Eosinophils promote CD8+ T cell memory generation to potentiate anti-bacterial immunity.

Memory CD8+ T cell generation is crucial for pathogen elimination and effective vaccination against infection. The cellular and molecular circuitry that underlies the generation of memory CD8+ T cells remains elusive. Eosinophils can modulate inflammatory allergic responses and interact with lymphocytes to regulate their functions in immune defense. Here we report that eosinophils are required for the generation of memory CD8+ T cells by inhibiting CD8+ T cell apoptosis. Eosinophil-deficient mice display significantly impaired memory CD8+ T cell response and weakened resistance against Listeria monocytogenes (L.m.) infection. Mechanistically, eosinophils secrete interleukin-4 (IL-4) to inhibit JNK/Caspase-3 dependent apoptosis of CD8+ T cells upon L.m. infection in vitro. Furthermore, active eosinophils are recruited into the spleen and secrete more IL-4 to suppress CD8+ T cell apoptosis during early stage of L.m. infection in vivo. Adoptive transfer of wild-type (WT) eosinophils but not IL-4-deficient eosinophils into eosinophil-deficient mice could rescue the impaired CD8+ T cell memory responses. Together, our findings suggest that eosinophil-derived IL-4 promotes the generation of CD8+ T cell memory and enhances immune defense against L.m. infection. Our study reveals a new adjuvant role of eosinophils in memory T cell generation and provides clues for enhancing the vaccine potency via targeting eosinophils and related cytokines.

Customizing cancer treatment at the nanoscale: a focus on anaplastic thyroid cancer therapy.

Anaplastic thyroid cancer (ATC) is a rare but highly aggressive kind of thyroid cancer. Various therapeutic methods have been considered for the treatment of ATC, but its prognosis remains poor. With the advent of the nanomedicine era, the use of nanotechnology has been introduced in the treatment of various cancers and has shown great potential and broad prospects in ATC treatment. The current review meticulously describes and summarizes the research progress of various nanomedicine-based therapeutic methods of ATC, including chemotherapy, differentiation therapy, radioiodine therapy, gene therapy, targeted therapy, photothermal therapy, and combination therapy. Furthermore, potential future challenges and opportunities for the currently developed nanomedicines for ATC treatment are discussed. As far as we know, there are few reviews focusing on the nanomedicine of ATC therapy, and it is believed that this review will generate widespread interest from researchers in a variety of fields to further expedite preclinical research and clinical translation of ATC nanomedicines.

Aptamer-functionalised metal-organic frameworks as an 'on-off-on' fluorescent sensor for bisphenol S detection.

Bisphenol S (BPS) is an industrial chemical that is widely used to manufacture daily items, such as plastic water bottles, milk bottles, water cups, and paper products. BPS is a biologically toxic environmental endocrine disruptor. Long-term exposure to BPS can disrupt the reproductive system, endanger health, and increase the risk of cancer. The metal-organic framework UiO-66 is characterised with high thermal and chemical stability, a simple synthetic route, and low preparation cost. In this study, we modified UiO-66 with nucleic acid aptamers to prepare an 'on-off-on' fluorescent sensor for the simple and rapid detection of BPS. The FAM-labelled aptamer was selected as the fluorescent probe (i.e. 'on'). In the presence of UiO-66, the FAM-labelled aptamer adsorbed onto the surface of the UiO-66 material, and the fluorescence of FAM was quenched by photoinduced electron transfer (i.e. 'off'). When BPS was introduced into the system, the configuration of the FAM-labelled aptamer changed after binding to BPS, and the adsorption of FAM on UiO-66 weakened, resulting in fluorescence recovery (i.e. 'on'). Based on this principle, the reaction system was optimised, and the BPS content was analysed according to the change in the fluorescence signal. The signals changed linearly in the BPS concentration range of 2.0 × 10-4-4.0 × 10-2 mmol L-1, and the system had a detection limit of 1.84 × 10-4 mmol L-1. The sensor was successfully used to detect the BPS content in commercial plastic bottled water.

