Butyrate and propionate inhibit antigen-specific CD8⁺ T cell activation by suppressing IL-12 production by antigen-presenting cells

Abstract Short chain fatty acids (SCFAs), such as acetate, butyrate and propionate, are products of microbial macronutrients fermentation that distribute systemically and are believed to modulate host immune responses. Recent data have indicated that certain SCFAs, such as butyrate and propionate, directly modulate human dendritic cell (DC) function. Given the role of DCs in initiating and shaping the adaptive immune response, we now explore how SCFAs affect the activation of antigen-specific CD8+ T cells stimulated with autologous, MART1 peptide-pulsed DC. We show that butyrate reduces the frequency of peptide-specific CD8+ T cells and, together with propionate, inhibit the activity of those cells. On the contrary, acetate does not affect them. Importantly, butyrate and propionate inhibit the production of IL-12 and IL-23 in the DCs and exogenous IL-12 fully restores the activation of the MART-1-specific CD8+ T cells, whereas IL-23 has no effect. In conclusion, these results point to a pivotal role of butyrate and propionate in modulating CD8+ T cell activation via the inhibition of IL-12 secretion from DCs. These findings reveal a novel mechanism whereby bacterial fermentation products may modulate CD8+ T cell function with possible implications in anti-cancer immunotherapy

Performance Evaluation of Lighting and Daylighting Retrofits: Results from IEA SHC Task 50

AbstractThis article presents some results from a large monitoring campaign performed in 22 buildings around the world as part of International Energy Agency (IEA) Task 50 “Advanced lighting solutions for retrofitting buildings”. This article mainly addresses the work of Subtask D, which aims to demonstrate sound lighting retrofit solutions in a selection of representative, typical Case Studies. In order to evaluate the Case Studies, a monitoring protocol was developed to assess the overall lighting performance taking into consideration: 1) Energy use, 2) Retrofit costs, 3) Photometric assessment, and 4) User assessment. The monitoring was carried out from June 2014 to December 2015 in 22 non-residential buildings in ten countries. This article presents results from selected Case Studies, drawing conclusions regarding retrofit solutions as well as reflecting on methodological procedures for the measurements and data collection. Measured data as well as key conclusions from Subtask D will be summarized in an electronic web and portable sourcebook at the end of the IEA Task 50 (December 2015), which will be freely available through the Internet

The effect of short-chain fatty acids on human monocyte-derived dendritic cells

The gut microbiota is essential for human health and plays an important role in the pathogenesis of several diseases. Short-chain fatty acids (SCFA), such as acetate, butyrate and propionate, are end-products of microbial fermentation of macronutrients that distribute systemically via the blood. The aim of this study was to investigate the transcriptional response of immature and LPS-matured human monocyte-derived DC to SCFA. Our data revealed distinct effects exerted by each individual SCFA on gene expression in human monocyte-derived DC, especially in the mature ones. Acetate only exerted negligible effects, while both butyrate and propionate strongly modulated gene expression in both immature and mature human monocyte-derived DC. An Ingenuity pathway analysis based on the differentially expressed genes suggested that propionate and butyrate modulate leukocyte trafficking, as SCFA strongly reduced the release of several pro-inflammatory chemokines including CCL3, CCL4, CCL5, CXCL9, CXCL10, and CXCL11. Additionally, butyrate and propionate inhibited the expression of lipopolysaccharide (LPS)-induced cytokines such as IL-6 and IL-12p40 showing a strong anti-inflammatory effect. This work illustrates that bacterial metabolites far from the site of their production can differentially modulate the inflammatory response and generally provides new insights into host-microbiome interactions

Origin of Aging of a P2-Nax_xMn3/4_{3/4}Ni1/4_{1/4}O2_2 Cathode Active Material for Sodium-Ion Batteries

Sodium-ion batteries (SIB) are currently being developed and commercialized as a promising new technology for cost-effective and powerful electrical energy storage. In this study, we investigate the origin of capacity fading in P2-type layered sodium cathode materials for SIBs using a micron-sized single-crystalline P2-Na$_x$Mn$_{3/4}$Ni$_{1/4}$O$_2$ model cathode active material. Using various electrochemical techniques, we identify the following aging effects upon cycling: (i) a state of charge (SOC)-independent increase in polarization, (ii) a SOC-dependent increase in polarization at high voltage, and (iii) a loss of active material due to electronic disconnection after prolonged cycling. With high-resolution transmission electron microscopy (HRTEM) and energy-dispersive X-ray (EDX) spectroscopy, we identify surface densification, resulting in 5–10 nm thick surface layers on cycled cathode active materials as the origin for SOC-independent increase of polarization. The corresponding oxygen loss is in accordance with gas evolution in differential electrochemical mass spectrometry (DEMS) measurements. Furthermore, with scanning electron microscopy (SEM) electrode cross sections, we identify (partly) reversible cracking at a high SOC as the cause for increased polarization depending on SOC. Operando X-ray diffraction (XRD) identifies significant anisotropic volume change, which suggests mechanical stress as the cause for cracking at a high SOC and loss of active material after prolonged cycling. We believe that the herein provided understanding on the aging of this highly attractive class of cathode active materials for SIBs will enable the development of future powerful and stable layered oxide cathode materials for SIBs

