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.     

AQP3 Increases Intercellular Cohesion in NSCLC A549 Cell Spheroids through Exploratory Cell Protrusions

Tumor cell aggregation is critical for cell survival following the loss of extracellular matrix attachment and dissemination. However, the underlying mechanotransduction of clustering solitary tumor cells is poorly understood, especially in non-small cell lung cancers (NSCLC). Here, we examined whether cell surface protrusions played an important role in facilitating the physical contact between floating cells detached from a substrate. We employed poly-2-hydroxyethyl methacrylate-based 3D culture methods to mimic in vivo tumor cell cluster formation. The suprastructural analysis of human NSCLC A549 cell spheroids showed that finger-like protrusions clung together via the actin cytoskeleton. Time-lapse holotomography demonstrated that the finger-like protrusions of free-floating cells in 3D culture displayed exploratory coalescence. Global gene expression analysis demonstrated that the genes in the organic hydroxyl transport were particularly enriched in the A549 cell spheroids. Particularly, the knockdown of the water channel aquaporin 3 gene (AQP3) impaired multicellular aggregate formation in 3D culture through the rearrangement of the actomyosin cytoskeleton. Moreover, the cells with reduced levels of AQP3 decreased their transmigration. Overall, these data indicate that cell detachment-upregulated AQP3 contributes to cell surface protrusions through actomyosin cytoskeleton remodeling, causing the aggressive aggregation of free-floating cells dependent on the property of the substratum and collective metastasis.     

Diphenyl-Methane Based Thyromimetic Inhibitors for Transthyretin Amyloidosis

Thyromimetics, whose physicochemical characteristics are analog to thyroid hormones (THs) and their derivatives, are promising candidates as novel therapeutics for neurodegenerative and metabolic pathologies. In particular, sobetirome (GC-1), one of the initial halogen-free thyromimetics, and newly synthesized IS25 and TG68, with optimized ADME-Tox profile, have recently attracted attention owing to their superior therapeutic benefits, selectivity, and enhanced permeability. Here, we further explored the functional capabilities of these thyromimetics to inhibit transthyretin (TTR) amyloidosis. TTR is a homotetrameric transporter protein for THs, yet it is also responsible for severe amyloid fibril formation, which is facilitated by tetramer dissociation into non-native monomers. By combining nuclear magnetic resonance (NMR) spectroscopy, computational simulation, and biochemical assays, we found that GC-1 and newly designed diphenyl-methane-based thyromimetics, namely IS25 and TG68, are TTR stabilizers and efficient suppressors of TTR aggregation. Based on these observations, we propose the novel potential of thyromimetics as a multi-functional therapeutic molecule for TTR-related pathologies, including neurodegenerative diseases.     

YOLSO: You Only Look Small Object

Small object detection is challenging and far from satisfactory. Most general object detectors suffer from two critical issues with small objects: (1) Feature extractor based on classification network cannot express the characteristics of small objects reasonably due to insufficient appearance information of targets and a large amount of background interference around them. (2) The detector requires a much higher location accuracy for small objects than for general objects. This paper proposes an effective and efficient small object detector YOLSO to address the above problems. For feature representation, we analyze the drawbacks in previous backbones and present a Half-Space Shortcut(HSSC) module to build a background-aware backbone. Furthermore, a coarse-to-fine Feature Pyramid Enhancement(FPE) module is introduced for layer-wise aggregation at a granular level to enhance the semantic discriminability. For loss function, we propose an exponential L1 loss to promote the convergence of regression, and a focal IOU loss to focus on prime samples with high classification confidence and high IOU. Both of them significantly improves the location accuracy of small objects. The proposed YOLSO sets state-of-the-art results on two typical small object datasets, MOCOD and VeDAI, at a speed of over 200 FPS. In the meantime, it also outperforms the baseline YOLOv3 by a wide margin on the common COCO dataset.     

A novel and sensitive colorimetric detection of PABA by asymmetrically functionalized TA-AuNPs-PEG-FITC based on oriented aggregation

A colorimetric assay based on the oriented TA-AuNPs-PEG-FITC for rapid and sensitive PABA detection was proposed. Initially, the negatively charged TA modified on the surface of AuNPs enabled rapid binding to PABA due to the electrostatic interaction and hydrogen bond, resulting in a visible color change. However, particles were aggregated in a non-oriented way, leading to an unstable testing system which failed to realize the accurate quantification. Thus, the asymmetrically functionalized TA-AuNPs-PEG-FITC were prepared, in which the stabilizer agent of HS-PEG-FITC was attached to the specific sites on the surface of TA-AuNPs. Such a way of modification resulted in an oriented aggregation manner, the addition of PABA induced the formation of oligomers. Moreover, the introduction of FITC group acted as fluorescent marker, providing a simple, fast and quantitative method for characterization of PEG chain. The molar ratio between TA-AuNPs and modified PEG-FITC was further determined. A linear regression was established in a wide range from 10 μM to 1 mM with the LOD of 6.9 μM. Finally, the sensor was successfully applied in the health food. This was the first example in which TA-AuNPs-PEG-FITC were fabricated for colorimetric detection of PABA, and an indirect method based on fluorescence marker was well used to quantify the content of PEG chain.     

