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.     

Blends of Bio-Based Poly(Limonene Carbonate) with Commodity Polymers

In this study, blends of the bio-based poly(limonene carbonate) (PLimC) with different commodity polymers are investigated in order to explore the potential of PLimC toward generating more sustainable polymer materials by reducing the amount of petro- or food-based polymers. PLimC is employed as minority component in the blends. Next to the morphology and thermal properties of the blends the impact of PLimC on the mechanical properties of the matrix polymers is studied. The interplay of incompatibility and zero-shear melt viscosity contrast determines the blend morphology, leading for all blends to a dispersed droplet morphology for PLimC. Blends with polymers of similar structure to PLimC (i.e., aliphatic/aromatic polyester) show the best performance with respect to mechanical properties, whereas blends with polystyrene or poly(methyl methacrylate) are too brittle and polyamide 12 blends show very low elongations at break. In blends with Ecoflex (poly(butylene adipate-co-terephthalate)) and Arnitel EM400 (copoly(ether ester)) with poly(butylene terephthalate) hard and polytetrahydrofuran soft segments) a threefold increase in E-modulus can be achieved, while keeping the elongation at break at reasonable high values of ≈200%, making these blends highly interesting for applications.     

Heteroalleles in Common Wheat: Multiple Differences between Allelic Variants of the Gli-B1 Locus

The Gli-B1-encoded γ-gliadins and non-coding γ-gliadin DNA sequences for 15 different alleles of common wheat have been compared using seven tests: electrophoretic mobility (EM) and molecular weight (MW) of the encoded major γ-gliadin, restriction fragment length polymorphism patterns (RFLPs) (three different markers), Gli-B1-γ-gliadin-pseudogene known SNP markers (Single nucleotide polymorphisms) and sequencing the pseudogene GAG56B. It was discovered that encoded γ-gliadins, with contrasting EM, had similar MWs. However, seven allelic variants (designated from I to VII) differed among them in the other six tests: I (alleles Gli-B1i, k, m, o), II (Gli-B1n, q, s), III (Gli-B1b), IV (Gli-B1e, f, g), V (Gli-B1h), VI (Gli-B1d) and VII (Gli-B1a). Allele Gli-B1c (variant VIII) was identical to the alleles from group IV in four of the tests. Some tests might show a fine difference between alleles belonging to the same variant. Our results attest in favor of the independent origin of at least seven variants at the Gli-B1 locus that might originate from deeply diverged genotypes of the donor(s) of the B genome in hexaploid wheat and therefore might be called “heteroallelic”. The donor’s particularities at the Gli-B1 locus might be conserved since that time and decisively contribute to the current high genetic diversity of common wheat.     

Effect of α-Lipoic Acid on the Development of Human Skin Equivalents Using a Pumpless Skin-on-a-Chip Model

Owing to the prohibition of cosmetic animal testing, various attempts have recently been made using skin-on-a-chip (SOC) technology as a replacement for animal testing. Previously, we reported the development of a pumpless SOC capable of drug testing with a simple drive using the principle that the medium flows along the channel by gravity when the chip is tilted using a microfluidic channel. In this study, using pumpless SOC, instead of drug testing at the single-cell level, we evaluated the efficacy of α-lipoic acid (ALA), which is known as an anti-aging substance in skin equivalents, for skin tissue and epidermal structure formation. The expression of proteins and changes in genotyping were compared and evaluated. Hematoxylin and eosin staining for histological analysis showed a difference in the activity of fibroblasts in the dermis layer with respect to the presence or absence of ALA. We observed that the epidermis layer became increasingly prominent as the culture period was extended by treatment with 10 μM ALA. The expression of epidermal structural proteins of filaggrin, involucrin, keratin 10, and collagen IV increased because of the effect of ALA. Changes in the epidermis layer were noticeable after the ALA treatment. As a result of aging, damage to the skin-barrier function and structural integrity is reduced, indicating that ALA has an anti-aging effect. We performed a gene analysis of filaggrin, involucrin, keratin 10, integrin, and collagen I genes in ALA-treated human skin equivalents, which indicated an increase in filaggrin gene expression after ALA treatment. These results indicate that pumpless SOC can be used as an in vitro skin model similar to human skin, protein and gene expression can be analyzed, and it can be used for functional drug tests of cosmetic materials in the future. This technology is expected to contribute to the development of skin disease models.     

