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.     

Agro-Waste Generated Pd/CAP-Ash Catalyzed Ligand-Free Approach for Suzuki–Miyaura Coupling Reaction

Catalysis Letters - We converted agro-waste Custard Apple Peels (CAP) to ash via thermal treatment, on which Pd(OAc)2 was immobilized easily that produced a low-cost, highly efficient Pd/CAP-ash...     

Dual effect synergistically triggered Ce:(Y,Tb)3(Al,Mn)5O12 transparent ceramics enabling a high color-rendering index and excellent thermal stability for white LEDs

Ce:Y₃Al₅O₁₂ transparent ceramics (TCs) with appropriate emission light proportion and high thermal stability are significant to construct white light emitting diode devices with excellent chromaticity parameters. In this work, strategies of controlling crystal-field splitting around Ce³⁺ ion and doping orange-red emitting ion, were adopted to fabricate Ce:(Y,Tb)₃(Al,Mn)₅O₁₂ TCs via vacuum sintering technique. Notably, 85.4 % of the room-temperature luminescence intensity of the TC was retained at 150 °C, and the color rendering index was as high as 79.8. Furthermore, a 12 nm red shift and a 16.2 % increase of full width at half maximum were achieved owing to the synergistic effects of Tb³⁺ and Mn²⁺ ions. By combining TCs with a 460 nm blue chip, a warm white light with a low correlated color temperature of 4155 K was acquired. Meanwhile, the action mechanism of Tb³⁺ ion and the energy transfer between Ce³⁺ and Mn²⁺ ions were verified in prepared TCs.     

深共融溶剂催化制备二酯类化合物

二酯类化合物广泛应用于有机中间体、药物、增塑剂、香料等领域,开发其绿色、高效的合成新方法具有重要意义.报道了以二元羧酸(或二羧酸酐)和脂肪醇为原料,以深共融溶剂(DESs)为催化剂催化合成二酯类化合物.以n(氯化胆碱):n(对甲苯磺酸)=1:2为催化剂,产率最高可达95％,并且DESs使用8次后产率仍保持在88％以上.运用1HNMR和13CNMR对产物进行了结构表征.该方法具有操作简单、产率高、易分离和催化剂可循环使用等优点.     

Biodegradable Polymeric Nanoparticles Containing an Immune Checkpoint Inhibitor (aPDL1) to Locally Induce Immune Responses in the Central Nervous System

Immunotherapy is an efficient approach to clinical oncology. However, the immune privilege of the central nervous system (CNS) limits the application of immunotherapeutic strategies for brain cancers, especially glioblastoma (GBM). Tumor resistance to immune checkpoint inhibitors is a further challenge in immunotherapies. To overcome the immunological tolerance of brain tumors, a novel multifunctional nanoparticle (NP) for highly efficient synergetic immunotherapy is reported. The NP contains an anti-PDL1 antibody (aPDL1), upconverting NPs, and the photosensitizer 5-ALA; the surface of the NP is conjugated with the B1R kinin ligand to facilitate transport across the blood-tumor-barrier. Upon irradiation with a 980 nm laser, 5-ALA is transformed into protoporphyrin IX, generating reactive oxygen species. Photodynamic therapy (PDT) further promotes intratumoral infiltration of cytotoxic T lymphocytes and sensitizes tumors to PDL1 blockade therapy. It is demonstrated that combining PDT and aPDL1 can effectively suppress GBM growth in mouse models. The proposed NPs provide a novel and effective strategy for boosting anti-GBM photoimmunotherapy.     

Inhibition of RANKL-Induced Osteoclastogenesis by Novel Mutant RANKL

Background: Recently, it was reported that leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4, also called GPR48) is another receptor for RANKL and was shown to compete with RANK to bind RANKL and suppress canonical RANK signaling during osteoclast differentiation. The critical role of the protein triad RANK–RANKL in osteoclastogenesis has made their binding an important target for the development of drugs against osteoporosis. In this study, point-mutations were introduced in the RANKL protein based on the crystal structure of the RANKL complex and its counterpart receptor RANK, and we investigated whether LGR4 signaling in the absence of the RANK signal could lead to the inhibition of osteoclastogenesis.; Methods: The effects of point-mutated RANKL (mRANKL-MT) on osteoclastogenesis were assessed by tartrate-resistant acid phosphatase (TRAP), resorption pit formation, quantitative real-time polymerase chain reaction (qPCR), western blot, NFATc1 nuclear translocation, micro-CT and histomorphological assay in wild type RANKL (mRANKL-WT)-induced in vitro and in vivo experimental mice model. Results: As a proof of concept, treatment with the mutant RANKL led to the stimulation of GSK-3β phosphorylation, as well as the inhibition of NFATc1 translocation, mRNA expression of TRAP and OSCAR, TRAP activity, and bone resorption, in RANKL-induced mouse models; and Conclusions: The results of our study demonstrate that the mutant RANKL can be used as a therapeutic agent for osteoporosis by inhibiting RANKL-induced osteoclastogenesis via comparative inhibition of RANKL. Moreover, the mutant RANKL was found to lack the toxic side effects of most osteoporosis treatments.     

