Aerosol Profile Measurements from the NASA Langley Research Center Airborne High Spectral Resolution Lidar

Since achieving first light in December of 2005, the NASA Langley Research Center (LaRC) Airborne High Spectral Resolution Lidar (HSRL) has been involved in seven field campaigns, accumulating over 450 hours of science data across more than 120 flights. Data from the instrument have been used in a variety of studies including validation and comparison with the Cloud- Aerosol Lidar and Infrared Pathfinder Satellite Observation (CALIPSO) satellite mission, aerosol property retrievals combining passive and active instrument measurements, aerosol type identification, aerosol-cloud interactions, and cloud top and planetary boundary layer (PBL) height determinations. Measurements and lessons learned from the HSRL are leading towards next-generation HSRL instrument designs that will enable even further studies of aerosol intensive and extensive parameters and the effects of aerosols on the climate system. This paper will highlight several of the areas in which the NASA Airborne HSRL is making contributions to climate science

Loss of Function of TET2 Cooperates with Constitutively Active KIT in Murine and Human Models of Mastocytosis

Systemic Mastocytosis (SM) is a clonal disease characterized by abnormal accumulation of mast cells in multiple organs. Clinical presentations of the disease vary widely from indolent to aggressive forms, and to the exceedingly rare mast cell leukemia. Current treatment of aggressive SM and mast cell leukemia is unsatisfactory. An imatinib-resistant activating mutation of the receptor tyrosine kinase KIT (KIT D816V) is most frequently present in transformed mast cells and is associated with all clinical forms of the disease. Thus the etiology of the variable clinical aggressiveness of abnormal mast cells in SM is unclear. TET2 appears to be mutated in primary human samples in aggressive types of SM, suggesting a possible role in disease modification. In this report, we demonstrate the cooperation between KIT D816V and loss of function of TET2 in mast cell transformation and demonstrate a more aggressive phenotype in a murine model of SM when both mutations are present in progenitor cells. We exploit these findings to validate a combination treatment strategy targeting the epigenetic deregulation caused by loss of TET2 and the constitutively active KIT receptor for the treatment of patients with aggressive SM

Analysis of an Electromagnetic Mitigation Scheme for Reentry Telemetry Through Plasma

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/76726/1/AIAA-37395-105.pd

Epidermal mammalian target of rapamycin complex 2 controls lipid synthesis and filaggrin processing in epidermal barrier formation

Background: Perturbation of epidermal barrier formation will profoundly compromise overall skin function, leading to a dry and scaly, ichthyosis-like skin phenotype that is the hallmark of a broad range of skin diseases, including ichthyosis, atopic dermatitis, and a multitude of clinical eczema variants. An overarching molecular mechanism that orchestrates the multitude of factors controlling epidermal barrier formation and homeostasis remains to be elucidated. Objective: Here we highlight a specific role of mammalian target of rapamycin complex 2 (mTORC2) signaling in epidermal barrier formation. Methods: Epidermal mTORC2 signaling was specifically disrupted by deleting rapamycin-insensitive companion of target of rapamycin (Rictor), encoding an essential subunit of mTORC2 in mouse epidermis (epidermis-specific homozygous Rictor deletion [Ric(EKO)] mice). Epidermal structure and barrier function were investigated through a combination of gene expression, biochemical, morphological and functional analysis in Ric(EKO) and control mice. Results: Ric(EKO) newborns displayed an ichthyosis-like phenotype characterized by dysregulated epidermal de novo lipid synthesis, altered lipid lamellae structure, and aberrant filaggrin (FLG) processing. Despite a compensatory transcriptional epidermal repair response, the protective epidermal function was impaired in Ric(EKO) mice, as revealed by increased transepidermal water loss, enhanced corneocyte fragility, decreased dendritic epidermal T cells, and an exaggerated percutaneous immune response. Restoration of Akt-Ser473 phosphorylation in mTORC2-deficient keratinocytes through expression of constitutive Akt rescued FLG processing. Conclusion: Our findings reveal a critical metabolic signaling relay of barrier formation in which epidermal mTORC2 activity controls FLG processing and de novo epidermal lipid synthesis during cornification. Our findings provide novel mechanistic insights into epidermal barrier formation and could open up new therapeutic opportunities to restore defective epidermal barrier conditions.Peer reviewe