Effect of Prenatal Perineal Massage on Postpartum Perineal Injury and Postpartum Complications: A Meta-Analysis.

Background: The efficacy of perineal massage is controversial. The study was aimed at comparing the effects of perineal massage on perineal injury and complications. Methods: PubMed, Embase, the Cochrane Library, and ISI Web of Science were searched for literature on the relationship between prenatal perineal massage and postpartum perineal injury and complications until April 2022. Indicators included postpartum perineal tears, perineotomy, postpartum perineal pain, natural labour, and postpartum incontinence. Finally, RevMan5.4 software was used to analyze the extracted data. Results: A total of 6487 subjects in 16 studies were included, with 3211 who received perineal massage and 3276 did not. There was no significant difference in 1-2 degree perineal tearing between the intervention group and the control group (RR = 0.96, 95% CI [0.90, 1.03], P = 0.30), and there was no heterogeneity between studies (P = 0.62, I 2 = 0%), indicating publication bias. Compared with the control group, prenatal perineal massage significantly reduced the incidence of 3-4 degree perineal tears (RR = 0.56, 95% CI [0.47, 0.67], P < 0.00001), and there was no heterogeneity between studies (P = 0.16, I 2 = 30%), indicating publication bias. Compared with the control group, prenatal perineal massage reduced the risk of lateral perineal resection (RR = 0.87, 95% CI [0.80, 0.95], P = 0.001), and there was no heterogeneity between studies (P = 0.14, I 2 = 31%), and there was no publication bias. Compared with the control group, prenatal perineal massage reduced the risk of postpartum pain at 3 months (RR = 0.64, 95% CI [0.51, 0.81], P = 0.0002). There was no significant heterogeneity among studies (P = 0.23, I 2 = 31%). Conclusion: Compared with no prenatal perineal massage, prenatal perineal massage can reduce the risk of perineal injury, the incidence of lateral perineal resection, and the incidence of long-term pain.

[Value of autotaxin in predicting refractory Mycoplasma pneumoniae pneumonia in children and its correlation with inflammatory cytokines]. / Autotaxinå¯¹å„¿ç«¥éš¾æ²»æ€§è‚ºç‚Žæ”¯åŽŸä½“è‚ºç‚Žçš„é¢„æµ‹ä»·å€¼åŠå ¶ä¸Žç‚Žæ€§ç»†èƒžå› å­çš„ç›¸å ³æ€§.

OBJECTIVES: To study the value of autotaxin (an autocrine motility factor) level in serum and bronchoalveolar lavage fluid (BALF) in predicting refractory Mycoplasma pneumoniae pneumonia (RMPP) in children and its correlation with interleukin-6 (IL-6), interleukin-8 (IL-8), and C-reactive protein (CRP). METHODS: A retrospective analysis was performed on 238 children with Mycoplasma pneumoniae pneumonia who were admitted from January 2019 to December 2021. According to disease severity, they were divided into two groups: RMPP (n=82) and general Mycoplasma pneumoniae pneumonia (GMPP; n=156). The two groups were compared in terms of the levels of autotaxin, IL-6, IL-8, and CRP in serum and BALF to study the value of autotaxin level in serum and BALF in predicting RMPP in children, as well as the correlation of autotaxin level with IL-6, IL-8, and CRP in children with RMPP. RESULTS: Compared with the GMPP group, the RMPP group had significantly higher levels of autotaxin, IL-6, IL-8, and CRP in serum and BALF (P<0.05). For the children with RMPP, the levels of autotaxin, IL-6, IL-8, and CRP in serum and BALF in the acute stage were significantly higher than those in the convalescent stage (P<0.05). The receiver operating characteristic (ROC) curve showed that the level of autotaxin in serum and BALF had a good value in predicting RMPP in children, with an area under the curve of 0.874 (95%CI: 0.816-0.935) and 0.862 (95%CI: 0.802-0.924), respectively. The correlation analysis showed that the level of autotaxin in serum and BALF was positively correlated with IL-6, IL-8, and CRP levels (P<0.001). CONCLUSIONS: The level of autotaxin in serum and BALF increases and is correlated with the degree of disease recovery and inflammatory cytokines in children with RMPP. Autotaxin can be used as a predictive indicator for RMPP in children.

