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"Cao, T"
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Facing China as a new global superpower : domestic and international dynamics from a multidisciplinary angle
\"This book brings together diverse perspectives from the newest generation of scholars from Canada and China to better understand China in the 21st century. It examines China's socio-political structure, its particular relationship with Canada, and interaction with the international community; and discusses how to overcome the ideological differences between the two countries to establish positive and sustainable Canada-China bilateral relations for the future. Importantly, the perspectives are from young authors, with a different relationship to China (and Canada) than more established authors. This compilation helps breathe new life into the study of Sino-Canada relations from both countries, and to reassess and re-frame issues related to China in the 21st century\" -- Provided by publisher.
Book
The Mediator complex regulates enhancer-promoter interactions
Enhancer-mediated gene activation generally requires physical proximity between enhancers and their target gene promoters. However, the molecular mechanisms by which interactions between enhancers and promoters are formed are not well understood. Here, we investigate the function of the Mediator complex in the regulation of enhancer-promoter interactions, by combining rapid protein depletion and high-resolution MNase-based chromosome conformation capture approaches. We show that depletion of Mediator leads to reduced enhancer-promoter interaction frequencies, which are associated with a strong decrease in gene expression. In addition, we find increased interactions between CTCF-binding sites upon Mediator depletion. These changes in chromatin architecture are associated with a redistribution of the Cohesin complex on chromatin and a reduction in Cohesin occupancy at enhancers. Together, our results indicate that the Mediator and Cohesin complexes contribute to enhancer-promoter interactions and provide insights into the molecular mechanisms by which communication between enhancers and promoters is regulated.
Here, the authors map chromatin conformation at high resolution after rapid Mediator depletion to show that its loss reduces the frequency of enhancer-promoter interactions and associated gene expression, with a corresponding redistribution of Cohesin.
Journal Article
Comprehensive prediction of secondary metabolite structure and biological activity from microbial genome sequences
Novel antibiotics are urgently needed to address the looming global crisis of antibiotic resistance. Historically, the primary source of clinically used antibiotics has been microbial secondary metabolism. Microbial genome sequencing has revealed a plethora of uncharacterized natural antibiotics that remain to be discovered. However, the isolation of these molecules is hindered by the challenge of linking sequence information to the chemical structures of the encoded molecules. Here, we present PRISM 4, a comprehensive platform for prediction of the chemical structures of genomically encoded antibiotics, including all classes of bacterial antibiotics currently in clinical use. The accuracy of chemical structure prediction enables the development of machine-learning methods to predict the likely biological activity of encoded molecules. We apply PRISM 4 to chart secondary metabolite biosynthesis in a collection of over 10,000 bacterial genomes from both cultured isolates and metagenomic datasets, revealing thousands of encoded antibiotics. PRISM 4 is freely available as an interactive web application at
http://prism.adapsyn.com
.
Large-scale sequencing efforts have uncovered a large number of secondary metabolic pathways, but the chemicals they synthesise remain unknown. Here the authors present PRISM 4, which predicts the chemical structures encoded by microbial genome sequences, including all classes of bacterial antibiotics in clinical use.
Journal Article
Microbiota metabolite short-chain fatty acid acetate promotes intestinal IgA response to microbiota which is mediated by GPR43
Intestinal IgA, which is regulated by gut microbiota, has a crucial role in maintenance of intestinal homeostasis and in protecting the intestines from inflammation. However, the means by which microbiota promotes intestinal IgA responses remain unclear. Emerging evidence suggests that the host can sense gut bacterial metabolites in addition to pathogen-associated molecular patterns and that recognition of these small molecules influences host immune response in the intestines and beyond. We reported here that microbiota metabolite short-chain fatty acid acetate promoted intestinal IgA responses, which was mediated by “metabolite-sensing” GPR43. GPR43−/− mice demonstrated lower levels of intestinal IgA and IgA+ gut bacteria compared with those in wild type (WT) mice. Feeding WT but not GPR43−/− mice acetate but not butyrate promoted intestinal IgA response independent of T cells. Acetate promoted B-cell IgA class switching and IgA production in vitro in the presence of WT but not GPR43−/− dendritic cells (DCs). Mechanistically, acetate-induced DC expression of Aldh1a2, which converts Vitamin A into its metabolite retinoic acid (RA). Moreover, blockade of RA signaling inhibited the acetate induction of B-cell IgA production. Our studies thus identified a new pathway by which microbiota promotes intestinal IgA response through its metabolites.