Methods for a dynamisation of climate impact studies in the Elbe River basin

Die Elbe und ihr Einzugsgebiet sind vom Klimawandel betroffen. Um die Wirkkette von projizierten Klimaveränderungen auf den Wasserhaushalt und die daraus resultierenden Nährstoffeinträge und -frachten für große Einzugsgebiete wie das der Elbe zu analysieren, können integrierte Umweltmodellsysteme eingesetzt werden. Fallstudien, die mit diesen Modellsystemen ad hoc durchgeführt werden, repräsentieren den Istzustand von Modellentwicklungen und -unsicherheiten und sind damit statisch. Diese Arbeit beschreibt den Einstieg in die Dynamisierung von Klimafolgenanalysen im Elbegebiet. Dies umfasst zum einen eine Plausibilitätsprüfung von Auswirkungsrechnungen, die mit Szenarien des statistischen Szenariengenerators STARS durchgeführt wurden, durch den Vergleich mit den Auswirkungen neuerer Klimaszenarien aus dem ISI-MIP Projekt, die dem letzten Stand der Klimamodellierung entsprechen. Hierfür wird ein integriertes Modellsystem mit "eingefrorenem Entwicklungsstand" verwendet. Die Klimawirkungsmodelle bleiben dabei unverändert. Zum anderen wird ein Bestandteil des integrierten Modellsystems – das ökohydrologische Modell SWIM – zu einer "live"-Version weiterentwickelt. Diese wird durch punktuelle Testung an langjährigen Versuchsreihen eines Lysimeterstandorts sowie an aktuellen Abflussreihen validiert und verbessert. Folgende Forschungsfragen werden bearbeitet: (i) Welche Effekte haben unterschiedliche Klimaszenarien auf den Wasserhaushalt im Elbegebiet und ist eine Neubewertung der Auswirkung des Klimawandels auf den Wasserhaushalt notwendig?, (ii) Was sind die Auswirkungen des Klimawandels auf die Nährstoffeinträge und -frachten im Elbegebiet sowie die Wirksamkeit von Maßnahmen zur Reduktion der Nährstoffeinträge?, (iii) Ist unter der Nutzung (selbst einer sehr geringen Anzahl) verfügbarer tagesaktueller Witterungsdaten in einem stark heterogenen Einzugsgebiet eine valide Ansprache der aktuellen ökohydrologischen Situation des Elbeeinzugsgebiets möglich? Die aktuellen Szenarien bestätigen die Richtung, jedoch nicht das Ausmaß der Klimafolgen: Die Rückgänge des mittleren jährlichen Gesamtabflusses und der monatlichen Abflüsse an den Pegeln bis Mitte des Jahrhunderts betragen für das STARS-Szenario ca. 30 %. Die Rückgänge bei den auf dem ISI-MIP-Szenario basierenden Modellstudien liegen hingegen nur bei ca. 10 %. Hauptursachen für diese Divergenz sind die Unterschiede in den Niederschlagsprojektionen sowie die Unterschiede in der jahreszeitlichen Verteilung der Erwärmung. Im STARS-Szenario gehen methodisch bedingt die Niederschläge zurück und der Winter erwärmt sich stärker als der Sommer. In dem ISI-MIP-Szenario bleiben die Niederschläge nahezu stabil und die Erwärmung im Sommer und Winter unterscheidet sich nur geringfügig. Generell nehmen die Nährstoffeinträge und -frachten mit den Abflüssen in beiden Szenarien unterproportional ab, wobei die Frachten jeweils stärker als die Einträge zurückgehen. Die konkreten Effekte der Abflussänderungen sind gering und liegen im einstelligen Prozentbereich. Gleiches gilt für die Unterschiede zwischen den Szenarien. Der Effekt von zwei ausgewählten Maßnahmen zur Reduktion der Nährstoffeinträge und -frachten unterscheidet sich bei verschiedenen Abflussverhältnissen, repräsentiert durch unterschiedliche Klimaszenarien in unterschiedlich feuchter Ausprägung, ebenfalls nur geringfügig. Die Beantwortung der ersten beiden Forschungsfragen zeigt, dass die Aktualisierung von Klimaszenarien in einem ansonsten "eingefrorenen" Verbund von ökohydrologischen Daten und Modellen eine wichtige Prüfoption für die Plausibilisierung von Klimafolgenanalysen darstellt. Sie bildet die methodische Grundlage für die Schlussfolgerung, dass bei der Wassermenge eine Neubewertung der Klimafolgen notwendig ist, während dies bei den Nährstoffeinträgen und -frachten nicht der Fall ist. Die zur Beantwortung der dritten Forschungsfrage mit SWIM-live durchgeführten Validierungsstudien ergeben Diskrepanzen am Lysimeterstandort und bei den Abflüssen aus den Teilgebieten Saale und Spree. Sie lassen sich zum Teil mit der notwendigen Interpolationsweite der Witterungsdaten und dem Einfluss von Wasserbewirtschaftungsmaßnahmen erklären. Insgesamt zeigen die Validierungsergebnisse, dass schon die Pilotversion von SWIM-live für eine ökohydrologische Ansprache des Gebietswasserhaushaltes im Elbeeinzugsgebiet genutzt werden kann. SWIM-live ermöglicht eine unmittelbare Betrachtung und Beurteilung simulierter Daten. Dadurch werden Unsicherheiten bei der Modellierung direkt offengelegt und können infolge dessen reduziert werden. Zum einen führte die Verdichtung der meteorologischen Eingangsdaten durch die Verwendung von nun ca. 700 anstatt 19 Klima- bzw. Niederschlagstationen zu einer Verbesserung der Ergebnisse. Zum anderen wurde SWIM-live beispielhaft für einen Zyklus aus punktueller Modellverbesserung und flächiger Überprüfung der Simulationsergebnisse genutzt. Die einzelnen Teilarbeiten tragen jeweils zur Dynamisierung von Klimafolgenanalysen im Elbegebiet bei. Der Anlass hierfür war durch die fehlerhaften methodischen Grundlagen von STARS gegeben. Die Sinnfälligkeit der Dynamisierung