Clinical efficacy and safety of the Jinfeng pill in the adjuvant treatment of infertility in patients with polycystic ovary syndrome: a systematic review and meta-analysis of randomized controlled trial.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a common endocrine disease leading to infertility in women of childbearing age. Adjuvant therapy with Jinfeng pills (a traditional Chinese medicine) can increase ovarian blood flow, regulate female endocrine levels, and achieve good therapeutic effect. A systematic review and meta-analysis were conducted to examine the efficacy and safety of Jinfeng pills. METHODS: The PubMed (2000 to August 2021), Excerpta Medica Database (2000 to August 2021), Chinese Biomedical Literature (2000 to August 2021), and China National Knowledge Infrastructure (2000 to August 2021) databases were searched. All patients with PCOS were included in the randomized controlled study of Jinfeng pills combined with an adjuvant Western medicine treatment. After screening and a risk of bias assessment, Stata16.0 software was used for the analysis. RESULTS: A total 7 of articles (comprising 691 patients; 26-83 participants per group) were included in the meta-analysis. The meta-analysis showed that the effective rate the experimental group treated with Jinfeng pills combined with adjuvant Western medicine was higher than that of the control group treated with Western medicine only [relative risk (RR) =1.15, 95% confidence interval (CI): 1.03 to 1.28; P=0.015]. After treatment, the follicle-stimulating hormone level of the experimental group was significantly lower than that of the control group [mean difference (MD) =-5.10, 95% CI: -7.95 to -2.24; P=0.0005], the estradiol level of the experimental group was significantly higher than that of the control group (MD =10.74, 95% CI: 4.19 to 17.29; P=0.001), the testosterone level of the experimental group was significantly lower than that of the control group (MD =-1.17, 95% CI: -2.09 to -0.25; P=0.01), and the pregnancy rate of the experimental group was significantly higher than that of the control group (RR =1.36, 95% CI: 1.13 to 1.64; Z=3.183; P=0.001). DISCUSSION: The therapeutic effect of Jinfeng pills combined with Western medicine in treating PCOS was better than that of Western medicine alone, and there was no increase in adverse reactions.

Situated impoliteness revisited: Blunt anti-epidemic slogans and conflicting comments during the coronavirus outbreak in China.

In this paper, blunt slogans used in China's health campaign against coronavirus are closely examined and the public's conflicting comments on them are analyzed. These slogans, due to their extreme effectiveness in making the public comply with the health preventive measures suggested by the government, are called Yinghe or "hardcore" slogans by the Chinese people. Containing harsh and taboo language, they convey threats of death and disease, insults or negative evaluation, and harsh demands. Despite their impolite nature, "hardcore" slogans have received significantly more positive judgment than negative judgment, especially when they made their debut in rural areas in Henan, an agricultural province in China. Criticism towards these blunt slogans then gradually increased after their initial appearance. Plausible factors contributing to the change of judgment are analyzed. The public's conflicting judgment regarding the impoliteness of the slogans may be related to the public's different positioning across time and space. This study shows that impoliteness is a practice situated not only in discourse, genres, and institutions, but also in social, cultural, and political contexts. More attention should be paid to impoliteness in special social configurations (e.g., rural areas) and social emergencies, which not only contextualize a discourse event but also define it.

Application of a titanium-based metal-organic framework to protein kinase activity detection and inhibitor screening.

