The histone deacetylase inhibitor cambinol prevents acidic pHe-induced anterograde lysosome trafficking independently of sirtuin activity

AbstractCommon features of the solid tumor microenvironment, such as acidic extracellular pH and growth factors, are known to induce the redistribution of lysosomes from a perinuclear region to a position near the plasma membrane. Lysosome/plasma membrane juxtaposition facilitates invasion by allowing for the release of lysosomal proteases, including cathepsin B, which contribute to matrix degradation. In this study we identified the sirtuin 1/sirtuin 2 (SIRT1/2) inhibitor cambinol acts as a drug that inhibits lysosome redistribution and tumor invasion. Treatment of cells with cambinol resulted in a juxtanuclear lysosome aggregation (JLA) similar to that seen upon treatment with the PPARγ agonist, troglitazone (Tro). Like Tro, cambinol required the activity of ERK1/2 in order to induce this lysosome clustering phenotype. However, cambinol did not require the activity of Rab7, suggesting that this drug causes JLA by a mechanism different from what is known for Tro. Additionally, cambinol-induced JLA was not a result of autophagy induction. Further investigation revealed that cambinol triggered JLA independently of its activity as a SIRT1/2 inhibitor, suggesting that this drug could have effects in addition to SIRT1/2 inhibition that could be developed into a novel anti-cancer therapy

Implementation, evaluation, and recommendations for extension of AHRQ Common Formats to capture patient- and carepartner-generated safety data

Abstract Objectives The Common Formats, published by the Agency for Healthcare Research and Quality, represent a standard for safety event reporting used by Patient Safety Organizations (PSOs). We evaluated its ability to capture patient-reported safety events. Materials and methods We formally evaluated gaps between the Common Formats and a safety concern reporting system for use by patients and their carepartners (ie friends/families) at Brigham and Women’s Hospital. Results Overall, we found large gaps between Common Formats (versions 1.2, 2.0) and our patient/carepartner reporting system, with only 22–30% of the data elements matching. Discussion We recommend extensions to the Common Formats, including concepts that capture greater detail about the submitter and safety categories relevant to unsafe conditions and near misses that patients and carepartners routinely observe. Conclusion Extensions to the Common Formats could enable more complete safety data sets and greater understanding of safety from key stakeholder perspectives, especially patients, and carepartners. </jats:sec

Dynamics of the circulation in the Sea of Marmara: numerical modeling experiments and observations from the Turkish straits system experiment

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Safety and efficacy of fluticasone propionate in the topical treatment of skin diseases

Fluticasone propionate - the first carbothioate corticosteroid - has been classified as a potent anti-inflammatory drug for dermatological use. It is available as 0.05% cream and 0.005% ointment formulations for the acute and maintenance treatment of patients with dermatological disorders such as atopic dermatitis, psoriasis and vitiligo. This glucocorticoid is characterized by high lipophilicity, high glucocorticoid receptor binding and activation, and a rapid metabolic turnover in skin. Although skin blanching following fluticasone propionate exceeds that of corticosteroids of medium strength, several clinical trials demonstrate a low potential for cutaneous and systemic side-effects, even in difficult-to-treat areas like the face, the eyelids and intertriginous areas. Even among paediatric patients with atopic dermatitis, fluticasone propionate proved to be safe and effective. These pharmacological and clinical properties are reflected by the high therapeutic index of this glucocorticoid

Decoding the absolute stoichiometric composition and structural plasticity of α-carboxysomes

Carboxysomes are anabolic bacterial microcompartments that play an essential role in carbon fixation in cyanobacteria and some chemoautotrophs. This self-assembling organelle encapsulates the key CO 2 -fixing enzymes, Rubisco, and carbonic anhydrase using a polyhedral protein shell that is constructed by hundreds of shell protein paralogs. The α-carboxysome from the chemoautotroph Halothiobacillus neapolitanus serves as a model system in fundamental studies and synthetic engineering of carboxysomes. Here we adopt a QconCAT-based quantitative mass spectrometry to determine the absolute stoichiometric composition of native α-carboxysomes from H. neapolitanus . We further performed an in-depth comparison of the protein stoichiometry of native and recombinant α-carboxysomes heterologously generated in Escherichia coli to evaluate the structural variability and remodeling of α-carboxysomes. Our results provide insight into the molecular principles that mediate carboxysome assembly, which may aid in rational design and reprogramming of carboxysomes in new contexts for biotechnological applications

Ecologically Valid Carbohydrate Intake during Soccer-Specific Exercise Does Not Affect Running Performance in a Fed State.

This study assessed the effect of carbohydrate intake on self-selected soccer-specific running performance. Sixteen male soccer players (age 23 ± 4 years; body mass 76.9 ± 7.2 kg; predicted VO2max = 54.2 ± 2.9 mL∙kg-1∙min-1; soccer experience 13 ± 4 years) completed a progressive multistage fitness test, familiarisation trial and two experimental trials, involving a modified version of the Loughborough Intermittent Shuttle Test (LIST) to simulate a soccer match in a fed state. Subjects completed six 15 min blocks (two halves of 45 min) of intermittent shuttle running, with a 15-min half-time. Blocks 3 and 6, allowed self-selection of running speeds and sprint times, were assessed throughout. Subjects consumed 250 mL of either a 12% carbohydrate solution (CHO) or a non-caloric taste matched placebo (PLA) before and at half-time of the LIST. Sprint times were not different between trials (CHO 2.71 ± 0.15 s, PLA 2.70 ± 0.14 s; p = 0.202). Total distance covered in self-selected blocks (block 3: CHO 2.07 ± 0.06 km; PLA 2.09 ± 0.08 km; block 6: CHO 2.04 ± 0.09 km; PLA 2.06 ± 0.08 km; p = 0.122) was not different between trials. There was no difference between trials for distance covered (p ≥ 0.297) or mean speed (p ≥ 0.172) for jogging or cruising. Blood glucose concentration was greater (p < 0.001) at the end of half-time during the CHO trial. In conclusion, consumption of 250 mL of 12% CHO solution before and at half-time of a simulated soccer match does not affect self-selected running or sprint performance in a fed state

The US Navy coupled ocean-wave prediction system

A new coupled ocean-wave model has been developed and tested as a new component of the Coupled Ocean/Atmosphere Mesoscale Prediction System (COAMPS(circle)). The modeling system is comprised of the Simulating WAves Nearshore (SWAN) wave model and the Navy Coastal Ocean Model (NCOM). The models are two-way coupled using the Earth System Modeling Framework (ESMF). The ocean model has been modified to incorporate the effect of the Stokes drift current, wave radiation stresses due to horizontal gradients of the momentum flux of surface waves, enhancement of bottom drag in shallow water, and enhanced vertical mixing due to Langmuir turbulence. The wave model ingests surface currents (wave-current interaction) and water levels. The system is designed to support the Navy's ocean forecast requirements for regional and coastal domains. Validation studies for the Florida Straits and Virginia coastal area are presented. The system will run at the Naval Oceanographic Office and at the Fleet Numerical Meteorology and Oceanography Center