Cell organization in soft media due to active mechanosensing

Adhering cells actively probe the mechanical properties of their environment and use the resulting information to position and orient themselves. We show that a large body of experimental observations can be consistently explained from one unifying principle, namely that cells strengthen contacts and cytoskeleton in the direction of large effective stiffness. Using linear elasticity theory to model the extracellular environment, we calculate optimal cell organization for several situations of interest and find excellent agreement with experiments for fibroblasts, both on elastic substrates and in collagen gels: cells orient in the direction of external tensile strain, they orient parallel and normal to free and clamped surfaces, respectively, and they interact elastically to form strings. Our method can be applied for rational design of tissue equivalents. Moreover our results indicate that the concept of contact guidance has to be reevaluated. We also suggest that cell-matrix contacts are upregulated by large effective stiffness in the environment because in this way, build-up of force is more efficient.Comment: Revtex, 7 pages, 4 Postscript files include

Towards optimum smoking cessation interventions during pregnancy: a household model to explore cost‐effectiveness

BACKGROUND AND AIMS: Previous economic evaluations of smoking cessation interventions for pregnant women are limited to single components, which do not in isolation offer sufficient potential impact to address smoking cessation targets. To inform the development of more appropriate complex interventions, we (1) describe the development of the Economics of Smoking in Pregnancy: Household (ESIP.H) model for estimating the life‐time cost‐effectiveness of smoking cessation interventions aimed at pregnant women and (2) use a hypothetical case study to demonstrate how ESIP.H can be used to identify the characteristics of optimum smoking cessation interventions. METHODS: The hypothetical intervention was based on current evidence relating to component elements, including financial incentives, partner smoking, intensive behaviour change support, cigarettes consumption and duration of support to 12 months post‐partum. ESIP.H was developed to assess the life‐time health and cost impacts of multi‐component interventions compared with standard National Health Service (NHS) care in England. ESIP.H considers cigarette consumption, partner smoking and some health conditions (e.g. obesity) that were not included in previous models. The Markov model's parameters were estimated based on published literature, expert judgement and evidence‐based assumptions. The hypothetical intervention was evaluated from an NHS perspective. RESULTS: The hypothetical intervention was associated with an incremental gain in quitters (mother and partner) at 12 months postpartum of 249 [95% confidence interval (CI) = 195–304] per 1000 pregnant smokers. Over the long‐term, it had an incremental negative cost of £193 (CI = –£779 to 344) and it improved health, with a 0.50 (CI = 0.36–0.69) increase in quality‐adjusted life years (QALYs) for mothers, partners and offspring, with a 100% probability of being cost‐effective. CONCLUSIONS: The Economics of Smoking in Pregnancy: Household model for estimating cost‐effectiveness of smoking cessation interventions aimed at pregnant women found that a hypothetical smoking cessation intervention would greatly extend reach, reduce smoking and be cost‐effective

Foliar wheat diseases and cereal smuts and control of Pleiochaeta setosa in lupins.

Disease complexes in field screening trials. Glasshouse screening for resistance. Reinfection of barley loose smut. Barley loose smut – varietal susceptibility. Seed dressings for barley loose smut. Seed dressings for barley leaf stripe. Seed dressings for molybdenum application and fungicidal control of soil-borne flag smut. Chemical control of Pleiochaeta setosa in lupins. Effect of cereal stubble and seed dressing fungicide on brown leaf spot (P. setosa) in lupins. Stubble retention and Rovral for control of P. setosa in lupins. Fungicide sprays for control of P. setosa in lupins. Data summary for chemical trials

A systematic review of the effectiveness of adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis in adults and an economic evaluation of their cost-effectiveness

