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Background: Hyperhomocysteinemia (HHcy) is an independent risk factor for atherosclerosis (AS). Endothelial mesenchymal transition (EndMT) refers to the process in which endothelial cells lose endothelial cell morphology and characteristic gene expression, and acquire phenotypic characteristics and gene expression related to mesenchymal cells. Numerous studies have confirmed that EndMT is involved in the formation of atherosclerosis. Catalpol is one of the active components of Rehmannia, which has antioxidant, anti-inflammatory, anti-tumor, neuroprotective and other biological activities. Studies have shown that catalpol can reduce atherosclerotic plaque induced by high sugar or fat. However, the effect of catalpol on HHCY-induced EndMT is unclear. Methods and results: In vitro HHcy-treated primary human umbilical vein endothelial cells (HUVECs) were used to construct a cell model, and the antioxidants N-acetylcysteine (NAC) and catalase alcohol were administered. In vivo C57BL/6N mice were given a diet fed with 4.4% high methionine chow to construct a HHcy mice model and were treated with catalpol. The results showed that hhcy could induce morphological transformation of endothelial cells into mesenchymal cells, increase intracellular ROS content, up-regulate α-SMA, N-cadherin, p-p65 protein expression, down-regulate VE-cadherin, CD31 protein expression, induce pathological changes of aortic root endothelium, and increase aortic endothelial ROS content. Catalpol reversed these hhcy induced outcomes. Conclusions: Catalpol inhibits HHcy-induced EndMT, and the underlying mechanism may be related to the ROS/NF-κB signaling pathway. Catalpol may be a potential drug for the treatment of HHcy-related AS. [ABSTRACT FROM AUTHOR]

Background: Desensitization of G protein–coupled receptors (GPCRs) refers to the attenuation of receptor responsiveness by prolonged or intermittent exposure to agonists. The binding of β-arrestin to the cytoplasmic cavity of the phosphorylated receptor, which competes with the G protein, has been widely accepted as an extensive model for explaining GPCRs desensitization. However, studies on various GPCRs, including dopamine D2-like receptors (D2R, D3R, D4R), have suggested the existence of other desensitization mechanisms. The present study employed D2R/D3R variants with different desensitization properties and utilized loss-of-function approaches to uncover the mechanisms underlying GPCRs homologous desensitization, focusing on the signaling cascade that regulates the ubiquitination of AKT. Results: AKT undergoes K8/14 ubiquitination by TRAF6, which occurs in the nucleus and promotes its membrane recruitment, phosphorylation and activation under receptor desensitization conditions. The nuclear entry of TRAF6 relies on the presence of the importin complex. Src regulates the nuclear entry of TRAF6 by mediating the interaction between TRAF6 and importin β1. Ubiquitinated AKT translocates to the plasma membrane where it associates with Mdm2 to phosphorylate it at the S166 and S186 residues. Thereafter, phosphorylated Mdm2 is recruited to the nucleus, resulting in the deubiquitination of β-Arr2. The deubiquitinated β-Arr2 then forms a complex with Gβγ, which serves as a biomarker for GPCRs desensitization. Like in D3R, ubiquitination of AKT is also involved in the desensitization of β2 adrenoceptors. Conclusion: Our study proposed that the property of a receptor that causes a change in the subcellular localization of TRAF6 from the cytoplasm to the nucleus to mediate AKT ubiquitination could initiate the desensitization of GPCRs. [ABSTRACT FROM AUTHOR]

The insulin and dopaminergic systems in the brain are associated with schizophrenia and Parkinson's disease with respect to etiology and treatment. The present study investigated the crosstalk between the insulin receptor (IR) and dopamine receptor and found that insulin stimulation selectively inhibits signaling of D3R in a PKCβII‐dependent manner. Upon insulin stimulation, E3 ligase enzyme Mdm2 moves out of the nucleus to ubiquitinate PKCβII. Subsequently, ubiquitinated PKCβII translocates to the cell membrane and interacts with D3R in a phosphorylation‐dependent manner at S229/257, resulting in the attenuation of D3R signaling and initiating clathrin‐mediated endocytosis and downregulation. Considering that both IR and D3R are closely related to some neuropsychosis, this study could provide new molecular insight into the etiology of the disorder. [ABSTRACT FROM AUTHOR]

