Laser-heated capillary discharge plasma waveguides for electron acceleration to 8 GeV

A plasma channel created by the combination of a capillary discharge and inverse Bremsstrahlung laser heating enabled the generation of electron bunches with energy up to 7.8 GeV in a laser-driven plasma accelerator. The capillary discharge created an initial plasma channel and was used to tune the plasma temperature, which optimized laser heating. Although optimized colder initial plasma temperatures reduced the ionization degree, subsequent ionization from the heater pulse created a fully ionized plasma on-axis. The heater pulse duration was chosen to be longer than the hydrodynamic timescale of ≈ 1 ns, such that later temporal slices were more efficiently guided by the channel created by the front of the pulse. Simulations are presented which show that this thermal self-guiding of the heater pulse enabled channel formation over 20 cm. The post-heated channel had lower on-axis density and increased focusing strength compared to relying on the discharge alone, which allowed for guiding of relativistically intense laser pulses with a peak power of 0.85 PW and wakefield acceleration over 15 diffraction lengths. Electrons were injected into the wake in multiple buckets and times, leading to several electron bunches with different peak energies. To create single electron bunches with low energy spread, experiments using localized ionization injection inside a capillary discharge waveguide were performed. A single injected bunch with energy 1.6 GeV, charge 38 pC, divergence 1 mrad, and relative energy spread below 2% full-width half-maximum was produced in a 3.3 cm-long capillary discharge waveguide. This development shows promise for mitigation of energy spread and future high efficiency staged acceleration experiments

Evolution of Taxis Responses in Virtual Bacteria: Non-Adaptive Dynamics

Bacteria are able to sense and respond to a variety of external stimuli, with responses that vary from stimuli to stimuli and from species to species. The best-understood is chemotaxis in the model organism Escherichia coli, where the dynamics and the structure of the underlying pathway are well characterised. It is not clear, however, how well this detailed knowledge applies to mechanisms mediating responses to other stimuli or to pathways in other species. Furthermore, there is increasing experimental evidence that bacteria integrate responses from different stimuli to generate a coherent taxis response. We currently lack a full understanding of the different pathway structures and dynamics and how this integration is achieved. In order to explore different pathway structures and dynamics that can underlie taxis responses in bacteria, we perform a computational simulation of the evolution of taxis. This approach starts with a population of virtual bacteria that move in a virtual environment based on the dynamics of the simple biochemical pathways they harbour. As mutations lead to changes in pathway structure and dynamics, bacteria better able to localise with favourable conditions gain a selective advantage. We find that a certain dynamics evolves consistently under different model assumptions and environments. These dynamics, which we call non-adaptive dynamics, directly couple tumbling probability of the cell to increasing stimuli. Dynamics that are adaptive under a wide range of conditions, as seen in the chemotaxis pathway of E. coli, do not evolve in these evolutionary simulations. However, we find that stimulus scarcity and fluctuations during evolution results in complex pathway dynamics that result both in adaptive and non-adaptive dynamics depending on basal stimuli levels. Further analyses of evolved pathway structures show that effective taxis dynamics can be mediated with as few as two components. The non-adaptive dynamics mediating taxis responses provide an explanation for experimental observations made in mutant strains of E. coli and in wild-type Rhodobacter sphaeroides that could not be explained with standard models. We speculate that such dynamics exist in other bacteria as well and play a role linking the metabolic state of the cell and the taxis response. The simplicity of mechanisms mediating such dynamics makes them a candidate precursor of more complex taxis responses involving adaptation. This study suggests a strong link between stimulus conditions during evolution and evolved pathway dynamics. When evolution was simulated under conditions of scarce and fluctuating stimulus conditions, the evolved pathway contained features of both adaptive and non-adaptive dynamics, suggesting that these two types of dynamics can have different advantages under distinct environmental circumstances

