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941.
In 2005, the European Respiratory Society (ERS) launched a project to harmonise education and training and to address the heterogeneity of respiratory health training across Europe. Since then, various educational activities have been developed for different target audiences. This article will describe the overall methodology and the projects developed over the years, detailing their objectives and target audiences. Moving forward, ERS strives to provide a structure for the continuing professional development of respiratory physicians. 相似文献
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943.
Virulence‐targeted Antibacterials: Concept,Promise, and Susceptibility to Resistance Mechanisms
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Ségolène Ruer Nikos Pinotsis David Steadman Gabriel Waksman Han Remaut 《Chemical biology & drug design》2015,86(4):379-399
In view of the relentless increase in antibiotic resistance in human pathogens, efforts are needed to safeguard our future therapeutic options against infectious diseases. In addition to regulatory changes in our antibiotic use, this will have to include the development of new therapeutic compounds. One area that has received growing attention in recent years is the possibility to treat or prevent infections by targeting the virulence mechanisms that render bacteria pathogenic. Antivirulence targets include bacterial adherence, secretion of toxic effector molecules, bacterial persistence through biofilm formation, quorum sensing and immune evasion. Effective small‐molecule compounds have already been identified that suppress such processes. In this review, we discuss the susceptibility of such compounds to the development of resistance, by comparison with known resistance mechanisms observed for classical bacteriostatic or bacteriolytic antibiotics, and by review of available experimental case studies. Unfortunately, appearance of resistance mechanisms has already been demonstrated for some, showing that the quest of new, lasting drugs remains complicated. 相似文献
944.
Searching for Dual Inhibitors of the MDM2‐p53 and MDMX‐p53 Protein–Protein Interaction by a Scaffold‐Hopping Approach
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Andrey Zaytsev Barry Dodd Matteo Magnani Chiara Ghiron Bernard T. Golding Roger J. Griffin Junfeng Liu Xiaohong Lu Iolanda Micco David R. Newell Alessandro Padova Graeme Robertson John Lunec Ian R. Hardcastle 《Chemical biology & drug design》2015,86(2):180-189
Two libraries of substituted benzimidazoles were designed using a ‘scaffold‐hopping’ approach based on reported MDM2‐p53 inhibitors. Substituents were chosen following library enumeration and docking into an MDM2 X‐ray structure. Benzimidazole libraries were prepared using an efficient solution‐phase approach and screened for inhibition of the MDM2‐p53 and MDMX‐p53 protein–protein interactions. Key examples showed inhibitory activity against both targets. 相似文献
945.
Structure‐Based Design and Synthesis of a Small Molecule that Exhibits Anti‐inflammatory Activity by Inhibition of MyD88‐mediated Signaling to Bacterial Toxin Exposure
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Shahabuddin Alam Sacha Javor Melissa Degardin Dariush Ajami Mitra Rebek Teri L. Kissner David M. Waag Julius Rebek Jr Kamal U. Saikh 《Chemical biology & drug design》2015,86(2):200-209
Both Gram‐positive and Gram‐negative pathogens or pathogen‐derived components, such as staphylococcal enterotoxins (SEs) and endotoxin (LPS) exposure, activate MyD88‐mediated pro‐inflammatory cellular immunity for host defense. However, dysregulated MyD88‐mediated signaling triggers exaggerated immune response that often leads to toxic shock and death. Previously, we reported a small molecule compound 1 mimicking BB‐loop structure of MyD88 was capable of inhibiting pro‐inflammatory response to SEB exposure in mice. In this study, we designed a dimeric structure compound 4210 covalently linked with compound 1 by a non‐polar cyclohexane linker which strongly inhibited the production of pro‐inflammatory cytokines in human primary cells to SEB (IC50 1–50 μm ) or LPS extracted from Francisella tularensis, Escherichia coli, or Burkholderia mallei (IC50 10–200 μm ). Consistent with cytokine inhibition, in a ligand‐induced cell‐based reporter assay, compound 4210 inhibited Burkholderia mallei or LPS‐induced MyD88‐mediated NF‐kB‐dependent expression of reporter activity (IC50 10–30 μm ). Furthermore, results from a newly expressed MyD88 revealed that 4210 inhibited MyD88 dimer formation which is critical for pro‐inflammatory signaling. Importantly, a single administration of compound 4210 in mice showed complete protection from lethal toxin challenge. Collectively, these results demonstrated that compound 4210 inhibits toxin‐induced inflated pro‐inflammatory immune signaling, thus displays a potential bacterial toxin therapeutic. 相似文献
946.
《Asian Journal of Pharmaceutical Sciences》2015,10(4):292-305
Over the recent few decades, many groups of formulation scientists are concentrating on rapid release dosage forms in oral cavity. Among all fast release dosage forms, orodispersible films are successful to attract pharmaceutical industry due to ease of formulation and extension patent life. Films are popular in patients too because of quick onset and user friendliness of dosage form. From the beginning, solvent casting has been selected as method of choice for manufacturing of orodispersible films. Solvent casting has been proved as a benchmark technology because of ease in product development, process optimization, process validation and technology transfer to production scale despite of some drawbacks like more number of unit operations involved and consumption of large quantity of solvents with controlled limits of organic volatile impurities in final formulation. The application of hot-melt extrusion (HME) in the pharmaceutical industry is consecutively increasing due to its proven innumerable advantages like solvent free continuous process with fewer unit operations and better content uniformity. Very few development activities has been initiated in the field of hot melt extruded orodispersible films so far. This extensive review covers detailed discussion of heavy duty industrial extruders, selection of downstream equipments, selection of excipients, common problems found in formulations and their remedies. Successive part of review addresses identification of critical quality attributes, quality target profile of product, criticality in selection of process parameters and material for substantial simulation in laboratory scale and production for successful technology transfer. 相似文献
947.
948.
949.
Christopher N. Johnson Christophe Adelinet Valerio Berdini Lijs Beke Pascal Bonnet Dirk Brehmer Frederick Calo Joseph E. Coyle Phillip J. Day Martyn Frederickson Eddy J. E. Freyne Ron A. H. J. Gilissen Christopher C. F. Hamlett Steven Howard Lieven Meerpoel Laurence Mevellec Rachel McMenamin Elisabeth Pasquier Sahil Patel DavidC. Rees Joannes T. M. Linders 《ACS medicinal chemistry letters》2015,6(1):31-36
950.
Influence of Relative Displacement on Surface Roughness in Longitudinal Turning of X37CrMoV5-1 Steel
The shaping process of surface texture is complicated and depends on many factors and phenomena accompanying them. This article presents the author’s test stand for the measurement of relative displacements in a tool–workpiece system during longitudinal turning. The aim of this study was to determine the influence of edge radius on the relative displacement between the tool and workpiece. The cutting process was carried out with inserts with different edge radii for X37CrMoV5-1 steel. As a result of the research, vibration charts of the tool–workpiece system were obtained. In the range of feed 0.03–0.18 mm/rev, the values of the standard deviation of relative displacements in the x-axis were obtained in the range of 0.36–0.78 μm for the insert with an edge radius of rn = 48.8 μm. As a result of the work, it was determined that for the feed value of 0.12 mm/rev for all inserts, the relative displacements are the smallest. As the final effect, the formula for forecasting the Ra roughness parameter was presented. 相似文献