Journal Article
Luminescent Ink Based on Upconversion of NaYF4:Er,Yb@MA Nanoparticles: Environmental Friendly Synthesis and Structural and Spectroscopic Assessment
NaYF4:Er,Yb upconversion luminescent nanoparticles (UCNPs) were prepared by hydrothermal methods at 180 °C for 24 h. The X-ray diffraction (XRD) and TEM (transmission electron microscopy) images show that the resulting 60 nm UCNPs possess a hexagonal structure. In this work, maleic anhydride (MA) was grafted on the surface of UCNPs to induce hydrophilic properties. The photoluminescence spectra (PL) show upconversion emissions centered around 545 nm and 660 nm under excitation at 980 nm. The luminescent inks, including UCNPs@MA, polyvinyl alcohol (PVA), deionized water (DI), and ethylene glycol (EG), exhibit suitable properties for screen printing, such as high stability, emission intensity, and tunable dynamic viscosity. The printed patterns with a height of 5 mm and a width of 1.5 mm were clearly observed under the irradiation of a 980 nm laser. Our strategy provides a new route for the controlled synthesis of hydrophilic UCNPs, and shows that the UCNPs@MAs have great potential in applications of anti-counterfeiting packing.
Journal Article
Whole-brain estimates of directed connectivity for human connectomics
Connectomics is essential for understanding large-scale brain networks but requires that individual connection estimates are neurobiologically interpretable. In particular, a principle of brain organization is that reciprocal connections between cortical areas are functionally asymmetric. This is a challenge for fMRI-based connectomics in humans where only undirected functional connectivity estimates are routinely available. By contrast, whole-brain estimates of effective (directed) connectivity are computationally challenging, and emerging methods require empirical validation.
Here, using a motor task at 7T, we demonstrate that a novel generative model can infer known connectivity features in a whole-brain network (>200 regions, >40,000 connections) highly efficiently. Furthermore, graph-theoretical analyses of directed connectivity estimates identify functional roles of motor areas more accurately than undirected functional connectivity estimates. These results, which can be achieved in an entirely unsupervised manner, demonstrate the feasibility of inferring directed connections in whole-brain networks and open new avenues for human connectomics.
Journal Article
RIPK3 deficiency or catalytically inactive RIPK1 provides greater benefit than MLKL deficiency in mouse models of inflammation and tissue injury
Necroptosis is a caspase-independent form of cell death that is triggered by activation of the receptor interacting serine/threonine kinase 3 (RIPK3) and phosphorylation of its pseudokinase substrate mixed lineage kinase-like (MLKL), which then translocates to membranes and promotes cell lysis. Activation of RIPK3 is regulated by the kinase RIPK1. Here we analyze the contribution of RIPK1, RIPK3, or MLKL to several mouse disease models. Loss of RIPK3 had no effect on lipopolysaccharide-induced sepsis, dextran sodium sulfate-induced colitis, cerulein-induced pancreatitis, hypoxia-induced cerebral edema, or the major cerebral artery occlusion stroke model. However, kidney ischemia–reperfusion injury, myocardial infarction, and systemic inflammation associated with A20 deficiency or high-dose tumor necrosis factor (TNF) were ameliorated by RIPK3 deficiency. Catalytically inactive RIPK1 was also beneficial in the kidney ischemia–reperfusion injury model, the high-dose TNF model, and in
A20
−/−
mice. Interestingly, MLKL deficiency offered less protection in the kidney ischemia–reperfusion injury model and no benefit in
A20
−/−
mice, consistent with necroptosis-independent functions for RIPK1 and RIPK3. Combined loss of RIPK3 (or MLKL) and caspase-8 largely prevented the cytokine storm, hypothermia, and morbidity induced by TNF, suggesting that the triggering event in this model is a combination of apoptosis and necroptosis. Tissue-specific RIPK3 deletion identified intestinal epithelial cells as the major target organ. Together these data emphasize that MLKL deficiency rather than RIPK1 inactivation or RIPK3 deficiency must be examined to implicate a role for necroptosis in disease.
