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Abstract Tuberculosis (TB) is an airborne disease caused by Mycobacterium tuberculosis (Mtb). Whilst a functional role for humoral immunity in Mtb protection remains poorly defined, previous studies have suggested that antibodies can contribute towards host defense. Thus, identifying the critical components in the antibody repertoires from immune, chronically exposed, healthy individuals represents an approach for identifying new determinants for natural protection. In this study, we performed a thorough analysis of the IgG/IgA memory B cell repertoire from occupationally exposed, immune volunteers. We detail the identification and selection of a human monoclonal antibody that exhibits protective activity in vivo and show that it targets a virulence factor LpqH. Intriguingly, protection in both human ex vivo and murine challenge experiments was isotype dependent, with most robust protection being mediated via IgG2 and IgA. These data have important implications for our understanding of natural mucosal immunity for Mtb and highlight a new target for future vaccine development.

Aim: To establish a light-independent functionality of gold nanorods (AuNRs) with a human serum (HS) protein corona loaded with photosensitizer Chlorin e6 (AuNR-HS-Ce6) in M1 polarization of macrophages. Methods: RT-qPCR and ELISA were used to determine gene and protein expression, respectively. Uptake of AuNR-HS-Ce6 was determined via flow cytometry, inductively coupled plasma mass spectrometry and fluorescence microscopy. Cell viability was determined using PrestoBlue® cell viability assay. Results: An increase in M1 gene and protein expression was observed in AuNR-HS-Ce6-treated macrophages. Delivery of high Ce6 payload via AuNR-HS-Ce6 was the primary contributor toward M1 polarization. Finally, DLD-1 cells treated with conditioned media from AuNR-HS-Ce6-treated macrophages showed significantly reduced proliferation. Conclusion: Our study suggests an immunomodulatory potential of Ce6 in inducing light-independent M1 polarization outside of its role as a photosensitizer. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease is currently the most common liver disease and is a leading cause of liver‐related morbidity and mortality. However, its pathogenesis remains largely unclear. We previously showed that mice deficient in mitogen‐activated protein kinase (MAPK) phosphatase 5 (MKP5) spontaneously developed insulin resistance and glucose intolerance, which are associated with visceral obesity and adipose tissue inflammation. In this study, we discovered that mice deficient in MKP5 developed more severe hepatic steatosis and steatohepatitis with age or with feeding on a high‐fat diet (HFD) compared to wild‐type (WT) mice, and this was associated with increased expression of proinflammatory cytokines and collagen genes. Increased p38 activation in MKP5 knockout (KO) liver compared to that in WT liver was detected, which contributed to increased expression of lipid droplet‐associated protein cell death‐inducing DFF45‐like effector A (CIDEA) and CIDEC/fat‐specific protein 27 but not CIDEB through activating transcription factor 2 (ATF2). In addition, MKP5 KO liver had higher peroxisome proliferator‐activated receptor gamma (PPARγ) expression compared with WT liver. On the other hand, overexpression of MKP5 or inhibition of p38 activation in hepatocytes resulted in reduced expression of PPARγ. Inhibition of p38 resulted in alleviation of hepatic steatosis in KO liver in response to HFD feeding, and this was associated with reduced expression of CIDEA, CIDEC, and proinflammatory cytokines. Conclusion: MKP5 prevents the development of nonalcoholic steatohepatitis by suppressing p38–ATF2 and p38–PPARγ to reduce hepatic lipid accumulation, inflammation, and fibrosis. [ABSTRACT FROM AUTHOR]

Abstract: Protease activated receptor 2 (PAR2) is a G protein-coupled receptor implicated in inflammation and cancer. Only a few peptide agonists are known with greater potency than the native agonist SLIGRL-NH2. Here we report 52 peptide agonists of PAR2, 26 with activity at sub-micromolar concentrations, and one being iodinated for radioligand experiments. Potency was highest when the N- or C-termini of SLIGRL-NH2 were modified, pointing to a new ligand pharmacophore model that may aid development of drug-like PAR2 modulators. [Copyright &y& Elsevier]