Gypsum-DL: an open-source program for preparing small-molecule libraries for structure-based virtual screening

Computational techniques such as structure-based virtual screening require carefully prepared 3D models of potential small-molecule ligands. Though powerful, existing commercial programs for virtual-library preparation have restrictive and/or expensive licenses. Freely available alternatives, though often effective, do not fully account for all possible ionization, tautomeric, and ring-conformational variants. We here present Gypsum-DL, a free, robust open-source program that addresses these challenges. As input, Gypsum-DL accepts virtual compound libraries in SMILES or flat SDF formats. For each molecule in the virtual library, it enumerates appropriate ionization, tautomeric, chiral, cis/trans isomeric, and ring-conformational forms. As output, Gypsum-DL produces an SDF file containing each molecular form, with 3D coordinates assigned. To demonstrate its utility, we processed 1558 molecules taken from the NCI Diversity Set VI and 56,608 molecules taken from a Distributed Drug Discovery (D3) combinatorial virtual library. We also used 4463 high-quality protein-ligand complexes from the PDBBind database to show that Gypsum-DL processing can improve virtual-screening pose prediction. Gypsum-DL is available free of charge under the terms of the Apache License, Version 2.0

Lipid coated liquid crystal droplets for the on-chip detection of antimicrobial peptides

We describe a novel biosensor based on phospholipid-coated nematic liquid crystal (LC) droplets and demonstrate the detection of Smp43, a model antimicrobial peptide (AMP) from the venom of North African scorpion Scorpio maurus palmatus. Mono-disperse lipid-coated LC droplets of diameter 16.7 ± 0.2 μm were generated using PDMS microfluidic devices with a flow-focusing configuration and were the target for AMPs. The droplets were trapped in a bespoke microfluidic trap structure and were simultaneously treated with Smp43 at gradient concentrations in six different chambers. The disruption of the lipid monolayer by the Smp43 was detected (<6 μM) at concentrations well within its biologically active range, indicated by a dramatic change in the appearance of the droplets associated with the transition from a typical radial configuration to a bipolar configuration, which is readily observed by polarizing microscopy. This suggests the system has feasibility as a drug-discovery screening tool. Further, compared to previously reported LC droplet biosensors, this LC droplet biosensor with a lipid coating is more biologically relevant and its ease of use in detecting membrane-related biological processes and interactions has the potential for development as a reliable, low-cost and disposable point of care diagnostic tool

The central density of a neutron star is unaffected by a binary companion at linear order in μ/R\mu/R

Recent numerical work by Wilson, Mathews, and Marronetti [J. R. Wilson, G. J. Mathews and P. Marronetti, Phys. Rev. D 54, 1317 (1996)] on the coalescence of massive binary neutron stars shows a striking instability as the stars come close together: Each star's central density increases by an amount proportional to 1/(orbital radius). This overwhelms any stabilizing effects of tidal coupling [which are proportional to 1/(orbital radius)^6] and causes the stars to collapse before they merge. Since the claimed increase of density scales with the stars' mass, it should also show up in a perturbation limit where a point particle of mass $\mu$ orbits a neutron star. We prove analytically that this does not happen; the neutron star's central density is unaffected by the companion's presence to linear order in $\mu/R$. We show, further, that the density increase observed by Wilson et. al. could arise as a consequence of not faithfully maintaining boundary conditions.Comment: 3 pages, REVTeX, no figures, submitted to Phys Rev D as a Rapid Communicatio

Does the McNeill Alexander model accurately predict maximum walking speed in novice and experienced race walkers?

Background: Mathematical models propose leg length as a limiting factor in determining the maximum walking velocity. This study evaluated the effectiveness of a leg length-based model in predicting maximum walking velocity in an applied race walking situation, by comparing experienced and novice race walkers during conditions where strictly no flight time (FT) was permitted and in simulated competition conditions (i.e., FT ≤ 40 ms). Methods: Thirty-four participants (18 experienced and 16 novice race walkers) were recruited for this investigation. An Optojump Next system (8 m) was used to determine walking velocity, step frequency, step length, ground contact time, and FT during race walking over a range of velocities. Comparisons were made between novice and experienced participants in predicted maximum velocity and actual velocities achieved with no flight and velocities with FT ≤ 40 ms. The technical effectiveness of the participants was assessed using the ratio of maximum velocity to predicted velocity. Results: In novices, no significant difference was found between predicted and maximum walking speeds without flight time but there was a small 5.8% gain in maximum speed when FT ≤ 40 ms. In experienced race walkers, there was a significant reduction in maximum walking speed compared with predicted maximum (p < 0.01) and a 11.7% gain in maximum walking speed with FT ≤ 40 ms. Conclusion: The analysis showed that leg length was a good predictor of maximal walking velocity in novice walkers but not a good predictor of maximum walking speed in well-trained walkers who appear to have optimised their walking technique to make use of non-visible flight periods of less than 40 ms. The gain in velocity above predicted maximum may be a useful index of race walking proficiency

Precipitation scaling with temperature in warm and cold climates: an analysis of CMIP5 simulations

