Pilots’ Decision-Making under High Workload: Recognition-Primed or Not – An Engineering Point of View

The objective of this study is to analyse pilots' decision-making behaviour in terms of naturalistic decision-making. In line with the highly experienced group of pilots (n = 120), recognition-primed decisions are expected to dominate. In a full-flight simulator experiment, with two groups of pilots (short-haul and long-haul pilots) with different levels of practice and training, we were able to show that only about one-third of the pilots make recognition-primed decisions. Results may indicate that the current training practice helps pilots to handle foreseeable problems very well, yet does not support pilots in ambivalent and new decision-making situations. Based on these findings, we recommend the incorporation of more unforeseen events in recurrent training simulator missions to train pilots in handling unknown situations. Practitioner Summary: The results from a flight-simulator study showed that pilots' decision-making is more analytical than recognition-primed. A possible reason for this could be the pressure for justification, or simply that pilots cannot use their experience in unforeseen situations. Hence, training should include more unforeseen events

Effect of everolimus-based drug regimens on CMV-specific T-cell functionality after renal transplantation: 12-month ATHENA subcohort-study results

Post-transplant cytomegalovirus (CMV) infections and increased viral replication are associated with CMV-specific T-cell anergy. In the ATHENA-study, de-novo everolimus (EVR) with reduced-exposure tacrolimus (TAC) or cyclosporine (CyA) showed significant benefit in preventing CMV infections in renal transplant recipients as compared to standard TAC + mycophenolic acid (MPA). However, immunomodulatory mechanisms for this effect remain largely unknown. Ninety patients from the ATHENA-study completing the 12-month visit on-treatment (EVR + TAC n = 28; EVR + CyA n = 19; MPA + TAC n = 43) were included in a posthoc analysis. Total lymphocyte subpopulations were quantified. CMV-specific CD4 T cells were determined after stimulation with CMV-antigen, and cytokine-profiles and various T-cell anergy markers were analyzed using flow cytometry. While 25.6% of MPA + TAC-treated patients had CMV-infections, no such events were reported in EVR-treated patients. Absolute numbers of lymphocyte subpopulations were comparable between arms, whereas the percentage of regulatory T cells was significantly higher with EVR + CyA versus MPA + TAC (p = 0.019). Despite similar percentages of CMV-specific T cells, their median expression of CTLA-4 and PD-1 was lower with EVR + TAC (p < 0.05 for both) or EVR + CyA (p = 0.045 for CTLA-4) compared with MPA + TAC. Moreover, mean percentages of multifunctional CMV-specific T cells were higher with EVR + TAC (27.2%) and EVR + CyA (29.4%) than with MPA + TAC (19.0%). In conclusion, EVR-treated patients retained CMV-specific T-cell functionality, which may contribute to enhanced protection against CMV infections

HnRNP L and L-like cooperate in multiple-exon regulation of CD45 alternative splicing

CD45 encodes a trans-membrane protein-tyrosine phosphatase expressed in diverse cells of the immune system. By combinatorial use of three variable exons 4–6, isoforms are generated that differ in their extracellular domain, thereby modulating phosphatase activity and immune response. Alternative splicing of these CD45 exons involves two heterogeneous ribonucleoproteins, hnRNP L and its cell-type specific paralog hnRNP L-like (LL). To address the complex combinatorial splicing of exons 4–6, we investigated hnRNP L/LL protein expression in human B-cells in relation to CD45 splicing patterns, applying RNA-Seq. In addition, mutational and RNA-binding analyses were carried out in HeLa cells. We conclude that hnRNP LL functions as the major CD45 splicing repressor, with two CA elements in exon 6 as its primary target. In exon 4, one element is targeted by both hnRNP L and LL. In contrast, exon 5 was never repressed on its own and only co-regulated with exons 4 and 6. Stable L/LL interaction requires CD45 RNA, specifically exons 4 and 6. We propose a novel model of combinatorial alternative splicing: HnRNP L and LL cooperate on the CD45 pre-mRNA, bridging exons 4 and 6 and looping out exon 5, thereby achieving full repression of the three variable exons

