Modeling of arylamide helix mimetics in the p53 peptide binding site of hDM2 suggests parallel and anti-parallel conformations are both stable.

The design of novel α-helix mimetic inhibitors of protein-protein interactions is of interest to pharmaceuticals and chemical genetics researchers as these inhibitors provide a chemical scaffold presenting side chains in the same geometry as an α-helix. This conformational arrangement allows the design of high affinity inhibitors mimicking known peptide sequences binding specific protein substrates. We show that GAFF and AutoDock potentials do not properly capture the conformational preferences of α-helix mimetics based on arylamide oligomers and identify alternate parameters matching solution NMR data and suitable for molecular dynamics simulation of arylamide compounds. Results from both docking and molecular dynamics simulations are consistent with the arylamides binding in the p53 peptide binding pocket. Simulations of arylamides in the p53 binding pocket of hDM2 are consistent with binding, exhibiting similar structural dynamics in the pocket as simulations of known hDM2 binders Nutlin-2 and a benzodiazepinedione compound. Arylamide conformations converge towards the same region of the binding pocket on the 20 ns time scale, and most, though not all dihedrals in the binding pocket are well sampled on this timescale. We show that there are two putative classes of binding modes for arylamide compounds supported equally by the modeling evidence. In the first, the arylamide compound lies parallel to the observed p53 helix. In the second class, not previously identified or proposed, the arylamide compound lies anti-parallel to the p53 helix

Effects of whole body cryotherapy and cold water immersion on immune and inflammatory markers following exercise induced muscle damage

Introduction: Cold therapies are used regularly in medicine for their analgesic and anti-inflammatory effects. Whole-body cryotherapy (WBC) involves exposure to air maintained between -110 and -160oC, and is hypothesised to reduce pain, local and systemic inflammation. WBC has recently become popular in an exercise and sporting context as a recovery method after skeletal muscle damage. However, research examining the efficacy of WBC in an athletic context is minimal, in particular, studies comparing WBC to currently accepted recovery methods are lacking. Cold water immersion (CWI) is a widely researched and applied method of skeletal muscle recovery in sport science. As yet, no study has compared the proposed new method of WBC and the currently practiced method of CWI. We have designed a randomised control trial to examine the efficacy of WBC, as compared with CWI on recovery from a bout of eccentric muscle damage. Methods: Sixty healthy male subjects will perform skeletal muscle function tests and an eccentric muscle damage protocol of their left quadriceps femoris, using an isokinetic dynamometer. They will then be randomly assigned to one of 3 groups, WBC, CWI or a passive recovery control (PAS). The WBC will expose subjects to -160°C for 3min, using cold air. The CWI condition involves whole body exposure for 3min, in water maintained at 12°C. The PAS will have subjects seated comfortably at room temperature following the exercise protocol. Blood samples, muscle functional measurements and pain reports will be taken before muscle damage, immediately following damage, prior to therapy administration and post therapy. Further follow up measures to be taken 6 h post, 24 h and 7 days post. Blood samples will be analysed for changes in interleukins 6, 8 and 10, creatine kinase and leukocyte population kinetics. Results: Testing is being conducted. Results to be presented at the international society of exercise immunology (ISEI) symposium in September 2013

Intelligent viewpoint selection for efficient CT to video registration in laparoscopic liver surgery

PURPOSE: Minimally invasive surgery offers advantages over open surgery due to a shorter recovery time, less pain and trauma for the patient. However, inherent challenges such as lack of tactile feedback and difficulty in controlling bleeding lower the percentage of suitable cases. Augmented reality can show a better visualisation of sub-surface structures and tumour locations by fusing pre-operative CT data with real-time laparoscopic video. Such augmented reality visualisation requires a fast and robust video to CT registration that minimises interruption to the surgical procedure. METHODS: We propose to use view planning for efficient rigid registration. Given the trocar position, a set of camera positions are sampled and scored based on the corresponding liver surface properties. We implement a simulation framework to validate the proof of concept using a segmented CT model from a human patient. Furthermore, we apply the proposed method on clinical data acquired during a human liver resection. RESULTS: The first experiment motivates the viewpoint scoring strategy and investigates reliable liver regions for accurate registrations in an intuitive visualisation. The second experiment shows wider basins of convergence for higher scoring viewpoints. The third experiment shows that a comparable registration performance can be achieved by at least two merged high scoring views and four low scoring views. Hence, the focus could change from the acquisition of a large liver surface to a small number of distinctive patches, thereby giving a more explicit protocol for surface reconstruction. We discuss the application of the proposed method on clinical data and show initial results. CONCLUSION: The proposed simulation framework shows promising results to motivate more research into a comprehensive view planning method for efficient registration in laparoscopic liver surgery

