Although the neutrophil recruitment cascade during inflammation has been well described, the molecular players that halt neutrophil chemotaxis remain unclear. In this study, we found that ...lipopolysaccharide (LPS) was a potent stop signal for chemotactic neutrophil migration. Treatment with an antagonist of the ATP receptor (P2X1) in primary human neutrophils or knockout of the P2X1 receptor in neutrophil-like differentiated HL-60 (dHL-60) cells recovered neutrophil chemotaxis. Further observations showed that LPS-induced ATP release through connexin 43 (Cx43) hemichannels was responsible for the activation of the P2X1 receptor and the subsequent calcium influx. Increased intracellular calcium stopped neutrophil chemotaxis by activating myosin light chain (MLC) through the myosin light chain kinase (MLCK)-dependent pathway. Taken together, these data identify a previously unknown function of LPS-induced autocrine ATP signaling in inhibiting neutrophil chemotaxis by enhancing MLC phosphorylation, which provides important evidence that stoppage of neutrophil chemotaxis at infectious foci plays a key role in the defense against invading pathogens.
After the cold war, some countries gradually seek to regional cooperation when they could not handle various transnational challenges alone. Shanghai Cooperation Organization (SCO) is a good example. ...It brought Central Asian countries together. This paper applies the text-mining method, using co-word analysis, co-occurrence matrix, cluster analysis, and strategic diagram to analyze the selected articles from newspapers quantitatively and visually. In order to investigate the Chinese government's attitude toward the SCO, this study collected data from the China Core Newspaper Full-text Database, which contains high-impact government newspapers revealing the Chinese government's perception of the SCO. This study characterizes the changing role of SCO as perceived by the Chinese government from 2001 to 2019. Beijing's changing expectations in each of the three identified subperiods are described.
The individual and social burdens associated with chronic pain have been escalating globally. Accurate pain measurement facilitates early diagnosis, disease progression monitoring and therapeutic ...efficacy evaluation, thus is a key for the management of chronic pain. Although the "golden standards" of pain measurement are self-reported scales in clinical practice, the reliability of these subjective methods could be easily affected by patients' physiological and psychological status, as well as the assessors' predispositions. Therefore, objective pain assessment has attracted substantial attention recently. Previous studies of functional magnetic resonance imaging (fMRI) revealed that certain cortices and subcortical areas are commonly activated in subjects suffering from pain. Dynamic pain connectome analysis also found various alterations of neural network connectivity that are correlated with the severity of clinical pain symptoms. Electroencephalograph (EEG) demonstrated suppressed spontaneous oscillations during pain experience. Spectral power and coherence analysis of EEG also identified signatures of different types of chronic pain. Furthermore, fMRI and EEG can visualize objective brain activities modulated by analgesics in a mechanism-based way, thus bridge the gaps between animal studies and clinical trials. Using fMRI and EEG, researchers are able to predict therapeutic efficacy and identify personalized optimal first-line regimens. In the future, the emergence of magnetic resonance spectroscopy and cell labelling in MRI would encourage the investigation on metabolic and cellular pain biomarkers. The incorporation of machine learning algorithms with neuroimaging or behavior analysis could further enhance the specificity and accuracy of objective pain assessments.
Rubrivivax gelatinosus has the advantage of using wastewater to realize biomass recovery. However, they still cannot be applied large scale because they cannot directly treat the wastewater ...containing macromolecular organics. Thus, this article investigated the effects of light-oxygen conditions on R. gelatinosus by directly recycling wastewater containing macromolecular organics to produce biomass, poly-β-hydroxybutyrate (PHB), 5-aminolevulinic acid (5-ALA), and pigment. Results showed that R. gelatinosus directly treated the macromolecule organic (soybean protein and starch) wastewaters and achieved biomass recovery under light-anaerobic and light-micro-oxygen in six conditions. Chemical oxygen demand, protein, and starch removals for two wastewaters all reached above 70%. Renewable bio-resources such as biomass, PHB, 5-ALA, and pigment production were 10 times the initial content. Theoretical analysis indicated that light activated the synthesis of protease and amylase. However, oxygen concentration decided the number of enzymes. When oxygen was at micro-oxygen or anaerobic, the aforementioned expression and synthesis were conducted. In summary, this study expanded the viewpoint ignored by traditional theory. It was realized that R. gelatinosus directly treated wastewater and accumulated nutrients (biomass, PHB, pigment, and 5-ALA) for recycling, which reduced the secondary pollution of excess sludge into the environment.