ist jedoch nicht an diesen konkreten Anlass gebunden, sondern beruht auf der grundlegenden Einsicht, dass Ad-hoc-Szenarienanalysen immer auch pragmatische Vereinfachungen zugrunde liegen, die fortlaufend überprüft werden müssen.The Elbe River basin is affected by climate change. To analyse the chain of effects of projected climate change on the water balance and the resulting nutrient emissions and loads in large river basins such as the Elbe, integrated environmental model systems can be applied. Case studies that are conducted ad hoc with these model systems represent the current state of model developments and uncertainties - therefore, they are static. This thesis describes access to a dynamisation of climate impact studies in the Elbe River basin. On the one hand, this comprises a verification of impact simulations that are conducted with scenarios from the statistical scenario generator STARS, with the impacts of newer climate scenarios from the ISI-MIP project, that represent state-of-the-art climate modelling. For this purpose, an integrated model system with a "frozen" development status is used. At the same time, the climate impact models remain unchanged. On the other hand, one component of the integrated model system - the ecohydrological model SWIM - is enhanced as a "live"-system. This is validated and improved by punctual testing with experimental long time series from a lysimeter site and with recent runoff time series. The following research questions are addressed: (i) What are the effects of different climate scenarios on the water balance in the Elbe River basin, and is a reassessment of the impacts of climate change on the water balance necessary?, (ii) What are the impacts of climate change on the nutrient emissions and loads in the Elbe River basin as well as the effectiveness of measures for reducing nutrient emissions?, (iii) Is a valid assessment of the actual ecohydrological situation in the Elbe River basin possible, using (only a small amount of) available day-to-day weather data in a highly heterogeneous river basin? The recent scenarios confirm the direction, but not the magnitude, of climate impacts: In the STARS scenario, the decrease in mean annual discharge and mean monthly stream ow until the middle of the century is approx. 30 %. However, the model studies based on the ISI-MIP scenarios show only a decrease of approx. 10 %. The main reason for this divergence can be attributed to differences in the precipitation projections and differences in the seasonal distribution of the warming. In the STARS scenario, the precipitation decreases due to the methodological principles applied and the warming in winter is stronger than in summer. In the ISI-MIP scenario, the precipitation is almost stable and the warming differs only slightly between summer and winter. In general, the nutrient emissions and loads decrease underproportionally with the river basin discharge in both scenarios, with loads declining more sharply than the emissions. The concrete effects of the change in river basin discharge are small, reaching only single-digit percentages. The same holds true for the difference between the scenarios. The effect of selected measures for the reduction of nutrient emissions and loads also differs only slightly between varying runoff conditions, represented by different climate scenarios with dry, mean and wet specifications. Answering the first two research questions shows that the actualisation of climate scenarios in an otherwise "frozen" combination of ecohydrological data and models represents an important testing option for the plausibilisation of climate impact studies. It forms the methodological basis for the conclusion that a reassessment of climate impact is necessary in terms of water quantity, whereas this is not the case for the nutrient emissions and loads. The validation studies that were conducted to answer the third research question show discrepancies at the lysimeter site and in the flows from the sub-catchments of the Saale and Spree Rivers. They can be explained in part by the low spatial density of the climate data and the influences from water-management practices. However, the validation results show that the pilot version of SWIM-live can already be used for an eco-hydrological assessment of the water balance in the Elbe River basin. SWIM-live provides an immediate visualisation and assessment of the simulated data. By this means, uncertainties in the simulations are directly revealed and can be reduced. On the one hand, a concentration of the meteorological input data using approx. 700 instead of 19 climate and precipitation stations leads to an improvement of the results. On the other hand, SWIM-live is used exemplarily for a cycle of punctual model improvement and spatial verification of the simulations. The individual parts of this thesis contribute to the dynamisation of climate impact studies in the Elbe River basin. The motivation for the study was the flawed methodological basis of STARS. Dynamisation is relevant not only for this reason, but is also based on the underlying understanding that ad hoc scenario analyses involve pragmatic simplifications that must be verified continuously

