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51.
In this work, we present an algorithm developed to handle biomolecular structural recognition problems, as part of an interdisciplinary research endeavor of the Computer Vision and Molecular Biology fields. A key problem in rational drug design and in biomolecular structural recognition is the generation of binding modes between two molecules, also known as molecular docking. Geometrical fitness is a necessary condition for molecular interaction. Hence, docking a ligand (e.g., a drug molecule or a protein molecule), to a protein receptor (e.g., enzyme), involves recognition of molecular surfaces. Conformational transitions by "hinge-bending" involves rotational movements of relatively rigid parts with respect to each other. The generation of docked binding modes between two associating molecules depends on their three dimensional structures (3-D) and their conformational flexibility. In comparison to the particular case of rigid-body docking, the computational difficulty grows considerably when taking into account the additional degrees of freedom intrinsic to the flexible molecular docking problem. Previous docking techniques have enabled hinge movements only within small ligands. Partial flexibility in the receptor molecule is enabled by a few techniques. Hinge-bending motions of protein receptors domains are not addressed by these methods, although these types of transitions are significant, e.g., in enzymes activity. Our approach allows hinge induced motions to exist in either the receptor or the ligand molecules of diverse sizes. We allow domains/subdomains/group of atoms movements in either of the associating molecules. We achieve this by adapting a technique developed in Computer Vision and Robotics for the efficient recognition of partially occluded articulated objects. These types of objects consist of rigid parts which are connected by rotary joints (hinges). Our method is based on an extension and generalization of the Hough transform and the Geometric Hashing paradigms for rigid object recognition. We show experimental results obtained by the successful application of the algorithm to cases of bound and unbound molecular complexes, yielding fast matching times. While the "correct" molecular conformations of the known complexes are obtained with small RMS distances, additional, predictive good-fitting binding modes are generated as well. We conclude by discussing the algorithm's implications and extensions, as well as its application to investigations of protein structures in Molecular Biology and recognition problems in Computer Vision. 相似文献
52.
53.
Lara J. Wolfson Anna Walker Robert Hettle Xiaoyan Lu Chrispin Kambili Andrew Murungi Gerhart Knerer 《PloS one》2015,10(3)
Objective
To evaluate the cost-effectiveness of adding bedaquiline to a background regimen (BR) of drugs for multidrug-resistant tuberculosis (MDR-TB) in the United Kingdom (UK).Methods
A cohort-based Markov model was developed to estimate the incremental cost-effectiveness ratio of bedaquiline plus BR (BBR) versus BR alone (BR) in the treatment of MDR-TB, over a 10-year time horizon. A National Health Service (NHS) and personal social services perspective was considered. Cost-effectiveness was evaluated in terms of Quality-Adjusted Life Years (QALYs) and Disability-Adjusted Life Years (DALYs). Data were sourced from a phase II, placebo-controlled trial, NHS reference costs, and the literature; the US list price of bedaquiline was used and converted to pounds (£18,800). Costs and effectiveness were discounted at a rate of 3.5% per annum. Probabilistic and deterministic sensitivity analysis was conducted.Results
The total discounted cost per patient (pp) on BBR was £106,487, compared with £117,922 for BR. The total discounted QALYs pp were 5.16 for BBR and 4.01 for BR. The addition of bedaquiline to a BR resulted in a cost-saving of £11,434 and an additional 1.14 QALYs pp over a 10-year period, and is therefore considered to be the dominant (less costly and more effective) strategy over BR. BBR remained dominant in the majority of sensitivity analyses, with a 81% probability of being dominant versus BR in the probabilistic analysis.Conclusions
In the UK, bedaquiline is likely to be cost-effective and cost-saving, compared with the current MDR-TB standard of care under a range of scenarios. Cost-savings over a 10-year period were realized from reductions in length of hospitalization, which offset the bedaquiline drug costs. The cost-benefit conclusions held after several sensitivity analyses, thus validating assumptions made, and suggesting that the results would hold even if the actual price of bedaquiline in the UK were higher than in the US. 相似文献54.