Integrated Assessment of Heavy Metal Contamination in Sediments from a Coastal Industrial Basin, NE China

The purpose of this study is to investigate the current status of metal pollution of the sediments from urban-stream, estuary and Jinzhou Bay of the coastal industrial city, NE China. Forty surface sediment samples from river, estuary and bay and one sediment core from Jinzhou bay were collected and analyzed for heavy metal concentrations of Cu, Zn, Pb, Cd, Ni and Mn. The data reveals that there was a remarkable change in the contents of heavy metals among the sampling sediments, and all the mean values of heavy metal concentration were higher than the national guideline values of marine sediment quality of China (GB 18668-2002). This is one of the most polluted of the world’s impacted coastal systems. Both the correlation analyses and geostatistical analyses showed that Cu, Zn, Pb and Cd have a very similar spatial pattern and come from the industrial activities, and the concentration of Mn mainly caused by natural factors. The estuary is the most polluted area with extremely high potential ecological risk; however the contamination decreased with distance seaward of the river estuary. This study clearly highlights the urgent need to make great efforts to control the industrial emission and the exceptionally severe heavy metal pollution in the coastal area, and the immediate measures should be carried out to minimize the rate of contamination, and extent of future pollution problems

Onset and progression of diabetes in kidney transplant patients receiving everolimus or cyclosporine therapy: an analysis of two randomized, multicenter trials

Background: Conversion from calcineurin inhibitor (CNI) therapy to a mammalian target of rapamycin (mTOR) inhibitor following kidney transplantation may help to preserve graft function. Data are sparse, however, concerning the impact of conversion on posttransplant diabetes mellitus (PTDM) or the progression of pre-existing diabetes. Methods: PTDM and other diabetes-related parameters were assessed post hoc in two large open-label multicenter trials. Kidney transplant recipients were randomized (i) at month 4.5 to switch to everolimus or remain on a standard cyclosporine (CsA)-based regimen (ZEUS, n = 300), or (ii) at month 3 to switch to everolimus, remain on standard CNI therapy or convert to everolimus with reduced-exposure CsA (HERAKLES, n = 497). Results: There were no significant differences in the incidence of PTDM between treatment groups (log rank p = 0.97 [ZEUS], p = 0.90 [HERAKLES]). The mean change in random blood glucose from randomization to month 12 was also similar between treatment groups in both trials for patients with or without PTDM, and with or without pre-existing diabetes. The change in eGFR from randomization to month 12 showed a benefit for everolimus versus comparator groups in all subpopulations, but only reached significance in larger subgroups (no PTDM or no pre-existing diabetes). Conclusions: Within the restrictions of this post hoc analysis, including non-standardized diagnostic criteria and limited glycemia laboratory parameters, these data do not indicate any difference in the incidence or severity of PTDM with early conversion from a CsA-based regimen to everolimus, or in the progression of pre-existing diabetes. Trial registration: clinicaltrials.gov , NCT00154310 (registered September 2005) and NCT00514514 (registered August 2007); EudraCT ( 2006-007021-32 and 2004-004346-40 )