We investigate the scaling between precipitation and temperature changes in warm and cold climates using six models that have simulated the response to both increased CO2 and Last Glacial Maximum (LGM) boundary conditions. Globally, precipitation increases in warm climates and decreases in cold climates by between 1.5%/°C and 3%/°C. Precipitation sensitivity to temperature changes is lower over the land than over the ocean and lower over the tropical land than over the extratropical land, reflecting the constraint of water availability. The wet tropics get wetter in warm climates and drier in cold climates, but the changes in dry areas differ among models. Seasonal changes of tropical precipitation in a warmer world also reflect this “rich get richer” syndrome. Precipitation seasonality is decreased in the cold-climate state. The simulated changes in precipitation per degree temperature change are comparable to the observed changes in both the historical period and the LGM

Temocillin: a new candidate antibiotic for local antimicrobial delivery in orthopaedic surgery?

Objectives - To assess the performance of the Gram-negative-specific antibiotic temocillin in polymethylmethacrylate bone cement pre-loaded with gentamicin, as a strategy for local antibiotic delivery. Methods - Temocillin was added at varying concentrations to commercial gentamicin-loaded bone cement. The elution of the antibiotic from cement samples over a 2 week period was quantified by LC-MS. The eluted temocillin was purified by fast protein liquid chromatography and the MICs for a number of antibiotic-resistant Escherichia coli were determined. The impact strength of antibiotic-loaded samples was determined using a Charpy-type impact testing apparatus. Results - LC-MS data showed temocillin eluted to clinically significant concentrations within 1 h in this laboratory system and the eluted temocillin retained antimicrobial activity against all organisms tested. Impact strength analysis showed no significant difference between cement samples with or without temocillin. Conclusions - Temocillin can be added to bone cement and retains its antimicrobial activity after elution. The addition of up to 10% temocillin did not affect the impact strength of the cement. The results show that temocillin is a promising candidate for use in antibiotic-loaded bone cement.</p

Nature-inspired trapped air cushion surfaces for environmentally sustainable antibiofouling

Feathers of seabirds and waterfowl (for example the mallard duck (Anas platyrhynchos)) consist of hierarchical fibrillar structures encapsulated with hydrophobic preen oil. These characteristics afford waterproofing through the entrapment of air pockets, enabling swimming and diving for such bird species. This liquid repellency mechanism for bird feathers is mimicked by surface hydrophobisation of fibrous nonwoven polypropylene textiles to create large volumes of trapped air at the solid–liquid interface (plastron). Higher static water contact angle values correlate to a greater resistance towards water ingress (akin to the behaviour of mallard feathers). In order to extend the trapped gas layer lifetimes, the transportation of air from the water surface to a submerged air bubble by the diving bell spider (Argyroneta aquatica) for respiration is mimicked via short duration (< 1 s) solar-powered air bubble bursts once every 2 h. This combination of ornithological and arachnological inspired approaches yields stable trapped gas layers at the solid–liquid interface which are shown to inhibit biofouling in real-world outdoor wet environments

Multiple circulating cytokines are coelevated in chronic obstructive pulmonary disease

Inflammatory biomarkers, including cytokines, are associated with COPD, but the association of particular circulating cytokines with systemic pathology remains equivocal. To investigate this, we developed a protein microarray system to detect multiple cytokines in small volumes of serum. Fourteen cytokines were measured in serum from never-smokers, ex-smokers, current smokers, and COPD patients (GOLD stages 1–3). Certain individual circulating cytokines (particularly TNFa and IL-1b) were significantly elevated in concentration in the serum of particular COPD patients (and some current/ex-smokers without COPD) and may serve as markers of particularly significant systemic inflammation. However, numerous circulating cytokines were raised such that their combined, but not individual, elevation was significantly associated with severity of disease, and these may be further indicators of, and contributors to, the systemic inflammatory manifestations of COPD. The coelevation of numerous circulating cytokines in COPD is consistent with the insidious development, chronic nature, and systemic comorbidities of the disease

Development and validation of protein microarray technology for simultaneous inflammatory mediator detection in human sera

Biomarkers, including cytokines, can help in the diagnosis, prognosis, and prediction of treatment response across a wide range of disease settings. Consequently, the recent emergence of protein microarray technology, which is able to quantify a range of inflammatory mediators in a large number of samples simultaneously, has become highly desirable. However, the cost of commercial systems remains somewhat prohibitive. Here we show the development, validation, and implementation of an in-house microarray platform which enables the simultaneous quantitative analysis of multiple protein biomarkers. The accuracy and precision of the in-house microarray system were investigated according to the Food and Drug Administration (FDA) guidelines for pharmacokinetic assay validation. The assay fell within these limits for all but the very low-abundant cytokines, such as interleukin- (IL-) 10. Additionally, there were no significant differences between cytokine detection using our microarray system and the “gold standard” ELISA format. Crucially, future biomarker detection need not be limited to the 16 cytokines shown here but could be expanded as required. In conclusion, we detail a bespoke protein microarray system, utilizing well-validated ELISA reagents, that allows accurate, precise, and reproducible multiplexed biomarker quantification, comparable with commercial ELISA, and allowing customization beyond that of similar commercial microarrays