Journal Article
miR-10a inhibits dendritic cell activation and Th1/Th17 cell immune responses in IBD
ObjectiveAlthough both innate and adaptive responses to microbiota have been implicated in the pathogenesis of IBD, it is still largely unknown how they are regulated during intestinal inflammation. In this report, we investigated the role of microRNA (miR)-10a, a small, non-coding RNA, in the regulation of innate and adaptive responses to microbiota in IBD.MethodsmiR-10a expression was analysed in the inflamed mucosa of IBD patients treated with or without antitumour necrosis factor (anti-TNF) monoclonal antibodies (mAb) (infliximab) by qRT-PCR. Human monocyte-derived dendritic cells (DC) and IBD CD4+ T cells were transfected with miR-10a precursor to define their effect on the function of DC and CD4+ T cells.ResultsThe expression of miR-10a was markedly decreased, while NOD2 and interleukin (IL)-12/IL-23p40 were significantly increased, in the inflamed mucosa of IBD patients compared with those in healthy controls. Commensal bacteria, TNF and interferon-γ inhibited human DC miR-10a expression in vitro. Anti-TNF mAb treatment significantly promoted miR-10a expression, whereas it markedly inhibited NOD2 and IL-12/IL-23p40 in the inflamed mucosa. We further identified NOD2, in addition to IL-12/IL-23p40, as a target of miR-10a. The ectopic expression of the miR-10a precursor inhibited IL-12/IL-23p40 and NOD2 in DC. Moreover, miR-10a was found to markedly suppress IBD T helper (Th)1 and Th17 cell responses.ConclusionsOur data indicate that miR-10a is decreased in the inflamed mucosa of IBD and downregulates mucosal inflammatory response through inhibition of IL-12/IL-23p40 and NOD2 expression, and blockade of Th1/Th17 cell immune responses. Thus, miR-10a could play a role in the pathogenesis and progression of IBD.
Journal Article
Interleukin (IL)-21 promotes intestinal IgA response to microbiota
Commensal microbiota-specific T helper type 17 (Th17) cells are enriched in the intestines, which can convert into T follicular helper (Tfh) in Peyer's patches, and are crucial for production of intestinal immunoglobulin A (IgA) against microbiota; however, the role of Th17 and Tfh cytokines in regulating the mucosal IgA response to enteric microbiota is still not completely known. In this study, we found that intestinal IgA was impaired in mice deficient in interleukin (IL)-17 or IL-21 signaling. IL-21, but not IL-17, is able to augment B-cell differentiation to IgA+ cells as mediated by transforming growth factor β1 (TGFβ1) and accelerate IgA class switch recombination (CSR). IL-21 and retinoic acid (RA) induce IgA+ B-cell development and IgA production and drives autocrine TGFβ1 production to initiate IgA CSR. Repletion of T-cell-deficient TCRβxδ−/− mice with Th17 cells specific for commensal bacterial antigen increased the levels of IgA+ B cells and IgA production in the intestine, which was blocked by neutralizing IL-21. Thus IL-21 functions to strongly augment IgA production under intestinal environment. Furthermore, IL-21 promotes intestinal B-cell homing through α4β7 expression, alone or with TGFβ and RA. Together, IL-21 from microbiota-specific Th17 and/or Tfh cells contributes to robust intestinal IgA levels by enhancing IgA+ CSR, IgA production and B-cell trafficking into the intestine.
Journal Article
How Will the End of Bear Bile Farming in Vietnam Influence Consumer Choice?
The Vietnamese Government committed to closing all bear farms in the country by 2022. Some researchers have expressed concerns that ending the commercial farming of bears, while demand for bear bile persists, could lead to increased hunting pressure on wild bear populations. In this article, we used mixed methods of questionnaires, Discrete Choice Experiments (DCEs), and interviews to investigate current consumer demand for bear bile in Vietnam, with a specific aim of understanding the potential for consumers to seek out wild bear bile. We sampled at seven areas across the country of Vietnam (total respondents = 2,463). We found low use of farmed and wild bear bile. Despite widespread belief in farmed and wild bear bile’s efficacy, we found that individuals were apathetic about continuing to use bear bile. Coupled with a strong preference for using synthetic bear bile over wild and farmed bear bile found in the DCEs, we posit that bear bile consumers in Vietnam will be willing to use non animal-based products, including bear bile plant and Western medicine, to treat future ailments.
Journal Article