Project description:<p>Antimicrobial resistance (AMR) is one of the most urgent challenges in public health, and the horizontal transfer of antibiotic resistance genes (ARGs) mediated by mobile genetic elements (MGEs) drives its widespread global dissemination. Although integrative conjugative elements (ICEs) outnumber conjugative plasmids, research on ICE-mediated horizontal gene transfer (HGT) remains largely lacking, especially concerning SXT ICEs, which are highly prevalent, pose significant risks, and are directly related to human health. Cyromazine is a widely used feed additive, with high detection rates in the feces of farmed animals and related environments. It has also been shown to increase the abundance of ARGs, and the potential driving mechanisms urgently require further exploration. Thus, we investigated the impact of cyromazine on SXT ICE-mediated ARGs transfer and elucidated its underlying mechanisms. Our study demonstrates that cyromazine promotes SXT ICE conjugative transfer both intra- and inter-species. This facilitating effect confirmed in mouse intraperitoneal and intestinal conjugation models. The potential mechanisms include cyromazine-induced ROS accumulation and triggering of the SOS response, which could promote SXT ICE excision and activate conjugation-related operons. Furthermore, enhanced energy metabolism and altered lipid metabolism further facilitate SXT ICE transfer. Collectively, our study partially fills the gap in understanding ICE-mediated AMR transmission dynamics, and highlighting that the exacerbated AMR crisis is associated with cyromazine-stimulated high-frequency SXT ICE conjugation in vitro and in vivo.</p>
Project description:Acutely activated enhancers require the actions of Topo1cc, including those induced by 17β-oestradiol (E2), dihydrotestosterone (DHT) and tumor necrosis factor alpha (TNFa). Topo1cc at these acutely activated enhancers is “read” by Ku70, which in this context serves as a required transcriptional coactivator, based on nucleating a Ku70/heterochromatin protein1 gamma (HP1γ) complex to facilitate the recruitment of mediator subunit Med26 for eRNA transcription.
Project description:Foxp3+ regulatory T cells (Treg) play a central role for tolerance against self and innocuous environmental antigens. However, the role of antigen-specificity for Treg-mediated tolerance is only incompletely understood. Here we show by direct ex vivo characterization of human CD4+ T cells, that the response against innocuous airborne antigens, such as plant pollen or fungal spores, is dominated by memory-like antigen-specific Treg. Surprisingly, breakdown of tolerance in atopic donors was not accompanied by a quantitatively or qualitatively altered Treg response, but instead correlated with a striking dichotomy of Treg versus Th2 target specificity. Allergenic proteins, are selectively targeted by Th2 cells, but not Treg. Thus human Treg specific for airborne antigens maintain tolerance at mucosal sites and the failure to generate specific Treg against a subgroup of antigens provides a window of opportunity for allergy development. PBMCs from sex and age matched birch pollen allergic patients and healthy controls, were stimulated (7h) with airborne fungal (A. fumigatus) or birch pollen antigen (birch) and sorted into antigen specific conventional and regulatory T cells according to their expression of CD154+ and CD137+ on CD4+ T cells, respectively. Number of samples per group in parentheses: Healthy controls stimulated with A. fumigatus (n=5), allergic patients stimulated with A. fumigatus (n=6), healthy controls stimulated with birch (n=6), allergic patients stimulated with birch (n=4).
Project description:Vertical distribution of airborne microorganisms over forest environments: Estimation of microbial ice nucleation in forest atmosphere
