Mechanisms governing the pioneering and redistribution capabilities of the non-classical pioneer PU.1

Establishing gene regulatory networks during differentiation or reprogramming requires master or pioneer transcription factors (TFs) such as PU.1, a prototype master TF of hematopoietic lineage differentiation. To systematically determine molecular features that control its activity, here we analyze DNA-binding in vitro and genome-wide in vivo across different cell types with native or ectopic PU.1 expression. Although PU.1, in contrast to classical pioneer factors, is unable to access nucleosomal target sites in vitro, ectopic induction of PU.1 leads to the extensive remodeling of chromatin and redistribution of partner TFs. De novo chromatin access, stable binding, and redistribution of partner TFs both require PU.1's N-terminal acidic activation domain and its ability to recruit SWI/SNF remodeling complexes, suggesting that the latter may collect and distribute co-associated TFs in conjunction with the non-classical pioneer TF PU.1

Physiological levels of 25‐hydroxyvitamin D₃ induce a suppressive CD4⁺ T cell phenotype not reflected in the epigenetic landscape

1,25-dihydroxyvitamin D3 (1,25(OH)2D3), the active metabolite of vitamin D3 has a strong impact on the differentiation and function of immune cells. Here we analysed the influence of its precursor 25-hydroxyvitamin D3 (25(OH)D3) on the differentiation of human CD4+ T cells applying physiological concentrations in vitro. Our data show that 25(OH)D3 is converted to its active form 1,25(OH)2D3 by T cells, which in turn supports FOXP3, CD25 and CTLA-4 expression and inhibits IFN-γ production. These changes were not reflected in the demethylation of the respective promoters. Furthermore, we investigated the impact of vitamin D3 metabolites under induced Treg (iTreg) polarization conditions using TGF-β. Surprisingly, no additive effect but a decreased percentage of FOXP3 expressing cells was observed. However, the combination of 25(OH)D3 or 1,25(OH)2D3 together with TGF-β further upregulated CD25 and CTLA-4 and significantly increased soluble CTLA-4 and IL-10 secretion whereas IFN-γ expression of iTreg was decreased. Our data suggest that physiological levels of 25(OH)D3 act as potent modulator of human CD4+ T cells and autocrine or paracrine production of 1,25(OH)2D3 by T cells might be crucial for the local regulation of an adaptive immune response. However, since no epigenetic changes are detected by 25(OH)D3 a rather transient phenotype is induced

Donor regulatory T cells rapidly adapt to recipient tissues to control murine acute graft-versus-host disease

The adoptive transfer of regulatory T cells is a promising strategy to prevent graft-versus-host disease after allogeneic bone marrow transplantation. Here, we use a major histocompatibility complex-mismatched mouse model to follow the fate of in vitro expanded donor regulatory T cells upon migration to target organs. Employing comprehensive gene expression and repertoire profiling, we show that they retain their suppressive function and plasticity after transfer. Upon entering non-lymphoid tissues, donor regulatory T cells acquire organ-specific gene expression profiles resembling tissue-resident cells and activate hallmark suppressive and cytotoxic pathways, most evidently in the colon, when co-transplanted with graft-versus-host disease-inducing conventional T cells. Dominant T cell receptor clonotypes overlap between organs and across recipients and their relative abundance correlates with protection efficacy. Thus, this study reveals donor regulatory T cell selection and adaptation mechanisms in target organs and highlights protective features of Treg to guide the development of improved graft-versus-host disease prevention strategies

Added Value of Molecular Biological Analysis in Diagnosis and Clinical Management of Liposarcoma: A 30-Year Single-Institution Experience

Biological, physical and clinical aspects of cancer treatment with ionising radiatio