In this work, we used a titanium-based metal-organic framework (MOF, Ti-MIL125-NH2) as a novel enrichment platform to detect protein kinase A (PKA) activity and to screen relevant kinase inhibitors. This method took advantage of the highly specific recognition of phosphate groups by the Ti-MIL125-NH2 nanoparticle. In the presence of PKA and adenosine 5'-triphosphate (ATP), the fluorophore-labeled peptide substrate was phosphorylated, and the generated phosphopeptide could then specifically bind to the titanium sites of Ti-MIL125-NH2. This resulted in fluorescence enrichment, which could be efficiently detected by the system. Under optimal conditions, the method presented a linear relationship in the experimental range of 0.00005-0.01 U µL-1, and the limit of detection was 0.00003 U µL-1 (3σ, n = 11). Furthermore, protein kinase Akt1 was tested to verify the universality of this method. The method was also successfully applied in cell lysates for kinase activity analysis and inhibitor screening. Thus, the new, highly sensitive fluorescence method based on MOF for detecting PKA activity is an excellent tool that has potential applications in kinase-related disease and basic research.

[Simultaneous determination of amino acid and monoamine neurotransmitters in serum by high performance liquid chromatography coupled with precolumn derivatization].

Using o-phthalaldehyde (OPA) as the derivatization reagent, a precolumn derivatized -high performance liquid chromatography (HPLC) method was developed for the simultaneous determination of amino acid neurotransmitters taurine (Tau), glutamic acid (Glu), glycine(Gly), and γ -aminobutyric acid (γ-GABA), as well as the monoamine neurotransmitter dopamine (DA), in serum samples. The samples and ethanol were mixed at a volume ratio of 1:2 (v/v) for protein precipitation. After centrifugation, the supernatant was withdrawn and blown to dryness using nitrogen. The residue was pre-column derivatized with OPA, and the derivatized product was isolated by gradient elution ona Luna 5u C18 column (250 mm×4.6 mm, 5 µm). Under the optimal experimental conditions, the five neurotransmitters showed good linearities (r2 ≥ 0.9866). The limits of detection were between 0.10 and 0.40 µmol/L. The spiked recoveries at different spiked levels were 87.57%-115.31%, and the RSDs were below 7.80%. This method is simple, sensitive, and it can be promised for the simultaneous detection of amino acid and monoamine neurotransmitters.

mKLRL1 regulates the maturation of dendritic cells and plays important roles in immune tolerance.

KLRL1 is a member of C-type lectin-like receptors (CLEC) and preferentially expressed on the surface of immune cells. We have previously illustrated its inhibitory role in Natural killer (NK) cells. Though cloned from dendritic cells (DCs), its role in DCs has not been fully identified. Here, we found that mKLRL1 markedly decreased during DC maturation; mKLRL1-modifed DCs showed enhanced phagocytic capability and reduced ability to induce T cell proliferation, which mimics immature DCs. Further investigation revealed that IL-10 was indispensable for mKLRL1 to suppress DC maturation. And p38 activation was responsible for preferential IL-10 production. Pretreatment with mKLRL1-modified DCs protected mice from subsequently EAE induction, indicating a role in immune tolerance. Taken together, our results have revealed an inhibitory role of KLRL1 in mouse DCs.

Tumor-educated B cells selectively promote breast cancer lymph node metastasis by HSPA4-targeting IgG.

Primary tumors may create the premetastatic niche in secondary organs for subsequent metastasis. Humoral immunity contributes to the progression of certain cancers, but the roles of B cells and their derived antibodies in premetastatic niche formation are poorly defined. Using a mouse model of spontaneous lymph node metastasis of breast cancer, we show that primary tumors induced B cell accumulation in draining lymph nodes. These B cells selectively promoted lymph node metastasis by producing pathogenic IgG that targeted glycosylated membrane protein HSPA4, and activated the HSPA4-binding protein ITGB5 and the downstream Src/NF-κB pathway in tumor cells for CXCR4/SDF1α-axis-mediated metastasis. High serum anti-HSPA4 IgG was correlated with high tumor HSPA4 expression and poor prognosis of breast cancer subjects. Our findings identify a key role for tumor-educated B cells and their derived antibodies in lymph node premetastatic niche formation, providing potential targets for cancer intervention.

Fluorescence Method for the Detection of Protein Kinase Activity by Using a Zirconium-Based Metal-Organic Framework as an Affinity Probe.

