922017 research outputs found
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Mechanisms of Electron Transfer Rate Modulations in Cytochrome P450 BM3.
No full textThe bacterial cytochromes P450 BM3 (CYP450 BM3) catalyzes reactions of industrial importance. Despite many successful biotransformations, robust re(design) for novel applications remains challenging. Rational design and evolution-ary approaches are not always successful highlighting a lack of complete understanding of the mechanisms of electron trans-fer (ET) modulations. Thus, the full potential of CYP450 reactions remains under-exploited. In this work, we report the first MD-based explicit prediction of BM3 ET parameters (reorganization energies; λ and ET free energies; ΔG°), and log ET rates (log kET) using Marcus theory. Overall, the calculated ET rates for the BM3 wild-type (WT), mutants (F393 and L86), ligand-bound state, and ion concentrations agree well with experimental data. In ligand-free (LF) BM3, mutations modulate kET via ET ΔG°. Simulations show that the experimental ET rate enhancement is due to increased driving force (more negative ΔG°) upon ligation. This increase is related to the protein reorganization required to accommodate the ligand in the binding pocket, rather than binding interaction with the ligand. Our methodology (CYPWare 1.0) automates all the stages of MD simulation step-up, energy calculations, and estimation of ET parameters. CYPWare 1.0 and this work, thus represent an important advancement in the CYP450 ET rate predictions which has the potential to guide the redesign of ET enzymes. This program and a web tool are available on GitHub for academic research
Psychologically informed health care
No full textThe term ‘psychologically informed health care’ refers to the comprehensive integration of psychological principles into health care. Psychologically informed health care has the potential to lead to a transformation of care, resulting in truly transdisciplinary care. To facilitate its future development, we discuss key characteristics of this approach. These include the direct mode (psychologists assessing and treating patients themselves) and indirect mode (psychologists working through other health care providers) of integrating psychological principles into healthcare; the range of health domains targeted using this approach; transdisciplinary care, transcending traditional disciplinary boundaries; and the positioning of care. We describe a framework for transdisciplinary care, which we refer to as the Framework for Catalytic Collaboration. This framework comprises six dimensions: setting, disciplines, patients/clients, mode of psychological care, primary components of care, and primary targets of care. We also provide four brief illustrations of psychologically informed health care. Finally, we discuss future directions, including the need for professional recognition of the indirect mode, financing of the indirect mode, cross-disciplinary training and trans-disciplinary research
PHANGS-JWST First Results: Spurring on Star Formation:JWST Reveals Localised Star Formation in a Spiral Arm Spur of NGC 628
No full textWe combine JWST observations with ALMA CO and VLT-MUSE Hα data to examine off-spiral arm star formation in the face-on, grand-design spiral galaxy NGC 628. We focus on the northern spiral arm, around a galactocentric radius of 3-4 kpc, and study two spurs. These form an interesting contrast, as one is CO-rich and one CO-poor, and they have a maximum azimuthal offset in MIRI 21μm and MUSE Hα of around 40∘ (CO-rich) and 55∘ (CO-poor) from the spiral arm. The star formation rate is higher in the regions of the spurs near to spiral arms, but the star formation efficiency appears relatively constant. Given the spiral pattern speed and rotation curve of this galaxy and assuming material exiting the arms undergoes purely circular motion, these offsets would be reached in 100-150 Myr, significantly longer than the 21μm and Hα star formation timescales (bot
Current insights into skin lipids and their roles in cutaneous health and disease
No full textPurpose of review: The unique and complex array of cutaneous lipids include essential components of the skin structure and signalling molecules mediating homeostasis and inflammation. Understanding skin lipid biology and metabolism can support our comprehension of health and disease, including systemic conditions with cutaneous involvement. Recent findings: Lipids found on the skin surface, produced by both the host and resident microbes, maintain and regulate the skin microbiome and the epidermal barrier, whilst altered contributions from either source can be detrimental to skin health. The unique lipid composition of the epidermal barrier is essential for its function, and recent studies have expanded our understanding of epidermal ceramide production. This has been supported by improved models available for skin research, including organotypic skin models enabling in vitro production of complex acylceramides for the first time, and model systems facilitating in silico exploration of the lipid profile changes observed in clinical samples. Studies have revealed further involvement of lipid mediators such as eicosanoids in cutaneous inflammation, as well as immune regulation in both healthy and diseased skin.Summary: Skin lipids offer exciting opportunities as therapeutic targets for many conditions, whether through topical interventions or nutritional supplementation.<br/
The effects of smoothing length on the onset of wave breaking inSmoothed Particle Hydrodynamics (SPH) simulations of highlydirectionally spread waves
No full textOcean wave breaking is a difficult-to-model oceanographic process, which has implications forextreme wave statistics, the dissipation of wave energy, and air-sea interaction. Numerical methods capable of reliably simulating real-world directionally spread breaking waves are useful for investigating the physics of wave breaking and for the design of offshore structures and floating bodies. Smoothed Particle Hydrodynamics (SPH) is capable of modelling highly steep and overturning free surfaces, which makes it a promising method for simulating breaking waves. This paper investigates the effect of smoothing length on simulated wave breaking in both following and crossing seas. To do so, we reproduce numerically the experiments of highly directionally spread breaking waves in McAllister et al. [J. Fluid Mech. vol. 860, 2019, pp. 767{786] using a range of normalised smoothing lengths: h=dp =1.4, 1.7, 2.0, 2.3, with h smoothing length and dp particle spacing. The smallest smoothing length we use appears to adversely affect the fidelity of the simulated surface elevation, so that the tallest wave crest observed in experiments is not fully reproduced (coefficient of determination r2 ≈ 0:7). For smoothing lengths h=dp = 1:7, 2:0, and 2:3, the experiments are well reproduced (r2 ≥ 0:88); in these simulations smoothing length predominantly affects the spatial extent and duration of breaking. Qualitative and quantitative comparison of our simulations show that values of h=dp in the range 1:7 - 2 best reproduce the wave breaking phenomena observed in experiments