Host and Donor B Cell-Derived IL-10 Ameliorates Murine Graft-Versus-Host Disease

Allogeneic hematopoetic stem cell transplantation (HSCT) is the treatment of choice for a variety of hematologic malignancies. Graft-versus-Host disease (GvHD) is a key contributor to treatment related morbidity and mortality and consequently limits the efficacy of allogeneic HSCT. Interleukin 10 (IL-10) is a well-known cytokine with immunoregulatory and anti-inflammatory properties, also important in context of GvHD. B cells have been described as potent IL-10 producers in various situations. Here we show how host as well as donor derived B cells contribute to GvHD amelioration through IL-10 production. We address the role of IL-10 in GvHD in an acute murine MHC mismatch model: Mice on a C57BL/6 background received bone marrow and CD90+ T cells from mice on a BALB/c background or vice versa. Transplantation experiments with IL-10 deficient donor or host cells clearly show the importance of donor derived IL-10 in general. To further dissect the cells contributing to IL-10 production in this situation we employed an IL-10 knock-in reporter mouse in which expression of eGFP is under control of the Il-10 locus. Lethal irradiation as used in the conditioning regiment before transplantation revealed B cells as major contributors of host derived IL-10. In addition, transfer of cells from reporter mice into preconditioned recipients showed also donor B cells as contributors to IL-10 production. A phenotypical characterization of the eGFP+ B cells exhibited a CD1d+TIM-1+CD5int phenotype, in line with immunoregulatory B cells. To finally confirm the relevance of B cells derived IL-10 in GvHD, we employed B6.B-IL-10-/- mice that have a B cell specific IL-10 knock-out as donors or recipients. Here we found a reduced survival associated with the incapability of the B cells to produce IL-10 in both cases. Taken together, our results provide new insights in the mechanisms and the variety of cells contributing to the course of GvHD. An improved understanding of these aspects might help to pave the way for new treatment options to overcome current limitations of allogenic HSCT. Disclosures: No relevant conflicts of interest to declare. </jats:sec

