Stereoselective pharmacokinetics of ketamine and norketamine after racemic ketamine or S-ketamine administration during isoflurane anaesthesia in Shetland ponies

Background The arterial pharmacokinetics of ketamine and norketamine enantiomers after racemic ketamine or S-ketamine i.v. administration were evaluated in seven gelding ponies in a crossover study (2-month interval). Methods Anaesthesia was induced with isoflurane in oxygen via a face-mask and then maintained at each pony's individual MAC. Racemic ketamine (2.2mgkg−1) or S-ketamine (1.1mgkg−1) was injected in the right jugular vein. Blood samples were collected from the right carotid artery before and at 1, 2, 4, 8, 16, 32, 64, and 128min after ketamine administration. Ketamine and norketamine enantiomer plasma concentrations were determined by capillary electrophoresis. Individual R-ketamine and S-ketamine concentration vs time curves were analysed by non-linear least square regression two-compartment model analysis using PCNonlin. Plasma disposition curves for R-norketamine and S-norketamine were described by estimating AUC, Cmax, and Tmax. Pulse rate (PR), respiratory rate (Rf), tidal volume (VT), minute volume ventilation (VE), end-tidal partial pressure of carbon dioxide (Pe′CO2), and mean arterial blood pressure (MAP) were also evaluated. Results The pharmacokinetic parameters of S- and R-ketamine administered in the racemic mixture or S-ketamine administered separately did not differ significantly. Statistically significant higher AUC and Cmax were found for S-norketamine compared with R-norketamine in the racemic group. Overall, Rf, VE, Pe′CO2, and MAP were significantly higher in the racemic group, whereas PR was higher in the S-ketamine group. Conclusions Norketamine enantiomers showed different pharmacokinetic profiles after single i.v. administration of racemic ketamine in ponies anaesthetised with isoflurane in oxygen (1 MAC). Cardiopulmonary variables require further investigatio

Evaluating Conversational Recommender Systems via User Simulation

Conversational information access is an emerging research area. Currently, human evaluation is used for end-to-end system evaluation, which is both very time and resource intensive at scale, and thus becomes a bottleneck of progress. As an alternative, we propose automated evaluation by means of simulating users. Our user simulator aims to generate responses that a real human would give by considering both individual preferences and the general flow of interaction with the system. We evaluate our simulation approach on an item recommendation task by comparing three existing conversational recommender systems. We show that preference modeling and task-specific interaction models both contribute to more realistic simulations, and can help achieve high correlation between automatic evaluation measures and manual human assessments.Comment: Proceedings of the 26th ACM SIGKDD Conference on Knowledge Discovery and Data Mining (KDD '20), 202

On the functional use of the membrane compartmentalized pool of ATP by the Na+ and Ca++ pumps in human red blood cell ghosts

Previous evidence established that a sequestered form of adenosine triphosphate (ATP pools) resides in the membrane/cytoskeletal complex of red cell porous ghosts. Here, we further characterize the roles these ATP pools can perform in the operation of the membrane's Na+ and Ca2+ pumps. The formation of the Na+- and Ca2+-dependent phosphointermediates of both types of pumps (ENa-P and ECa-P) that conventionally can be labeled with trace amounts of [γ-3P]ATP cannot occur when the pools contain unlabeled ATP, presumably because of dilution of the [γ-3P]ATP in the pool. Running the pumps forward with either Na+ or Ca2+ removes pool ATP and allows the normal formation of labeled ENa-P or ECa-P, indicating that both types of pumps can share the same pools of ATP. We also show that the halftime for loading the pools with bulk ATP is 10–15 minutes. We observed that when unlabeled “caged ATP” is entrapped in the membrane pools, it is inactive until nascent ATP is photoreleased, thereby blocking the labeled formation of ENa-P. We also demonstrate that ATP generated by the membrane-bound pyruvate kinase fills the membrane pools. Other results show that pool ATP alone, like bulk ATP, can promote the binding of ouabain to the membrane. In addition, we found that pool ATP alone functions together with bulk Na+ (without Mg2+) to release prebound ouabain. Curiously, ouabain was found to block bulk ATP from entering the pools. Finally, we show, with red cell inside-outside vesicles, that pool ATP alone supports the uptake of 45Ca by the Ca2+ pump, analogous to the Na+ pump uptake of 22Na in this circumstance. Although the membrane locus of the ATP pools within the membrane/cytoskeletal complex is unknown, it appears that pool ATP functions as the proximate energy source for the Na+ and Ca2+ pumps

