Rapid Downregulation of H3K4me3 Binding to Immunoregulatory Genes in Altered Gravity in Primary Human M1 Macrophages

The sensitivity of human immune system cells to gravity changes has been investigated in numerous studies. Human macrophages mediate innate and thus rapid immune defense on the one hand and activate T- and B-cell-based adaptive immune response on the other hand. In this process they finally act as immunoeffector cells, and are essential for tissue regeneration and remodeling. Recently, we demonstrated in the human Jurkat T cell line that genes are differentially regulated in cluster structures under altered gravity. In order to study an in vivo near system of immunologically relevant human cells under physically real microgravity, we performed parabolic flight experiments with primary human M1 macrophages under highly standardized conditions and performed chromatin immunoprecipitation DNA sequencing (ChIP-Seq) for whole-genome epigenetic detection of the DNA-binding loci of the main transcription complex RNA polymerase II and the transcription-associated epigenetic chromatin modification H3K4me3. We identified an overall downregulation of H3K4me3 binding loci in altered gravity, which were unequally distributed inter- and intrachromosomally throughout the genome. Three-quarters of all affected loci were located on the p arm of the chromosomes chr5, chr6, chr9, and chr19. The genomic distribution of the downregulated H3K4me3 loci corresponds to a substantial extent to immunoregulatory genes. In microgravity, analysis of RNA polymerase II binding showed increased binding to multiple loci at coding sequences but decreased binding to central noncoding regions. Detection of altered DNA binding of RNA polymerase II provided direct evidence that gravity changes can lead to altered transcription. Based on this study, we hypothesize that the rapid transcriptional response to changing gravitational forces is specifically encoded in the epigenetic organization of chromatin

Transformation of terrestrial organic matter along thermokarst-affected permafrost coasts in the Arctic

The changing climate in the Arctic has a profound impact on permafrost coasts, which are subject to intensified thermokarst formation and erosion. Consequently, terrestrial organic matter (OM) is mobilized and transported into the nearshore zone. Yet, little is known about the fate of mobilized OM before and after entering the ocean. In this study we investigated a retrogressive thaw slump (RTS) on Qikiqtaruk - Herschel Island (Yukon coast, Canada). The RTS was classified into an undisturbed, a disturbed (thermokarst-affected) and a nearshore zone and sampled systematically along transects. Samples were analyzed for total and dissolved organic carbon and nitrogen (TOC, DOC, TN, DN), stable carbon isotopes (δ13C-TOC, δ13C-DOC), and dissolved inorganic nitrogen (DIN), which were compared between the zones. C/N-ratios, δ13C signatures, and ammonium (NH4-N) concentrations were used as indicators for OM degradation along with biomarkers (n-alkanes, n-fatty acids, n-alcohols). Our results show that OM significantly decreases after disturbance with a TOC and DOC loss of 77 and 55% and a TN and DN loss of 53 and 48%, respectively. C/N-ratios decrease significantly, whereas NH4-N concentrations slightly increase in freshly thawed material. In the nearshore zone, OM contents are comparable to the disturbed zone. We suggest that the strong decrease in OM is caused by initial dilution with melted massive ice and immediate offshore transport via the thaw stream. In the mudpool and thaw stream, OM is subject to degradation, whereas in the slump floor the nitrogen decrease is caused by recolonizing vegetation. Within the nearshore zone of the ocean, heavier portions of OM are directly buried in marine sediments close to shore. We conclude that RTS have profound impacts on coastal environments in the Arctic. They mobilize nutrients from permafrost, substantially decrease OM contents and provide fresh water and nutrients at a point source

Klimafolgen und Anpassung - 2023: Aus den Arbeiten zur Basisprojektion des INFORGE-Modells

