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B lymphocytes are an important cell population of the immune system. However, until recently it was not possible to transduce resting B lymphocytes with retro- or lentiviral vectors, making them unsusceptible for genetic manipulations by these vectors. Lately, we demonstrated that lentiviral vectors pseudotyped with modified measles virus (MV) glycoproteins hemagglutinin, responsible for receptor recognition, and fusion protein were able to overcome this transduction block. They use either the natural MV receptors, CD46 and signaling lymphocyte activation molecule (SLAM), for cell entry (MV-LV) or the vector particles were further modified to selectively enter via the CD20 molecule, which is exclusively expressed on B lymphocytes (CD20-LV). It has been shown previously that transduction by MV-LV does not induce B lymphocyte activation. However, if this is also true for CD20-LV is still unknown. Here, we generated a vector specific for another B lymphocyte marker, CD19, and compared its ability to transduce resting B lymphocytes with CD20-LV. The vector (CD19ds-LV) was able to stably transduce unstimulated B lymphocytes, albeit with a reduced efficiency of about 10% compared to CD20-LV, which transduced about 30% of the cells. Since CD20 as well as CD19 are closely linked to the B lymphocyte activation pathway, we investigated if engagement of CD20 or CD19 molecules by the vector particles induces activating stimuli in resting B lymphocytes. Although, activation of B lymphocytes often involves calcium influx, we did not detect elevated calcium levels. However, the activation marker CD71 was substantially up-regulated upon CD20-LV transduction and most importantly, B lymphocytes transduced with CD20-LV or CD19ds-LV entered the G1b phase of cell cycle, whereas untransduced or MV-LV transduced B lymphocytes remained in G0. Hence, CD20 and CD19 targeting vectors induce activating stimuli in resting B lymphocytes, which most likely renders them susceptible for lentiviral vector transduction.
Introduction: In this article three research questions are addressed: (1) Is there an association between socioeconomic status (SES) and patient-reported outcomes in a cohort of multimorbid patients? (2) Does the association vary according to SES indicator used (income, education, occupational position)? (3) Can the association between SES and patient-reported outcomes (self-rated health, health-related quality of life and functional status) be (partly) explained by burden of disease?
Methods: Analyses are based on the MultiCare Cohort Study, a German multicentre, prospective, observational cohort study of multimorbid patients from general practice. We analysed baseline data and data from the first follow-up after 15 months (N = 2,729). To assess burden of disease we used the patients’ morbidity data from standardized general practitioner (GP) interviews based on a list of 46 groups of chronic conditions including the GP’s severity rating of each chronic condition ranging from marginal to very severe.
Results: In the cross-sectional analyses SES was significantly associated with the patient-reported outcomes at baseline. Associations with income were more consistent and stronger than with education and occupational position. Associations were partly explained (17% to 44%) by burden of disease. In the longitudinal analyses only income (but not education and occupational position) was significantly related to the patient-reported outcomes at follow-up. Associations between income and the outcomes were reduced by 18% to 27% after adjustment for burden of disease.
Conclusions: Results indicate social inequalities in self-rated health, functional status and health related quality of life among older multimorbid patients. As associations with education and occupational position were inconsistent, these inequalities were mainly due to income. Inequalities were partly explained by burden of disease. However, even among patients with a similar disease burden, those with a low income were worse off in terms of the three patient-reported outcomes under study.
Sepsis is characterized by dysregulated gene expression, provoking a hyper-inflammatory response occurring in parallel to a hypo-inflammatory reaction. This is often associated with multi-organ failure, leading to the patient’s death. Therefore, reprogramming of these pro- and anti-inflammatory, as well as immune-response genes which are involved in acute systemic inflammation, is a therapy approach to prevent organ failure and to improve sepsis outcomes. Considering epigenetic, i.e., reversible, modifications of chromatin, not altering the DNA sequence as one tool to adapt the expression profile, inhibition of factors mediating these changes is important. Acetylation of histones by histone acetyltransferases (HATs) and initiating an open-chromatin structure leading to its active transcription is counteracted by histone deacetylases (HDACs). Histone deacetylation triggers a compact nucleosome structure preventing active transcription. Hence, inhibiting the activity of HDACs by specific inhibitors can be used to restore the expression profile of the cells. It can be assumed that HDAC inhibitors will reduce the expression of pro-, as well as anti-inflammatory mediators, which blocks sepsis progression. However, decreased cytokine expression might also be unfavorable, because it can be associated with decreased bacterial clearance.
