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Background Understanding the status of intratumoural immune microenvironment is necessary to ensure the efficacy of immune-checkpoint (IC) blockade therapy. Cortisol plays pivotal roles in glucocorticoid interactions in the immune system. We examined the correlation between intratumourally synthesised cortisol through 11β hydroxysteroid dehydrogenase (HSD) 1 and the immune microenvironment in non-small-cell lung carcinoma (NSCLC). Methods We correlated 11βHSD1 immunoreactivity in 125 cases of NSCLC with the amount of intratumoural immune cells present, and 11βHSD1 immunoreactivity with the efficacy of IC blockade therapy in 18 specimens of NSCLC patients. In vitro studies were performed to validate the immunohistochemical examination. Results 11βHSD1 immunoreactivity showed a significant inverse correlation with the number of tumour-infiltrating lymphocytes and CD3- or CD8-positive T cells. 11βHSD1 immunoreactivity tended to be inversely correlated with the clinical efficacy of the IC blockade therapy. In vitro studies revealed that 11βHSD1 promoted the intratumoural synthesis of cortisol. This resulted in a decrease in cytokines and in the inhibition of monocyte migration. Conclusions Our study is the first report clarifying the inhibitory effects of intratumourally synthesised cortisol through 11βHSD1 on immune cell migration. We propose that the response to IC blockade therapy in NSCLC may be predicted by 11βHSD1.

ER-to-Golgi protein transport involves transport vesicles of which formation is initiated by assembly of Sar1. The assembly of Sar1 is suppressed by protein kinase inhibitor H89, suggesting that ER-to-Golgi transport is regulated progressively by H89 sensitive kinase. ER-resident G i2 protein suppresses vesicle formation with inhibition of Sar1 assembly. This study examined whether these promotion and suppression of vesicle transport share the same signal pathway, by examining the effects of G i/o protein activator mastoparan 7 (Mp-7) and H89 on Sar1 and Sec23 recruitment onto microsomes. In a cell-free system for Sar1 translocation assay, GTPγS addition induced the translocation of Sar1 onto microsomes. Mp-7 and H89 decreased the Sar1 translocation. Double treatment of Mp-7 and H89 strongly decreased Sar1 translocation. In single and double treatments, however, G i/o protein inactivator pertussis toxin (IAP) partially restored the suppressive effect of Mp-7, but had not any effect on H89-induced effect. Then, the assembly of Sec23 onto the microsome was also increased by the addition of GTPγS. Sec23 translocation was decreased by Mp-7 and/or H89 treatment and recovered by IAP pretreatment except for H89 single treatment, similarly to Sar1 translocation in each treatment. Inhibitory effects of H89 and Mp-7on ER-to-Golgi vesicle transport by H89 or Mp-7 were also confirmed in a cell culture system by BFA-dispersion and BFA-reconstruction experiments. These findings indicate that promotion and suppression of ER-to-Golgi vesicle transport are modulated through separate signal pathways.

A small forbidden gap matched to low-energy photons (meV) and a quasi-Dirac electron system are both definitive characteristics of bilayer graphene (GR) that has gained it considerable interest in realizing a broadly tunable sensor for application in the microwave region around gigahertz (GHz) and terahertz (THz) regimes. In this work, a systematic study is presented which explores the GHz/THz detection limit of both bilayer and single-layer graphene field-effect transistor (GR-FET) devices. Several major improvements to the wiring setup, insulation architecture, graphite source, and bolometric heating of the GR-FET sensor were made in order to extend microwave photoresponse past previous reports of 40 GHz and to further improve THz detection.

Songs constitute a complex system of vocal signals for inter-individual communication in songbirds. Here, we elucidate the flexibility which songbirds exhibit in the organizing and sequencing of syllables within their songs. Utilizing a newly devised song decoder for quasi-real-time annotation, we execute an operant conditioning paradigm, with rewards contingent upon specific syllable syntax. Our analysis reveals that birds possess the capacity to modify the contents of their songs, adjust the repetition length of particular syllables and employing specific motifs. Notably, birds altered their syllable sequence in a goal-directed manner to obtain rewards. We demonstrate that such modulation occurs within a distinct song segment, with adjustments made within 10 minutes after cue presentation. Additionally, we identify the involvement of the parietal-basal ganglia pathway in orchestrating these flexible modulations of syllable sequences. Our findings unveil an unappreciated aspect of songbird communication, drawing parallels with human speech. Birdsong contains strings of syllables and is essential for their communication. Using a new song decoder to annotates song in a quasi-real-time manner, and rewarding specific syllable sequences, this study shows Bengalese finches can flexibly modify the content of their song in a goal-directed way.

C -Glycosides, in which a sugar moiety is linked via a carbon-carbon (C-C) bond to a non-sugar moiety (aglycone), are found in our food and medicine. The C-C bond is cleaved by intestinal microbes and the resulting aglycones exert various bioactivities. Although the enzymes responsible for the reactions have been identified, their catalytic mechanisms and the generality of the reactions in nature remain to be explored. Here, we present the identification and structural basis for the activation of xenobiotic C -glycosides by heterocomplex C -deglycosylation enzymes from intestinal and soil bacteria. They are found to be metal-dependent enzymes exhibiting broad substrate specificity toward C -glycosides. X-ray crystallographic and cryo-electron microscopic analyses, as well as structure-based mutagenesis, reveal the structural details of these enzymes and the detailed catalytic mechanisms of their remarkable C-C bond cleavage reactions. Furthermore, bioinformatic and biochemical analyses suggest that the C -deglycosylation enzymes are widely distributed in the gut, soil, and marine bacteria. In C-glycosides the sugar moiety is linked through a carbon-carbon bond to the non-sugar moiety, which can be cleaved by intestinal microbes. Here, the authors use bioinformatics analysis to identify C-glycoside deglycosidase enzymes in intestinal and soil bacteria, biochemically characterise them and determine their structures and probe catalytic important residues in mutagenesis experiments.