Objectives: This report reviews the clinical effectiveness and cost-effectiveness of adalimumab, etanercept and infliximab, agents that inhibit tumour necrosis factor-a (TNF-a), when used in the treatment of rheumatoid arthritis (RA) in adults. \ud \ud Data sources: Electronic databases were searched up to February 2005. \ud \ud Review methods: Systematic reviews of the literature on effectiveness and cost-effectiveness were undertaken and industry submissions to the National Institute for Health and Clinical Excellence (NICE) were reviewed. Meta-analyses of effectiveness data were also undertaken for each agent. The Birmingham Rheumatoid Arthritis Model (BRAM), a simulation model, was further developed and used to produce an incremental cost-effectiveness analysis. \ud \ud Results: Twenty-nine randomised controlled trials (RCTs), most of high quality, were included. The only head-to-head comparisons were against methotrexate. For patients with short disease duration (≤3 years) who were naïve to methotrexate, adalimumab was marginally less and etanercept was marginally more effective than methotrexate in reducing symptoms of RA. Etanercept was better tolerated than methotrexate. Both adalimumab and etanercept were more effective than methotrexate in slowing radiographic joint damage. Etanercept was also marginally more effective and better tolerated than methotrexate in patients with longer disease durations who had not failed methotrexate treatment. Infliximab is only licensed for use with methotrexate. All three agents, either alone (where so licensed) or in combination with ongoing disease-modifying antirheumatic drugs (DMARDs), were effective in reducing the symptoms and signs of RA in patients with established disease. At the licensed dose, the numbers needed to treat (NNTs) (95% CI) required to produce an American College for Rheumatology (ACR) response compared with placebo were: ACR20: adalimumab 3.6 (3.1 to 4.2), etanercept 2.1 (1.9 to 2.4), infliximab 3.2 (2.7 to 4.0); ACR50: adalimumab 4.2 (3.7 to 5.0), etanercept 3.1 (2.7 to 3.6), infliximab 5.0 (3.8 to 6.7); and ACR70: adalimumab 7.7 (5.9 to 11.1), etanercept 7.7 (6.3 to 10.0), infliximab 11.1 (7.7 to 20.0). In patients who were naïve to methotrexate, or who had not previously failed methotrexate treatment, a TNF inhibitor combined with methotrexate was significantly more effective than methotrexate alone. Infliximab combined with methotrexate had an increased risk of serious infections. All ten published economic evaluations met standard criteria for quality, but the incremental cost-effectiveness ratios (ICERs) ranged from being within established thresholds to being very high because of varying assumptions and parameters. All three sponsors who submitted economic models made assumptions favourable to their product. BRAM incorporates improvements in quality of life and mortality, but assumes no effect of TNF inhibitors on joint replacement. For use in accordance with current NICE guidance as the third DMARD in a sequence of DMARDs, the base-case ICER was around £30,000 per quality-adjusted life-year (QALY) in early RA and £50,000 per QALY in late RA. Sensitivity analyses showed that the results were sensitive to the estimates of Health Assessment Questionnaire (HAQ) progression while on TNF inhibitors and the effectiveness of DMARDs, but not to changes in mortality ratios per unit HAQ. TNF inhibitors are most cost-effective when used last. The ICER for etanercept used last is £24,000 per QALY, substantially lower than for adalimumab (£30,000 per QALY) or infliximab (£38,000 per QALY). First line use as monotherapy generates ICERs around £50,000 per QALY for adalimumab and etanercept. Using the combination of methotrexate and a TNF inhibitor as first line treatment generates much higher ICERs, as it precludes subsequent use of methotrexate, which is cheap. The ICERs for sequential use are of the same order as using the TNF inhibitor alone. \ud \ud Conclusions: Adalimumab, etanercept and infliximab are effective treatments compared with placebo for RA patients who are not well controlled by conventional DMARDs, improving control of symptoms, improving physical function, and slowing radiographic changes in joints. The combination of a TNF inhibitor with methotrexate was more effective than methotrexate alone in early RA, although the clinical relevance of this additional benefit is yet to be established, particularly in view of the well-established effectiveness of MTX alone. An increased risk of serious infection cannot be ruled out for the combination of methotrexate with adalimumab or infliximab. The results of the economic evaluation based on BRAM are consistent with the observations from the review of clinical effectiveness, including the ranking of treatments. TNF inhibitors are most cost-effective when used as last active therapy. In this analysis, other things being equal, etanercept may be the TNF inhibitor of choice, although this may also depend on patient preference as to route of administration. The next most cost-effective use of TNF inhibitors is third line, as recommended in the 2002 NICE guidance. Direct comparative RCTs of TNF inhibitors against each other and against other DMARDs, and sequential use in patients who have failed a previous TNF inhibitor, are needed. Longer term studies of the quality of life in patients with RA and the impact of DMARDs on this are needed, as are longer studies that directly assess effects on joint replacement, other morbidity and mortality

