18 research outputs found
Identification of Novel BACE-1 Inhibitors through an Advanced Structure-Based Virtual Screening Protocol.
No full textAn Advanced Multiple Receptor Conformations Virtual Ligand Screening Protocol for the Identification of Novel BACE-1 Inhibitors
No full textDevelopment and Application of a Virtual Screening Protocol for the Identification of Multitarget Fragments
No full textIn this study, we report on a virtual ligand screening protocol optimized to identify fragments endowed with activity at multiple targets. Thanks to this protocol, we were able to identify a fragment that displays activity in the low-micromolar range at both β-secretase 1 (BACE-1) and glycogen synthase kinase 3β (GSK-3β). These two structurally and physiologically unrelated enzymes likely contribute, through different pathways, to the onset of Alzheimer′s disease (AD). Therefore, their simultaneous inhibition holds great potential in exerting a profound effect on AD. In perspective, the strategy outlined herein can be adapted to other target combinations.</p
Cooling Crystallization in an Oscillatory Flow Baffled Crystallizer (OFBC): Influence of Fluid Dynamics on Crystal Product
No full textThe Oscillatory Flow Baffled Crystallizer (OFBC) design has been proven to offer improved temperature control and near plug plow residence time distributions, while at the same time providing large residence times. These OFBC properties hold the promise of resulting in a narrow crystal size distribution, reduced residence time requirements and improved process control. However to obtain such results the operation of the OFBC along with the crystallization process should be optimized. One of the most important operational aspects to optimize is the local turbulence that results in setting the dispersion in the crystallizer to a minimum, without compromising on the mass and heat transfer processes. In this study the residence time distribution of a tracer resulting from various possible operating configurations (amplitude and frequency) in the OFBC is analyzed, for water flows with a net flow Reynolds number of 140 (flowrate 100 ml/min) using dye tracing with an in situ transmission dip probe (absorption spectrophotometry). The best combinations of frequency and amplitude at which narrowest distribution (least dispersion) of the tracer concentration profile is achieved are found to be 1 Hz and 1 mm, 2 Hz and 3.5 mm and 4 Hz and 1 mm. The experimental results show that the ratio of the oscillatory Reynolds number and the net flow Reynolds number should be between 0.7 and 5. This is a broader range than the reported 2 to 4 range in literature. The measured residence time distributions for the best oscillatory setting have been successfully fitted to a tanks-in-series model with a 3 % maximum error of the coefficient of determination. It can therefore be concluded that the number of tanks in series is an accurate characteristic parameter of the fluid dynamics. The assumption of ideal plug flow, which is shown to not resemble the real RTD well, can therefore be avoided when developing the model for crystallization in an OFBC. The results of a parameter sensitivity study, based on the developed model, shows that the final seed CSD is weakly related to secondary nucleation for the used kinetic parameters. This can be explained as the small mass of the nucleated crystals does not have a large effect on the supersaturation. Furthermore, the final seed CSD has a dependence on all varied parameters but mostly to the initial seed loading. This is logical as double the initial seed loading will consume double or more amount of solute and therefore slow down the growth rate significantly. Secondary nucleation is very sensitive to the supersaturation profile (with the used kinetics) and so to the imposed temperature profile and the seed loading. The degree of plug flow has very little effect on secondary nucleation because the supersaturation profile is hardly influenced upon variation. A temperature profile optimization showed that in order to minimize secondary nucleation using a five zone temperature control, both a constant zone temperature and a linear zone temperature approach could lower the secondary nucleation by a factor of 2 compared to a single linear zone temperature approach. This underlines the importance of optimization in the OFBC.Intensified Reaction and Seperation SystemProcess & EnergyMechanical, Maritime and Materials Engineerin
Nucleation Control: Microwave, Ultrasound and Laser as Tools to Control the Number of Nuclei in Crystallization Processes
No full textThe principal objective of the research focuses on the intensification of the batch and continuous crystallization processes through enhanced nucleation control, proper plug flow conditions in continuous tubular crystallizers and development of advanced image analysis based PAT tool for process monitoring. Nucleation control is addressed through manipulation of the number of crystals in the crystallizer; by either controlling the rate of nuclei formation or through dissolution of the excess nuclei to limit the nucleation overshoot or through continuous seeding in case of flow crystallizer to suppress nucleation in the tubes. The following topics are addressed: 1. The efficiency of the Direct Nucleation Control(DNC) strategy using microwave heating.2. Induction of high nucleation rates at low supersaturation by the application of laser or ultrasound energy. 3. Combination of the ultrasound assisted internal seed generation in the continuous tubular crystallizer, under plug flow conditions. 4. Characterization of nucleation and the crystal properties through development of in-situ imaging based PAT technology. <br/
Novel Design Integrating a Microwave Applicator into a Crystallizer for Rapid Temperature Cycling. A Direct Nucleation Control Study
No full textThe control of nucleation in crystallization processes is a challenging task due to the often lacking knowledge on the process kinetics. Inflexible (predetermined) control strategies fail to grow the nucleated crystals to the desired quality because of the variability in the process conditions, disturbances, and the stochastic nature of crystal nucleation. Previously, the concept of microwave assisted direct nucleation control (DNC) was demonstrated in a laboratory setup to control the crystal size distribution in a batch crystallization process by manipulating the number of particles in the system. Rapid temperature cycling was used to manipulate the super(under)saturation and hence the number of crystals. The rapid heating response achieved with the microwave heating improved the DNC control efficiency, resulting in halving of the batch time. As an extension, this work presents a novel design in which the microwave applicator is integrated in the crystallizer, hence avoiding the external loop though the microwaves oven. DNC implemented in the 4 L unseeded crystallizer, at various count set points, resulted in strong efficiency enhancement of DNC, when compared to the performance with a slow responding system. The demonstrated crystallizer design is a basis for extending the enhanced process control opportunity to other applications.</p