Dopamine D2 receptor (D2R) has been shown to activate extracellular signal‐regulated kinases (ERKs) via distinct pathways dependent on either G‐protein or β‐arrestin. However, there has not been a systematic study of the regulatory process of D2R‐mediated ERKs activation by G protein‐ versus β‐arrestin‐dependent signaling since D2R stimulation of ERKs reflects the simultaneous action of both pathways. Here, we investigated that differential regulation of D2R‐mediated ERKs activation via these two pathways. Our results showed that G protein‐dependent ERKs activation was transient, rapid, reached maximum level at around 2 min, and importantly, the activated ERKs were entirely confined to the cytoplasm. In contrast, β‐arrestin‐dependent ERKs activation was more sustained, slower, reached maximum level at around 10 min, and phosphorylated ERKs translocated into the nucleus. Src was found to be commonly involved in both the G protein‐ and β‐arrestin‐dependent pathway‐mediated ERKs activation. Pertussis toxin Gi/o inhibitor, GRK2‐CT, AG1478 epidermal growth factor receptor inhibitor, and wortmannin phosphoinositide 3‐kinase inhibitor all blocked G protein‐dependent ERKs activation. In contrast, GRK2 and β‐Arr2 played a main role in β‐arrestin‐dependent ERKs activation. Receptor endocytosis showed minimal effect on the activation of ERKs mediated by both pathways. Furthermore, we found that the formation of a complex composed of phospho‐ERKs, β‐Arr2, and importinβ1 promoted the nuclear translocation of activated ERKs. The differential regulation of various cellular components, as well as temporal and spatial patterns of ERKs activation via these two pathways, suggest the existence of distinct physiological outcomes. [ABSTRACT FROM AUTHOR]

A class-A GPCR dopamine D2 receptor (D2R) plays a critical role in the proper functioning of neuronal circuits through the downstream activation of both G-protein- and β-arrestin-dependent signaling pathways. Understanding the signaling pathways downstream of D2R is critical for developing effective therapies with which to treat dopamine (DA)-related disorders such as Parkinson's disease and schizophrenia. Extensive studies have focused on the regulation of D2R-mediated extracellular-signal-regulated kinase (ERK) 1/2 signaling; however, the manner in which ERKs are activated upon the stimulation of a specific signaling pathway of D2R remains unclear. The present study conducted a variety of experimental techniques, including loss-of-function experiments, site-directed mutagenesis, and the determination of protein interactions, in order to investigate the mechanisms underlying β-arrestin-biased signaling-pathway-mediated ERK activation. We found that the stimulation of the D2R β-arrestin signaling pathway caused Mdm2, an E3 ubiquitin ligase, to move from the nucleus to the cytoplasm and interact with tyrosine phosphorylated G-protein-coupled receptor kinase 2 (GRK2), which was facilitated by Src, a non-receptor tyrosine kinase. This interaction led to the ubiquitination of GRK2, which then moved to the plasma membrane and interacted with activated D2R, followed by the phosphorylation of D2R as well as the mediation of ERK activation. In conclusion, Mdm2-mediated GRK2 ubiquitination, which is selectively triggered by the stimulation of the D2R β-arrestin signaling pathway, is necessary for GRK2 membrane translocation and its interaction with D2R, which in turn mediates downstream ERK signaling. This study is primarily novel and provides essential information with which to better understand the detailed mechanisms of D2R-dependent signaling. [ABSTRACT FROM AUTHOR]

In this paper, a distributed adaptive finite-time consensus (FTC) control protocol for a high-order multi-agent system (MAS) with intermittent communications under switching topologies is proposed. Meanwhile, considering the problem of heterogeneous unknown nonlinearities and other uncertain disturbances, the adaptive neural network and the sliding mode control method are used to compensate the nonlinearity of each agent separately. The agents are homogeneous, so the system has symmetry. The switching topologies considered in this paper are asymmetric. Compared with consensus protocol for asymptotic convergence, simulation results show that the proposed method can effectively solve the presence of the nonlinear and accelerate the convergence speed of the system so that an FTC can be reached. [ABSTRACT FROM AUTHOR]

