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.
Lack of immunogenicity of cancer cells has been considered a major reason for their failure in induction of a tumor specific T cell response. In this paper, we present evidence that decitabine (DAC), ...a DNA methylation inhibitor that is currently used for the treatment of myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) and other malignant neoplasms, is capable of eliciting an anti-tumor cytotoxic T lymphocyte (CTL) response in mouse EL4 tumor model. C57BL/6 mice with established EL4 tumors were treated with DAC (1.0 mg/kg body weight) once daily for 5 days. We found that DAC treatment resulted in infiltration of IFN-γ producing T lymphocytes into tumors and caused tumor rejection. Depletion of CD8(+), but not CD4(+) T cells resumed tumor growth. DAC-induced CTL response appeared to be elicited by the induction of CD80 expression on tumor cells. Epigenetic evidence suggests that DAC induces CD80 expression in EL4 cells via demethylation of CpG dinucleotide sites in the promoter of CD80 gene. In addition, we also showed that a transient, low-dose DAC treatment can induce CD80 gene expression in a variety of human cancer cells. This study provides the first evidence that epigenetic modulation can induce the expression of a major T cell co-stimulatory molecule on cancer cells, which can overcome immune tolerance, and induce an efficient anti-tumor CTL response. The results have important implications in designing DAC-based cancer immunotherapy.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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.
Based on a spectral analysis of the X-ray continuum that employs a fully relativistic accretion disk model, we conclude that the compact primary of the binary X-ray source GRS 1915+105 is a rapidly ...rotating Kerr black hole. We find a lower limit on the dimensionless spin parameter of a sub(*) > 0.98. Our result is robust in the sense that it is independent of the details of the data analysis and insensitive to the uncertainties in the mass and distance of the black hole. Furthermore, our accretion disk model includes an advanced treatment of spectral hardening. Our data selection relies on a rigorous and quantitative definition of the thermal state of black hole binaries, which we used to screen all of the available RXTE and ASCA data for the thermal state of GRS 1915+105. In addition, we focus on those data for which the accretion disk luminosity is less than 30% of the Eddington luminosity. We argue that these low-luminosity data are most appropriate for the thin a-disk model that we employ. We assume that there is zero torque at the inner edge of the disk, as is likely when the disk is thin, although we show that the presence of a significant torque does not affect our results. Our model and the model of the relativistic jets observed for this source constrain the distance and black hole mass and could thus be tested by determining a VLBA parallax distance and improving the measurement of the mass function. Finally, we comment on the significance of our results for relativistic jet and core-collapse models and for the detection of gravitational waves.
China is one of the countries with the highest incidence of gastric cancer. There are differences in epidemiological characteristics, clinicopathological features, tumor biological characteristics, ...treatment patterns, and drug selection between gastric cancer patients from the Eastern and Western countries. Non‐Chinese guidelines cannot specifically reflect the diagnosis and treatment characteristics for the Chinese gastric cancer patients. The Chinese Society of Clinical Oncology (CSCO) arranged for a panel of senior experts specializing in all sub‐specialties of gastric cancer to compile, discuss, and revise the guidelines on the diagnosis and treatment of gastric cancer based on the findings of evidence‐based medicine in China and abroad. By referring to the opinions of industry experts, taking into account of regional differences, giving full consideration to the accessibility of diagnosis and treatment resources, these experts have conducted experts’ consensus judgement on relevant evidence and made various grades of recommendations for the clinical diagnosis and treatment of gastric cancer to reflect the value of cancer treatment and meeting health economic indexes. This guideline uses tables and is complemented by explanatory and descriptive notes covering the diagnosis, comprehensive treatment, and follow‐up visits for gastric cancer.
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."
China had been free of wild-type poliovirus transmission and infection for nearly 20 years when a 2011 outbreak of imported wild-type poliovirus was identified in Xinjiang. Efforts to control the ...outbreak are described, including the administration of 44 million doses of vaccine.
The World Health Assembly established the Global Polio Eradication Initiative in 1988.
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The World Health Organization (WHO) Western Pacific region, including China, was certified as a poliomyelitis-free region in 2000.
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However, the transmission of wild-type poliovirus has not yet been stopped in Afghanistan, Pakistan, or Nigeria. Globally, some countries have had outbreaks of imported wild-type poliovirus, and in others the circulation of outbreak strains has been reestablished.
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China has the world's largest population (1.347 billion in 2011).
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By 1963, live, attenuated oral poliovirus vaccine (OPV) was being administered in annual campaigns conducted during the winter. OPV has been included . . .
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