Infections with multiresistant pathogens are a leading cause for mortality worldwide. Just recently, the World Health Organization (WHO) increased the threat rating for multiresistant Pseudomonas aeruginosa to the highest possible level. With this background, it is crucial to develop novel materials and procedures in the fight against multiresistant pathogens. In this study, we present a novel antimicrobial material, which could find applications as a wound dressing or antimicrobial coating. Lectins are multivalent sugar-binding proteins, which can be found in a variety of plants and bacteria, where they are associated with biofilm formation. By immobilizing lectin B on a protein-based hydrogel surface, we provided the hydrogel with the ability to immobilize ("catch") pathogens upon contact. Furthermore, another hydrogel layer was added which inhibits biofilm formation and releases a highly potent antimicrobial peptide to eradicate microorganisms ("kill"). The composite hydrogel showed a high antimicrobial activity against the reference strain Pseudomonas aeruginosa PAO1 as well as against a carbapenem-resistant clinical isolate (multiresistant Gram-negative class 4) and may thus represent a novel material to develop a new type of antimicrobial wound dressings to prevent infections with this problematic pathogen of burn or other large wounds.

The pathogenesis of obesity-related metabolic diseases has been linked to the inflammation of white adipose tissue (WAT), but the molecular interconnections are still not fully understood. MiR-146a controls inflammatory processes by suppressing pro-inflammatory signaling pathways. The aim of this study was to characterize the role of miR-146a in obesity and insulin resistance. MiR-146a−/− mice were subjected to a high-fat diet followed by metabolic tests and WAT transcriptomics. Gain- and loss-of-function studies were performed using human Simpson–Golabi–Behmel syndrome (SGBS) adipocytes. Compared to controls, miR-146a−/− mice gained significantly more body weight on a high-fat diet with increased fat mass and adipocyte hypertrophy. This was accompanied by exacerbated liver steatosis, insulin resistance, and glucose intolerance. Likewise, adipocytes transfected with an inhibitor of miR-146a displayed a decrease in insulin-stimulated glucose uptake, while transfecting miR-146a mimics caused the opposite effect. Natriuretic peptide receptor 3 (NPR3) was identified as a direct target gene of miR-146a in adipocytes and CRISPR/Cas9-mediated knockout of NPR3 increased insulin-stimulated glucose uptake and enhanced de novo lipogenesis. In summary, miR-146a regulates systemic and adipocyte insulin sensitivity via downregulation of NPR3.

Materials and Methods ethical note. All procedures involving human subjects were approved by the ethics committee of the University of Ulm (entry number 300/16). Written informed consent was obtained from all subjects and all associated methods were conducted in accordance with approved guidelines for human experimental research.

Objective Activation of brown adipose tissue (BAT) in humans has been proposed as a new treatment approach for combating obesity and its associated diseases, as BAT participates in the regulation of energy homeostasis as well as glucose and lipid metabolism. Genetic contributors driving brown adipogenesis in humans have not been fully understood. Methods Profiling the gene expression of progenitor cells from subcutaneous and deep neck adipose tissue, we discovered new secreted factors with potential regulatory roles in white and brown adipogenesis. Among these, members of the latent transforming growth factor beta-binding protein (LTBP) family were highly expressed in brown compared to white adipocyte progenitor cells, suggesting that these proteins are capable of promoting brown adipogenesis. To investigate this potential, we used CRISPR/Cas9 to generate LTBP-deficient human preadipocytes. Results We demonstrate that LTBP2 and LTBP3 deficiency does not affect adipogenic differentiation, but diminishes UCP1 expression and function in the obtained mature adipocytes. We further show that these effects are dependent on TGFβ2 but not TGFβ1 signaling: TGFβ2 deficiency decreases adipocyte UCP1 expression, whereas TGFβ2 treatment increases it. The activity of the LTBP3–TGFβ2 axis that we delineate herein also significantly correlates with UCP1 expression in human white adipose tissue (WAT), suggesting an important role in regulating WAT browning as well. Conclusions These results provide evidence that LTBP3, via TGFβ2, plays an important role in promoting brown adipogenesis by modulating UCP1 expression and mitochondrial oxygen consumption.

Allogeneic bone marrow transplantation (BMT) is a curative therapy for various hematological malignancies, such as leukemias and lymphomas. Donor-derived alloantigenspecific T cells eradicate residual tumor cells, however, these T cells are also responsible for the induction of graftversus-host disease (GVHD). Therefore, one major challenge in BMT is the identification of T-cell subsets provoking antitumor cytotoxicity without causing GVHD. T helper (Th) subsets are programmed into various lineages dependent on ligand interactions and the cytokine milieu [1]. Th9 cells, which can be generated from naïve CD4 cells after activation in the presence of IL-4 and TGF-β are characterized by increased secretion of IL-9 and have been proven to exhibit efficient antitumor capacity especially toward melanomas [2][3][4]. Likewise, a few studies linked the presence of Th9/IL-9 with enhanced solid organ acceptance and decreased GVHD development [5][6][7]. However, the therapeutic effect of adoptive Th9 cell transfer on GVHD development and eradication of tumor cells is currently not well defined.To clarify whether Th9 cells are suitable for donor lymphocyte infusion in BMT settings, we differentiated naïve splenic CD4 + T cells derived from B6 mice on anti-CD3/CD28 coated plates in the presence of IL-4, TGF-β and the TNF-family cytokine TL1A. About 60% of the cells expressed IL-9 intracellulary after 5 days of differentiation and exhibited high IL-9 RNA expression. Expression of the Th1-specific cytokine IFN-γ was undetectable while IL-5, -13 and TNF-α were weakly expressed (Fig. 1a). Most importantly, Tregs were not differentiated, because Foxp3 expression was undetectable (Fig. S1). To clarify the impact of Th9 cells on GVHD induction, we used an allogeneic CD4 + -dependent parent → F1 BMT model with a 50% mismatch for MHC class I and II molecules (B6 → B6D2F1). The alloantigen H-2 d expressed on recipient tissue of lethally irradiated B6D2F1 (H-2 bxd ) mice activates transplanted B6-derived (H-2 b ) donor T cells. Acute, lethal GVHD in this model only develops if the transplant contains mature CD4 + T cells since the transfer of CD8 +