Die Folgen und daraus resultierenden Kosten des Klimawandels sind inzwischen unvermeidbar. In makroökonomischen Modellen wie INFORGE, welche Abschätzungen zur Zukunft bis 2050 liefern, müssen die Folgen des Klimawandels in der Projektion daher berücksichtigt werden. Ziel dieses Beitrags ist es, eine wahrscheinliche Zielgröße für die Szenarien abzuleiten, Narrative zu entwickeln und die zugrundeliegenden Annahmen und Ergebnisse offen zu legen. Auf Basis der bereits bekannten historischen Kosten der Klimakrise wurde ein Möglichkeitsraum aufgespannt, in dem sich die Kosten des Klimawandels mit hoher Wahrscheinlichkeit bewegen werden. Er dient zur Plausibilisierung der gesetzten Annahmen in der Szenariorechnung. Basierend auf der Klimawirkungs- und Risikoanalyse wurden zudem Klimawirkungen identifiziert, welche mit hoher Wahrscheinlichkeit bis zur Mitte des Jahrhunderts als Kostenfaktoren bei den Folgen des Klimawandels monetarisierbar und relevant sind. Die Annahmen wurden vor dem Hintergrund von Forschungsergebnissen und Literatur sowie Expert:innenwissen gesetzt. Es zeigt sich, dass die gesetzten Annahmen zum Klimawandel dafür geeignet sind, zukünftige Kosten bis 2050 in einem Ausmaß zu projizieren, das sich mit den Beobachtungen aus der Vergangenheit plausibilisieren lässt. Die zukünftigen Kosten des Klimawandels werden sich in einer Größenordnung von 450 Mrd. Euro (kumulierte Verluste im preisbereinigten Bruttoinlandsprodukt bis 2050) bewegen. Gleichzeitig lohnen sich Investitionen in Anpassungsmaßnahmen und sind in Kombination mit Klimaschutz dringend geboten. So können sich die kumulierten Kosten des Klimawandels auf Basis der Szenariorechnung durch Klimaanpassungsmaßnahmen bis 2050 um 40 % verringern

G-rich DNA-induced stress response blocks type-I-IFN but not CXCL10 secretion in monocytes

Excessive inflammation can cause damage to host cells and tissues. Thus, the secretion of inflammatory cytokines is tightly regulated at transcriptional, post-transcriptional and post-translational levels and influenced by cellular stress responses, such as endoplasmic reticulum (ER) stress or apoptosis. Here, we describe a novel type of post-transcriptional regulation of the type-I-IFN response that was induced in monocytes by cytosolic transfection of a short immunomodulatory DNA (imDNA), a G-tetrad forming CpG-free derivative of the TLR9 agonist ODN2216. When co-transfected with cytosolic nucleic acid stimuli (DNA or 3P-dsRNA), imDNA induced caspase-3 activation, translational shutdown and upregulation of stress-induced genes. This stress response inhibited the type-I-IFN induction at the translational level. By contrast, the induction of most type-I-IFN-associated chemokines, including Chemokine (C-X-C Motif) Ligand (CXCL) 10 was not affected, suggesting a differential translational regulation of chemokines and type-I-IFN. Pan-caspase inhibitors could restore IFN-beta secretion, yet, strikingly, caspase inhibition did not restore global translation but instead induced a compensatory increase in the transcription of IFN-beta but not CXCL10. Altogether, our data provide evidence for a differential regulation of cytokine release at both transcriptional and post-transcriptional levels which suppresses type-I-IFN induction yet allows for CXCL10 secretion during imDNA-induced cellular stress

Rapid Downregulation of H3K4me3 Binding to Immunoregulatory Genes in Altered Gravity in Primary Human M1 Macrophages

The sensitivity of human immune system cells to gravity changes has been investigated in numerous studies. Human macrophages mediate innate and thus rapid immune defense on the one hand and activate T- and B-cell-based adaptive immune response on the other hand. In this process they finally act as immunoeffector cells, and are essential for tissue regeneration and remodeling. Recently, we demonstrated in the human Jurkat T cell line that genes are differentially regulated in cluster structures under altered gravity. In order to study an in vivo near system of immunologically relevant human cells under physically real microgravity, we performed parabolic flight experiments with primary human M1 macrophages under highly standardized conditions and performed chromatin immunoprecipitation DNA sequencing (ChIP-Seq) for whole-genome epigenetic detection of the DNA-binding loci of the main transcription complex RNA polymerase II and the transcription-associated epigenetic chromatin modification H3K4me3. We identified an overall downregulation of H3K4me3 binding loci in altered gravity, which were unequally distributed inter- and intrachromosomally throughout the genome. Three-quarters of all affected loci were located on the p arm of the chromosomes chr5, chr6, chr9, and chr19. The genomic distribution of the downregulated H3K4me3 loci corresponds to a substantial extent to immunoregulatory genes. In microgravity, analysis of RNA polymerase II binding showed increased binding to multiple loci at coding sequences but decreased binding to central noncoding regions. Detection of altered DNA binding of RNA polymerase II provided direct evidence that gravity changes can lead to altered transcription. Based on this study, we hypothesize that the rapid transcriptional response to changing gravitational forces is specifically encoded in the epigenetic organization of chromatin