BackgroundImmune checkpoint inhibitors (ICPis) are associated with multi-organ immune-related adverse effects. Here, we examined the incidence rate, recovery rate, and risk factors of acute kidney injury complicated with ICPis (ICPi-AKI) and evaluted the association between ICPi-AKI and mortality in Japanese patients.MethodsWe analyzed 152 consecutive patients receiving ICPis between 2015 and 2019. A logistic regression analysis was performed to identify risk factors for ICPi-AKI incidence and Cox regression analysis was performed to evaluate the association between ICPi-AKI and mortality.ResultsThe mean patient age was 67 ± 10 years, with the median baseline serum creatinine level of 0.78 mg/dL. Twenty-seven patients (18%) developed ICPi-AKI, and 19 (73%) of them recovered. Pembrolizumab use and liver diseases were significant risk factors for the ICPi-AKI incidence. During the follow-up, 85 patients (59%) died, 17 patients (63%) with ICPi-AKI and 68 (54%) patients without ICPi-AKI, respectively. The ICPi-AKI incidence was not independently associated with mortality (adjusted hazard ratio, 0.85; 95% confidence intervals, 0.46–1.61).ConclusionsOur finding suggest that pembrolizumab use and liver diseases are associated with a higher risk of ICPi-AKI development, but ICPi-AKI did not affect mortality. Future multi-center studies are needed to develop optimal management and prevention strategies for this complication in patients receiving ICPis.

Long-duration spaceflight creates a variety of stresses due to the unique environment, which can lead to compromised functioning of the skeletal and immune systems. However, the mechanisms by which organisms respond to this stress remain unclear. The present study aimed to investigate the impact of three different gravitational loadings (microgravity, 1/6  g [lunar gravity], and 1  g ) on the behavior, bone, thymus, and spleen of mice housed for 25–35 days in the International Space Station. The bone density reduction under microgravity was mostly recovered by 1  g but only partially recovered by 1/6  g . Both 1  g and 1/6  g suppressed microgravity-induced changes in some osteoblast and osteoclast marker gene expression. Thymus atrophy induced by microgravity was half recovered by both 1  g and 1/6  g , but gene expression changes were not fully recovered by 1/6  g . While no histological changes were observed due to low gravity, alterations in gene expression were noted in the spleen. We found that in bone and thymus, lunar gravity reduced microgravity-induced histological alterations and partially reversed gene expression changes. This study highlighted organ-specific variations in responsiveness to gravity, serving as an animal test for establishing a molecular-level gravity threshold for maintaining a healthy state during future spaceflight.

Microbial transglutaminase (MTG) is an enzyme that catalyzes the cross-linking of glutamine and lysine residues in proteins. Because of its ability to modify proteins, MTG has various applications in the medical and food industries. Most studies have aimed to enhance the thermal stability of MTG by focusing only on point mutations. Introducing a disulfide (S-S) bond in the N-terminal region has been found to be effective, whereas S-S bonds in other regions were considered ineffective. Therefore, this study aimed to evaluate the impact of introducing an additional S-S bond on the thermal stability of an MTG mutant. We found that adding S-S bonds to regions other than the N-terminal, in conjunction with the N-terminal S-S bond, significantly enhanced thermal stability. This finding demonstrates the importance of reinforcing the weakest part of the protein first, followed by strengthening other regions for optimal thermal stability. The MTG variant with two S-S bonds retained its catalytic activity and substrate specificity towards protein substrates, making it a promising candidate for industrial applications. Thus, introducing S-S bonds could be an effective strategy to increase thermal stability of MTG and other industrial enzymes, thereby contributing to their potential industrial applications.

Fusions of fatty acids and peptides expand the structural diversity of natural products; however, polyketide/ribosomally synthesized and post-translationally modified peptides (PK/RiPPs) hybrid lipopeptides are relatively rare. Here we report a family of PK/RiPPs called goadvionins, which inhibit the growth of Gram-positive bacteria, and an acyltransferase, GdvG, which catalyses the condensation of the PK and RiPP moieties. Goadvionin comprises a trimethylammonio 32-carbon acyl chain and an eight-residue RiPP with an avionin structure. The positions of six hydroxyl groups and one double bond in the very-long acyl chain were determined by radical-induced dissociation tandem mass spectrometry, which collides radical ion species to generate C–C bond cleavage fragments. GdvG belongs to the Gcn5-related N-acetyltransferase superfamily. Unlike conventional acyltransferases, GdvG transfers a very long acyl chain that is tethered to an acyl carrier protein to the N-terminal amino group of the RiPP moiety. gdvG homologues flanked by PK/fatty acid and RiPP biosynthesis genes are widely distributed in microbial species, suggesting that acyltransferase-catalysed condensation of PKs and RiPPs is a general strategy in biosynthesis of similar lipopeptides.The biosynthesis of goadvionins—hybrid lipopeptide antibiotics—is not fully understood. An unusual acyltransferase, GdvG, has now been identified and shown to catalyse a condensation reaction between an acyl-carrier-protein-tethered very-long-chain fatty acid and an eight-residue ribosomally synthesized and post-translationally modified peptide. The position of functional groups in the very-long acyl chain have been determined by tandem mass spectrometry.