Distinct Pharmacological Properties of Gaseous CO and CO-Releasing Molecule in Human Platelets

Carbon monoxide (CO)—gaseous or released by CO-RMs—both possess antiplatelet properties; however, it remains uncertain whether the mechanisms involved are the same. Here, we characterise the involvement of soluble guanylate cyclase (sGC) in the effects of CO—delivered by gaseous CO–saturated buffer (CO_G) and generated by CORM-A1—on platelet aggregation and energy metabolism, as well as on vasodilatation in aorta, using light transmission aggregometry, Seahorse XFe technique, and wire myography, respectively. ODQ completely prevented the inhibitory effect of CO_G on platelet aggregation, but did not modify antiplatelet effect of CORM-A1. In turn, CO_G did not affect, whereas CORM-A1 substantially inhibited energy metabolism in platelets. Even though activation of sGC by BAY 41-2272 or BAY 58-2667 inhibited significantly platelet aggregation, their effects on energy metabolism in platelets were absent or weak and could not contribute to antiplatelet effects of sGC activation. In contrast, vasodilatation of murine aortic rings, induced either by CO_G or CORM-A1, was dependent on sGC. We conclude that the source (CO_G vs. CORM-A1) and kinetics (rapid vs. slow) of CO delivery represent key determinants of the mechanism of antiplatelet action of CO, involving either impairment of energy metabolism or activation of sGG.     

Topology optimization of flexure hinges with a prescribed compliance matrix based on the adaptive spring model and stress constraint

This paper focuses on the configuration design of flexure hinges with a prescribed compliance matrix and preset rotational center position. A new method for the topology optimization of flexure hinges is proposed based on the adaptive spring model and stress constraint. The hinge optimization model is formulated by maximizing the bending displacement with a spring while optimizing the compliance matrix to a prescribed value. To avoid numerical instability, an artificial spring is used as an auxiliary calculation, and a new strategy is developed for adaptively adjusting the spring stiffness according to the prescribed compliance matrix. The maximum stress of flexure hinge is limited by using a normalized P-norm of the effective von Mises stress, and a position constraint of rotational center is proposed to predetermine the position of the rotational center. In addition, to reduce the error of the stress measurement, a simple but effective filtering method is presented to obtain a complete black-and-white design. Numerical examples are used to verify the proposed method. Topology results show that the obtained flexure hinges have the prescribed compliance matrix and preset rotational center position while also meeting the stress requirements.     

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.     

The Age-Sensitive Efficacy of Calorie Restriction on Mitochondrial Biogenesis and mtDNA Damage in Rat Liver

Calorie restriction (CR) is the most efficacious treatment to delay the onset of age-related changes such as mitochondrial dysfunction. However, the sensitivity of mitochondrial markers to CR and the age-related boundaries of CR efficacy are not fully elucidated. We used liver samples from ad libitum-fed (AL) rats divided in: 18-month-old (AL-18), 28-month-old (AL-28), and 32-month-old (AL-32) groups, and from CR-treated (CR) 28-month-old (CR-28) and 32-month-old (CR-32) counterparts to assay the effect of CR on several mitochondrial markers. The age-related decreases in citrate synthase activity, in TFAM, MFN2, and DRP1 protein amounts and in the mtDNA content in the AL-28 group were prevented in CR-28 counterparts. Accordingly, CR reduced oxidative mtDNA damage assessed through the incidence of oxidized purines at specific mtDNA regions in CR-28 animals. These findings support the anti-aging effect of CR up to 28 months. Conversely, the protein amounts of LonP1, Cyt c, OGG1, and APE1 and the 4.8 Kb mtDNA deletion content were not affected in CR-28 rats. The absence of significant differences between the AL-32 values and the CR-32 counterparts suggests an age-related boundary of CR efficacy at this age. However, this only partially curtails the CR benefits in counteracting the generalized aging decline and the related mitochondrial involvement.     