Ultrafast structural changes direct the first molecular events of vision

視覚に関わるタンパク質の超高速分子動画 --薄暗いところで光を感じる仕組み--. 京都大学プレスリリース. 2023-03-23.Vision is initiated by the rhodopsin family of light-sensitive G protein-coupled receptors (GPCRs). A photon is absorbed by the 11-cis retinal chromophore of rhodopsin, which isomerizes within 200 femtoseconds to the all-trans conformation, thereby initiating the cellular signal transduction processes that ultimately lead to vision. However, the intramolecular mechanism by which the photoactivated retinal induces the activation events inside rhodopsin remains experimentally unclear. Here we use ultrafast time-resolved crystallography at room temperature to determine how an isomerized twisted all-trans retinal stores the photon energy that is required to initiate the protein conformational changes associated with the formation of the G protein-binding signalling state. The distorted retinal at a 1-ps time delay after photoactivation has pulled away from half of its numerous interactions with its binding pocket, and the excess of the photon energy is released through an anisotropic protein breathing motion in the direction of the extracellular space. Notably, the very early structural motions in the protein side chains of rhodopsin appear in regions that are involved in later stages of the conserved class A GPCR activation mechanism. Our study sheds light on the earliest stages of vision in vertebrates and points to fundamental aspects of the molecular mechanisms of agonist-mediated GPCR activation

Bildung für Nachhaltige Entwicklung. Ein Thema für die Schulentwicklung

Fehse P, Gebhard U, Textor A. Bildung für Nachhaltige Entwicklung. Ein Thema für die Schulentwicklung. Lernende Schule. 2022;25(99):4-7

Bildung für Nachhaltige Entwicklung

Fehse P, Gebhard U, Textor A, eds. Bildung für Nachhaltige Entwicklung. Lernende Schule. 2022;25(99)

Digitalisierung und Zivile Sicherheit: Zivilgesellschaftliche und betriebliche Kontinuität in Katastrophenlagen (KontiKat)

Das Thema Sicherheit durchzieht sowohl das Leben Einzelner als auch das Zusammenleben von Personenkollektiven. In diesem Heft geht es um das Wahrnehmen und Wertschätzen sowie die Stabilisierung von Situationen, in denen Gefahren und Risiken reduziert werden. Außerdem stehen die Instrumentarien, Methoden und Maßnahmen im Fokus, mit denen Sicherheit geschaffen werden soll. Besonders in komplexen Systemen wird Sicherheit zu einem schwierig zu fassenden Thema, zu dessen Begleiterscheinungen beispielsweise die Beschneidung von Freiheit zählt. Sicherheit wird in allen Lebensgebieten relevant – von der Politik, Gesellschaft, Wirtschaft und Recht über die Arbeitswelt bis hin in Medien, Technologie, ökologie und Medizin. Zudem ist der Umgang mit Sicherheit landeskulturell geprägt

Neurochemical Monitoring of Traumatic Brain Injury by the Combined Analysis of Plasma Beta-Synuclein, NfL, and GFAP in Polytraumatized Patients

Traumatic brain injury (TBI) represents a major determining factor of outcome in severely injured patients. However, reliable brain-damage-monitoring markers are still missing. We therefore assessed brain-specific beta-synuclein as a novel blood biomarker of synaptic damage and measured the benchmarks neurofilament light chain (NfL), as a neuroaxonal injury marker, and glial fibrillary acidic protein (GFAP), as an astroglial injury marker, in patients after polytrauma with and without TBI. Compared to healthy volunteers, plasma NfL, beta-synuclein, and GFAP were significantly increased after polytrauma. The markers demonstrated highly distinct time courses, with beta-synuclein and GFAP peaking early and NfL concentrations gradually elevating during the 10-day observation period. Correlation analyses revealed a distinct influence of the extent of extracranial hemorrhage and the severity of head injury on biomarker concentrations. A combined analysis of beta-synuclein and GFAP effectively discriminated between polytrauma patients with and without TBI, despite the comparable severity of injury. Furthermore, we found a good predictive performance for fatal outcome by employing the initial plasma concentrations of NfL, beta-synuclein, and GFAP. Our findings suggest a high diagnostic value of neuronal injury markers reflecting distinct aspects of neuronal injury for the diagnosis of TBI in the complex setting of polytrauma, especially in clinical surroundings with limited imaging opportunities