Retrogressive thaw slumps along permafrost coasts transform organic matter before release into the Arctic Ocean

Changing environmental conditions in the Arctic have profound impacts on permafrost coasts, which erode at great pace. Although numbers exist on annual carbon and sediment fluxes from coastal erosion, little is known on how terrestrial organic matter (OM) is transformed by thermokarst and –erosional processes on transit from land to sea. Here, we investigated a retrogressive thaw slump (RTS) on Qikiqtaruk - Herschel Island in the western Canadian Arctic. The RTS was classified into an undisturbed, disturbed and nearshore zone and systematically sampled along transects. Collected sediments were analyzed for organic carbon (OC), nitrogen (N), stable carbon isotopes (δ13C-OC) and ammonium. C/N-ratios, δ13C-signatures and ammonium concentrations were used as general indicator for OM degradation. Permafrost sediments from the RTS headwall and mud lobe sediments from the thaw stream outlet were incubated to further assess OM degradation and potential greenhouse gas formation during slumping and upon release into the nearshore zone. Our results show that OM concentrations significantly decrease upon slumping in the disturbed zone with OC and N decreasing by >70% and >50%, respectively. Whereas δ13C-signatures remain fairly stable, C/N-ratios decrease significantly and ammonium concentrations increase slightly in fresh slumping material. Nearshore sediments have low OM contents and a terrestrial signature comparable to disturbed sites on land. The incubations show that carbon dioxide (CO2) forms quickly from thawing permafrost deposits and mud debris with ~2-3 mg CO2 per gram dry weight being cumulatively produced within two months. We suggest that the initial strong decrease in OM concentration after slumping is caused by a combination of OC degradation, dilution with melted massive ice and immediate offshore transport via the thaw stream. After stabilization in the slump floor, recolonizing vegetation takes up N from the disturbed sediment. Upon release into the nearshore zone, larger portions of OM are directly deposited in marine sediments, where they further degrade or being buried. The incubations indicate that CO2 is rapidly produced upon slumping and potentially continues to form within the nearshore zone that receives eroded material. We conclude that coastal RTS systems profoundly change the characteristic of modern and ancient permafrost terrestrial OM during transit from land to sea - a process which is likely linked to the production of greenhouse gases. Our study provides valuable information on the potential fate of terrestrial OM along eroding permafrost coasts under the trajectory of a warming Arctic

Application and Validation of the Tricuspid Annular Plane Systolic Excursion/Systolic Pulmonary Artery Pressure Ratio in Patients with Ischemic and Non-Ischemic Cardiomyopathy

The main aim of this study was to assess the prognostic utility of TAPSE/PASP as an echocardiographic parameter of maladaptive RV remodeling in cardiomyopathy patients using cardiac magnetic resonance (CMR) imaging. Furthermore, we sought to compare TAPSE/PASP to TAPSE. The association of the echocardiographic parameters TAPSE/PASP and TAPSE with CMR parameters of RV and LV remodeling was evaluated in 111 patients with ischemic and non-ischemic cardiomyopathy and cut-off values for maladaptive RV remodeling were defined. In a second step, the prognostic value of TAPSE/PASP and its cut-off value were analyzed regarding mortality in a validation cohort consisting of 221 patients with ischemic and non-ischemic cardiomyopathy. A low TAPSE/PASP (<0.38 mm/mmHg) and TAPSE (<16 mm) were associated with a lower RVEF and a long-axis RV global longitudinal strain (GLS) as well as higher RVESVI, RVEDVI and NT-proBNP. A low TAPSE/PASP, but not TAPSE, was associated with a lower LVEF and long-axis LV GLS, and a higher LVESVI, LVEDVI and T1 relaxation time at the interventricular septum and the RV insertion points. Furthermore, in the validation cohort, low TAPSE/PASP was associated with a higher mortality and TAPSE/PASP was an independent predictor of mortality. TAPSE/PASP is a predictor of maladaptive RV and LV remodeling associated with poor outcomes in cardiomyopathy patients