A role for microRNAs during plasma cell differentiation and in multiple myeloma

B-Zellen differenzieren nach Aktivierung entweder direkt zu IgM-sezernierenden Plasmazellen oder vollziehen im Keimzentrum durch somatische Hypermutation der Immunglobulin (Ig)-Gene die Affinitätsreifung ihres B-Zellrezeptors und durch Klassenwechsel den Sprung zu sekundären Ig-Isotypen. Die beiden Transkriptionsfaktoren IRF-4 und Blimp-1 sind essentiell für die Initiation, Durchführung und Termination der Plasmazelldifferenzierung. In Plasmazellen sorgen sie für die Expression von stadienspezifischen Genen und reprimieren die Expression von B-Zell-Identitätsgenen wie Pax5 und Bcl6. Für die Affinitätsreifung und den Ig-Klassenwechsel sind Bcl6, Bach2 und Mitf notwendig. Sie inhibieren die Transkriptionsfaktoren Blimp-1 und IRF-4 während der Keimzentrumsreaktionen, um eine vorzeitige Plasmazelldifferenzierung zu verhindern. Wie es zur Aufhebung der Bach2-vermittelten Repression von Blimp-1 und der Mitf-vermittelten Repression von IRF-4 kommt, ist noch ungeklärt. Das Multiple Myelom ist ein maligner Plasmazelltumor, der durch sekretorisch hyperaktive Plasmazellen gekennzeichnet ist, die das Knochenmark infiltrieren. Die Pathogenese-Mechanismen sind vielfältig. MicroRNAs (miRNAs) sind nicht-Protein-kodierende, kleine RNA-Moleküle, die auf posttranskriptioneller Ebene nach Bindung an ihre spezifische Zielsequenz in der 3'UTR einer mRNA die Genexpression negativ regulieren. Ob miRNAs an der terminalen Differenzierung der B-Zellen zu Plasmazellen beteiligt sind, ist bisher unbekannt. Ebenso ist die Rolle der miRNAs im Multiplen Myelom nur wenig erforscht. Welche Rolle miRNAs bei der Plasmazelldifferenzierung und im Multiplen Myelom spielen, war Gegenstand der Untersuchungen dieser Arbeit. Durch deep sequencing Analysen humaner naiver B-Zellen, Plasmablasten und Knochenmarks-Plasmazellen sowie primärer Myelome und verschiedener muriner Plsmazellpopulationen konnten sowohl einige während der Plasmazelldifferenzierung als auch im Myelom differentiell exprimierte miRNAs identifiziert werden. In silico und in vitro Zielgen-Analysen dieser miRNAs zeigten, dass sie eine potentielle regulatorische Rolle in Plasmazellen und während der Plasmazelldifferenzierung spielen könnten und in die onkogene Transformation von Myelomzellen involviert sein könnten.After antigen encounter B cells differentiate either directly into IgM-secreting plasma cells or enter germinal center reactions during which somatic hypermutation of the immunoglobulin-genes and class switch recombination lead to affinity maturation and generation of highly specific antibodies of isotypes different from IgM. The differentiation of mature B cells into plasma cells is tightly controlled by a regulatory network of transcription factors. IRF-4 and Blimp-1 have been shown to be essential for initiation and termination of plasma cell differentiation as well as for maintenance of plasma cell phenotype as they provide expression of critical plasma cell genes and as they negatively regulate B cell identity genes like Pax5 and Bcl6. During germinal centre reaction Bcl6, Bach2 and Mitf are crucial for affinity maturation and class switch recombination as they repress expression of IRF-4 and Blimp-1 and thereby inhibit initiation of plasma cell differentiation. How Bach2- and Mitf- mediated repression of Blimp-1 and IRF-4 is alleviated to allow onset of plasma cell differentiation is thus far not known. MicroRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression at the post-transcriptional level. Whether miRNAs are crucial during plasma cell differentiation is barely known. Dysregulation of miRNAs contributes to the pathogenesis of various hematopoetic malignancies. Multiple Myeloma is a plasma cell malignancy characterized by hypersecretory plasma cells that infiltrate the bone marrow. Currently only little is known about the role of miRNAs in Multiple Myeloma. The specific aim of this work was to investigate the role of miRNAs during plasma cell differentiation and their involvement in pathogenesis of Multiple Myeloma. By deep sequencing of cloned miRNAs we established the miRNA expression profile of human naîve B cells, plasmablasts and normal as well as malignant bone marrow-derived plasma cells and of murine plasma cell subsets. This analysis identified numerous differentially expressed miRNAs during plasma cell differentiation as well as in malignant plasma cells from Myeloma patients. Target analysis revealed potential functions of these miRNAs during normal plasma cell differentiation and malignant transformation

'Kolonialismus' im Geschichtsunterricht: Repräsentation und Rezeption historischen 'Wissens'