5-Lipoxygenase contributes to PPAR [gamma] activation in macrophages in response to apoptotic cells
(2012)
Background: One hallmark contributing to immune suppression during the late phase of sepsis is macrophage polarization to an anti-inflammatory phenotype upon contact with apoptotic cells (AC). Taking the important role of the nuclear receptor PPARγ for this phenotype switch into consideration, it remains elusive how AC activate PPARγ in macrophages. Therefore, we were interested to characterize the underlying principle.
Methods: Apoptosis was induced by treatment of Jurkat T cells for 3 hours with 0.5 μg/ml staurosporine. Necrotic cells (NC) were prepared by heating cells for 20 minutes to 65°C. PPARγ activation was followed by stably transducing RAW264.7 macrophages with a vector encoding the red fluorescent protein mRuby after PPARγ binding to 4 × PPRE sites downstream of the reporter gene sequence. This readout was established by treatment with the PPARγ agonist rosiglitazone (1 μM) and AC (5:1). Twenty-four hours after stimulation, mRuby expression was analysed by fluorescence microscopy. Lipid rafts of AC, NC, as well as living cells (LC) were enriched by sucrose gradient centrifugation. Fractions were analysed for lipid raft-associated marker proteins. Lipid rafts were incubated with transduced RAW264.7 macrophages as described above. 5-Lipoxygenase (5-LO) involvement was verified by pharmacological inhibition (MK-866, 1 μM) and overexpression.
Results: Assuming that the molecule responsible for PPARγ activation in macrophages is localized in the cell membrane of AC, most probably associated to lipid rafts, we isolated lipid rafts from AC, NC and LC. Mass spectrometric analysis of lipid rafts of AC showed the expression of 5-LO, whereas lipid rafts of LC did not. Moreover, incubating macrophages with lipid rafts of AC induced mRuby expression. In contrast, lipid rafts of NC and LC did not. To verify the involvement of 5-LO in activating PPARγ in macrophages, Jurkat T cells were incubated for 30 minutes with the 5-LO inhibitor MK-866 (1 μM) before apoptosis induction. In line with our hypothesis, these AC did not induce mRuby expression. Finally, although living Jurkat T cells overexpressing 5-LO did not activate PPARγ in macrophages, mRuby expression was significantly increased when AC were generated from 5-LO overexpressing compared with wild-type Jurkat cells.
Conclusion: Our results suggest that induction of apoptosis activates 5-LO, localizing to lipid rafts, necessary for PPARγ activation in macrophages. Therefore, it will be challenging to determine whether 5-LO activity in AC, generated from other cell types, correlates with PPARγ activation, contributing to an immune-suppressed phenotype in macrophages.
Acute respiratory distress syndrome (ARDS) is a major cause of patient mortality in intensive care units (ICUs) worldwide. Considering that no causative treatment but only symptomatic care is available, it is obvious that there is a high unmet medical need for a new therapeutic concept. One reason for a missing etiologic therapy strategy is the multifactorial origin of ARDS, which leads to a large heterogeneity of patients. This review summarizes the various kinds of ARDS onset with a special focus on the role of reactive oxygen species (ROS), which are generally linked to ARDS development and progression. Taking a closer look at the data which already have been established in mouse models, this review finally proposes the translation of these results on successful antioxidant use in a personalized approach to the ICU patient as a potential adjuvant to standard ARDS treatment.
Tolerizing CTL by sustained hepatic PD-L1 expression provides a new therapy spproach in mouse sepsis
(2019)
Cytotoxic T lymphocyte (CTL) activation contributes to liver damage during sepsis, but the mechanisms involved are largely unknown. Understanding the underlying principle will permit interference with CTL activation and thus, provide a new therapeutic option.
Methods: To elucidate the mechanism leading to CTL activation we used the Hepa1-6 cell line in vitro and the mouse model of in vivo polymicrobial sepsis, following cecal-ligation and -puncture (CLP) in wildtype, myeloid specific NOX-2, global NOX2 and NOX4 knockout mice, and their survival as a final readout. In this in vivo setting, we also determined hepatic mRNA and protein expression as well as clinical parameters of liver damage - aspartate- and alanine amino-transaminases. Hepatocyte specific overexpression of PD-L1 was achieved in vivo by adenoviral infection and transposon-based gene transfer using hydrodynamic injection.