Alpha Synuclein only Forms Fibrils In Vitro when Larger than its Critical Size of 70 Monomers

The aggregation of α-synuclein into small soluble aggregates and then fibrils is important in the development and spreading of aggregates through the brain in Parkinson's disease. Fibrillar aggregates can grow by monomer addition and then break into fragments that could spread into neighboring cells. The rate constants for fibril elongation and fragmentation have been measured but it is not known how large an aggregate needs to be before fibril formation is thermodynamically favorable. This critical size is an important parameter controlling at what stage in an aggregation reaction fibrils can form and replicate. We determined this value to be approximately 70 monomers using super-resolution and atomic force microscopy imaging of individual α-synuclein aggregates formed in solution over long time periods. This represents the minimum size for a stable α-synuclein fibril and we hypothesis the formation of aggregates of this size in a cell represents a tipping point at which rapid replication occurs.     

Influence of Glycerophosphate Salt Solubility on the Gelation Mechanism of Colloidal Chitosan Systems

Recently, thermosensitive chitosan systems have attracted the interest of many researchers due to their growing application potential. Nevertheless, the mechanism of the sol-gel phase transition is still being discussed, and the glycerophosphate salt role is ambiguous. The aim of the work is to analyze the possibility of the exclusive use of a non-sodium glycerophosphate salt and to determine its impact on the gelation conditions determined by rheological and turbidimetric measurements as well as the stability of the systems by measuring changes in the Zeta potential value. It was found that ensuring the same proportions of glycerophosphate ions differing in cation to amino groups present in chitosan chains, leads to obtaining systems significantly different in viscoelastic properties and phase transition conditions. It was clearly shown that the systems with the calcium glycerophosphate, the insoluble form of which may constitute additional aggregation nuclei, undergo the gelation the fastest. The use of magnesium glycerophosphate salt delays the gelation due to the heat-induced dissolution of the salt. Thus, it was unequivocally demonstrated that the formulation of the gelation mechanism of thermosensitive chitosan systems based solely on the concentration of glycerophosphate without discussing its type is incorrect.     

基于k-shell的复杂网络最短路径近似算法

复杂网络最短路径经典算法的处理效率较低，不适用于大规模复杂网络，而现有近似算法通用性有限，且计算准确率不理想，不能满足规模日益扩大的复杂网络中的最短路径计算需求。针对于此，提出基于[k]-shell的复杂网络最短路径近似算法。算法利用节点的[k]-shell值进行网络划分并引导搜索路径，利用超点聚合处理[k]-shell子网来降低路径搜索中节点和连边的规模，通过在路径搜索过程使用双向搜索树方法提高算法的计算效率和准确率。实验结果表明，算法通用性较好，在现实与仿真大规模复杂网络中均具有较高的计算效率和准确率。     

Some q-rung orthopair uncertain linguistic aggregation operators and their application to multiple attribute group decision making

q-Rung orthopair fuzzy sets (q-ROFSs), originally presented by Yager, are a powerful fuzzy information representation model, which generalize the classical intuitionistic fuzzy sets and Pythagorean fuzzy sets and provide more freedom and choice for decision makers (DMs) by allowing the sum of the $q\mathrm{t}\mathrm{h}$ power of the membership and the $q\mathrm{t}\mathrm{h}$ power of the nonmembership to be less than or equal to 1. In this paper, a new class of fuzzy sets called q-rung orthopair uncertain linguistic sets (q-ROULSs) based on the q-ROFSs and uncertain linguistic variables (ULVs) is proposed, and this can describe the qualitative assessment of DMs and provide them more freedom in reflecting their belief about allowable membership grades. On the basis of the proposed operational rules and comparison method of q-ROULSs, several q-rung orthopair uncertain linguistic aggregation operators are developed, including the q-rung orthopair uncertain linguistic weighted arithmetic average operator, the q-rung orthopair uncertain linguistic ordered weighted average operator, the q-rung orthopair uncertain linguistic hybrid weighted average operator, the q-rung orthopair uncertain linguistic weighted geometric average operator, the q-rung orthopair uncertain linguistic ordered weighted geometric operator, and the q-rung orthopair uncertain linguistic hybrid weighted geometric operator. Then, some desirable properties and special cases of these new operators are also investigated and studied, in particular, some existing intuitionistic fuzzy aggregation operators and Pythagorean fuzzy aggregation operators are proved to be special cases of these new operators. Furthermore, based on these proposed operators, we develop an approach to solve the multiple attribute group decision making problems, in which the evaluation information is expressed as q-rung orthopair ULVs. Finally, we provide several examples to illustrate the specific decision-making steps and explain the validity and feasibility of two methods by comparing with other methods.     

改进的区间犹豫算子应用于物流企业选择决策

针对现有区间犹豫模糊Hamacher算子存在的缺陷，构建了一种基于改进的区间犹豫模糊Hamacher加权算子的群决策方法。在分析现有区间犹豫模糊Hamacher算子不能满足幂等性的基础上，定义新的区间犹豫模糊Hamacher四则运算；提出两种改进的区间犹豫模糊Hamacher加权算子，包括改进的区间犹豫模糊Hamacher有序加权平均（I-IVHFHOWA）算子和改进的区间犹豫模糊Hamacher有序加权几何（I-IVHFHOWG）算子，并详细探究它们的常用算子形式以及算子之间的内在联系；建立基于I-IVHFHOWA算子和I-IVHFHOWG算子的物流企业选择决策模型，并通过实例说明模型的有效性。