In cell-signaling pathways, protein kinases are critical and ubiquitous regulators. Abnormal kinase activity leads to many major diseases; therefore, simple and efficient methods for detecting protein kinases are in high demand. This study proposed a simple, rapid fluorescence-based sensor for protein kinase activity analysis, using the zirconium-based metal organic framework UiO-66 as a highly efficient affinity probe. UiO-66 has a large specific surface area, good stability, and a large number of Zr defect sites, which can efficiently identify phosphorylation sites. UiO-66 is an ideal nanoreactor that can efficiently enrich phosphorylated peptides. Under optimal experimental conditions, the increased fluorescence intensity was directly proportional to the protein kinase activity. The lower limit of detection was 0.00005 U·µL-1. The assay could also be used for the screening of protein kinase inhibitors, could determine the activity of other kinds of kinases, and was universally applicable. This method was used for protein kinase activity detection in drug-stimulated MCF-7 cell lysates and demonstrated its potential applicability in kinase-related research.

Phosphorylation-Mediated IFN-γR2 Membrane Translocation Is Required to Activate Macrophage Innate Response.

As a critical step during innate response, the cytoplasmic ß subunit (IFN-γR2) of interferon-γ receptor (IFN-γR) is induced and translocates to plasma membrane to join α subunit to form functional IFN-γR to mediate IFN-γ signaling. However, the mechanism driving membrane translocation and its significance remain largely unknown. We found, unexpectedly, that mice deficient in E-selectin, an endothelial cell-specific adhesion molecule, displayed impaired innate activation of macrophages upon Listeria monocytogenes infection yet had increased circulating IFN-γ. Inflammatory macrophages from E-selectin-deficient mice had less surface IFN-γR2 and impaired IFN-γ signaling. BTK elicited by extrinsic E-selectin engagement phosphorylates cytoplasmic IFN-γR2, facilitating EFhd2 binding and promoting IFN-γR2 trafficking from Golgi to cell membrane. Our findings demonstrate that membrane translocation of cytoplasmic IFN-γR2 is required to activate macrophage innate response against intracellular bacterial infection, identifying the assembly of functional cytokine receptors on cell membrane as an important layer in innate activation and cytokine signaling.

Tumor-Induced Generation of Splenic Erythroblast-like Ter-Cells Promotes Tumor Progression.

Identifying tumor-induced leukocyte subsets and their derived circulating factors has been instrumental in understanding cancer as a systemic disease. Nevertheless, how primary tumor-induced non-leukocyte populations in distal organs contribute to systemic spread remains poorly defined. Here, we report one population of tumor-inducible, erythroblast-like cells (Ter-cells) deriving from megakaryocyte-erythroid progenitor cells with a unique Ter-119+CD45-CD71+ phenotype. Ter-cells are enriched in the enlarged spleen of hosts bearing advanced tumors and facilitate tumor progression by secreting neurotrophic factor artemin into the blood. Transforming growth factor ß (TGF-ß) and Smad3 activation are important in Ter-cell generation. In vivo blockade of Ter-cell-derived artemin inhibits hepatocellular carcinoma (HCC) growth, and artemin deficiency abolishes Ter-cells' tumor-promoting ability. We confirm the presence of splenic artemin-positive Ter-cells in human HCC patients and show that significantly elevated serum artemin correlates with poor prognosis. We propose that Ter-cells and the secreted artemin play important roles in cancer progression with prognostic and therapeutic implications.

Inflammation-induced CD69+ Kupffer cell feedback inhibits T cell proliferation via membrane-bound TGF-ß1.