Results: We observed downregulation of PD-L1 on hepatocytes in the murine sepsis model. Adenoviral and transposon-based gene transfer to restore PD-L1 expression, significantly improved survival and reduced the release of liver damage, as PD-L1 is a co-receptor that negatively regulates T cell function. Similar protection was observed during pharmacological intervention using recombinant PD-L1-Fc. N-acetylcysteine blocked the downregulation of PD-L1 suggesting the involvement of reactive oxygen species. This was confirmed in vivo, as we observed significant upregulation of PD-L1 expression in NOX4 knockout mice, following sham operation, whereas its expression in global as well as myeloid lineage NOX2 knockout mice was comparable to that in the wild type animals. PD-L1 expression remained high following CLP only in total NOX2 knockouts, resulting in significantly reduced release of liver damage markers.
Conclusion: These results suggest that, contrary to common assumption, maintaining PD-L1 expression on hepatocytes improves liver damage and survival of mice during sepsis. We conclude that administering recombinant PD-L1 or inhibiting NOX2 activity might offer a new therapeutic option in sepsis.
During evolution of an RNA world, the development of enzymatic function was essential. Such enzymatic function was linked to RNA sequences capable of adopting specific RNA folds that possess catalytic pockets to promote catalysis. Within this primordial RNA world, initially evolved self-replicating ribozymes presumably mutated to ribozymes with new functions. Schultes and Bartel (Science 2000, 289, 448–452) investigated such conversion from one ribozyme to a new ribozyme with distinctly different catalytic functions. Within a neutral network that linked these two prototype ribozymes, a single RNA chain could be identified that exhibited both enzymatic functions. As commented by Schultes and Bartel, this system possessing one sequence with two enzymatic functions serves as a paradigm for an evolutionary system that allows neutral drifts by stepwise mutation from one ribozyme into a different ribozyme without loss of intermittent function. Here, we investigated this complex functional diversification of ancestral ribozymes by analyzing several RNA sequences within this neutral network between two ribozymes with class III ligase activity and with self-cleavage reactivity. We utilized rapid RNA sample preparation for NMR spectroscopic studies together with SHAPE analysis and in-line probing to characterize secondary structure changes within the neutral network. Our investigations allowed delineation of the secondary structure space and by comparison with the previously determined catalytic function allowed correlation of the structure-function relation of ribozyme function in this neutral network.
Background: The impact of climate change on public health may occur through a number of main pathways including increased temperature, ground-level ozone levels and ultra-violet radiation, which have a range of consequences for human health. One strategy for adaptation to the predicted effects of climate change on health that has been proposed, is to ‘green’ urban areas, essentially by increasing the abundance and cover of vegetation. This protocol is for an update of a systematic review which aimed to address the question: How effective is ‘greening’ of urban areas in reducing human exposure to ground-level ozone concentrations, UV exposure and the ‘urban heat island effect’?
Methods: A sensitive search of multiple databases and relevant journals for relevant published articles will be conducted. A search for relevant unpublished articles will be undertaken through an internet search and of websites of relevant organisations. Inclusion criteria will be applied at title, abstract and full-text. Repeatability checks of this screening process will be undertaken. Articles included at full-text will be critically appraised using a standardised checklist. A repeatability check will be made of this process. Pre-defined data items will be extracted from included articles. If appropriate, quantitative synthesis will be undertaken through meta-analysis and/or a narrative synthesis will be undertaken.
The Generalized Uncertainty Principle (GUP) arises from Quantum Gravity thought experiments and contains a minimal lenght. In this thesis I calculate Schwarzschild Black Holes that are modified by the GUP. These Black Holes have the property, that their temperature does not diverge for small masses, although they still posses a curvature singularity. I calculate analytically that in more than 3+1 dimensions the temperature diverges again.
In thesis I investigate the possibility that at the smallest length scale (Planck scale) the very notion of "dimension" needs to be revisited. Due to "quantum effects" spacetime might become very turbulent at these scales and properties like those of "fractals" emerge, including a "scale dependent dimension". It seems that this "spontaneous dimensional reduction" and the appearance of a minimal physical length are very general effects that most approaches to quantum gravity share. Main emphasis is given to the"spectral dimension" and its calculation for strings and p-branes.
The endoplasmic-reticulum-associated protein degradation pathway ensures quality control of newly synthesized soluble and membrane proteins of the secretory pathway. Proteins failing to fold into their native structure are processed in a multistep process and finally ubiquitinated and degraded by the proteasome in order to protect the cell from proteotoxic stress. My thesis covers structural as well as functional studies of various protein components that constitute the protein complexes that are responsible for this process.
One sub-project addressed the mechanism of glycan recognition by Yos9 as part of the ERAD substrate selection. NMR solution structures of the mannose-6-phosphate homology (MRH) domain of Yos9 both in a free and glycan bound conformation reveal a gripping movement of loop regions upon binding of correctly processed glycan structures.
