Drug‐mediated or medical condition‐mediated disruption of hERG function accounts for the main cause of acquired long‐QT syndrome (acLQTs), which predisposes affected individuals to ventricular ...arrhythmias (VA) and sudden death. Many Chinese herbal medicines, especially alkaloids, have risks of arrhythmia in clinical application. The characterized mechanisms behind this adverse effect are frequently associated with inhibition of cardiac hERG channels. The present study aimed to assess the potent effect of Rutaecarpine (Rut) on hERG channels. hERG‐HEK293 cell was applied for evaluating the effect of Rut on hERG channels and the underlying mechanism. hERG current (IhERG) was measured by patch‐clamp technique. Protein levels were analysed by Western blot, and the phosphorylation of Sp1 was determined by immunoprecipitation. Optical mapping and programmed electrical stimulation were used to evaluate cardiac electrophysiological activities, such as APD, QT/QTc, occurrence of arrhythmia, phase singularities (PSs), and dominant frequency (DF). Our results demonstrated that Rut reduced the IhERG by binding to F656 and Y652 amino acid residues of hERG channel instantaneously, subsequently accelerating the channel inactivation, and being trapped in the channel. The level of hERG channels was reduced by incubating with Rut for 24 hours, and Sp1 in nucleus was inhibited simultaneously. Mechanismly, Rut reduced threonine (Thr)/ tyrosine (Tyr) phosphorylation of Sp1 through PI3K/Akt pathway to regulate hERG channels expression. Cell‐based model unables to fully reveal the pathological process of arrhythmia. In vivo study, we found that Rut prolonged QT/QTc intervals and increased induction rate of ventricular fibrillation (VF) in guinea pig heart after being dosed Rut for 2 weeks. The critical reasons led to increased incidence of arrhythmias eventually were prolonged APD90 and APD50 and the increase of DF, numbers of PSs, incidence of early after‐depolarizations (EADs). Collectively, the results of this study suggest that Rut could reduce the IhERG by binding to hERG channels through F656 and Y652 instantaneously. While, the PI3K/Akt/Sp1 axis may play an essential role in the regulation of hERG channels, from the perspective of the long‐term effects of Rut (incubating for 24 hours). Importantly, the changes of electrophysiological properties by Rut were the main cause of VA.
Gravitational waves and electromagnetic radiations from a neutron star merger were discovered on 2017 August 17. Multiband observations of the optical transient have identified brightness and ...spectrum features broadly consistent with theoretical predictions. According to the theoretical model, the optical radiation from a neutron star merger originates from the radioactive decay of unstable nuclides freshly synthesized in the merger ejecta. In about a day the ejecta transits from an optically thick state to an optically thin state owing to its subrelativistic expansion. Hence, we expect that about a day after the merger the gamma-ray photons produced by radioactive decays start to escape from the ejecta and make it bright in the MeV band. In this paper, we study the features of the radioactive gamma-ray emission from a neutron star merger, including the brightness and the spectrum, and discuss the observability of the gamma-ray emission. We find that more than 95% of the radiated gamma-ray energy is carried by photons of 0.2-4 MeV, with a spectrum shaped by the nucleosynthesis process and the subrelativistic expansion of the ejecta. Under favorable conditions, a prominent pair annihilation line can be present in the gamma-ray spectrum with the energy flux about 3%-5% of the total. For a merger event similar to GW170817, the gamma-ray emission attains a peak luminosity of 2 × 1041 erg s−1 at 1.2 days after the merger and fades by a factor of two in about 2 days. Such a source will be detectable by satellite-ETCC if it occurs at a distance 12 Mpc.
Accumulation of evidence indicates that miRNAs have crucial roles in the regulation of EMT-associated properties, such as proliferation, migration and invasion. However, the underlying molecular ...mechanisms are not entirely illustrated. Here, we investigated the role of miR-296-5p in hepatocellular carcinoma (HCC) progression.