A meta-analytic review of stand-alone interventions to improve body image

Objective Numerous stand-alone interventions to improve body image have been developed. The present review used meta-analysis to estimate the effectiveness of such interventions, and to identify the specific change techniques that lead to improvement in body image. Methods The inclusion criteria were that (a) the intervention was stand-alone (i.e., solely focused on improving body image), (b) a control group was used, (c) participants were randomly assigned to conditions, and (d) at least one pretest and one posttest measure of body image was taken. Effect sizes were meta-analysed and moderator analyses were conducted. A taxonomy of 48 change techniques used in interventions targeted at body image was developed; all interventions were coded using this taxonomy. Results The literature search identified 62 tests of interventions (N = 3,846). Interventions produced a small-to-medium improvement in body image (d+ = 0.38), a small-to-medium reduction in beauty ideal internalisation (d+ = -0.37), and a large reduction in social comparison tendencies (d+ = -0.72). However, the effect size for body image was inflated by bias both within and across studies, and was reliable but of small magnitude once corrections for bias were applied. Effect sizes for the other outcomes were no longer reliable once corrections for bias were applied. Several features of the sample, intervention, and methodology moderated intervention effects. Twelve change techniques were associated with improvements in body image, and three techniques were contra-indicated. Conclusions The findings show that interventions engender only small improvements in body image, and underline the need for large-scale, high-quality trials in this area. The review identifies effective techniques that could be deployed in future interventions

Evolution of response dynamics underlying bacterial chemotaxis

© 2011 Soyer and Goldstein; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background: The ability to predict the function and structure of complex molecular mechanisms underlying cellular behaviour is one of the main aims of systems biology. To achieve it, we need to understand the evolutionary routes leading to a specific response dynamics that can underlie a given function and how biophysical and environmental factors affect which route is taken. Here, we apply such an evolutionary approach to the bacterial chemotaxis pathway, which is documented to display considerable complexity and diversity.Results: We construct evolutionarily accessible response dynamics starting from a linear response to absolute levels of attractant, to those observed in current-day Escherichia coli. We explicitly consider bacterial movement as a two-state process composed of non-instantaneous tumbling and swimming modes. We find that a linear response to attractant results in significant chemotaxis when sensitivity to attractant is low and when time spent tumbling is large. More importantly, such linear response is optimal in a regime where signalling has low sensitivity. As sensitivity increases, an adaptive response as seen in Escherichia coli becomes optimal and leads to 'perfect' chemotaxis with a low tumbling time. We find that as tumbling time decreases and sensitivity increases, there exist a parameter regime where the chemotaxis performance of the linear and adaptive responses overlap, suggesting that evolution of chemotaxis responses might provide an example for the principle of functional change in structural continuity.Conclusions: Our findings explain several results from diverse bacteria and lead to testable predictions regarding chemotaxis responses evolved in bacteria living under different biophysical constraints and with specific motility machinery. Further, they shed light on the potential evolutionary paths for the evolution of complex behaviours from simpler ones in incremental fashion

Inside-Out Regulation of ICAM-1 Dynamics in TNF-α-Activated Endothelium

Background: During transendothelial migration, leukocytes use adhesion molecules, such as ICAM-1, to adhere to the endothelium. ICAM-1 is a dynamic molecule that is localized in the apical membrane of the endothelium and clusters upon binding to leukocytes. However, not much is known about the regulation of ICAM-1 clustering and whether membrane dynamics are linked to the ability of ICAM-1 to cluster and bind leukocyte integrins. Therefore, we studied the dynamics of endothelial ICAM-1 under non-clustered and clustered conditions. Principal Findings: Detailed scanning electron and fluorescent microscopy showed that the apical surface of endothelial cells constitutively forms small filopodia-like protrusions that are positive for ICAM-1 and freely move within the lateral plane of the membrane. Clustering of ICAM-1, using anti-ICAM-1 antibody-coated beads, efficiently and rapidly recruits ICAM-1. Using fluorescence recovery after photo-bleaching (FRAP), we found that clustering increased the immobile fraction of ICAM-1, compared to non-clustered ICAM-1. This shift required the intracellular portion of ICAM-1. Moreover, biochemical assays showed that ICAM-1 clustering recruited beta-actin and filamin. Cytochalasin B, which interferes with actin polymerization, delayed the clustering of ICAM-1. In addition, we could show that cytochalasin B decreased the immobile fraction of clustered ICAM-1-GFP, but had no effect on non-clustered ICAM-1. Also, the motor protein myosin-II is recruited to ICAM-1 adhesion sites and its inhibition increased the immobile fraction of both non-clustered and clustered ICAM-1. Finally, blocking Rac1 activation, the formation of lipid rafts, myosin-II activity or actin polymerization, but not Src, reduced the adhesive function of ICAM-1, tested under physiological flow conditions. Conclusions: Together, these findings indicate that ICAM-1 clustering is regulated in an inside-out fashion through the actin cytoskeleton. Overall, these data indicate that signaling events within the endothelium are required for efficient ICAM-1-mediated leukocyte adhesio