Integrin β1–mediated mast cell immune-surveillance of blood vessel content

Background: IgE-mediated degranulation of mast cells (MCs) provides rapid protection against environmental hazards, including animal venoms. A fraction of tissue-resident MCs intimately associates with blood vessels. These perivascular MCs were reported to extend projections into the vessel lumen and to be the first MCs to acquire intravenously injected IgE, suggesting that IgE loading of MCs depends on their vascular association. Objective: We sought to elucidate the molecular basis of the MC–blood vessel interaction and to determine its relevance for IgE-mediated immune responses. Methods: We selectively inactivated the Itgb1 gene, encoding the β1 chain of integrin adhesion molecules (ITGB1), in MCs by conditional gene targeting in mice. We analyzed skin MCs for blood vessel association, surface IgE density, and capability to bind circulating antibody specific for MC surface molecules, as well as in vivo responses to antigen administered via different routes. Results: Lack of ITGB1 expression severely compromised MC–blood vessel association. ITGB1-deficient MCs showed normal densities of surface IgE but reduced binding of intravenously injected antibodies. While their capacity to degranulate in response to IgE ligation in vivo was unimpaired, anaphylactic responses to antigen circulating in the vasculature were largely abolished. Conclusions: ITGB1-mediated association of MCs with blood vessels is key for MC immune surveillance of blood vessel content, but is dispensable for slow steady-state loading of endogenous IgE onto tissue-resident MCs

B cell-derived IL-10 does not regulate spontaneous systemic autoimmunity in MRL.Fas lpr mice

B cells contribute to the pathogenesis of chronic autoimmune disorders like systemic lupus erythematosus (SLE) via multiple effector functions. However, B cells are also implicated in regulating SLE and other autoimmune syndromes via release of IL-10. B cells secreting IL-10 have been termed “Breg” and have been proposed as a separate subset of cells, a concept that remains controversial. The balance between pro- and anti-inflammatory effects could determine the success of B cell targeted therapies for autoimmune disorders and it is therefore pivotal to understand the significance of B cell-secreted IL-10 in spontaneous autoimmunity. By lineage specific deletion of Il10 from B cells we demonstrate that B cell-derived IL-10 is ineffective in suppressing the spontaneous activation of self-reactive B and T cells during lupus. Correspondingly, severity of organ disease and survival rates in mice harboring Il10 deficient B cells are unaltered. Genetic marking of cells that transcribe Il10 illustrates that the pool of IL-10 competent cells is dominated by CD4 T cells and macrophages. IL-10 competent cells of the B lineage are rare in vivo and among them short-lived plasmablasts have the highest frequency, suggesting an activation rather than lineage-driven phenotype. Putative Breg phenotypic subsets such as CD1d(hi)CD5(+) and CD21(hi)CD23(hi) B cells are not enriched in Il10 transcription. These genetic studies demonstrate that in a spontaneous model of murine lupus, IL-10 dependent B cell regulation does not restrain disease and thus the pathogenic effects of B cells are not detectably counterbalanced by their IL-10 dependent regulatory functions