest that online self-help CBT and MBT tools may provide a cost-effective method for delivering mental health support to those autistic adults who can engage effectively with online support tools

Stretched exponentials and power laws in granular avalanching

We introduce a model for granular avalanching which exhibits both stretched exponential and power law avalanching over its parameter range. Two modes of transport are incorporated, a rolling layer consisting of individual particles and the overdamped, sliding motion of particle clusters. The crossover in behaviour observed in experiments on piles of rice is attributed to a change in the dominant mode of transport. We predict that power law avalanching will be observed whenever surface flow is dominated by clustered motion. Comment: 8 pages, more concise and some points clarified

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