A novel approach for bulk micromachining of 4H-SiC by tool-based electrolytic plasma etching in HF-free aqueous solution

Bulk micromachining of single-crystal SiC has been challenging due to its extreme stability both mechanically and chemically. To address this issue, a novel tool-based electrolytic plasma etching method is proposed, with which micropatterns and micro-holes are fabricated in SiC in a hydrofluoric acid-free aqueous solution with no need for masks. The material removal is the result of the combined effects of electrolytic plasma chemistry and physics. The chemistry refers to the reaction of Si with hydroxyl radical to form various SiO_x and with H to form silanes, and the reactions of C to form volatile carbon oxides or hydrocarbons, all of which are accomplished and enhanced under the electrolytic plasma atmosphere. Besides, the local high temperature of plasma thermally promotes the evaporation or dissolution of SiO₂ in NaOH solution. The tool-based electrolytic plasma etching method provides alternative approaches for the fabrication of SiC-based MEMS and devices.     

Phase,domain, and microstructures in Sr2+ substituted low-temperature sintering PZT-based relaxor ferroelectrics

The Ag-Pd internal electrode of multilayer piezoelectric ceramics needs to be sintered below 1000°C, and lead wires and components need to be welded with lead-free solder at 260°C. PNN–PMW–PZT–xSr piezoelectric ceramics with high Curie temperature (T_c > 260°C) were synthesized at a low sintering temperature (960°C) to meet the requirements of multilayer piezoelectric devices. The relationship between structures (phase, domain, and microstructures) and electrical properties (piezo/ferroelectric properties, and dielectric relaxation) in the Sr²⁺ substituted ceramics was investigated. Rietveld refinement and Raman spectra show that Sr²⁺ substitution can cause the phase change and increase the force constant of [BO₆] octahedron. The piezoelectric response increases with increasing the content of the tetragonal phase (CTP) in the rhombohedral-tetragonal (R-T) coexisted ceramics. The ceramics with 0.6 mol% Sr²⁺ substitution have minimum activation energy for domain wall movement (E_a) of 0.0362 eV which favors the formation of nanometer-sized domains, and possess excellent electrical properties (d₃₃ = 623 pC/N, d₃₃^* =783 pm/V, T_c =295°C). The higher the CTP, the lower the E_a. The lower E_a favors the rotation of polarization direction and extension, and is beneficial to the generation of the nanometer-size domains, resulting in high piezoelectric properties.     

超大型塔器整体两侧直线度检测

在传统检测手段无法满足越来越趋向大型化、超大型化的塔器整体两侧直线度的过程检测和控制保障背景下,打破传统思维,大胆创新检测手段,自行设计开发出超大型塔器整体两侧直线度检测整套技术,充分解决超大型塔器整体两侧直线度的检测难题.     

Turbulent boundary layer control with a spanwise array of DBD plasma actuators

The turbulent boundary layer control on NACA 0012 airfoil with Mach number ranging from 0.3 to 0.5 by a spanwise array of dielectric barrier discharge(DBD)plasma actuators by hot-film sensor technology is investigated.Due to temperature change mainly caused through heat produced along with plasma will lead to measurement error of shear stress measured by hot-film sensor,the correction method that takes account of the change measured by another sensor is used and works well.In order to achieve the value of shear stress change,we combine computational fluid dynamics computation with experiment to calibrate the hot-film sensor.To test the stability of the hot-film sensor,seven repeated measurements of shear stress at Ma = 0.3 are conducted and show that confidence interval of hot-film sensor measurement is from-0.18 to 0.18 Pa and the root mean square is 0.11 Pa giving a relative error 0.5％over all Mach numbers in this experiment.The research on the turbulent boundary layer control with DBD plasma actuators demonstrates that the control makes shear stress increase by about 6％over the three Mach numbers,which is thought to be reliable through comparing it with the relative error 0.5％,and the value is hardly affected by burst frequency and excitation voltage.