Prediction of Chameleonic Efficiency

Chameleonic properties, i. e., the capacity of a molecule to hide polarity in non-polar environments and expose it in water, help achieving sufficient permeability and solubility for drug molecules with high MW. We present models of experimental measures of polarity for a set of 24 FDA approved drugs (MW 405-1113) and one PROTAC (MW 1034). Conformational ensembles in aqueous and non-polar environments were generated using molecular dynamics. A linear regression model that predicts chromatographic apparent polarity (EPSA) with a mean unsigned error of 10 Ų was derived based on separate terms for donor, acceptor, and total molecular SASA. A good correlation (R²=0.92) with an experimental measure of hydrogen bond donor potential, Δlog P_oct-tol, was found for the mean hydrogen bond donor SASA of the conformational ensemble scaled with Abraham's A hydrogen bond acidity. Two quantitative measures of chameleonic behaviour, the chameleonic efficiency indices, are introduced. We envision that the methods presented herein will be useful to triage designed molecules and prioritize those with the best chance of achieving acceptable permeability and solubility.     

Simulation of the submerged energy nozzle-mold water model system using laser-optical and computational fluid dynamics methods

The present work describes quantitative digital particle image velocimetry measurements of a full-scale water model of a thin slab mold. Different casting speeds and two submerged entry nozzles with one and two outlet ports have been investigated. The flow pattern of the single-port nozzle shows a counterclockwise-rotating double vortex that is nearly steady-state but leads to high stationary surface waves. The flow jets out of the two-port nozzle oscillate and produce a transient flow pattern with low wave amplitudes. The amplitudes for the one-port nozzle show a linear variation with the volumetric flow rate. The experimental results lead to a good interpretation of the flow phenomena and are used to validate steady-state numerical simulations with the commercial program, CFX, on the basis of the Reynolds equations. To describe anisotropic turbulence effects, the Reynolds stress model (RSM) is used for the flat single-port nozzle and the standard k-ɛ model for the mold flow. The calculated mean velocities and wave amplitudes, predicted from pressure distribution at the water surface, are generally in the consensus of the experimental data. An erratum to this article is available at .     

Three-dimensional MHD high-resolution computations with CWENO employing adaptive mesh refinement

Until recently, numerical simulations of discontinuities in highly super-Alfvénic plasmas have been severely limited by comparatively crude resolution and accuracy. Significant progress in the numerical simulation of such plasmas was achieved with the recently implemented Central Weighted Essentially Non-Oscillatory (CWENO) scheme. Combining this technique with that of adaptive mesh refinement (AMR), we have developed a third-order numerical scheme, which is able to efficiently capture strong gradients on spatial scales being small compared to the overall scale of the plasma system considered. Here, we first describe important algorithmic aspects of the scheme as well as the physics included in it. Second, we present the results of various performance tests. And, third, we illustrate its application to ‘real world problems’ using the example of the dynamics of a Sedov-type explosion.     

Apolipoprotein A, fibrinogen, age, and history of stroke are predictors of death in dialysed diabetic patients: a prospective study in 412 subjects

BACKGROUND: Diabetic patients with end-stage renal failure (ESRD) have a high cardiovascular morbidity and mortality. The underlying mechanisms are not completely elucidated. The aim of our study was to define predictors of death in diabetic patients with end-stage renal disease. PATIENTS AND METHODS: We performed a prospective study in 35 dialysis centres in Germany between 1985 and 1994. To evaluate predictors and risk factors in this population we examined 412 diabetic patients at the time of admission to dialysis treatment (peritoneal dialysis (PD) or haemodialysis (HD)). Classification of the type of diabetes was done according the criteria of the National Diabetes Data Group [1,2]. Items assessed at the time of admission were coronary artery disease (CAD), peripheral occlusive disease (POD), and stroke. CAD was defined as a history of myocardial infarction with the corresponding changes in the ECG or luminal narrowing by more than 50% in at least one coronary artery upon coronarangiography; POD was defined as claudication and/or brachial-tibial ratio (BTR) less than 0.9 or a history of amputation. Assessment of the nutritional state comprised body mass index, skinfold thickness of the upper arm and lateral thorax area, and urea concentration. Cholesterol, HDL, LDL, apolipoprotein A (ApoA-I) and B (ApoB), triglycerides, lipoprotein(a) (Lp(a)), and fibrinogen were measured. As an index of disturbed cardiac innervation beat-to-beat variation was measured. Outcome measurements were causes of death (i.e. cardiac and non-cardiac) and time of survival. RESULTS: One hundred and eighty of 412 (44%) patients died during the observation period. Patients who died were older (61 +/- 12 versus 53 +/- 15 years P < 0.0001), had lower skin fold thickness (13.1 +/- 6.0 versus 15.1 +/- 7.3 mm P < 0.04), lower ApoA-I (100 +/- 35 versus 111 +/- 32 mg/dl P < 0.005) and higher fibrinogen (515 +/- 146 versus 451 +/- 155 mg/dl P < 0.02). Type II diabetic patients had a lower mean survival time than type I (34 versus 66 months P < 0.0006). The mode of renal replacement therapy (PD or HD) had no adverse effect on survival time. Survivors less frequently had a history of CAD, POD and stroke than non-survivors. In multivariate analysis ApoA-I, fibrinogen, age and stroke were independent predictors of cardiac and non-cardiac death in diabetic patients with end-stage renal failure. Lipid values and nutritional state did not independently predict the overall and cardiovascular mortality. CONCLUSION: This study in dialysed diabetic patients identifies several predictors of death, some of which are susceptible to intervention.     

Picosecond photodiffraction in semiconductor multiquantum wells and microcavities

We study the transient gratings photogenerated in the picosecond regime in three families of structures, namely : - structures of thickness in the order of one micron, including quantum wells (GaAs/GaAlAs, CdTe/ CdZnTe). A transmission modulation due to the electric field has been observed. We show that, in accordance with our calculations, this modulation is screened faster than 10 ps at a fluence of a few µJ/cm2. - A structure including GalnAs/GalnAsP MQWS in a cavity. This structure shows a top diffraction efficiency of 2.5 × 10-² at 1.55 µm for an energy of excitation in the order of 100 µJ/cm2. The diffraction efficiency exhibits several oscillations due to Fabry-Pårot effects. By introducing cavity effects in our model, we show that the diffraction efficiency is amplified by more than a factor 2 with respect to the no-cavity case. Calculations show that the diffraction efficiency may reach 6 × 10-² around 1.625 µm, for a front mirror reflectivity of 90 %. - Structures including bulk GaAs microcavities. The risetime is lower or in the order of 1 ps while the diffraction efficiency attains 1 %, with an average power of 4 mW (i.e. an energy of 2 µJ/cm²/pulse), compatible with a commutation of packets at 80 MHz.