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Unlike chemosynthetic drugs designed for specific molecular and disease targets, active small-molecule natural products typically have a wide range of bioactivities and multiple targets, necessitating extensive screening and development. To address this issue, we propose a strategy for the direct in situ microdynamic examination of potential drug candidates to rapidly identify their effects and mechanisms of action. As a proof-of-concept, we investigated the behavior of mussel oligosaccharide (MOS-1) by tracking the subcellular dynamics of fluorescently labeled MOS-1 in cultured cells. We recorded the entire dynamic process of the localization of fluorescein isothiocyanate (FITC)-MOS-1 to the lysosomes and visualized the distribution of the drug within the cell. Remarkably, lysosomes containing FITC-MOS-1 actively recruited lipid droplets, leading to fusion events and increased cellular lipid consumption. These drug behaviors confirmed MOS-1 is a candidate for the treatment of lipid-related diseases. Furthermore, in a high-fat HepG2 cell model and in high-fat diet-fed apolipoprotein E (ApoE) -/- mice, MOS-1 significantly promoted triglyceride degradation, reduced lipid droplet accumulation, lowered serum triglyceride levels, and mitigated liver damage and steatosis. Overall, our work supports the prioritization of in situ visual monitoring of drug location and distribution in subcellular compartments during the drug development phase, as this methodology contributes to the rapid identification of drug indications. Collectively, this methodology is significant for the screening and development of selective small-molecule drugs, and is expected to expedite the identification of candidate molecules with medicinal effects.

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BACKGROUND & AIMS: Gamma delta (γδ) T cells are heterogeneous and functionally committed to producing interferon (IFN)-γ and interleukin (IL)-17. γδT cells are defined as tissue-resident lymphocytes in barrier tissues. Among them, IL-17-producing γδT cells are relatively abundant in the liver. However, a systematic and comprehensive understanding of the residency characteristics and function of hepatic IL-17A+ γδT cells is lacking. METHODS: We undertook a single-cell analysis of γδT17 cells derived from murine livers. A parabiosis model was used to assess tissue residency. Fluorescence-activated cell sorting and adoptive transfer experiments were used to investigate the response and protective role of liver-resident CD44hiCD27- γδT cells in Listeria monocytogenes infection. Transwell assay was used to assess the role of macrophages in the chemotaxis of liver-resident CD44hiCD27- γδT cells. RESULTS: We identified hepatic IL-17A-producing γδT cells as CD44hiCD27- γδT cells. They had tissue-resident characteristics and resided principally within the liver. Vγ6+ T cells also exhibited liver-resident features. Liver-resident CD44hiCD27- γδT cells had significantly increased proliferation capacity, and their proportion rapidly increased after infection. Some CD44hiCD27- γδT cells could produce IL-17A and IFN-γ simultaneously in response to Lm infection. Adoptive transfer of hepatic CD44hiCD27- γδT cells into Lm-infected TCRδ-/- mice led to markedly lower bacterial numbers in the liver. Hepatic macrophages promoted the migration and accumulation of liver-resident CD44hiCD27- γδT cells into infection sites. CONCLUSIONS: Liver-resident CD44hiCD27- γδT cells protect against Lm infection. Hepatic macrophages coordinate with liver-resident CD44hiCD27- γδT cells and contribute to the clearance of Lm at the early stage of infection corporately.

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The γδT-cells recognize infected or transformed cells. However, unlike αßT-cells, γδT-cells are innate-like immune cells, with no major histocompatibility complex restriction requirements. γδT-cells are the main population of intestinal intraepithelial lymphocytes (IELs) and are associated with the antitumor immune response, particularly in colorectal cancer (CRC). Although CD8+ T-cells exhibit dysfunction and even exhaustion in the tumor microenvironment (TME), which contributes to tumor immune escape, whether the same applies to tumor-infiltrating (TI)-γδT-cells is not completely understood. Here, we sought to investigate the expression pattern of inhibitory receptors and functional state of TI-γδT-cells, and reveal the features of exhausted TI-γδT-cells in the CRC TME. We demonstrated that TI-γδT-cells exhibited exhaustion phenotypes and displayed more severe functional exhaustion than TI-CD8+ T-cells or NK-cells in the TME of CRC. In addition, scRNA-seq analysis of TI-γδT-cells revealed three exhausted subsets with remarkable heterogeneity. The presence of three heterogeneous exhausted γδT-cell (Tex) populations, including Texprog , Textran and Texterm were further confirmed by flow cytometry, on the basis of PD-1 and TIM-3 expression. Finally, we revealed that c-Maf not only contributed to γδT-cell exhaustion via upregulation of inhibitory receptors, but also involved in the exhaustion of CD8+ T and NK-cells. c-Maf may also be an important contributor to γδT-cell exhaustion in CRC patients. These findings indicated that TI-γδT-cells exhibit phenotypic and functional exhaustion in the CRC TME. The revealed features of exhausted TI-γδT-cells may provide help for understanding the mechanisms and the association of γδT-cell exhaustion with tumor development and pathogenesis.