Fluorescence Nanoscopy in Whole Cells by Asynchronous Localization of Photoswitching Emitters

We demonstrate nanoscale resolution in far-field fluorescence microscopy using reversible photoswitching and localization of individual fluorophores at comparatively fast recording speeds and from the interior of intact cells. These advancements have become possible by asynchronously recording the photon bursts of individual molecular switching cycles. We present images from the microtubular network of an intact mammalian cell with a resolution of 40 nm

Cosmic queuing: galaxy satellites, building blocks and the hierarchical clustering paradigm

We study the properties of building blocks (BBs, i.e. accreted satellites) and surviving satellites of present-day galaxies using the SAG semi-analytic model of galaxy formation in the context of a concordance Lambda Cold Dark Matter (LCDM) cosmology. We consider large numbers of DM halo merger trees spanning a wide range of masses (~1x10^10 - 2.14x10^15 Msun). We find higher metallicities for BBs with respect to surviving satellites, an effect produced by the same processes behind the build-up of the mass-metallicity relation. We prove that these metallicity differences arise from the higher peak height in the density fluctuation field occupied by BBs and central galaxies which have collapsed into a single object earlier than surviving satellites. BBs start to form stars earlier, during the peak of the merger activity in LCDM, and build-up half of their final stellar mass (measured at the moment of disruption) up to four times faster than surviving satellites. Surviving satellites keep increasing their stellar masses rather quiescently down to z~1. The difference between the metallicities of satellites, BBs and central galaxies depends on the host DM halo mass, in a way that can be used as a further test for the concordance cosmology.Comment: 5 pages, 4 figures. Accepted for publication in MNRAS Letter

Jak3, STAT3, and STAT5 inhibit expression of miR-22, a novel tumor suppressor microRNA, in cutaneous T-Cell lymphoma

Aberrant activation of Janus kinase-3 (Jak3) and its key down-stream effectors, Signal Transducer and Activator of Transcription-3 (STAT3) and STAT5, is a key feature of malignant transformation in cutaneous T-cell lymphoma (CTCL). However, it remains only partially understood how Jak3/STAT activation promotes lymphomagenesis. Recently, non-coding microRNAs (miRNAs) have been implicated in the pathogenesis of this malignancy. Here, we show that (i) malignant T cells display a decreased expression of a tumor suppressor miRNA, miR-22, when compared to non-malignant T cells, (ii) STAT5 binds the promoter of the miR-22 host gene, and (iii) inhibition of Jak3, STAT3, and STAT5 triggers increased expression of pri-miR-22 and miR-22. Curcumin, a nutrient with anti-Jak3 activity and histone deacetylase inhibitors (HDACi) also trigger increased expression of pri-miR-22 and miR-22. Transfection of malignant T cells with recombinant miR-22 inhibits the expression of validated miR-22 targets including NCoA1, a transcriptional co-activator in others cancers, as well as HDAC6, MAX, MYCBP, PTEN, and CDK2, which have all been implicated in CTCL pathogenesis. In conclusion, we provide the first evidence that de-regulated Jak3/STAT3/STAT5 signalling in CTCL cells represses the expression of the gene encoding miR-22, a novel tumor suppressor miRNA

Jak3, STAT3, and STAT5 inhibit expression of miR-22, a novel tumor suppressor microRNA, in cutaneous T-Cell lymphoma

Aberrant activation of Janus kinase-3 (Jak3) and its key down-stream effectors, Signal Transducer and Activator of Transcription-3 (STAT3) and STAT5, is a key feature of malignant transformation in cutaneous T-cell lymphoma (CTCL). However, it remains only partially understood how Jak3/STAT activation promotes lymphomagenesis. Recently, non-coding microRNAs (miRNAs) have been implicated in the pathogenesis of this malignancy. Here, we show that (i) malignant T cells display a decreased expression of a tumor suppressor miRNA, miR-22, when compared to non-malignant T cells, (ii) STAT5 binds the promoter of the miR-22 host gene, and (iii) inhibition of Jak3, STAT3, and STAT5 triggers increased expression of pri-miR-22 and miR-22. Curcumin, a nutrient with anti-Jak3 activity and histone deacetylase inhibitors (HDACi) also trigger increased expression of pri-miR-22 and miR-22. Transfection of malignant T cells with recombinant miR-22 inhibits the expression of validated miR-22 targets including NCoA1, a transcriptional co-activator in others cancers, as well as HDAC6, MAX, MYCBP, PTEN, and CDK2, which have all been implicated in CTCL pathogenesis. In conclusion, we provide the first evidence that de-regulated Jak3/STAT3/STAT5 signalling in CTCL cells represses the expression of the gene encoding miR-22, a novel tumor suppressor miRNA