The macro-economic effects of health co-benefits associated with climate change mitigation strategies

The UK government has specific targets for greenhouse gas (GHG) emission reduction to lower the risk of dangerous climate change. Strategies to reduce GHG emissions are sometimes perceived as expensive and difficult to implement but previous work has demonstrated significant potential health co-benefits from ‘Active Travel and low carbon driving’, ‘Housing Insulation/Ventilation’, and ‘Healthy Diet’ scenarios which may be attractive to policymakers. Here a Computable General Equilibrium model is used to assess the financial effects of such health co-benefits on the wider economy including changes in labour force, social security payments and healthcare costs averted. Results suggest that for all scenarios the financial impacts of the health co-benefits will be positive and increased active travel in particular is likely to make a substantial contribution, largely due to health care costs averted. Strategies to reduce GHG emissions and improve health are likely to result in substantial and increasing positive contributions to the economy which may offset some potential economic costs and thereby be seen more favourably in times of economic austerity

Smoking in asthma is associated with elevated levels of corticosteroid resistant sputum cytokines—an exploratory study

<p>Background: Current cigarette smoking is associated with reduced acute responses to corticosteroids and worse clinical outcomes in stable chronic asthma. The mechanism by which current smoking promotes this altered behavior is currently unclear. Whilst cytokines can induce corticosteroid insensitivity in-vitro, how current and former smoking affects airway cytokine concentrations and their responses to oral corticosteroids in stable chronic asthma is unclear.</p> <p>Objectives: To examine blood and sputum cytokine concentrations in never, ex and current smokers with asthma before and after oral corticosteroids.</p> <p>Methods: Exploratory study utilizing two weeks of oral dexamethasone (equivalent to 40 mg/day prednisolone) in 22 current, 21 never and 10 ex-smokers with asthma. Induced sputum supernatant and plasma was obtained before and after oral dexamethasone. 25 cytokines were measured by multiplex microbead system (Invitrogen, UK) on a Luminex platform.</p> <p>Results: Smokers with asthma had elevated sputum cytokine interleukin (IL) -6, -7, and -12 concentrations compared to never smokers with asthma. Few sputum cytokine concentrations changed in response to dexamethasone IL-17 and IFNα increased in smokers, CCL4 increased in never smokers and CCL5 and CXCL10 reduced in ex-smokers with asthma. Ex-smokers with asthma appeared to have evidence of an ongoing corticosteroid resistant elevation of cytokines despite smoking cessation. Several plasma cytokines were lower in smokers wi</p> <p>Conclusion: Cigarette smoking in asthma is associated with a corticosteroid insensitive increase in multiple airway cytokines. Distinct airway cytokine profiles are present in current smokers and never smokers with asthma and could provide an explanatory mechanism for the altered clinical behavior observed in smokers with asthma.</p&gt

Approximately coloring graphs without long induced paths

It is an open problem whether the 3-coloring problem can be solved in polynomial time in the class of graphs that do not contain an induced path on $t$ vertices, for fixed $t$. We propose an algorithm that, given a 3-colorable graph without an induced path on $t$ vertices, computes a coloring with $\max\{5,2\lceil{\frac{t-1}{2}}\rceil-2\}$ many colors. If the input graph is triangle-free, we only need $\max\{4,\lceil{\frac{t-1}{2}}\rceil+1\}$ many colors. The running time of our algorithm is $O((3^{t-2}+t^2)m+n)$ if the input graph has $n$ vertices and $m$ edges

On Pattern Selection for Laparoscope Calibration

Camera calibration is a key requirement for augmented reality in surgery. Calibration of laparoscopes provides two challenges that are not sufficiently addressed in the literature. In the case of stereo laparoscopes the small distance (less than 5mm) between the channels means that the calibration pattern is an order of magnitude more distant than the stereo separation. For laparoscopes in general, if an external tracking system is used, hand-eye calibration is difficult due to the long length of the laparoscope. Laparoscope intrinsic, stereo and hand-eye calibration all rely on accurate feature point selection and accurate estimation of the camera pose with respect to a calibration pattern. We compare 3 calibration patterns, chessboard, rings, and AprilTags. We measure the error in estimating the camera intrinsic parameters and the camera poses. Accuracy of camera pose estimation will determine the accuracy with which subsequent stereo or hand-eye calibration can be done. We compare the results of repeated real calibrations and simulations using idealised noise, to determine the expected accuracy of different methods and the sources of error. The results do indicate that feature detection based on rings is more accurate than a chessboard, however this doesn’t necessarily lead to a better calibration. Using a grid with identifiable tags enables detection of features nearer the image boundary, which may improve calibration