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Persistent infection with the hepatitis B virus (HBV) can aggravate the state of immune tolerance, inhibit the function of immune cells, and even lead to immune cell exhaustion in the liver microenvironment. The dysfunction of immune cells causes HBV to escape immune surveillance and eradication. Increasing evidence has revealed the molecular and cellular mechanisms of the induction of T-cell exhaustion during chronic viral persistence. However, the exact mechanisms of T cell exhaustion during chronic persistence of HBV infection are not fully understood. In this study, we analyzed the expression of inhibitory receptors and the exhausted status of liver T cells in a murine model with persistent HBV. We observed higher expression of the inhibitory receptors PD-1, LAG-3, and CD160 on liver CD8+ T cells accompanied by lower production of IFN-γ and TNF-α in HBV persistence mice. T cell-specific deficiency of the transcription factor Eomes significantly decreased the expression of the inhibitory receptors, restored the cytokine production of hepatic CD8+ T cells, and promoted HBV clearance. Similar phenomena were observed in peripheral blood CD8+ T cells from CHB patients. Mechanistically, Eomes not only directly promoted CD160 expression but also indirectly facilitated the coexpression of inhibitory receptors (PD-1, LAG-3, CD160) and T cell exhaustion by enhancing the transcription capacity of other key transcription factors (NFATc1, Blimp1, and FoxO1). These findings provide insight into the transcriptional regulation mechanisms of T cell exhaustion during chronic persistence of HBV and suggest novel therapeutic targets to reverse T cell exhaustion and eradicate HBV persistence.

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The intestinal immune system is crucial for protection from pathogenic infection and maintenance of mucosal homeostasis. We studied the intestinal immune microenvironment in a Salmonella enterica serovar Typhimurium intestinal infection mouse model. Intestinal lamina propria macrophages are the main effector cells in innate resistance to intracellular microbial pathogens. We found that S Typhimurium infection augmented Tim-3 expression on intestinal lamina propria CD4+ T cells and enhanced galectin-9 expression on F4/80+ CD11b+ macrophages. Moreover, CD4+ T cells promoted the activation and bactericidal activity of intestinal F4/80+ CD11b+ macrophages via the Tim-3/galectin-9 interaction during S Typhimurium infection. Blocking the Tim-3/galectin-9 interaction with α-lactose significantly attenuated the bactericidal activity of intracellular S Typhimurium by macrophages. Furthermore, the Tim-3/galectin-9 interaction promoted the formation and activation of inflammasomes, which led to caspase-1 cleavage and interleukin 1ß (IL-1ß) secretion. The secretion of active IL-1ß further improved bactericidal activity of macrophages and galectin-9 expression on macrophages. These results demonstrated the critical role of the cross talk between CD4+ T cells and macrophages, particularly the Tim-3/galectin-9 interaction, in antimicrobial immunity and the control of intestinal pathogenic infections.

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Due to their high adsorption capacities, carbon-based nanomaterials such as carbon nanotubes, activated carbons, fullerene and graphene are widely used as the currently most promising functional materials. Since its discovery in 2004, graphene has exhibited great potential in many technological fields, such as energy storage materials, supercapacitors, resonators, quantum dots, solar cells, electronics, and sensors. The large theoretical specific surface area of graphene nanosheets (2630 m(2)·g(-1)) makes them excellent candidates for adsorption technologies. Further, graphene nanosheets could be used as substrates for decorating the surfaces of nanoparticles, and the corresponding nanocomposites could be applied as novel adsorbents for the removal of low concentrated contaminants from aqueous solutions. Therefore, graphene nanosheets will challenge the current existing adsorbents, including other types of carbon-based nanomaterials.

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Organic contaminants have become one of the most serious environmental problems, and the removal of organic contaminants (e.g., dyes, pesticides, and pharmaceuticals/drugs) and common industrial organic wastes (e.g., phenols and aromatic amines) from aqueous solutions is of special concern because they are recalcitrant and persistent in the environment. In recent years, carbon nanotubes (CNTs) have been gradually applied to the removal of organic contaminants from wastewater through adsorption processes. This paper reviews recent progress (145 studies published from 2010 to 2013) in the application of CNTs and their composites for the removal of toxic organic pollutants from contaminated water. The paper discusses removal efficiencies and adsorption mechanisms as well as thermodynamics and reaction kinetics. CNTs are predicted to have considerable prospects for wider application to wastewater treatment in the future.

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As an incomplete renal replacement for the patients with either acute or chronic renal failure, membrane-based hemodialysis therapy is progressing rapidly. However, the mortality and morbidity remain unacceptably high. Much effort has been put into improving the biocompatibility of the hemodialysis membranes. To effectively remove small solutes and 'middle molecules' in compact cartridges, the hydraulic and permselective properties of the hemodialysis membranes have also been deeply investigated. An overview of recent progress of different kinds of hemodialysis membranes and their preparation technology, as well as their modification techniques, is presented. The advantages and deficiencies of many synthetic membranes, including cellulose, cellulose acetate (CA), chitosan (CS), polysulfone (PS), poly(ether sulfone) (PES), polyacrylonitrile (PAN), ethylene-vinyl alcohol copolymer (EVOH), poly (methyl methacrylate) (PMMA) and poly(vinyl alcohol) (PVA), etc. are elaborated upon.

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