Das Konzept ›Lesart‹ als bedeutungsgenerierenden Prozess im Zusammenspiel von Repräsentation und Rezeption zu erfassen bedeutet in der vorliegenden Dissertation, sich der multimodalen Repräsentation von ›Kolonialismus‹ in aktuellen Geschichtslehrbüchern zuzuwenden und zusätzlich zu eruieren, wie Rezipient*innen (13-jährige Schüler*innen) implizit/explizit repräsentierte Ideologien wahrnehmen und/oder ko-konstruieren und diese Wahrnehmungen auf Sichtweisen der modernen Migrationsgesellschaft übertragen. Ein Zweiphasen-Verfahren ermöglicht die Analyse genuin schriftlicher und mündlicher Texte anhand derselben linguistischen Parameter; die analytische Klammer zwischen konzeptioneller ›Schriftlichkeit‹ und ›Mündlichkeit‹ bilden die Phänomene der Diskursebene Metapragmatik und Indexikalität. Dadurch wird das Interagieren zweier Subdisziplinen der Linguistik, der Diskurs- und der Soziolinguistik, ermöglicht. Die Befunde zeigen, dass die Repräsentation des ›Kolonialismus‹, durch welche die ›kolonialen Akteure‹ als Täter vs. Opfer prädiziert werden, in der Rezeption auf eine Weise reproduziert wurde, die zu einer gesellschaftlichen Dichotomisierung von überlegen vs. unterlegen und damit zur Stigmatisierung der Kolonisierten führte. Diese extreme Polarisierung der kolonialen Gesellschaft findet sich in der Sicht auf die moderne Gesellschaft wieder, wo eine Normierung (und Legitimierung) der Bipolarität des sozio-kulturellen Status von Mitgliedern der Aufnahmegesellschaft vs. dem von Menschen mit Migrations- und vor allem Fluchtbiographien erkennbar wird.It is the overall goal of this dissertation to perceive the concept of ›reading‹ as a meaning making process resulting from the interaction of representation and reception. Hence, the interest of the study is directed towards the scriptural and pictural representations of ›colonialism‹ in current history textbooks and towards the perception (or co-construction) of explicitly or implicitly conveyed ideologies by the recipients of the text (13-year-old pupils). Furthermore, it is intended to investigate the impact these ideologies might have on the recipients’ views of the current heterogeneous society. Thus, a two-phase procedure is employed, enabling the interaction of two linguistic sub-disciplines: discourse linguistics and sociolinguistics. The two phenomena of the discourse level – indexicality and metapragmatics – are intended to function as the common denominator of conceptual written and spoken texts. Regarding textbook representation, this study has found that there is a tendency for the examined textbooks to portray the colonized world in a simplified dichotomous way pursuing a strong Eurocentric perspective where ideologies of a superior ›West‹ vs. an inferior ›Non-European World‹ are primarily conveyed. This view of an ultimately polarized colonial society was mirrored in the pupils’ attitudes toward impressions of society in the past as well as in the present: It became evident that the pupils normed and legitimized the bipolarity of the socio-cultural status of members of the host society in contrast to that of migrants, asylum seekers and refugees, regarding these opinions as matters of fact

B cell homeostasis and plasma cell homing controlled by Krüppel-like factor 2

Krüppel-like factor 2 (KLF2) controls T lymphocyte egress from lymphoid organs by regulating sphingosin-1 phosphate receptor 1 (S1Pr1). Here we show that this is not the case for B cells. Instead, KLF2 controls homeostasis of B cells in peripheral lymphatic organs and homing of plasma cells to the bone marrow, presumably by controlling the expression of β7-integrin. In mice with a B cell-specific deletion of KLF2, S1Pr1 expression on B cells was only slightly affected. Accordingly, all splenic B cell subsets including B1 cells were present, but their numbers were increased with a clear bias for marginal zone (MZ) B cells. In contrast, fewer peyers patches harboring fewer B cells were found, and fewer B1 cells in the peritoneal cavity as well as recirculating B cells in the bone marrow were detected. Upon thymus-dependent immunization, IgG titers were diminished, and antigen-specific plasma cells were absent in the bone marrow, although numbers of antigen-specific splenic plasmablasts were normal. KLF2 plays also a role in determining the identity of follicular B cells, as KLF2-deficient follicular B cells showed calcium responses similar to those of MZ B cells and failed to down-regulate MZ B cell signature genes, such as CD21 and CXCR7