32 research outputs found

    New insights into the key role of HIF-1α in IL-10-producing B cells

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    Hypoxia-inducible factors (HIFs) are essential transcription factors for the cellular response to hypoxia. Expression and stabilization of HIFs can be triggered by hypoxia or by other factors under pathological stress such as inflammation and infection. Indeed, regulatory function of HIFs has been implicated in a variety of different immune cells like macrophages and T cells. In our recent study, we delineated HIF-1α and HIF-2α roles in B cells (Nat Commun, 9:251). We demonstrated that lack of HIF-1α in B cells leads to impaired IL-10-producing CD1dhiCD5+ B cells expansion by modulating their glycolytic metabolism. We identified HIF-1α as a critical transcriptional factor involved in IL-10 production by B cells, thereby influencing the course of autoimmune diseases

    Design of the Anti-tuberculosis Drugs induced Adverse Reactions in China National Tuberculosis Prevention and Control Scheme Study (ADACS)

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    <p>Abstract</p> <p>Background</p> <p>More than 1 million tuberculosis (TB) patients are receiving the standard anti-TB treatment provided by China National Tuberculosis Prevention and Control Scheme (CNTS) in China every year. Adverse reactions (ADRs) induced by anti-TB drugs could both do harm to patients and lead to anti-TB treatment failure. The ADACS aimed to explore ADRs' incidences, prognoses, economical and public health impacts for TB patients and TB control, and build a DNA bank of TB patients.</p> <p>Methods/Design</p> <p>Multiple study designs were adopted. Firstly, a prospective cohort with 4488 sputum smears positive pulmonary tuberculosis patients was established. Patients were followed up for 6-9 months in 52 counties of four regions. Those suspected ADRs should be checked and confirmed by Chinese State Food and Drug Administration (SFDA). Secondly, if the suspected ADR was anti-TB drug induced liver injury (ATLI), a nested case-control study would be performed which comprised choosing a matched control and doing a plus questionnaire inquiry. Thirdly, health economical data of ADRs would be collected to analyze financial burdens brought by ADRs and cost-effectiveness of ADRs' treatments. Fourthly, a drop of intravenous blood for each patient was taken and saved in FTA card for DNA banking and genotyping. Finally, the demographic, clinical, environmental, administrative and genetic data would be merged for the comprehensive analysis.</p> <p>Discussion</p> <p>ADACS will give an overview of anti-TB drugs induced ADRs' incidences, risk factors, treatments, prognoses, and clinical, economical and public health impacts for TB patients applying CNTS regimen in China, and provide suggestions for individualized health care and TB control policy.</p

    Die Rolle von Hypoxie-induzierender Faktor-1a für IL-10-produzierende B-Zellen in Autoimmunkrankheiten