Understanding Non-Photochemical Laser Induced Nucleation
No full textNucleation is the initial step for the creation of new crystalline phase. A precise control over nucleation and its kinetics is important for both research and industries. Thus, alternative methods are sought after to extend the toolbox for controlling nucleation. In the 1990's, Non-Photochemical Laser Induced Nucleation (NPLIN) was suggested as a promising method to alter the nucleation kinetics. Since then, several reports have demonstrated that NPLIN dramatically reduces the nucleation induction time and controls polymorphism of various fine chemicals relevant for industrial practice. Although different hypotheses have been proposed in literature to explain the experimental observations, the mechanism behind NPLIN is still unknown.The objective of this work is to extend the mechanistic understanding of NPLIN. This has been approached by qualitatively studying the effect of different factors on the nucleation efficiency of the non-photochemical process using unfocused pulsed laser in aqueous supersaturated solution of KCl. The factors investigated include wavelength, peak intensity, supersaturation, mixing, and impurity level of the solution. Each of these parameters are studied using high number of samples (80-100) to generate a robust set of results and to avoid the stochastic nature of nucleation.In a separate series of experiments, an acoustic wave was detected in the solution due to the non-linear interaction of the unfocused laser with the system by measuring the pressure signal with a piezo-electric transducer placed just below the air-liquid interface. Further experiments were executed to understand the nature of the acoustic wave and its influence on NPLIN. The results show that laser could induce nucleation at significantly low peak intensities, much below the previously reported intensity threshold in literature. It is also observed that NPLIN shows a strong dependence on peak intensity, supersaturation, impurity level, and mixing of the solution while the dependence on wavelength was found to be weak. Furthermore, the acoustic wave experiments show that the laser induced pressure fluctuations do not affect the nucleation efficiency of the process. Overall, the results suggest that several mechanisms play a role during laser induced nucleation. To summarize, the research provides a robust analysis of different factors that can influence NPLIN. The results can be further utilized to enhance the understanding and applicability of the process
Multiparameter Investigation of laser-induced nucleation of supersaturated aqueous KCl solutions
No full textVarious mechanisms have been proposed to explain the nonphotochemical laser-induced nucleation (NPLIN). Identifying the dominant mechanism requires addressing a large set of experimental parameters with a statistically significant number of samples, forced by the stochastic nature of nucleation. In this study, with aqueous KCl system, we focus on the nucleation probability as a function of laser wavelength, laser intensity, and sample supersaturation, whereas the influence of filtration and the laser-induced radiation pressure on NPLIN activity is also studied. To account for the nucleation stochasticity, we used 80-100 samples. The NPLIN probability showed an increase with increasing laser intensity. The results are different from the previous report, as a supersaturation independent intensity threshold is not observed. No dependence of the NPLIN probability on the laser wavelength (355, 532, and 1064 nm) was observed. Filtration of samples reduced the nucleation probability suggesting a pronounced role of impurities on NPLIN. The magnitude and the propagation velocity of the laser-induced radiation pressure were quantified using a pressure sensor under laser intensities ranging from 0.5 to 80 MW/cm2. No correlation was found between the radiation pressure and NPLIN at our unfocused laser beam intensities ruling out the radiation pressure as a possible cause for nucleation.Green Open Access added to TU Delft Institutional Repository 'You share, we take care!' - Taverne project https://www.openaccess.nl/en/you-share-we-take-care Otherwise as indicated in the copyright section: the publisher is the copyright holder of this work and the author uses the Dutch legislation to make this work public.Intensified Reaction and Separation SystemsMicro and Nano Engineerin
Interethnic differences in the accuracy of anthropometric indicators of obesity in screening for high risk of coronary heart disease.
No full textBACKGROUND: Cut points for defining obesity have been derived from mortality data among Whites from Europe and the United States and their accuracy to screen for high risk of coronary heart disease (CHD) in other ethnic groups has been questioned. OBJECTIVE: To compare the accuracy and to define ethnic and gender-specific optimal cut points for body mass index (BMI), waist circumference (WC) and waist-to-hip ratio (WHR) when they are used in screening for high risk of CHD in the Latin-American and the US populations. METHODS: We estimated the accuracy and optimal cut points for BMI, WC and WHR to screen for CHD risk in Latin Americans (n=18 976), non-Hispanic Whites (Whites; n=8956), non-Hispanic Blacks (Blacks; n=5205) and Hispanics (n=5803). High risk of CHD was defined as a 10-year risk > or =20% (Framingham equation). The area under the receiver operator characteristic curve (AUC) and the misclassification-cost term were used to assess accuracy and to identify optimal cut points. RESULTS: WHR had the highest AUC in all ethnic groups (from 0.75 to 0.82) and BMI had the lowest (from 0.50 to 0.59). Optimal cut point for BMI was similar across ethnic/gender groups (27 kg/m(2)). In women, cut points for WC (94 cm) and WHR (0.91) were consistent by ethnicity. In men, cut points for WC and WHR varied significantly with ethnicity: from 91 cm in Latin Americans to 102 cm in Whites, and from 0.94 in Latin Americans to 0.99 in Hispanics, respectively. CONCLUSION: WHR is the most accurate anthropometric indicator to screen for high risk of CHD, whereas BMI is almost uninformative. The same BMI cut point should be used in all men and women. Unique cut points for WC and WHR should be used in all women, but ethnic-specific cut points seem warranted among men
