Specialized regulatory T (Treg) cells accumulate and perform homeostatic and regenerative functions in nonlymphoid tissues. Whether common precursors for nonlymphoid-tissue Treg cells exist and how ...they differentiate remain elusive. Using transcription factor nuclear factor, interleukin 3 regulated (Nfil3) reporter mice and single-cell RNA-sequencing (scRNA-seq), we identified two precursor stages of interleukin 33 (IL-33) receptor ST2-expressing nonlymphoid tissue Treg cells, which resided in the spleen and lymph nodes. Global chromatin profiling of nonlymphoid tissue Treg cells and the two precursor stages revealed a stepwise acquisition of chromatin accessibility and reprogramming toward the nonlymphoid-tissue Treg cell phenotype. Mechanistically, we identified and validated the transcription factor Batf as the driver of the molecular tissue program in the precursors. Understanding this tissue development program will help to harness regenerative properties of tissue Treg cells for therapy.
Display omitted
•Two precursor stages of ST2+ nonlymphoid-tissue Tregs are evident in the spleen and LNs•Precursor stages are defined by differential expression of Nfil3, PD1, and Klrg1•Chromatin accessibility and scRNA-seq suggests a stepwise precursor reprogramming•Batf drives the molecular tissue program in the precursors
Whether a common precursor exists for nonlymphoid-tissue Treg cells is unclear. Delacher et al. identify two precursor stages for tissue-resident ST2+ Treg cells. These precursors undergo a stepwise reprogramming in the lymphoid organs toward the nonlymphoid-tissue Treg cell phenotype. Chromatin accessibility profiling identified Batf as a key driver of the tissue program in the progenitor cells.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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.
Various single nucleotide polymorphisms (SNPs) in the oxytocin receptor (OXTR) gene have been associated with behavioral traits, autism spectrum disorder (ASD) and other diseases. The non-synonymous ...SNP rs4686302 results in the OXTR variant A218T and has been linked to core characteristics of ASD, trait empathy and preterm birth. However, the molecular and intracellular mechanisms underlying those associations are still elusive. Here, we uncovered the molecular and intracellular consequences of this mutation that may affect the psychological or behavioral outcome of oxytocin (OXT)-treatment regimens in clinical studies, and provide a mechanistic explanation for an altered receptor function. We created two monoclonal HEK293 cell lines, stably expressing either the wild-type or A218T OXTR. We detected an increased OXTR protein stability, accompanied by a shift in Ca
dynamics and reduced MAPK pathway activation in the A218T cells. Combined whole-genome and RNA sequencing analyses in OXT-treated cells revealed 7823 differentially regulated genes in A218T compared to wild-type cells, including 429 genes being associated with ASD. Furthermore, computational modeling provided a molecular basis for the observed change in OXTR stability suggesting that the OXTR mutation affects downstream events by altering receptor activation and signaling, in agreement with our in vitro results. In summary, our study provides the cellular mechanism that links the OXTR rs4686302 SNP with genetic dysregulations associated with aspects of ASD.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
•A method for workarounds identification, classification, and impact evaluation.•Process mining is utilized in a medium-sized enterprise for workaround analysis.•Process mining generates workaround ...indicators, but human input is still needed.•Implementation involves semantic linking of event logs with process terminology.•Incomplete de jure processes and related systems cause challenges for process mining.
Workarounds are deviations in the execution of designed, de jure, work processes. Process mining research has developed methods for unobtrusive workaround analysis using process-aware systems’ datasets. This study applies process mining for workaround analysis in a medium-sized enterprise (SME). SME contexts can be challenging for workaround mining because SMEs often lack de jure process designs and their process-supportive information systems may have ambiguous semantics. The identification of de jure models and the solving of systems data ambiguities are the first steps in workarounds identification. A semantically well-defined information system may enable factual, de facto, process mining. Comparing the de jure and de facto process models may give candidate workarounds. Our study shows that (1) incomplete de jure models hinder the use of process mining for detecting workarounds, and (2) human interpretation of process mining outcomes is needed to realize a useful triple loop organizational learning from workarounds mining.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Intestinal IgA is strongly involved in microbiota homeostasis. Since microbiota disruption is a major risk factor of acute GvHD, we addressed the kinetics of intestinal IgA-positive (IgA+) plasma ...cells by immunohistology in a series of 430 intestinal biopsies obtained at a median of 1,5 months after allogeneic stem cell transplantation from 115 patients (pts) at our center. IgA+ plasma cells were located in the subepithelial lamina propria and suppressed in the presence of histological aGvHD (GvHD lerner stage 0: 131+/- 8 IgA+ plasma cells/mm2; stage 1-2: 108 +/-8 IgA+ plasma cells/ mm2; stage 3-4: 89+/-16 IgA+ plasma cells/ mm2, p 0.004). Overall, pts with IgA+ plasma cells below median had an increased treatment related mortality (p = 0.04). Time courses suggested a gradual recovery of IgA+ plasma cells after day 100 in the absence but not in the presence of GvHD. Vice versa IgA+ plasma cells above median early after SCT were predictive of relapse and relapse related mortality (RRM): Pts with low IgA+ cells had a 15% RRM at 2 and at 5 yrs, while pts with high IgA+ cells had a 31% RRM at 2 years and more than 46% at 5 years; multivariate analysis indicated high IgA+ plasma cells in biopsies (HR 2.7 (95% CI 1.04-7.00) as independent predictors of RRM, whereas Lerner stage and disease stage themselves did not affect RRM. In contrast, IgA serum levels at the time of biopsy were not predictive for RRM. In summary, our data indicate that IgA+ cells are highly sensitive indicators of alloreaction early after allo-SCT showing association with TRM but also allowing prediction of relapse independently from the presence of overt GvHD.