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    Hypoxia-inducible factors (HIFs) are key elements for controlling immune cell metabolism and functions. While HIFs are known to be involved in T cells and macrophages activation, their functions in B lymphocytes are poorly defined. Herein, we reported the unexpected finding that hypoxia-inducible factor-1α (HIF-1α), but not HIF-2α, is critically required for IL-10-producing B cells. Hif1α-deficient and Hif2α-deficient B cells show normal proliferation, apoptosis and antibody production. We found that B1a and Marginal zone (Mz) B cell subsets are significantly decrease in α-deficient mice, but not Hif2α-deficient mice. We also showed that HIF-1α transcriptionally regulates Il10 mRNA expression via binding to its promoter and that HIF-1α-dependent glycolysis facilitates CD1dhiCD5+ B cells expansion. Mice with B cell-specific deletion of Hif1α have reduced number of IL-10-producing B cells, which result in an exacerbated collagen-induced arthritis and experimental autoimmune encephalomyelitis. Wild-type CD1dhiCD5+ B cells, but not Hif1α-deficient CD1dhiCD5+ B cells, protect recipient mice from autoimmune disease, while the protective function of Hif1α-deficient CD1dhiCD5+ B cells is restored when their defective IL-10 expression is genetically corrected. Taken together, this study demonstrates the key function of the hypoxia-associated transcription factor HIF-1α in driving IL-10 expression in CD1dhiCD5+ B cells, and in controlling their protective activity in autoimmune disease.Hypoxie-induzierende Faktoren (Hypoxia-inducible factors, HIFs) sind Schlüsselelemente die den Stoffwechsel und die Funktion von Immunzellen kontrollieren. Obwohl bekannt ist, dass HIFs bei der Aktivierung von Makrophagen und T-Zellen involviert sind, wurde deren Funktion in B-Zellen bisher kaum beschrieben. Hier konnten wir zeigen, dass der Hypoxie-induzierender Faktor-1α (hypoxia-inducible factor-1α, HIF-1α) überraschenderweise unerlässlich für IL10-produzierende B-Zellen ist. HIF-1α und HIF-2α defiziente B-Zellen zeigen stereotype Proliferation, Apoptose und Antikörper Produktion. Außerdem haben wir beobachtet, dass B1a und Marginalzonen B-Zell Subtypen signifikant verringert sind in HIF-1α aber nicht HIF-2α defizienten Mäusen. Wir zeigten, dass HIF-1α durch Bindung an den eigenen Promotor die Il10-Expression transkriptionell reguliert. Außerdem zeigten wir, dass die HIF-1α abhängige Glykolyse die Expansion von CD1dhiCD5+ B-Zellen fördert. Mäuse mit einer B-Zell spezifischen Hif1α-Deletion haben weniger IL10-produzierenden B-Zellen, was zu einer akuten Verschlechterung der Kollagen-induzierten Arthritis sowie Experimentellen Autoimmunen Encephalomyelitis führt. Im Gegensatz zu Hif1α defizienten CD1dhiCD5+ B-Zellen, schützen Wildtyp CD1dhiCD5+ B-Zellen die Mäuse vor Autoimmunerkrankung und durch die Restoration der defekten IL10 Expression in Hif1α defizienten CD1dhiCD5+ B-Zellen, wird auch deren protektive Funktion wiederhergestellt. Zusammenfassend zeigt diese Arbeit, dass HIF-1α eine Schlüsselfunktion bei der Förderung der IL10 Expression in CD1dhiCD5+ B-Zellen, sowie bei der Kontrolle der protektiven Aktivität dieser Zellen in Autoimmunerkrankungen hat

    Reflection on EFL/ESL Teachers' Emotional Creativity and Students L2 Engagement

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    Emotions are one of the pillars of all human beings which can play a vital role in providing education. Emotions can affect all aspects of education. The feeling of creativity is one of the subsets of emotions. This feeling strongly affects the performance of education and the level of involvement of students. Student involvement has different aspects: social aspect; individual aspect, and emotional aspect. The present review shows that the emotional aspect of L2 engagement plays a pivotal role in the process of learning the language in English as a foreign language (EFL) and English as a second language (ESL) context. In dealing with the emotional aspect of teachers, the personal, social, and environmental aspects of the individual should be considered. The paper concludes with some pedagogical implications and provides some suggestions for future research

    Highly sensitive detection of organophosphorus pesticides represented by methamidophos via inner filter effect of Au nanoparticles on the fluorescence of CdTe quantum dots

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    A sensitive fluorescence detection method of organophosphate pesticides (OPs) represented by methamidophos was developed using the inner filter effect (IFE) of Au nanoparticles (AuNPs) on CdTe quantum dots (QDs). The fluorescence of CdTe QDs was remarkably quenched with the presence of AuNPs via IFE. Acetylcholinesterase (AChE) catalyzed the hydrolysis of acetylthiocholine into thiocholine, which could induce the aggregation of AuNPs and decrease their characteristic absorption, making IFE-decreased fluorescence of CdTe QDs recovered. OPs can inhibit the activity of AChE, thus preventing the aggregation of AuNPs and the fluorescence recovery of CdTe QDs. Therefore, the IFE of fluorescence between AuNPs and CdTe QDs could convert the absorption signal to fluorescence signal, which improved the detection sensitivity of OPs in vegetables. Under the optimum conditions, the response was linearly proportional to the concentration of methamidophos in the range of 0.06 similar to 0.78 mg/kg with a detection limit of 2 mu g/kg (3 sigma) which was superior to the method of GB/T 5009.199-2003. The proposed assay exhibited good reproducibility and accuracy, providing a simple and rapid method for the screening of OPs

    TBHQ Attenuates Neurotoxicity Induced by Methamphetamine in the VTA through the Nrf2/HO-1 and PI3K/AKT Signaling Pathways