Deanna Wolfson Michael Steck Martin Persson Gregory McNerney Ana Popovich Mattias Goksör Thomas Huser 《Journal of biophotonics》2015,8(3):208-216
We demonstrate an approach to rapidly characterize living suspension cells in 4 dimensions while they are immobilized and manipulated within optical traps. A single, high numerical aperture objective lens is used to separate the imaging plane from the trapping plane. This facilitates full control over the position and orientation of multiple trapped cells using a spatial light modulator, including directed motion and object rotation, while also allowing rapid 4D imaging. This system is particularly useful in the handling and investigation of the behavior of non‐adherent immune cells. We demonstrate these capabilities by imaging and manipulating living, fluorescently stained Jurkat T cells. (© 2015 WILEY‐VCH Verlag GmbH &Co. KGaA, Weinheim) 相似文献
55.
Shai Efrati Haim Golan Yair Bechor Yifat Faran Shir Daphna-Tekoah Gal Sekler Gregori Fishlev Jacob N. Ablin Jacob Bergan Olga Volkov Mony Friedman Eshel Ben-Jacob Dan Buskila 《PloS one》2015,10(5)
BackgroundFibromyalgia Syndrome (FMS) is a persistent and debilitating disorder estimated to impair the quality of life of 2–4% of the population, with 9:1 female-to-male incidence ratio. FMS is an important representative example of central nervous system sensitization and is associated with abnormal brain activity. Key symptoms include chronic widespread pain, allodynia and diffuse tenderness, along with fatigue and sleep disturbance. The syndrome is still elusive and refractory. The goal of this study was to evaluate the effect of hyperbaric oxygen therapy (HBOT) on symptoms and brain activity in FMS.ConclusionsThe study provides evidence that HBOT can improve the symptoms and life quality of FMS patients. Moreover, it shows that HBOT can induce neuroplasticity and significantly rectify abnormal brain activity in pain related areas of FMS patients.
Trial Registration
ClinicalTrials.gov NCT01827683相似文献56.
Elad Asher Haim Reuveni Nir Shlomo Yariv Gerber Roy Beigel Michael Narodetski Michael Eldar Jacob Or Hanoch Hod Arie Shamiss Shlomi Matetzky 《PloS one》2015,10(1)
Aims
The aim of this study was to compare in patients presenting with acute chest pain the clinical outcomes and cost-effectiveness of an accelerated diagnostic protocol utilizing contemporary technology in a chest pain unit versus routine care in an internal medicine department.Methods and Results
Hospital and 90-day course were prospectively studied in 585 consecutive low-moderate risk acute chest pain patients, of whom 304 were investigated in a designated chest pain center using a pre-specified accelerated diagnostic protocol, while 281 underwent routine care in an internal medicine ward. Hospitalization was longer in the routine care compared with the accelerated diagnostic protocol group (p<0.001). During hospitalization, 298 accelerated diagnostic protocol patients (98%) vs. 57 (20%) routine care patients underwent non-invasive testing, (p<0.001). Throughout the 90-day follow-up, diagnostic imaging testing was performed in 125 (44%) and 26 (9%) patients in the routine care and accelerated diagnostic protocol patients, respectively (p<0.001). Ultimately, most patients in both groups had non-invasive imaging testing. Accelerated diagnostic protocol patients compared with those receiving routine care was associated with a lower incidence of readmissions for chest pain [8 (3%) vs. 24 (9%), p<0.01], and acute coronary syndromes [1 (0.3%) vs. 9 (3.2%), p<0.01], during the follow-up period. The accelerated diagnostic protocol remained a predictor of lower acute coronary syndromes and readmissions after propensity score analysis [OR = 0.28 (CI 95% 0.14–0.59)]. Cost per patient was similar in both groups [($2510 vs. $2703 for the accelerated diagnostic protocol and routine care group, respectively, (p = 0.9)].Conclusion
An accelerated diagnostic protocol is clinically superior and as cost effective as routine in acute chest pain patients, and may save time and resources. 相似文献57.