A vision for care fit for the twenty-first century: Commission on Residential Care

In 2013-14, Demos is hosted a Commission into the future of residential care, chaired by former MP and Care Services Minister Paul Burstow. The Commission was formed with the aim of developing a vision of residential care that is fit for the 21st century

Disordered clock protein interactions and charge blocks turn an hourglass into a persistent circadian oscillator

Organismal physiology is widely regulated by the molecular circadian clock, a feedback loop composed of protein complexes whose members are enriched in intrinsically disordered regions. These regions can mediate protein-protein interactions via SLiMs, but the contribution of these disordered regions to clock protein interactions had not been elucidated. To determine the functionality of these disordered regions, we applied a synthetic peptide microarray approach to the disordered clock protein FRQ in Neurospora crassa. We identified residues required for FRQ\u27s interaction with its partner protein FRH, the mutation of which demonstrated FRH is necessary for persistent clock oscillations but not repression of transcriptional activity. Additionally, the microarray demonstrated an enrichment of FRH binding to FRQ peptides with a net positive charge. We found that positively charged residues occurred in significant blocks within the amino acid sequence of FRQ and that ablation of one of these blocks affected both core clock timing and physiological clock output. Finally, we found positive charge clusters were a commonly shared molecular feature in repressive circadian clock proteins. Overall, our study suggests a mechanistic purpose for positive charge blocks and yielded insights into repressive arm protein roles in clock function

Cell-Free Synthesis of the Mitochondrial ADP/ATP Carrier Protein of Neurospora crassa

ADP/ATP carrier protein was synthesized in heterologous cell-free systems programmed with Neurospora poly(A)-containing RNA and homologous cell-free systems from Neurospora. The apparent molecular weight of the product obtained in vitro was the same as that of the authentic mitochondrial protein. The primary translation product obtained in reticulocyte lysates starts with formylmethionine when formylated initiator methionyl-tRNA (fMet-tRNAfMet) was present. The product synthesized in vitro was released from the ribosomes into the postribosomal supernatant. The evidence presented indicates that the ADP/ATP carrier is synthesized as a polypeptide with the same molecular weight as the mature monomeric protein and does not carry an additional sequence

Experimental evaluation of 3D printed spiral phase plates for enabling an orbital angular momentum multiplexed radio system

This paper evaluates the performance of three-dimensionally (3D) printed spiral phase plates (SPPs) for enabling an orbital angular momentum (OAM) multiplexed radio system. The design and realization of the SPPs by means of additive manufacturing exploiting a high-permittivity material is described. Modes 1 and 2 SPPs are then evaluated at 15 GHz in terms of 3D complex radiation pattern, mode purity and beam collimation by means of a 3D printed dielectric lens. The results with the lens yield a crosstalk of −8 dB for between modes 1 and −1, and −11.4 dB for between modes 2 and −2. We suggest a mode multiplexer architecture that is expected to further reduce the crosstalk for each mode. An additional loss of 4.2 dB is incurred with the SPPs inserted into the communication link, which is undesirable for obtaining reliable LTE-based communications. Thus, we suggest: using lower loss materials, seeking ways to reduce material interface reflections or alternative ways of OAM multiplexing to realize a viable OAM multiplexed radio system