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    Methamphetamine (METH) leads to nervous system toxicity. Long-term exposure to METH results in damage to dopamine neurons in the ventral tegmental area (VTA), and depression-like behavior is a clinical symptom of this toxicity. The current study was designed to investigate whether the antioxidant tertiary butylhydroquinone (TBHQ) can alleviate neurotoxicity through both antioxidative stress and antiapoptotic signaling pathways in the VTA. Rats were randomly divided into a control group, a METH-treated group (METH group), and a METH+TBHQ-treated group (METH+TBHQ group). Intraperitoneal injections of METH at a dose of 10 mg/kg were administered to the rats in the METH and METH+TBHQ groups for one week, and METH was then administered at a dose that increased by 1 mg/kg per week until the sixth week, when the daily dosage reached 15 mg/kg. The rats in the METH+TBHQ group received 12.5 mg/kg TBHQ intragastrically. Chronic exposure to METH resulted in increased immobility times in the forced swimming test (FST) and tail suspension test (TST) and led to depression-like behavior. The production of reactive oxygen species (ROS) and apoptosis levels were increased in the VTA of animals in the METH-treated group. METH downregulated Nrf2, HO-1, PI3K, and AKT, key factors of oxidative stress, and the apoptosis signaling pathway. Moreover, METH increased the caspase-3 immunocontent. These changes were reversed by treatment with the antioxidant TBHQ. The results indicate that TBHQ can enhance Nrf2-induced antioxidative stress and PI3K-induced antiapoptotic effects, which can alleviate METH-induced ROS and apoptosis, and that the crosstalk between Nrf2 and PI3K/AKT is likely the key factor involved in the protective effect of TBHQ against METH-induced chronic nervous system toxicity

    Intratumor Heterogeneity Correlates With Reduced Immune Activity and Worse Survival in Melanoma Patients

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    Background Human malignant melanoma is a highly aggressive, heterogeneous and drug-resistant cancer. Due to a high number of clones, harboring various mutations that affect key pathways, there is an exceptional level of phenotypic variation and intratumor heterogeneity (ITH) in melanoma. This poses a significant challenge to personalized cancer medicine. Hitherto, it remains unclear to what extent the heterogeneity of melanoma affects the immune microenvironment. Herein, we explore the interaction between the tumor heterogeneity and the host immune response in a melanoma cohort utilizing The Cancer Genome Atlas (TCGA). Methods Clonal Heterogeneity Analysis Tool (CHAT) was used to estimate intratumor heterogeneity, and immune cell composition was estimated using CIBERSORT. The Overall Survival (OS) among groups was analyzed using Kaplan–Meier curves with the log-rank test and multivariate cox regression. RNA-seq data were evaluated to identify differentially expressed immunomodulatory genes. The reverse phase protein array (RPPA) data platform was used to validate immune responses at protein level. Results Tumors with high heterogeneity were associated with decreased overall survival (p = 0.027). High CHAT tumors were correlated with less infiltration by anti-tumor CD8 T cells (p = 0.0049), T follicular cells (p = 0.00091), and M1 macrophages (p = 0.0028), whereas tumor-promoting M2 macrophages were increased (p = 0.02). High CHAT tumors correlated with a reduced expression of immunomodulatory genes, particularly Programmed Cell Death 1 (PD1) and its ligand PD-L1. In addition, high CHAT tumors exhibited lower immune Cytotoxic T lymphocytes (CTLs)-mediated toxicity pathway score (p = 2.9E−07) and cytotoxic pathway score (p = 2.9E−08). High CHAT tumors were also associated with a lower protein level of immune-regulatory kinases, such as lymphocyte-specific protein tyrosine kinase (LCK) (p = 3.4e−5) and spleen tyrosine kinase (SYK) (p = 0.0011). Conclusions Highly heterogeneous melanoma tumors are associated with reduced immune cell infiltration and immune response activation as well as decreased survival. Our results reveal that intratumor heterogeneity is an indicative factor for patient survival due to its impact on anti-tumor immune response

    Hypoxia-inducible factor-1α is a critical transcription factor for IL-10-producing B cells in autoimmune disease

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    B cells are important for antigen presentation and antibody production in humoral immunity, but are also increasingly recognized for their immune regulatory functions. Here the authors show that HIF-1α, a hypoxia-induced transcription factor, is important for controlling IL-10 induction in and immune-suppressive activity of B cells
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