Indoline derivatives II: synthesis and factor Xa (FXa) inhibitory activities

Factor Xa (FXa) is well known to play a pivotal role in blood coagulation, so FXa inhibitor is a promising drug candidate for prophylaxis and treatment of thromboembolic diseases. In the course of our research, we have found that (R)-5-[1-(acetimidoyl)piperidin-4-yloxy]-2-(7-amidinonaphthalen-2-yl)-1-(ethanesulfonyl)indoline ((R)-1) showed potent FXa inhibitory activity in vitro. However, single oral administation (RS)-1 showed high toxicity in mice. Among newly synthesized compounds, ({(RS)-5-[1-(acetimidoyl)piperidin-4-yloxy]-2-(7-amidinonaphthalen-2-yl)indolin-1-yl}sulfonyl)acetic acid ((RS)-11d) showed more potent FXa inhibitory activity and higher safety than (RS)-1. The R-isoform of compound 11d ((R)-11d) exhibited potent in vitro anticoagulant activity in human and hamster plasma. Orally administered (R)-11d also showed dose-dependent potent anticoagulant activity in hamsters, marmosets and cynomolgus monkeys. Compound (R)-11d with potent anticoagulant activity and high safety is therefore favorable as a novel oral FXa inhibitor.     

Testing the anomaly mediation at the LHC

We consider a supersymmetric model in which gaugino masses are generated by the anomaly-mediation mechanism while scalar masses are from tree-level supergravity interaction. In such a model, scalar fermions as well as Higgsinos become as heavy as O(10–100 TeV)$\mathrm{O}(10\text{–}100\text{TeV})$ and hence only the gauginos are superparticles kinematically accessible to the LHC. We study how and how well the properties of gauginos can be studied. We also discuss the strategy to test the anomaly-mediation model at the LHC.     

Flow recovery downstream from a surface protuberance

A single roughness element and the beginning/end of a roughness patch represent common surface protuberances. The flow recovers from disruptions caused by such protuberances either by returning to its original state or by approaching a new state downstream from a protuberance. Understanding of the recovery process is important in the determination of the sensitivity of the laminar–turbulent transition to surface protuberances. The beginning/end of a roughness patch has been modeled as a small-height channel expansion/contraction, while a rectangular protuberance has been used in the analysis of disruptions caused by a single roughness element. The recovery process has been studied using semi-analytical methods, direct numerical simulations as well as experiments. The size of the recovery zone has been measured using two types of criteria, one based on the properties of the stationary flow and the other one based on the characteristics of the linear instability. It has been found that the flow remains stationary without any unsteady separation at the subcritical Reynolds number Re =  5000 of interest. The effects of the step persist very far in the downstream direction; for the step height of 1 % of the channel half-height, the two-dimensional TS wave reaches asymptotic form at about 500 channels half-heights (50,000 step’s heights) downstream from the step. The length of the recovery zone is reduced by an order of magnitude if the channel returns to its upstream form downstream from the protuberance, as demonstrated through analysis of a single roughness element. Smoothing of the downstream side of the protuberance eliminates flow separation but does not affect the flow characteristics.     

Liver function assessment with three 13C breath tests by two-point measurements

In this study, we performed three breath tests – l-[1-¹³C ]phenylalanine breath test (PBT), l-[1-¹³C ] methionine breath test, and [¹³C]methacetin breath test (MethaBT) – in patients with chronic liver disease to determine the optimal timing of expired air collection for diagnosing chronic liver disease and evaluating the grade of fibrosis. The subjects were 61 adults with normal livers, 98 chronic hepatitis patients, and 91 liver cirrhosis patients. We investigated the relationships of breath test results with routine biochemical tests and the Child–Pugh score, as well as the diagnostic capacities of the breath tests for liver dysfunction/cirrhosis and grade of liver fibrosis. For the diagnosis of liver cirrhosis and correlations with liver fibrosis, the accuracy of the PBT at 30 min (PBT30) was similar to that of the MethaBT at 15 min (Metha15). For liver function assessment by two-point measurement with ¹³C breath tests, we recommend the PBT30 and the Metha15.     

Surface pressure and flow field behind an oscillating fence submerged in turbulent boundary layer

Phase-locked PSP and PIV measurements were used to study the evolution of three-dimensional disturbances produced by an oscillating fence actuator immersed in a zero pressure gradient turbulent boundary layer. For the single fence frequency studied, strong three-dimensionality is observed in the vortical structure that varies along the span of the fence soon after the fence enters the flow. At the midspan, the structure grows, weakens, and convects faster than at other locations. As the fence height increases, the data indicate that the vortical structure terminates near the edge of the fence. In contrast, the vortex structure terminates on the plate surface adjacent to the fence edge as the fence descends, similar to a wake vortex of a stationary obstacle. This study demonstrates that the combined use of surface and flow-field diagnostics provide a link between flow field and surface features, yielding an understanding of the flow that would have not been possible with any one technique.     

Synthesis and characterization of Pr<Superscript>3+</Superscript>-doped glass scintillators prepared by the sol–gel method

Transparent and crack-free Pr-doped silica glass scintillators were successfully synthesized using the sol–gel method. A peak found at 301 nm in the photoluminescence spectrum was ascribed to a radiative transition of the Pr³⁺ emission center. The associated excitation peak was located at 276 nm. The energy of the excitation peak (4.50 eV) was significantly lower than the energy gap (5.83 eV) of the ¹S₀ to ³H₄ f–f transition. Therefore, the f–f transition was excluded as the origin, and the transition was attributed to 5d–4f. In the absorption spectrum, several bands of the f–f transition were observed. Fourier transform infrared spectroscopy was employed to understand the microstructural features and OH group concentration in the Pr³⁺-doped silica glass. It was revealed that a Si–O network had been successfully formed, and that the OH group concentration decreased with increasing thermal treatment temperature reaching a saturation value for temperatures higher than 750 °C. The absence of praseodymium oxide nanocrystalline clusters was confirmed by transmission electron microscopy (TEM), even in the sample with the highest Pr ion concentration. Scintillation properties of the Pr³⁺-doped silica glass were also characterized. The scintillation decay time constants were estimated to be approximately 1.3 and 14 ns, which supports the assignment of the luminescence to the 5d–4f transition. The scintillation light yield of the Pr³⁺-doped silica glass was estimated to be approximately 130 photons/MeV.