Systematic errors and combination of individual CRF solutions in the framework of the international pilot project for the next ICRF

A new international Pilot Project for the re-determination of the ICRF was initiated by the International VLBI Service for Geodesy and Astrometry (IVS) in January 2005. The purpose of this project is to compare the individual CRF solutions and to analyze their systematic and random errors with focus on the selection of the optimal strategy for the next ICRF realization. Eight radio source catalogues provided by the IVS Analysis Centers GA, SHAO, DGFI, GIUB-BKG, JPL, MAO NANU, GSFC, USNO were analyzed. In present study, four analytical models were used to investigate the systematic differences between solutions: solid rotation, rotation and deformation (IERS method), and expansion in orthogonal functions: Legendre-Fourier polynomials and spherical functions. It was found that expansions by orthogonal function describe the differences between individual catalogues better than the two former models. Finally, the combined CRF was generated. Using the radio source positions from this combined catalogue for estimation of EOP has shown improvement of the uncertainty of the celestial pole offset time series.Comment: 9 pages, 8 figures. Presented at the XXVIth IAU General Assembly, JD16, Prague, Czech Republic, 14-25 August 200

REGULATORY FRAMEWORK FOR A RISK-BASED APPROACH IN THE ENTERPRISE MANAGEMENT SYSTEM

This article is based on the analysis of regulatory and methodological documentation in the field of risk-based approach, presented in the form of a pyramid. The article also provides a description of the main management systems, reflecting the application of a particular standard in a specific area, which will facilitate the understanding of the essence of risk and a risk-based approach.Данная статья основана на анализе нормативной и методической документации в области риск-ориентированного подхода, представленном в виде пирамиды. Также в статье приведено описание основных систем менеджмента, отражающее применение того или иного стандарта в конкретной области, которые облегчат понимание сути риска и риск-ориентированного подхода

Plasmalogen enrichment in exosomes secreted by a nematode parasite versus those derived from its mouse host: implications for exosome stability and biology

Extracellular vesicles (EVs) mediate communication between cells and organisms across all 3 kingdoms of life. Several reports have demonstrated that EVs can transfer molecules between phylogenetically diverse species and can be used by parasites to alter the properties of the host environment. Whilst the concept of vesicle secretion and uptake is broad reaching, the molecular composition of these complexes is expected to be diverse based on the physiology and environmental niche of different organisms. Exosomes are one class of EVs originally defined based on their endocytic origin, as these derive from multivesicular bodies that then fuse with the plasma membrane releasing them into the extracellular environment. The term exosome has also been used to describe any small EVs recovered by high-speed ultracentrifugation, irrespective of origin since this is not always well characterized. Here, we use comparative global lipidomic analysis to examine the composition of EVs, which we term exosomes, that are secreted by the gastrointestinal nematode, Heligmosomoides polygyrus, in relation to exosomes secreted by cells of its murine host. Ultra-performance liquid chromatography – tandem mass spectrometry (UPLC-MS/MS) analysis reveals a 9- to 62-fold enrichment of plasmalogens, as well as other classes of ether glycerophospholipids, along with a relative lack of cholesterol and sphingomyelin (SM) in the nematode exosomes compared with those secreted by murine cells. Biophysical analyses of the membrane dynamics of these exosomes demonstrate increased rigidity in those from the nematode, and parallel studies with synthetic vesicles support a role of plasmalogens in stabilizing the membrane structure. These results suggest that nematodes can maintain exosome membrane structure and integrity through increased plasmalogens, compensating for diminished levels of other lipids, including cholesterol and SM. This work also illuminates the prevalence of plasmalogens in some EVs, which has not been widely reported and could have implications for the biochemical or immunomodulatory properties of EVs. Further comparative analyses such as those described here will shed light on diversity in the molecular properties of EVs that enable them to function in cross-species communication

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Human cardiac potassium channel DNA polymorphism modulates access to drug-binding site and causes drug resistance

Expression of voltage-gated K(+) channel, shaker-related subfamily, member 5 (KCNA5) underlies the human atrial ultra-rapid delayed rectifier K(+) current (I(Kur)). The KCNA5 polymorphism resulting in P532L in the C terminus generates I(Kur) that is indistinguishable from wild type at baseline but strikingly resistant to drug block. In the present study, truncating the C terminus of KCNA5 generated a channel with wild-type drug sensitivity, which indicated that P532 is not a drug-binding site. Secondary structure prediction algorithms identified a probable α-helix in P532L that is absent in wild-type channels. We therefore assessed drug sensitivity of I(Kur) generated in vitro in CHO and HEK cells by channels predicted to exhibit or lack this C-terminal α-helix. All constructs displayed near-identical I(Kur) in the absence of drug challenge. However, those predicted to lack the C-terminal α-helix generated quinidine-sensitive currents (43–51% block by 10 μM quinidine), while the currents generated by those constructs predicted to generate a C-terminal α-helix were inhibited less than 12%. Circular dichroism spectroscopy revealed an α-helical signature with peptides derived from drug-resistant channels and no organized structure in those associated with wild-type drug sensitivity. In conclusion, we found that this secondary structure in the KCNA5 C terminus, absent in wild-type channels but generated by a naturally occurring DNA polymorphism, does not alter baseline currents but renders the channel drug resistant. Our data support a model in which this structure impairs access of the drug to a pore-binding site

Modulation of Kv2.1 channel gating and TEA sensitivity by distinct domains of SNAP-25

Distinct domains within the SNARE (soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptor) proteins, STX1A (syntaxin 1A) and SNAP-25 (synaptosome-associated protein-25 kDa), regulate hormone secretion by their actions on the cell's exocytotic machinery, as well as voltage-gated Ca(2+) and K(+) channels. We examined the action of distinct domains within SNAP-25 on Kv2.1 (voltage gated K(+) 2.1) channel gating. Dialysis of N-terminal SNAP-25 domains, S197 (SNAP-25(1–197)) and S180 (SNAP-25(1–180)), but not S206 (full-length SNAP-25(1–206)) increased the rate of Kv2.1 channel activation and slowed channel inactivation. Remarkably, these N-terminal SNAP-25 domains, acting on the Kv2.1 cytoplasmic N-terminus, potentiated the external TEA (tetraethylammonium)-mediated block of Kv2.1. To further examine whether these are effects of the channel pore domain, internal K(+) was replaced with Na(+) and external K(+) was decreased from 4 to 1 mM, which decreased the IC(50) of the TEA block from 6.8±0.9 mM to >100 mM. Under these conditions S180 completely restored TEA sensitivity (7.9±1.5 mM). SNAP-25 C-terminal domains, SNAP-25(198–206) and SNAP-25(181–197), had no effect on Kv2.1 gating kinetics. We conclude that different domains within SNAP-25 can form distinct complexes with Kv2.1 to execute a fine allosteric regulation of channel gating and the architecture of the outer pore structure in order to modulate cell excitability