58.
Adi Wolfson Aviad Atyya Christina Dlugy Dorith Tavor 《Bioprocess and biosystems engineering》2010,33(3):363-366
Glycerol triacetate was successfully used as a green solvent and as the acyl donor in the transesterification of isoamyl alcohol
to produce isoamyl acetate using free and immobilized Candida antarctica lipase B. Immobilized lipase was more catalytically active than free lipase and could be easily separated from the reaction
mixture by filtration. In addition, it was found that increasing either the reaction temperature or the enzyme to substrate
ratio increased the conversion of isoamyl alcohol. Using triacetin as the solvent also enabled the separation of product by
simple extraction with petroleum ether and catalyst recycling. 相似文献
59.
The digitalis-like steroid hormones: new mechanisms of action and biological significance 总被引:3,自引:0,他引:3
Digitalis-like compounds (DLC) are a family of steroid hormones synthesized in and released from the adrenal gland. DLC, the structure of which resembles that of plant cardiac glycosides, bind to and inhibit the activity of the ubiquitous cell surface enzyme Na(+), K(+)-ATPase. However, there is a large body of evidence suggesting that the regulation of ion transport by Na(+), K(+)-ATPase is not the only physiological role of DLC. The binding of DLC to Na(+), K(+)-ATPase induces the activation of various signal transduction cascades that activate changes in intracellular Ca(++) homeostasis, and in specific gene expression. These, in turn, stimulate endocytosis and affect cell growth and proliferation. At the systemic level, DLC were shown to be involved in the regulation of major physiological parameters including water and salt homeostasis, cardiac contractility and rhythm, systemic blood pressure and behavior. Furthermore, the DLC system has been implicated in several pathological conditions, including cardiac arrhythmias, hypertension, cancer and depressive disorders. This review evaluates the evidence for the different aspects of DLC action and delineates open questions in the field. 相似文献
60.
Michael Habeck Haim Haviv Adriana Katz Einat Kapri-Pardes Sophie Ayciriex Andrej Shevchenko Haruo Ogawa Chikashi Toyoshima Steven J. D. Karlish 《The Journal of biological chemistry》2015,290(8):4829-4842
The activity of membrane proteins such as Na,K-ATPase depends strongly on the surrounding lipid environment. Interactions can be annular, depending on the physical properties of the membrane, or specific with lipids bound in pockets between transmembrane domains. This paper describes three specific lipid-protein interactions using purified recombinant Na,K-ATPase. (a) Thermal stability of the Na,K-ATPase depends crucially on a specific interaction with 18:0/18:1 phosphatidylserine (1-stearoyl-2-oleoyl-sn-glycero-3-phospho-l-serine; SOPS) and cholesterol, which strongly amplifies stabilization. We show here that cholesterol associates with SOPS, FXYD1, and the α subunit between trans-membrane segments αTM8 and -10 to stabilize the protein. (b) Polyunsaturated neutral lipids stimulate Na,K-ATPase turnover by >60%. A screen of the lipid specificity showed that 18:0/20:4 and 18:0/22:6 phosphatidylethanolamine (PE) are the optimal phospholipids for this effect. (c) Saturated phosphatidylcholine and sphingomyelin, but not saturated phosphatidylserine or PE, inhibit Na,K-ATPase activity by 70–80%. This effect depends strongly on the presence of cholesterol. Analysis of the Na,K-ATPase activity and E1-E2 conformational transitions reveals the kinetic mechanisms of these effects. Both stimulatory and inhibitory lipids poise the conformational equilibrium toward E2, but their detailed mechanisms of action are different. PE accelerates the rate of E1 → E2P but does not affect E2(2K)ATP → E13NaATP, whereas sphingomyelin inhibits the rate of E2(2K)ATP → E13NaATP, with very little effect on E1 → E2P. We discuss these lipid effects in relation to recent crystal structures of Na,K-ATPase and propose that there are three separate sites for the specific lipid interactions, with potential physiological roles to regulate activity and stability of the pump. 相似文献