Microrheological Characterisation of Anisotropic Materials

We describe the measurement of anisotropic viscoelastic moduli in complex soft materials, such as biopolymer gels, via video particle tracking microrheology of colloid tracer particles. The use of a correlation tensor to find the axes of maximum anisotropy, and hence the mechanical director, is described. The moduli of an aligned DNA gel are reported, as a test of the technique; this may have implications for high DNA concentrations in vivo. We also discuss the errors in microrheological measurement, and describe the use of frequency space filtering to improve displacement resolution, and hence probe these typically high modulus materials.Comment: 5 pages, 5 figures. Replaced after refereeing/ improvement. Main results are the same. The final, published version of the paper is here http://link.aps.org/abstract/PRE/v73/e03190

Scandinavian clinical practice guideline on fluid and drug therapy in adults with acute respiratory distress syndrome.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access.The objective of the Scandinavian Society of Anaesthesiology and Intensive Care Medicine (SSAI) task force on fluid and drug therapy in adults with acute respiratory distress syndrome (ARDS) was to provide clinically relevant, evidence-based treatment recommendations according to standards for trustworthy guidelines.The guideline was developed according to standards for trustworthy guidelines, including a systematic review of the literature and use of the GRADE methodology for assessment of the quality of evidence and for moving from evidence to recommendations.A total of seven ARDS interventions were assessed. We suggest fluid restriction in patients with ARDS (weak recommendation, moderate quality evidence). Also, we suggest early use of neuromuscular blocking agents (NMBAs) in patients with severe ARDS (weak recommendation, moderate quality evidence). We recommend against the routine use of other drugs, including corticosteroids, beta2 agonists, statins, and inhaled nitric oxide (iNO) or prostanoids in adults with ARDS (strong recommendations: low- to high-quality evidence). These recommendations do not preclude the use of any drug or combination of drugs targeting underlying or co-existing disorders.This guideline emphasizes the paucity of evidence of benefit - and potential for harm - of common interventions in adults with ARDS and highlights the need for prudence when considering use of non-licensed interventions in this patient population.Scandinavian Society of Anaesthesiology and Intensive Care Medicine (SSAI

A Revised Design for Microarray Experiments to Account for Experimental Noise and Uncertainty of Probe Response

Background Although microarrays are analysis tools in biomedical research, they are known to yield noisy output that usually requires experimental confirmation. To tackle this problem, many studies have developed rules for optimizing probe design and devised complex statistical tools to analyze the output. However, less emphasis has been placed on systematically identifying the noise component as part of the experimental procedure. One source of noise is the variance in probe binding, which can be assessed by replicating array probes. The second source is poor probe performance, which can be assessed by calibrating the array based on a dilution series of target molecules. Using model experiments for copy number variation and gene expression measurements, we investigate here a revised design for microarray experiments that addresses both of these sources of variance. Results Two custom arrays were used to evaluate the revised design: one based on 25 mer probes from an Affymetrix design and the other based on 60 mer probes from an Agilent design. To assess experimental variance in probe binding, all probes were replicated ten times. To assess probe performance, the probes were calibrated using a dilution series of target molecules and the signal response was fitted to an adsorption model. We found that significant variance of the signal could be controlled by averaging across probes and removing probes that are nonresponsive or poorly responsive in the calibration experiment. Taking this into account, one can obtain a more reliable signal with the added option of obtaining absolute rather than relative measurements. Conclusion The assessment of technical variance within the experiments, combined with the calibration of probes allows to remove poorly responding probes and yields more reliable signals for the remaining ones. Once an array is properly calibrated, absolute quantification of signals becomes straight forward, alleviating the need for normalization and reference hybridizations

Discrimination of Potent Inhibitors of Toxoplasma gondii Enoyl-Acyl Carrier Protein Reductase by a Thermal Shift Assay

Many microbial pathogens rely on a type II fatty acid synthesis (FASII) pathway that is distinct from the type I pathway found in humans. Enoyl-acyl carrier protein reductase (ENR) is an essential FASII pathway enzyme and the target of a number of antimicrobial drug discovery efforts. The biocide triclosan is established as a potent inhibitor of ENR and has been the starting point for medicinal chemistry studies. We evaluated a series of triclosan analogues for their ability to inhibit the growth of Toxoplasma gondii, a pervasive human pathogen, and its ENR enzyme (TgENR). Several compounds that inhibited TgENR at low nanomolar concentrations were identified but could not be further differentiated because of the limited dynamic range of the TgENR activity assay. Thus, we adapted a thermal shift assay (TSA) to directly measure the dissociation constant (Kd) of the most potent inhibitors identified in this study as well as inhibitors from previous studies. Furthermore, the TSA allowed us to determine the mode of action of these compounds in the presence of the reduced nicotinamide adenine dinucleotide (NADH) or nicotinamide adenine dinucleotide (NAD+) cofactor. We found that all of the inhibitors bind to a TgENR–NAD+ complex but that they differed in their dependence on NAD+ concentration. Ultimately, we were able to identify compounds that bind to the TgENR–NAD+ complex in the low femtomolar range. This shows how TSA data combined with enzyme inhibition, parasite growth inhibition data, and ADMET predictions allow for better discrimination between potent ENR inhibitors for the future development of medicine

Aluminium content of spanish infant formula

Aluminium toxicity has been relatively well documented in infants with impaired renal function and premature neonates. The aims of this study were to analyse the concentration of aluminium in the majority of infant formulae sold commercially in Spain, to determine the influence of aluminium content in the tap water in reconstituted powder formulae and to estimate the theoretical toxic aluminium intake in comparison with the PTWI, and lastly, to discuss the possible interactions of certain essential trace elements added to formulation with aluminium according to type or main protein based infant formula. A total of 82 different infant formulae from 9 different manufacturers were studied. Sample digestion was simulated in a closed acid-decomposition microwave system. Aluminium concentration was determined by atomic absorption spectrophotometry with graphite furnace. In general, the infant formulae studied provide an aluminium level higher than that found in human milk, especially in the case of soya, preterm or hydrolysed casein-based formulae. Standard formulae provide lower aluminium intakes amounting to about 4 % PTWI. Specialised and preterm formulae result in moderate intake (11 – 12 % and 8 – 10 % PTWI, respectively). Soya formulae contribute the highest intake (15 % PTWI). Aluminium exposure from drinking water used for powder formula reconstitution is not considered a clear potential risk. In accordance with the present state of knowledge about aluminium toxicity, it seems prudent to call for continued efforts to standardise routine quality control and reduce aluminium levels in infant formula as well as to keep the aluminium concentration under 300 g l-1 for all infant formulae, most specifically those formulae for premature and low birth neonates

Restricted three body problems at the nanoscale

In this paper, we investigate some of the classical restricted three body problems at the nanoscale, such as the circular planar restricted problem for three C60 fullerenes, and a carbon atom and two C60 fullerenes. We model the van der Waals forces between the fullerenes by the Lennard-Jones potential. In particular, the pairwise potential energies between the carbon atoms on the fullerenes are approximated by the continuous approach, so that the total molecular energy between two fullerenes can be determined analytically. Since we assume that such interactions between the molecules occur at sufficiently large distance, the classical three body problems analysis is legitimate to determine the collective angular velocity of the two and three C60 fullerenes at the nanoscale. We find that the maximum angular frequency of the two and three fullerenes systems reach the terahertz range and we determine the stationary points and the points which have maximum velocity for the carbon atom for the carbon atom and the two fullerenes system