Developing an understanding of sophorolipid synthesis through application of a central composite design model
No full textA key barrier to market penetration for sophorolipid biosurfactants is the ability to improve productivity and utilise alternative feedstocks to reduce the cost of production. To do this, a suitable screening tool is required that is able to model the interactions between media components and alter conditions to maximise productivity. In the following work a central composite design is applied to analyse the effects of altering glucose, rapeseed oil, cornsteep liquor and ammonium sulfate concentrations on sophorolipid production with Starmerella bombicola ATCC 222144 after 168 h. Sophorolipid production was analysed using standard least squares regression and the findings related to the growth (OD600) and broth conditions (glucose, glycerol and oil concentration). An optimum media composition was found that was capable of producing 39.5 g/L sophorolipid. Nitrogen and rapeseed oil sources were found to be significant, linked to their role in growth and substrate supply respectively. Glucose did not demonstrate a significant effect on production despite its importance to biosynthesis and its depletion in the broth within 96 h, instead being replaced by glycerol (via triglyceride breakdown) as the hydrophilic carbon source at the point of glucose depletion. A large dataset was obtained and a regression model with applications towards substrate screening and process optimisation developed
Childcare Support under Social Security in the UK: Is it Working?
No full textBy facilitating engagement in the labour force and thus potentially contributing to the amelioration of individual poverty, the availability of affordable childcare is an issue of both economic and social significance and is recognised as such across Europe. Since a large majority of the parents who assume caring responsibilities for young children, particularly lone parents, are women, childcare support is also seen as an equality issue in relation to employment. Children’s interest in the parents’ childcare support is also recognised under the UN Convention on the Rights of the Child. Support towards the cost of childcare has been an important feature of the UK social security system since the 1980s and is currently located within Universal Credit (UC) and Working Tax Credit (WTC) legislation. UC and WTC support sits alongside other childcare support schemes, including Tax-free Childcare. For the most disadvantaged, it is however the social security system’s role in this field that has the greatest importance, not least because the imposition of work conditionality and particularly its extension to lone parents with young children is premised on the claimant’s ability to access childcare arrangements. This article evaluates the framework for supporting childcare costs within the social security system in the light of the evidence to date on its operation, including the inherent discrimination that prompted the recent judicial review challenge in Salvato. It highlights flaws in the system and among other things calls for increased monitoring and public scrutiny of its operation
EULAR points to consider when analysing and reporting comparative effectiveness research using observational data in rheumatology
No full textBackgroundComparing treatment effectiveness over time in observational settings is hampered by several major threats, among them confounding and attrition bias. ObjectivesTo develop European Alliance of Associations for Rheumatology (EULAR) points to consider (PtC) when analysing and reporting comparative effectiveness research using observational data in rheumatology. MethodsThe PtC were developed using a three-step process according to the EULAR Standard Operating Procedures. Based on a systematic review of methods currently used in comparative effectiveness studies, the PtC were formulated through two in-person meetings of a multidisciplinary task force and a two-round online Delphi, using expert opinion and a simulation study. Finally, feedback from a larger audience was used to refine the PtC. Mean levels of agreement amongst the task force were calculated. ResultsThree overarching principles and 10 PtC were formulated, addressing, in particular, potential biases relating to attrition or confounding by indication. Building on STROBE guidelines, these PtC insist on the definition of the baseline for analysis and treatment effectiveness. They also focus on the reasons for stopping treatment as an important consideration when assessing effectiveness. Finally, the PtC recommend providing key information on missingness patterns. ConclusionTo improve the reliability of an increasing number of real-world comparative effectiveness studies in rheumatology, special attention is required to reduce potential biases. Adherence to clear recommendations for the analysis and reporting of observational comparative effectiveness studies will improve the trustworthiness of their results.<br/
SonOpt: Sonifying Bi-objective Population-Based Optimization Algorithms
No full textWe propose SonOpt, the first (open source) data sonification application for monitoring the progress of bi-objective populationbased optimization algorithms during search, to facilitate algorithm understanding. SonOpt provides insights into convergence/stagnation of search, the evolution of the approximation set shape, location of recurring points in the approximation set, and population diversity. The benefits of data sonification have been shown for various non-optimization related monitoring tasks. However, very few attempts have been made in the context of optimization and their focus has been exclusively on single-objective problems. In comparison, SonOpt is designed for biobjective optimization problems, relies on objective function values ofnon-dominated solutions only, and is designed with the user (listener) in mind; avoiding convolution of multiple sounds and prioritising ease of familiarizing with the system. This is achieved using two sonification paths relying on the concepts of wavetable and additive synthesis.This paper motivates and describes the architecture of SonOpt, and then validates SonOpt for two popular multi-objective optimization algorithms (NSGA-II and MOEA/D). Experience SonOpt yourself viahttps://github.com/tasos-a/SonOpt-1.0.Keywords: sonification · optimization · algorithmic behaviour · metaheuristics · evolutionary computation · process monitoring · SonOpt