高稳高效海上风电安装平台关键制造技术研究

海上风电作为可再生清洁能源之一,受到世界各国的高度重视与大力发展。我国将海上风电提升至解决能源危机、减缓气候变化、调整能源结构的国家战略高度,到2030年我国单位国内生产总值二氧化碳排放将比2005年下降65%以上,非化石能源占一次能源消费比重将达到25%左右。安装平台不足将是我国海上风电场无法如期建成投产的主要障碍。对自升自航式海上风电安装平台系列高端装备及其设计制造的三大技术难题——腿站立作业易“失稳”、大平台大跨距大倾覆力矩自升易“失控”、高空吊装巨型叶片逾百螺栓精准定位易“失准”,以及焊缝缺陷修复和局部裂纹损伤的激光锻造修复再制造进行了介绍,研制的具有不同规格的系列装备在中国、英国、丹麦、德国等国家的著名海上风电场建设应用情况良好。     

药物相互作用研究在新药研发和审评决策中的应用

药物相互作用改变了剂量效应关系，可能会降低疗效或增加毒性，是临床应用中合并用药治疗时重要的考虑因素。预测具有临床意义的药物相互作用是药物研发过程中获益风险评估的重要环节。本文概述了药物研发过程中药物相互作用研究的目的和意义，体内和体外研究的主要内容；梳理分析了2020年国家药品监督管理局（National Medical Products Administration, NMPA）和美国食品药品监督管理局（Food and Drug Administration, FDA）批准上市的新药药物相互作用研究情况，旨在为我国药物研发过程中药物相互作用研究及其监管审评提供参考。     

Agronomic performance of high oleic,low linolenic soybean in Tennessee

Soybean oil hydrogenation alters the linolenic acid molecule to prevent the oil from becoming rancid, however, health reports have indicated trans-fat caused by hydrogenation, is not generally regarded as safe. Typical soybeans contain approximately 80 g kg⁻¹ to 120 g kg⁻¹ linolenic acid and 240 g kg⁻¹ of oleic acid. In an effort to accommodate the need for high-quality oil, the United Soybean Board introduced an industry standard for a high oleic acid greater than 750 g kg⁻¹ and linolenic acid less than 30 g kg⁻¹ oil. By combing mutations in the soybean plant at four loci, FAD2-1A and FAD2-1B, oleate desaturase genes and FAD3A and FAD3C, linoleate desaturase genes, and seed oil will not require hydrogenation to prevent oxidation and produce high-quality oil. In 2017 and 2018, a study comparing four near-isogenic lines across multiple Tennessee locations was performed to identify agronomic traits associated with mutations in FAD3A and FAD3C loci, while holding FAD2-1A and FAD2-1B constant in the mutant (high oleic) state. Soybean lines were assessed for yield and oil quality based on mutations at FAD2-1 and FAD3 loci. Variations of wild-type and mutant genotypes were compared at FAD3A and FAD3C loci. Analysis using a generalized linear mixed model in SAS 9.4, indicated no yield drag or other negative agronomic traits associated with the high oleic and low linolenic acid genotype. All four mutations of fad2-1A, fad2-1B, fad3A, and fad3C were determined as necessary to produce a soybean with the new industry standard (>750 g kg⁻¹ oleic and <30 g kg⁻¹ linolenic acid) in a maturity group-IV-Late cultivar for Tennessee growers.     

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。     

Preparation and Evaluation of a Self-Nanoemulsifying Drug Delivery System Loaded with Heparin Phospholipid Complex

A self-nanoemulsifying drug delivery system (SNEDDS) was developed to enhance the absorption of heparin after oral administration, in which heparin was compounded with phospholipids to achieve better fat solubility in the form of heparin-phospholipid (HEP-Pc) complex. HEP-Pc complex was prepared using the solvent evaporation method, which increased the solubility of heparin in n-octanol. The successful preparation of HEP-Pc complex was confirmed by differential scanning calorimetry (DSC), Fourier-transform infrared (FT-IR) spectroscopy, NMR, and SEM. A heparin lipid microemulsion (HEP-LM) was prepared by high-pressure homogenization and characterized. HEP-LM can enhance the absorption of heparin after oral administration, significantly prolong activated partial thromboplastin time (APTT) and thrombin time (TT) in mice, and reduce fibrinogen (FIB) content. All these outcomes indicate that HEP-LM has great potential as an oral heparin formulation.