In vitro cell morphology, proliferation, migration and invasion were compared between HCC cell lines with up- or down-regulation of miR-296-5p. Immunofluorescence and Western blot immunofluorescence assays were used to detect the expression of EMT markers. Bioinformatics programs, luciferase reporter assay and rescue experiments were used to validate the downstream targets of miR-296-5p. Xenograft nude mouse models were established to observe tumor growth and metastasis. Immunohistochemical assays were conducted to study the relationships between miR-296-5p expression and Neuregulin-1 (NRG1)/EMT markers in human HCC samples and mice.
miR-296-5p was prominently downregulated in HCC tissues relative to adjacent normal liver tissues and associated with favorable prognosis. Overexpression of miR-296-5p inhibited EMT along with migration and invasion of HCC cells via suppressing NRG1/ERBB2/ERBB3/RAS/MAPK/Fra-2 signaling in vitro. More importantly, miR-296-5p disrupted intrahepatic and pulmonary metastasis in vivo. NRG1, as a direct target of miR-296-5p, mediates downstream biological responses. In HCC tissues from patients and mice, the levels of miR-296-5p and NRG1 also showed an inverse relationship.
miR-296-5p inhibited EMT-related metastasis of HCC through NRG1/ERBB2/ERBB3/RAS/MAPK/Fra-2 signaling.
In this article, an adaptive neural finite-time event-triggered consensus tracking problem is studied for nonlinear multiagent systems (MASs) under directed graphs. First, the unknown nonlinear ...functions of MASs can be approximated by neural networks. Then, a distributed adaptive event-triggered control scheme is proposed via command filter and backstepping technique. The newly designed control scheme cannot only circumvent the problem of the explosion of complexity, but also remove the singularity issue typical of conventional backstepping technique. In the meanwhile, an event-triggered mechanism with a dynamic threshold is devised to reduce the waste of network resources. Moreover, by using a novel finite-time stability criterion, it can be proved that the closed-loop system is finite-time stable and the consensus tracking errors can reach zero as time approaches to infinity. Finally, a numerical example is given to validate the feasibility of the proposed scheme.
Li critiques Berti and Simpson's argument that the orthodox theory of organizational paradox has two limitations, namely, a "presupposition that individuals are free and able to choose how to engage ...with paradoxical tensions" and "insufficient attention given to power and domination effects." In contrast, they claimed, the experience of organizational paradox is not power-neutral hut is shaped by power relations: organizational members are not free to act according to their wills, because "oppressive power conditions restrict the ability for organizational members to make legitimate choices in the face of interdependent contradictions (paradoxes)" and "powerless stakeholders, not in a position to question the status quo, accordingly experience helplessness, meaninglessness and paralysis." They posited that the remedies for such "pathological experience of pragmatic paradoxes" are either "attempts to reform' the system" that can "purposefully he planned and implemented" or "more 'revolutionary' transformations that can spontaneously emerge to disrupt the status quo."
Li comments on Tobias Hahn and Eric Knight's quantum approach to the ontology of organizational paradox. By addressing the problems of their application of quantum physics to organizational paradox ...research, he aims to move the mainstream thinking on organizational paradox beyond the dominant "both/and" toward a "neither/nor" approach that is the essence of the Copenhagen interpretation of quantum theory. He posits that embracing the "neither/nor" thinking, just like the shift from "either/or" to "both/and," affords management scholars a much broader cognitive space in which resolving paradox may not be, as the mainstream organizational paradox scholars currently consider it impossible. In his alternative quantum approach to organizational paradox, any paradox or paradoxical tension is caused by the asymmetry between one's capacity and expectation, and the principle of paradox resolution is then the reduction of the asymmetry through either increasing one's capacities or decreasing one's expectations, or by doing both simultaneously.
With the rapid development of the electric vehicle (EV) industry, the recycling of spent EV batteries has attracted considerable attention. The establishment and optimization of the collection mode ...is a key link in regulating the recycling of spent EV batteries. This paper investigates an EV battery supply chain including an EV manufacturer, an EV retailer, and a third-party collector and analyzes three dual-channel collection modes. The optimal pricing and collection decisions of the three dual-channel collection modes are obtained and compared. The collection mode choice strategy and the effects of third-party economies of scale are explored. Three interesting insights are derived: (i) Third-party economies of scale can improve the collection rate of spent EV batteries and the profit of the supply chain. (ii) The optimal collection mode choice depends on the intensity of collection competition and the third-party economies of scale. (iii) When the intensity of collection competition and the third-party economies of scale are high enough, the EV retailer and the third-party dual-channel collection mode is the optimal mode; otherwise, the EV manufacturer and the EV retailer dual-channel collection mode is optimal.
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