Lithium Depletion in Pre-Mainsequence Solar-Like Stars

We examine the internal structure of solar-like stars in detail between 0.8 and 1.4M Sun and during pre-main sequence phase. Recent opacity computations of OPAL along with a new hydrodynamical mixing process have been considered. We also introduce up-to-date nuclear reaction rates and explore the impact of accretion, mixing-length parameter, non-solar distributions among metals and realistic rotation history. We compare models predictions of lithium depletion to the $^7Li$ content observations of the Sun and to 4 young clusters of different metallicities and ages. We show that we can distinguish two phases in lithium depletion: 1- a rapid nuclear destruction in the T-Tauri phase before 20 Myrs : this is independent of the mass used within our range but largely dependent on the extension and temperature of the convective zone, 2- a second phase where the destruction is slow and moderate and which is largely dependent on the (magneto)hydrodynamic instability located at the base of the convective zone. In terms of composition, we show the interest on considering helium and especially the mixture of heavy elements : carbon, oxygen, silicium and iron. We outline the importance of O/Fe ratio. We note a reasonable agreement on lithium depletion for the two best known cases, the Sun and the Hyades cluster for solar-like stars. Other clusters suggest that processes which may partly inhibit the predicted premainsequence depletion cannot be excluded, in particular for stars below ~ 0.9M Sun. Finally we suggest different research areas such as initial stellar models and more realistic atmospheres which could contribute to a better understanding of this early phase of evolution and which should become the object of subsequent research.Comment: Astrophysical Journal, in pres

Identification of Extracellular Segments by Mass Spectrometry Improves Topology Prediction of Transmembrane Proteins

Transmembrane proteins play crucial role in signaling, ion transport, nutrient uptake, as well as in maintaining the dynamic equilibrium between the internal and external environment of cells. Despite their important biological functions and abundance, less than 2% of all determined structures are transmembrane proteins. Given the persisting technical difficulties associated with high resolution structure determination of transmembrane proteins, additional methods, including computational and experimental techniques remain vital in promoting our understanding of their topologies, 3D structures, functions and interactions. Here we report a method for the high-throughput determination of extracellular segments of transmembrane proteins based on the identification of surface labeled and biotin captured peptide fragments by LC/MS/MS. We show that reliable identification of extracellular protein segments increases the accuracy and reliability of existing topology prediction algorithms. Using the experimental topology data as constraints, our improved prediction tool provides accurate and reliable topology models for hundreds of human transmembrane proteins

Lithium abundances and extra mixing processes in evolved stars of M67

Aims. We present a spectroscopic analysis of a sample of evolved stars in M67 (turn-off, subgiant and giant stars) in order to bring observational constraints to evolutionary models taking into account non-standard transport processes. Methods. We determined the stellar parameters (Teff, log g, [Fe/H]), microturbulent and rotational velocities and, Lithium abundances (ALi) for 27 evolved stars of M67 with the spectral synthesis method based on MARCS model atmospheres. We also computed non-standard stellar evolution models, taking into account atomic diffusion and rotation-induced transport of angular momentum and chemicals that were compared with this set of homogeneous data. Results. The lithium abundances that we derive for the 27 stars in our sample follow a clear evolutionary pattern ranging from the turn-off to the Red Giant Branch. Our abundance determination confirms the well known decrease of lithium content for evolved stars. For the first time, we provide a consistent interpretation of both the surface rotation velocity and of the lithium abundance patterns observed in an homogeneous sample of TO and evolved stars of M67. We show that the lithium evolution is determined by the evolution of the angular momentum through rotation-induced mixing in low-mass stars, in particular for those with initial masses larger than 1.30 M_\odot at solar metallicity.Comment: 13 pages, 8 figure