Kupffer cells, tissue-resident macrophage lineage cell, are enriched in vertebrate liver. The mouse F4/80+ Kupffer cells have been subclassified into two subpopulations according to their phenotype and function: CD68+ subpopulation with potent reactive oxygen species (ROS) production and phagocytic capacities, and CD11b+ subpopulation with a potent capacity to produce T helper 1 cytokines. In addition, CD11b+ Kupffer cells/macrophages may be migrated from the bone marrow or spleen, especially in inflammatory conditions of the liver. For analyzing diverse Kupffer cell subsets, we infected mice with Listeria monocytogenes and analyzed the phenotype variations of hepatic Kupffer cells. During L. monocytogenes infection, hepatic CD69+ Kupffer cells were significantly induced and expanded, and CD69+ Kupffer cells expressed higher level of CD11b, and particularly high level of membrane-bound TGF-ß1 (mTGF-ß1) but lower level of F4/80. We also found that clodronate liposome administration did not eliminate hepatic CD69+ Kupffer cell subset. We consider the hepatic CD69+ Kupffer cell population corresponds to CD11b+ Kupffer cells, the bone marrow-derived population. Hepatic CD69+ Kupffer cells suppressed Ag-nonspecific and OVA-specific CD4 T cell proliferation through mTGF-ß1 both in vitro and in vivo, meanwhile, they did not interfere with activation of CD4 T cells. Thus, we have identified a new subset of inflammation-induced CD69+ Kupffer cells which can feedback inhibit CD4 T cell response via cell surface TGF-ß1 at the late stage of immune response against infection. CD69+ Kupffer cells may contribute to protect host from pathological injure by preventing overactivation of immune response.

Tumor Exosomal RNAs Promote Lung Pre-metastatic Niche Formation by Activating Alveolar Epithelial TLR3 to Recruit Neutrophils.

The pre-metastatic niche educated by primary tumor-derived elements contributes to cancer metastasis. However, the role of host stromal cells in metastatic niche formation and organ-specific metastatic tropism is not clearly defined. Here, we demonstrate that lung epithelial cells are critical for initiating neutrophil recruitment and lung metastatic niche formation by sensing tumor exosomal RNAs via Toll-like receptor 3 (TLR3). TLR3-deficient mice show reduced lung metastasis in the spontaneous metastatic models. Mechanistically, primary tumor-derived exosomal RNAs, which are enriched in small nuclear RNAs, activate TLR3 in lung epithelial cells, consequently inducing chemokine secretion in the lung and promoting neutrophil recruitment. Identification of metastatic axis of tumor exosomal RNAs and host lung epithelial cell TLR3 activation provides potential targets to control cancer metastasis to the lung.

Tet2 is required to resolve inflammation by recruiting Hdac2 to specifically repress IL-6.

Epigenetic modifiers have fundamental roles in defining unique cellular identity through the establishment and maintenance of lineage-specific chromatin and methylation status. Several DNA modifications such as 5-hydroxymethylcytosine (5hmC) are catalysed by the ten eleven translocation (Tet) methylcytosine dioxygenase family members, and the roles of Tet proteins in regulating chromatin architecture and gene transcription independently of DNA methylation have been gradually uncovered. However, the regulation of immunity and inflammation by Tet proteins independent of their role in modulating DNA methylation remains largely unknown. Here we show that Tet2 selectively mediates active repression of interleukin-6 (IL-6) transcription during inflammation resolution in innate myeloid cells, including dendritic cells and macrophages. Loss of Tet2 resulted in the upregulation of several inflammatory mediators, including IL-6, at late phase during the response to lipopolysaccharide challenge. Tet2-deficient mice were more susceptible to endotoxin shock and dextran-sulfate-sodium-induced colitis, displaying a more severe inflammatory phenotype and increased IL-6 production compared to wild-type mice. IκBζ, an IL-6-specific transcription factor, mediated specific targeting of Tet2 to the Il6 promoter, further indicating opposite regulatory roles of IκBζ at initial and resolution phases of inflammation. For the repression mechanism, independent of DNA methylation and hydroxymethylation, Tet2 recruited Hdac2 and repressed transcription of Il6 via histone deacetylation. We provide mechanistic evidence for the gene-specific transcription repression activity of Tet2 via histone deacetylation and for the prevention of constant transcription activation at the chromatin level for resolving inflammation.