Traditional Chinese medicine (TCM) lies at the basis of carrying forward Chinese culture, and the characteristics of Chinese culture can be elucidated on the basis of Confucianism. Although the original meanings of medicine and Confucianism are quite different, the two have been blended in the long history of Chinese civilization. This article first analyzes the unidirectional relationship between Confucianism and medical application, including the combination of technique and knowledge, the lack of essentials, failure to connect to each other, and difficulty in interpretation. Second, it horizontally explains the reverse creation of classic medical books with a Confucian interpretation, including improving the medical state, interpreting scriptures quoting scriptures to interpret scriptures, textual research of the medical compendium, and introducing new knowledge. Third, it expounds their mutual involvement and application in the multivariate harmony of medical and Confucian interests. Whether it is the benevolent talk of Confucianism by doctors or the sincere words on medicine by Confucianists, they areit is one of the powers that shape the style of Chinese medicine. Only by intensively studying classics detailing, deeply examining and reasoning, and seeking common grounds while preserving differences reserving differences, can we accurately explore the influence of academic thoughts on TCM and comprehensively describe the cultural trajectory of the integration of medicine and Confucianism. [ABSTRACT FROM AUTHOR]

Bi2Sn2O7 with flower-like hierarchical architecture was successfully synthesized via a facile template-free hydrothermal method. The structure–property relationships of such unique structured Bi2Sn2O7 were studied. The results show that the 3D flower-like Bi2Sn2O7 hierarchical architecture is composed of 2D Bi2Sn2O7 nanosheets, which increases the specific surface area of Bi2Sn2O7, which is about four times that of Bi2Sn2O7 nanoparticles. Meanwhile, 2D nanosheets result in an effective separation of photo-generated carries, and the average carrier lifetime of flower-like Bi2Sn2O7 is 3.26 ns, which is longer than that of Bi2Sn2O7 nanoparticles (1.88 ns). Therefore, the flower-like Bi2Sn2O7 displays excellent photocatalytic activity for degrading tetracycline hydrochloride compared with Bi2Sn2O7 nanoparticles. The active species trapping test confirmed that h+ and ˙O2− are dominant reactive species in the photocatalytic reaction. Moreover, this novel structure can also integrate the advantages of nano-sized materials with high surface area and micro-sized materials with good dispersion, exhibiting excellent properties of high photocatalytic activity, easy recyclability and good catalytic stability. [ABSTRACT FROM AUTHOR]

CcmG is a periplasmic, membrane-anchored protein widely distributed in a variety of species. In Escherichia coli, the CcmG protein always acts as a weak reductant in the electron transport chain during cytochrome c maturation (Ccm). Here we report H, N and C backbone and side-chain resonance assignments of the reduced CcmG protein (residues 19-185, renumbered as 1-167) from E. coli. This work lays the essential basis for the further structural and functional analysis of reduced CcmG. [ABSTRACT FROM AUTHOR]

Vertex concavity-convexity detection for spatial objects is a basic algorithm of computer graphics, as well as the foundation for the implementation of other graphics algorithms. In recent years, the importance of the vertex concavity-convexity detection algorithm for three-dimensional (3D) spatial objects has been increasingly highlighted, with the development of 3D modeling, artificial intelligence, and other graphics technologies. Nonetheless, the currently available vertex concavity-convexity detection algorithms mostly use two-dimensional (2D) polygons, with limited research on vertex concavity-convexity detection algorithms for 3D polyhedrons. This study investigates the correlation between the outer product and the topology of the spatial object based on the unique characteristic that the outer product operation in the geometric algebra has unified and definitive geometric implications in space, and with varied dimensionality. Moreover, a multi-dimensional unified vertex concavity-convexity detection algorithm framework for spatial objects is proposed, and this framework is capable of detecting vertex concavity-convexity for both 2D simple polygons and 3D simple polyhedrons. [ABSTRACT FROM AUTHOR]