Computational Investigation Identified Potential Chemical Scaffolds for Heparanase as Anticancer Therapeutics

Heparanase (Hpse) is an endo-β-D-glucuronidase capable of cleaving heparan sulfate side chains. Its upregulated expression is implicated in tumor growth, metastasis and angiogenesis, thus making it an attractive target in cancer therapeutics. Currently, a few small molecule inhibitors have been reported to inhibit Hpse, with promising oral administration and pharmacokinetic (PK) properties. In the present study, a ligand-based pharmacophore model was generated from a dataset of well-known active small molecule Hpse inhibitors which were observed to display favorable PK properties. The compounds from the InterBioScreen database of natural (69,034) and synthetic (195,469) molecules were first filtered for their drug-likeness and the pharmacophore model was used to screen the drug-like database. The compounds acquired from screening were subjected to molecular docking with Heparanase, where two molecules used in pharmacophore generation were used as reference. From the docking analysis, 33 compounds displayed higher docking scores than the reference and favorable interactions with the catalytic residues. Complex interactions were further evaluated by molecular dynamics simulations to assess their stability over a period of 50 ns. Furthermore, the binding free energies of the 33 compounds revealed 2 natural and 2 synthetic compounds, with better binding affinities than reference molecules, and were, therefore, deemed as hits. The hit compounds presented from this in silico investigation could act as potent Heparanase inhibitors and further serve as lead scaffolds to develop compounds targeting Heparanase upregulation in cancer.     

基于卓越工程师教育的频率特性分析课堂教学研究

频率特性分析在工程应用中具有重要的作用,在电路分析、模拟电子技术、信号与系统、自动控制理论等相关课程中都涉及到相关章节内容,在不同课程中如何根据工程应用和学生学习阶段把握具体的讲解内容和讲解方式非常重要。本文从频率特性的求解方法和具体物理意义角度开展在不同课程中讲解的方法,从时域和频域角度分别讨论其物理意义和具体的分析方法。通过渐进深化的教学过程和教学方法不断提高学生的知识掌握和应用技能,提高学生的工程意识、工程素质和工程创新能力,强化学生对于频率特性课程知识的综合应用能力。     

Thermal desorption and pyrolysis direct analysis in real time mass spectrometry of Nafion membrane

Perfluorosulfonic acid ionomer membranes have been widely used as proton conducting membranes in various electrochemical processes such as polymer electrolyte fuel cells and water electrolysis. While their thermal stability has been studied by thermogravimetry and analysis of low molecular weight products, their decomposition mechanism is little understood. In this study a newly developed methodology of thermal desorption and pyrolysis in combination with direct analysis in real time mass spectrometry is applied for Nafion membrane. An ambient ionization source and a high-resolution time-of-flight mass spectrometer enabled unambiguous assignment of gaseous products. Thermal decomposition is initiated by side chain detachment above 350°C, which leaves carbonyls on the main chain at the locations of the side chains. Perfluoroalkanes are released above 400°C by main chain scission and their further decomposition products dominate above 500 °C. DFT calculation of reaction energies and barrier heights of model compounds support proposed decomposition reactions.     

An integrated dimensionality reduction and surrogate optimization approach for plant-wide chemical process operation

With liquefied natural gas becoming increasingly prevalent as a flexible source of energy, the design and optimization of industrial refrigeration cycles becomes even more important. In this article, we propose an integrated surrogate modeling and optimization framework to model and optimize the complex CryoMan Cascade refrigeration cycle. Dimensionality reduction techniques are used to reduce the large number of process decision variables which are subsequently supplied to an array of Gaussian processes, modeling both the process objective as well as feasibility constraints. Through iterative resampling of the rigorous model, this data-driven surrogate is continually refined and subsequently optimized. This approach was not only able to improve on the results of directly optimizing the process flow sheet but also located the set of optimal operating conditions in only 2 h as opposed to the original 3 weeks, facilitating its use in the operational optimization and enhanced process design of large-scale industrial chemical systems.     

In Silico Investigation of Potential Applications of Gamma Carbonic Anhydrases as Catalysts of CO2 Biomineralization Processes: A Visit to the Thermophilic Bacteria Persephonella hydrogeniphila,Persephonella marina,Thermosulfidibacter takaii,and Thermus thermophilus

Carbonic anhydrases (CAs) have been identified as ideal catalysts for CO₂ sequestration. Here, we report the sequence and structural analyses as well as the molecular dynamics (MD) simulations of four γ-CAs from thermophilic bacteria. Three of these, Persephonella marina, Persephonella hydrogeniphila, and Thermosulfidibacter takaii originate from hydrothermal vents and one, Thermus thermophilus HB8, from hot springs. Protein sequences were retrieved and aligned with previously characterized γ-CAs, revealing differences in the catalytic pocket residues. Further analysis of the structures following homology modeling revealed a hydrophobic patch in the catalytic pocket, presumed important for CO₂ binding. Monitoring of proton shuttling residue His69 (P. marina γ-CA numbering) during MD simulations of P. hydrogeniphila and P. marina’s γ-CAs (γ-PhCA and γ-PmCA), showed a different behavior to that observed in the γ-CA of Escherichia coli, which periodically coordinates Zn²⁺. This work also involved the search for hotspot residues that contribute to interface stability. Some of these residues were further identified as key in protein communication via betweenness centrality metric of dynamic residue network analysis. T. takaii’s γ-CA showed marginally lower thermostability compared to the other three γ-CA proteins with an increase in conformations visited at high temperatures being observed. Hydrogen bond analysis revealed important interactions, some unique and others common in all γ-CAs, which contribute to interface formation and thermostability. The seemingly thermostable γ-CA from T. thermophilus strangely showed increased unsynchronized residue motions at 423 K. γ-PhCA and γ-PmCA were, however, preliminarily considered suitable as prospective thermostable CO₂ sequestration agents.     

Optimization of PEMFC system operating conditions based on neural network and PSO to achieve the best system performance

PEMFC system is a complex new clean power system. Based on MATLAB/Simulink, this paper develops a system-level dynamic model of PEMFC, including the gas supply system, hydrogen supply system, hydrothermal management system, and electric stack. The neural network fits the electric stack model to the simulation data. The effects of different operating conditions on the PEMFC stack power and system efficiency are analyzed. Combining the power of the reactor and the system efficiency to define the integrated performance index, the particle swarm optimization (PSO) algorithm is introduced to optimize the power density and system efficiency of the PEMFC with multiple objectives. The final optimal operating point increases the power density and system efficiency by 1.33% and 12.8%, respectively, which maximizes the output performance and reduces the parasitic power.     

Optimization of flow in additively manufactured porous columns with graded permeability

Chemical engineering systems often involve a functional porous medium, such as in catalyzed reactive flows, fluid purifiers, and chromatographic separations. Ideally, the flow rates throughout the porous medium are uniform, and all portions of the medium contribute efficiently to its function. The permeability is a property of a porous medium that depends on pore geometry and relates flow rate to pressure drop. Additive manufacturing techniques raise the possibilities that permeability can be arbitrarily specified in three dimensions, and that a broader range of permeabilities can be achieved than by traditional manufacturing methods. Using numerical optimization methods, we show that designs with spatially varying permeability can achieve greater flow uniformity than designs with uniform permeability. We consider geometries involving hemispherical regions that distribute flow, as in many glass chromatography columns. By several measures, significant improvements in flow uniformity can be obtained by modifying permeability only near the inlet and outlet.     

PID Control of Planar Nonlinear Uncertain Systems in the Presence of Actuator Saturation

This paper investigates PID control design for a class of planar nonlinear uncertain systems in the presence of actuator saturation. Based on the bounds on the growth rates of the nonlinear uncertain function in the system model, the system is placed in a linear differential inclusion. Each vertex system of the linear differential inclusion is a linear system subject to actuator saturation. By placing the saturated PID control into a convex hull formed by the PID controller and an auxiliary linear feedback law, we establish conditions under which an ellipsoid is contractively invariant and hence is an estimate of the domain of attraction of the equilibrium point of the closed-loop system. The equilibrium point corresponds to the desired set point for the system output. Thus, the location of the equilibrium point and the size of the domain of attraction determine, respectively, the set point that the output can achieve and the range of initial conditions from which this set point can be reached. Based on these conditions, the feasible set points can be determined and the design of the PID control law that stabilizes the nonlinear uncertain system at a feasible set point with a large domain of attraction can then be formulated and solved as a constrained optimization problem with constraints in the form of linear matrix inequalities (LMIs). Application of the proposed design to a magnetic suspension system illustrates the design process and the performance of the resulting PID control law.      

Local scour at offshore windfarm monopile foundations: A review

In this article, current research findings of local scour at offshore windfarm monopile foundations are presented. The scour mechanisms and scour depth prediction formulas under different hydrodynamic conditions are summarized, including the current-only condition, wave-only condition, combined wave-current condition, and complex dynamic condition. Furthermore, this article analyzes the influencing factors on the basis of classical equations for predicting the equilibrium scour depth under specific conditions. The weakness of existing researches and future prospects are also discussed. It is suggested that future research shall focus on physical experiments under unsteady tidal currents or other complex loadings. The computational fluid dynamics-discrete element method and artificial intelligence technique are suggested being adopted to study the scour at offshore windfarm foundations.     

Domain reversal and current transport property in BiFeO3 films

The electrical properties and domain reversal in BiFeO₃ ferroelectric films were studied using sandwiched heterostructures and piezoresponse force microscopy. A robust polarization state was observed, combined with a switchable domain pattern and a remanent polarization of approximately 100 μC cm^?2. In addition, domain reversal was explored using scanning probe microscopy. The results show that dipoles could be reversed along the direction of the electric field under a negative tip bias, leading to carrier gathering near the domain walls. The enhanced conductivity near the domain walls was owing to the discontinuous polarization boundary conditions. In addition, typical diode-like current transport properties are sensitive to various temperature conditions, which is attributed to the Schottky barriers at the contact interface. These findings extend the current understanding of domain texture reversal in ferroelectric films and shed light on their potential applications for future ferroelectric random-access memory operations over a wide temperature range.