Keratinocytes are the predominant block-building cells in the epidermis. Emerging evidence has elucidated the roles of keratinocytes in a wide range of pathophysiological processes including ...cutaneous nociception, pruritus, and inflammation. Intraepidermal free nerve endings are entirely enwrapped within the gutters of keratinocyte cytoplasm and form
synaptic-like contacts with keratinocytes. Keratinocytes can detect thermal, mechanical, and chemical stimuli through transient receptor potential ion channels and other sensory receptors. The activated keratinocytes elicit calcium influx and release ATP, which binds to P2 receptors on free nerve endings and excites sensory neurons. This process is modulated by the endogenous opioid system and endothelin. Keratinocytes also express neurotransmitter receptors of adrenaline, acetylcholine, glutamate, and γ-aminobutyric acid, which are involved in regulating the activation and migration, of keratinocytes. Furthermore, keratinocytes serve as both sources and targets of neurotrophic factors, pro-inflammatory cytokines, and neuropeptides. The autocrine and/or paracrine mechanisms of these mediators create a bidirectional feedback loop that amplifies neuroinflammation and contributes to peripheral sensitization.
As a novel histone deacetylase inhibitor (HDACi), LAQ824 (LAQ) effectively inhibits the proliferation of hematological malignancies and solid tumors. However, phase II trials of LAQ in solid tumors ...were terminated due to dose-dependent toxicity. Furthermore, LAQ has been shown to induce the activation of the Notch signaling pathway in hematopoietic stem cells, which is associated with tumor progression and drug resistance in colon and breast cancers. Therefore, in this study, we investigated the strategy of LAQ combined with a Notch signaling pathway inhibitor to treat solid tumors. We used RT-PCR and Western blot methods to demonstrate that LAQ upregulated the Notch signaling pathway in solid tumor cell lines at the molecular level. The combination of LAQ and a Notch signaling pathway inhibitor was shown by a Chou–Talalay assay to have a synergistic effect in inhibiting solid tumor cell line proliferation in vitro. We also demonstrated that the combination of LAQ and a Notch signaling pathway inhibitor significantly inhibited the growth of tumor cells in vivo using an allograft tumor model. This study indicates that inhibition of the Notch signaling pathway provides a valuable strategy for enhancing solid tumor sensitivity to LAQ.
Global water scarcity is exacerbating owing to climate change and pollution, making the demand for clean water more challenging with the growth of the global economy and population. Membrane ...filtration technologies have been widely applied in drinking water purification due to their energy efficiency while facing challenges like fouling, degradation and trade-offs, such as selectivity and permeability. The sustainable development of our society demands further understanding and improvement of those membranes. In this review, the basic structures of polymer-based water purification membranes including the effective layer for separation, the support layer and the possible top protective layer are presented. Details include the conventional membranes for microfiltration (MF) and ultrafiltration (UF), the effective layers for separation in thin-film composite (TFC) membranes, electrospun nanofibrous membranes for MF, UF, and membrane distillation (MD), as well as the emerging self-assembled block copolymer membranes. Furthermore, the conventional support layers and electrospun nanofibrous support layers for reverse osmosis (RO) and forward osmosis (FO) processes, and the top protective layers are discussed. The materials, membrane structures and properties, modification strategies, possible interlayers, interconnects, interpenetration, and interactions between different layers are discussed, with the emphasis on the cost-effectiveness of various membranes.
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Non-alcohol-associated fatty liver/steatohepatitis (NAFL/NASH) has become the leading cause of liver disease worldwide. NASH, an advanced form of NAFL, can be progressive and more susceptible to ...developing cirrhosis and hepatocellular carcinoma. Currently, lifestyle interventions are the most essential and effective strategies for preventing and controlling NAFL without the development of fibrosis. While there are still limited appropriate drugs specifically to treat NAFL/NASH, growing progress is being seen in elucidating the pathogenesis and identifying therapeutic targets. In this review, we discussed recent developments in etiology and prospective therapeutic targets, as well as pharmacological candidates in pre/clinical trials and patents, with a focus on diabetes, hepatic lipid metabolism, inflammation, and fibrosis. Importantly, growing evidence elucidates that the disruption of the gut-liver axis and microbe-derived metabolites drive the pathogenesis of NAFL/NASH. Extracellular vesicles (EVs) act as a signaling mediator, resulting in lipid accumulation, macrophage and hepatic stellate cell activation, further promoting inflammation and liver fibrosis progression during the development of NAFL/NASH. Targeting gut microbiota or EVs may serve as new strategies for the treatment of NAFL/NASH. Finally, other mechanisms, such as cell therapy and genetic approaches, also have enormous therapeutic potential. Incorporating drugs with different mechanisms and personalized medicine may improve the efficacy to better benefit patients with NAFL/NASH.
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