Anomalous relaxation kinetics of biological lattice-ligand binding models

We discuss theoretical models for the cooperative binding dynamics of ligands to substrates, such as dimeric motor proteins to microtubules or more extended macromolecules like tropomyosin to actin filaments. We study the effects of steric constraints, size of ligands, binding rates and interaction between neighboring proteins on the binding dynamics and binding stoichiometry. Starting from an empty lattice the binding dynamics goes, quite generally, through several stages. The first stage represents fast initial binding closely resembling the physics of random sequential adsorption processes. Typically this initial process leaves the system in a metastable locked state with many small gaps between blocks of bound molecules. In a second stage the gaps annihilate slowly as the ligands detach and reattach. This results in an algebraic decay of the gap concentration and interesting scaling behavior. Upon identifying the gaps with particles we show that the dynamics in this regime can be explained by mapping it onto various reaction-diffusion models. The final approach to equilibrium shows some interesting dynamic scaling properties. We also discuss the effect of cooperativity on the equilibrium stoichiometry, and their consequences for the interpretation of biochemical and image reconstruction results.Comment: REVTeX, 20 pages, 17 figures; review, to appear in Chemical Physics; v2: minor correction

Making history: intentional capture of future memories

Lifelogging' technology makes it possible to amass digital data about every aspect of our everyday lives. Instead of focusing on such technical possibilities, here we investigate the way people compose long-term mnemonic representations of their lives. We asked 10 families to create a time capsule, a collection of objects used to trigger remembering in the distant future. Our results show that contrary to the lifelogging view, people are less interested in exhaustively digitally recording their past than in reconstructing it from carefully selected cues that are often physical objects. Time capsules were highly expressive and personal, many objects were made explicitly for inclusion, however with little object annotation. We use these findings to propose principles for designing technology that supports the active reconstruction of our future past

Integration of genetics into a systems model of electrocardiographic traits using humanCVD BeadChip

<p>Background—Electrocardiographic traits are important, substantially heritable determinants of risk of arrhythmias and sudden cardiac death.</p> <p>Methods and Results—In this study, 3 population-based cohorts (n=10 526) genotyped with the Illumina HumanCVD Beadchip and 4 quantitative electrocardiographic traits (PR interval, QRS axis, QRS duration, and QTc interval) were evaluated for single-nucleotide polymorphism associations. Six gene regions contained single nucleotide polymorphisms associated with these traits at P<10−6, including SCN5A (PR interval and QRS duration), CAV1-CAV2 locus (PR interval), CDKN1A (QRS duration), NOS1AP, KCNH2, and KCNQ1 (QTc interval). Expression quantitative trait loci analyses of top associated single-nucleotide polymorphisms were undertaken in human heart and aortic tissues. NOS1AP, SCN5A, IGFBP3, CYP2C9, and CAV1 showed evidence of differential allelic expression. We modeled the effects of ion channel activity on electrocardiographic parameters, estimating the change in gene expression that would account for our observed associations, thus relating epidemiological observations and expression quantitative trait loci data to a systems model of the ECG.</p> <p>Conclusions—These association results replicate and refine the mapping of previous genome-wide association study findings for electrocardiographic traits, while the expression analysis and modeling approaches offer supporting evidence for a functional role of some of these loci in cardiac excitation/conduction.</p&gt

Far-field positive phase blast parameter characterisation of RDX and PETN based explosives

A significant amount of scientific effort has been dedicated to measuring and understanding the effects of explosions, leading to the development of semi-empirical methods for rapid prediction of blast load parameters. The most well-known of these, termed the Kingery and Bulmash method, makes use of polylogarithmic curves derived from a compilation of medium to large scale experimental tests performed over many decades. However, there is still no general consensus on the accuracy and validity of this approach, despite some researchers reporting consistently high levels of agreement. Further, it is still not known whether blast loading can be considered deterministic, or whether it is intrinsically variable, the extent of this variability, and the range and scales over which these variations are observed. This article critically reviews historic and contemporary blast experiments, including newly generated arena tests with RDX and PETN-based explosives, with a view to demonstrating the accuracy with which blast load parameters can be predicted using semi-empirical approaches

Australian recommendations on perioperative use of disease-modifying anti-rheumatic drugs in people with inflammatory arthritis undergoing elective surgery.

OnlinePublDisease-modifying antirheumatic drugs (DMARDs) are effective treatments for inflammatory arthritis but carry an increased risk of infection. For patients undergoing surgery there is a need to consider the trade-off between a theoretical increased risk of infection with continuation of DMARDs perioperatively versus an increased risk of disease flare if they are temporarily withheld. We used GRADE methodology to develop recommendations for perioperative use of DMARDs for people with inflammatory arthritis undergoing elective surgery. The recommendations form part of the NHMRC-endorsed Australian Living Guideline for the Pharmacological Management of Inflammatory Arthritis. Conditional recommendations were made against routinely discontinuing conventional synthetic (cs) and biologic (b) DMARDs in the perioperative period but to consider temporary discontinuation of bDMARDs in individuals with a high risk of infection or where the impact of infection would be severe. A conditional recommendation was made in favour of temporary discontinuation of targeted synthetic (ts) DMARDs in the perioperative period.Rachelle Buchbinder, Vanessa Glennon, Renea V. Johnston, Sue E. Brennan, Chris Fong, Suzie Edward May, Sean O, Neill, Peter Smitham, Lyndal Trevena, Glen Whittaker, Anita Wluka, and Samuel L. Whittl

Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases

Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r =-0.62, P = 5.30 × 10-5) but not between CCT and primary open-angle glaucoma (r =-0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation