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.     

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.     

超临界机组发生FAC的因素及相互关系分析

为了减轻因流动加速腐蚀(FAC)引起的锅炉结垢加速、汽水系统管道厚度减小甚至爆裂现象，对超临界机组发生流动加速腐蚀的机理及其主要影响因素进行了研究，并讨论了管壁内表面粗糙度、蒸汽含汽率、pH值、溶氧量对FAC的影响，以及温度与pH值、温度与流速、pH值与溶解氧量、溶解氧量与氢电导率等影响因素之间的相互作用关系，最后结合实际电厂的运行数据验证了分析结果。研究表明：减小工质流速、管壁粗糙度和氢电导率，增大给水的pH值和溶解氧含量可以使FAC的腐蚀速率减小，超临界加氧处理时pH值应在8.9～9.2之间，溶解氧量范围为45～100μg/L,氢电导率的期望值在0.1μS/cm以下。由于各影响因素之间的作用十分复杂，本文只给出了大致范围和趋势，并未给出准确数据。     

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.     

Suckling behavior of calves in seasonally calving pasture-based dairy systems,and possible environmental and management factors affecting suckling behaviors

In recent years, interest has been increasing in whether farmed animals are able to live a reasonably natural life, with one particular area of concern being calf-dam separation. The objectives of this study were to monitor the timing and frequency of suckling behavior of calves left on pasture to suckle their dams for up to 24 h (interquartile range 4.0–15.5 h) and to investigate possible risk factors that may contribute to any variability seen. Over 2 yr, a convenience sample of 8 farms (4 in the North Island, 4 in the South Island of New Zealand) were involved in an observational study where cows and calves were observed for 24 h a day over a 2-wk-long period per farm. During the observation period, farmers continued to remove calves at the same frequency they normally did (which ranged from once a day to 4 times a day). Cows (between 2 and 12 yr old) and calves were observed from a scissor lift in or beside the calving paddock. Cows had numbers written on them, and observers used binoculars and spotlights. Observers recorded the length of stage 2 labor, time of birth, standing, and first suckling, number of suckling events, time of calf removal from the dam, temperature where the cows were grazing, and size of the grazing area they were calving in. Dams were body condition scored before calving, and their age was extracted from farm records. A total of 697 calves were observed during the study. A total of 444 of 697 calves [63.7%; 95% confidence interval (CI) = 60.0–67.3%] suckled in the calving paddock (farm range 40.0% to 90.2%). Of the 444 calves that suckled in the calving paddock, 407 (58.4%; 95% CI 54.6–62.1%) suckled within the first 6 h after birth (farm range 33.0% to 83.6%). Individual risk factors associated with the hazard rate ratio (HR) for time to first suckling event were time to standing (calves who took more than 1.3 h to stand had a longer time from birth to first suckle) and age of the dam [compared with calves that were born from dams >7 years of age, calves born to dams that were 2–3 and 4–7 yr of age had a 1.49 (95% CI 1.07–2.06) and 1.19 (95% CI 0.89–1.60) HR, respectively, for time from birth to first suckle in the calving paddock]. Farm risk factors associated with the HR of suckling were frequency of calf collection [calves that were born on farms that collected calves once a day suckled earlier than calves on farms that removed calves more than once a day (HR 1.52; 95% CI 1.25–1.84)] and temperature [a minimum temperature of <10°C within 6 h of a calf being born was associated with a 0.69 (95% CI 0.53–0.89) hazard of suckling in the calving paddock]. We observed very large farm variability that urgently requires further investigation if pasture-based farms are ever to adopt a system where calves remain with their dams for longer than 24 h.