Abstract Floral nectar sugar composition is assumed to reflect the nutritional demands and foraging behaviour of pollinators, but the relative contributions of evolutionary and abiotic factors to ...nectar sugar composition remain largely unknown across the angiosperms. We compiled a comprehensive dataset on nectar sugar composition for 414 insect-pollinated plant species across central Europe, along with phylogeny, paleoclimate, flower morphology, and pollinator dietary demands, to disentangle their relative effects. We found that phylogeny was strongly related with nectar sucrose content, which increased with the phylogenetic age of plant families, but even more strongly with historic global surface temperature. Nectar sugar composition was also defined by floral morphology, though it was not related to our functional measure of pollinator dietary demands. However, specialist pollinators of current plant-pollinator networks predominantly visited plant species with sucrose-rich nectar. Our results suggest that both physiological mechanisms related to plant water balance and evolutionary effects related to paleoclimatic changes have shaped floral nectar sugar composition during the radiation and specialisation of plants and pollinators. As a consequence, the high velocity of current climate change may affect plant-pollinator interaction networks due to a conflicting combination of immediate physiological responses and phylogenetic conservatism.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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.
Accelerated glycolysis leads to secretion and accumulation of lactate and protons in the tumor environment and determines the efficacy of adoptive T cell and checkpoint inhibition therapy. Here, we ...analyzed effects of lactic acid on different human CD4 T cell subsets and aimed to increase CD4 T cell resistance towards lactic acid. In all CD4 T cell subsets analyzed, lactic acid inhibited metabolic activity (glycolysis and respiration), cytokine secretion, and cell proliferation. Overexpression of the lactate-metabolizing isoenzyme LDHB increased cell respiration and mitigated lactic acid effects on intracellular cytokine production. Strikingly, LDHB-overexpressing cells preferentially migrated into HCT116 tumor spheroids and displayed higher expression of cytotoxic effector molecules. We conclude, that LDHB overexpression might be a promising strategy to increase the efficacy of adoptive T cell transfer therapy.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
In 2016, according to the German Federal Statistical Office, 178 425 cases of intoxication (poisoning) were treated in German hospitals. The poison control centers in the German-speaking countries ...gave advice in a total of 268 787 instances of poisoning in that year, and use of activated charcoal was recommended in 4.37% of cases. The application of activated charcoal plays a major role in both primary and secondary detoxification. This article serves as an overview of the mechanism of action, indications, contraindications, modes of application, and dosing of activated charcoal.
This review is based on pertinent publications retrieved by a selective search in PubMed. The opinions of experts from the poison control centers in the German-speaking countries were considered in the interpretation of the data.
The administration of activated charcoal is indicated to treat moderately severe to life-threatening intoxication. It should be carried out as soon as possible, within the first hour of the ingestion; timed-release preparations can be given up to 6 hours after the ingestion. An important contraindication is impaired consciousness with the danger of aspiration in a patient whose air- way has not yet been secured. Activated charcoal is ineffective or inadequately effective in cases of poisoning with acids or bases, alcohols, organic solvents, inorganic salts, or metals. The proper dosage consists of an amount that is 10 to 40 times as much as that of the intoxicating substance, or else 0.5-1 g/kg body weight in children or 50 g in adults. Repeated application is indicated for intoxications with agents that persist for a longer time in the stomach and for intoxications with timed-release drugs or drugs with a marked enterohepatic or entero-enteric circulation. The routine combination of activated charcoal with a laxative is not recommended.
Even though intoxications are common, there is still no internationally valid guideline concerning the administration of activated charcoal. A precise analysis of the risks and benefits is needed for each administration, and a poison control center should be consulted for this purpose.
Zu Beginn des 20. Jahrhunderts versprachen wissenschaftliche Großprojekte den Akademien einen Prestigegewinn. Doch welchen Anteil hatten Frauen an der Realisierung dieser Forschungsprojekte? Petra ...Hoffmann untersucht am Beispiel der Berliner Wissenschaftsakademie die Einbeziehung von Frauen in die Wissenschaft und Forschungsverwaltung. Auf der Basis eines methodischen Ansatzes zum Arbeitssystem werden die Möglichkeiten ihres Zugangs, ihrer Teilnahme an der Forschungsarbeit und ihres Anerkennungserwerbs aufgezeigt.Die erste umfassende Arbeitsgeschichte der Akademieprojekte - und ein wichtiger Diskussionsbeitrag zur Frage nach dem Wandel des Geschlechterverhältnisses in der Wissenschaft zu Beginn des 20. Jahrhunderts.
PDF