Models for Prediction of Factor VIII Half-Life in Severe Haemophiliacs: Distinct Approaches for Blood Group O and Non-O Patients

BACKGROUND: Von Willebrand factor (VWF) is critical for the in vivo survival of factor VIII (FVIII). Since FVIII half-life correlates with VWF-antigen pre-infusion levels, we hypothesized that VWF levels are useful to predict FVIII half-life. METHODOLOGY: Standardized half-life studies and analysis of pre-infusion VWF and VWF-propeptide levels were performed in a cohort of 38 patients with severe haemophilia A (FVIII <1 IU/ml), aged 15-44 years. Nineteen patients had blood-group O. Using multivariate linear regression-analysis (MVLR-analysis), the association of VWF-antigen, VWF-propeptide, age and body-weight with FVIII half-life was evaluated. PRINCIPAL FINDINGS: FVIII half-life was shorter in blood-group O-patients compared to non-O-patients (11.5+/-2.6 h versus 14.3+/-3.0 h; p = 0.004). VWF-antigen levels correlated with FVIII half-life considerably better in patients with blood-group non-O than O (Pearson-rank = 0.70 and 0.47, respectively). Separate prediction models evolved from MVLR-analysis for blood-group O and non-O patients, based on VWF-antigen and VWF/propeptide ratio. Predicted half-lives deviated less than 3 h of observed half-life in 34/38 patients (89%) or less than 20% in 31/38 patients (82%). CONCLUSION: Our approach may identify patients with shorter FVIII half-lives, and adapt treatment protocols when half-life studies are unavailable. In addition, our data indicate that survival of FVIII is determined by survival of endogenous VWF rather than VWF levels per se

A single-blind randomised controlled trial of the effects of a web-based decision aid on self-testing for cholesterol and diabetes. study protocol

Background: Self-tests, tests on body materials to detect medical conditions, are widely available to the general public. Self-testing does have advantages as well as disadvantages, and the debate on whether self-testing should be encouraged or rather discouraged is still ongoing. One of the concerns is whether consumers have sufficient knowledge to perform the test and interpret the results. An online decision aid (DA) with information on self-testing in general, and test specific information on cholesterol and diabetes self-testing was developed. The DA aims to provide objective information on these self-tests as well as a decision support tool to weigh the pros and cons of self-testing. The aim of this study is to evaluate the effect of the online decision aid on knowledge on self-testing, informed choice, ambivalence and psychosocial determinants. Methods/Design: A single blind randomised controlled trial in which the online decision aid 'zelftestwijzer' is compared to short, non-interactive information on self-testing in general. The entire trial will be conducted online. Participants will be selected from an existing Internet panel. Consumers who are considering doing a cholesterol or diabetes self-test in the future will be included. Outcome measures will be assessed directly after participants have viewed either the DA or the control condition. Weblog files will be used to record participants' use of the decision aid. Discussion: Self-testing does have important pros and cons, and it is important that consumers base their decision whether they want to do a self-test or not on knowledge and personal values. This study is the first to evaluate the effect of an online decision aid for self-testing

Computational genes: a tool for molecular diagnosis and therapy of aberrant mutational phenotype

<p>Abstract</p> <p>Background</p> <p>A finite state machine manipulating information-carrying DNA strands can be used to perform autonomous molecular-scale computations at the cellular level.</p> <p>Results</p> <p>We propose a new finite state machine able to detect and correct aberrant molecular phenotype given by mutated genetic transcripts. The aberrant mutations trigger a cascade reaction: specific molecular markers as input are released and induce a spontaneous self-assembly of a wild type protein or peptide, while the mutational disease phenotype is silenced. We experimentally demostrated in <it>in vitro </it>translation system that a viable protein can be autonomously assembled.</p> <p>Conclusion</p> <p>Our work demostrates the basic principles of computational genes and particularly, their potential to detect mutations, and as a response thereafter administer an output that suppresses the aberrant disease phenotype and/or restores the lost physiological function.</p