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。     

车门铰链系统与车门下沉刚度的相关性

针对某型车门下沉问题,通过台架试验获得车门、铰链和车身等各单因素下沉量和车门绞链系统整体下沉量,对单因素下沉量与系统整体下沉刚度进行线性拟合分析,得到车门铰链系统各单因素与系统下沉刚度的相关度排序.对前、后车门分别选取相关度较高的单因素进行优化,最终改进方案的仿真和试验结果证明该方案可有效地提升车门下沉刚度.采用定量分析法可快速找出影响下沉刚度的敏感因素,并能够快速生成优化方案,为新车型设计提供参考.     

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.     

Achieving excellent energy storage density of Pb0.97La0.02(ZrxSn0.05Ti0.95-x)O3 ceramics by the B-site modification

The applications of antiferroelectric (AFE) materials in miniaturized and integrated electronic devices are limited by their low energy density. To address the above issue, the antiferroelectricity of the reinforced material was designed to improve its AFE-ferroelectric (FE) phase transition under electric fields. In this present study, the composition of Zr⁴⁺ (0.72 Å) and Ti⁴⁺ (0.605 Å) at B-site of Pb_0.97La_0.02(Zr_xSn_0.05Ti_0.95-x)O₃ ceramics with orthogonal reflections are synthesized via the tape-casting method. These ceramics are modified to enhance their antiferroelectricity by reducing their tolerance factor. A recoverable energy storage density W_rec 12.1 J/cm³ was obtained for x = 0.93 under 376 kV/cm, which is superior value than reported until now in lead-based energy storage systems. Moreover, the discharge energy density can reach 10.23 J/cm³, and 90 % of which can be released within 5.66 μs. This work provides a new window and potential materials for further industrialization of pulse power capacitors.     

Targeted editing of intronic-splicing silencer enhancement of SMN2 Exon 7 inclusion by CRISPR/Case 9

Spinal muscular atrophy (SMA) is an autosomal recessive hereditary neuromuscular disease. Exon 7 and 8 of survival of motor neuron 1 (SMN1) gene or only exon 7 homology deletion leads to the failure to produce a full-length SMN gene. The copy number of SMN2 gene with high homology of SMN1 affects the degree of disease and was the target gene for targeting therapy, in which splicing silencer in intron 7 was the key to suppress the inclusion of exon 7. In this study, we projected to use CRISPR/Case 9 for the targeted editing of intronic-splicing silencer (ISS) sequence to promote the inclusion of SMN2 exon 7 and increase the production of SMN2 full-length (FL) gene expression. It happens that there was a protospacer adjacent motif (PAM) at one end of the ISS sequence according to the design of sgRNA. The recombinant vector of sgRNA HSMN2 CRISPR/Case 9 was constructed and transfected into HEK293 cells. Sequencing results showed that the ISS sequence could be edited accurately and targeting in the predicted direction, in which deleting small fragments, inserting small amounts and mutation. Quantitative analysis of RT-PCR products by restriction enzyme of DdeI digestion showed that the FL of SMN2 increased by 8% (P < 0.05). In the primary cultured chondrocytes of SMA mice, in which sgRNA HSMN2 CRISPR/Case9 recombinant vector transfection could increase the SMN2 FL gene by 23% (P < 0.05) and significantly improve SMN protein levels (P < 0.05). CRISPR/Case 9 is an effective tool for gene editing and therapy of hereditary diseases, but it is rarely reported in the treatment of SMA diseases. This study shows that CRISPR/Case 9 was first used for the precision target of ISS sequence editing, which can effectively promote the production of SMN2 FL gene expressions, in which there was an important clinical reference value.     

Sustainable optimization of waste management network over extended planning time horizon

This study proposes a multiperiod mixed integer linear programming model for the management of a single municipal solid waste (MSW) treatment plant with sustainability as the objective. Discrete and continuous variables define the capacity selections for diverse MSW technologies, and the operation of the MSW network, respectively. The economic target is considered to maximize the net present value. The environmental impact is the minimization of a normalized environmental objective function (NEOF). The social target is the maximization of jobs. An interesting feature about the research work is the requirement of biodrying technologies for MSW moisture content control. Due to the conflicted nature among the sustainability components, a multiobjective optimization (MO) is carried out to find the Pareto optimal solutions. The MO results show that the Pareto optimal solutions vary around profit range of $4.9–8.5 billion, NEOF impact range of 3.2–3.6 units, and social benefit range of 2700–4828 jobs.