The main projects focused on revealing the mechanism of efficient ubiquitin chain assembly by the ERAD ubiquitination machinery. This included the investigation of the role of the ERAD components Cue1 and Ubc7 in processive ubiquitin chain formation, how ubiquitin chain conformations change during elongation, how the conformation of a chain is impacted by interacting proteins and finally understand the activity regulation of the ERAD E2 enzyme Ubc7 by its cognate RING E3 ligases. Nuclear magnetic resonance (NMR) analysis and fluorescence-based ubiquitination assays show that the CUE domain of Cue1 contributes with its proximal binding preference as well as with its position dependent accelerating effect to efficient ubiquitin chain formation. This is required to efficiently drive degradation of substrates. Specific ubiquitin binding events dictate and coordinate the spatial arrangement of the E2 enzyme relative to the distal tip of a chain. This process can be further accelerated by RING E3 ligases that promote Ubc7 activity by more than ~20 fold via inducing allosteric changes around the catalytic cysteine. My results additionally suggest a model where Ubc7 dimerization results in proximity induced activation of the E2. This data ensures rapid diubiquitin formation that is followed by a CUE domain assisted chain elongation mechanism where Cue1 acts in an E4 like fashion.
How ubiquitin binding events can modulate the conformations of a ubiquitin chain were investigated by pulsed electron-electron double resonance (PELDOR) spectroscopy combined with molecular modeling. This shows that K48-linked diubiquitin samples a broad conformational space which can be modulated in distinct ways. The CUE domain of Cue1 uses conformational selection of pre-populated open conformations to support ubiquitin chain elongation. In contrast, deubiquitinating enzymes shift the conformational distribution to weakly or even non-populated conformations to allow cleavage of the isopeptide bond that connects adjacent ubiquitins. Ubiquitin chain elongation increases the sampled conformational space and suggests that this high conformational flexibility might contribute to efficient proteasomal recognition.
Background: The exponential growth of image-based diagnostic and minimally invasive interventions requires a detailed three-dimensional anatomical knowledge and increases the demand towards the undergraduate anatomical curriculum. This randomized controlled trial investigates whether musculoskeletal ultrasound (MSUS) or arthroscopic methods can increase the anatomical knowledge uptake.
Methods: Second-year medical students were randomly allocated to three groups. In addition to the compulsory dissection course, the ultrasound group (MSUS) was taught by eight, didactically and professionally trained, experienced student-teachers and the arthroscopy group (ASK) was taught by eight experienced physicians. The control group (CON) acquired the anatomical knowledge only via the dissection course. Exposure (MSUS and ASK) took place in two separate lessons (75 minutes each, shoulder and knee joint) and introduced standard scan planes using a 10-MHz ultrasound system as well as arthroscopy tutorials at a simulator combined with video tutorials. The theoretical anatomic learning outcomes were tested using a multiple-choice questionnaire (MCQ), and after cross-over an objective structured clinical examination (OSCE). Differences in student's perceptions were evaluated using Likert scale-based items.
Results: The ASK-group (n = 70, age 23.4 (20--36) yrs.) performed moderately better in the anatomical MC exam in comparison to the MSUS-group (n = 84, age 24.2 (20--53) yrs.) and the CON-group (n = 88, 22.8 (20--33) yrs.; p = 0.019). After an additional arthroscopy teaching 1 % of students failed the MC exam, in contrast to 10 % in the MSUS- or CON-group, respectively. The benefit of the ASK module was limited to the shoulder area (p < 0.001). The final examination (OSCE) showed no significant differences between any of the groups with good overall performances. In the evaluation, the students certified the arthroscopic tutorial a greater advantage concerning anatomical skills with higher spatial imagination in comparison to the ultrasound tutorial (p = 0.002; p < 0.001).
Conclusions: The additional implementation of arthroscopy tutorials to the dissection course during the undergraduate anatomy training is profitable and attractive to students with respect to complex joint anatomy. Simultaneous teaching of basic-skills in musculoskeletal ultrasound should be performed by medical experts, but seems to be inferior to the arthroscopic 2D-3D-transformation, and is regarded by students as more difficult to learn. Although arthroscopy and ultrasound teaching do not have a major effect on learning joint anatomy, they have the potency to raise the interest in surgery.
Nach den Ergebnissen des IAB-Betriebspanels sind die rheinland-
pfälzischen Betriebe im Vergleich zu Westdeutschland etwas weniger innovativ. Insgesamt ist die Innovationstätigkeit in Rheinland-Pfalz jedoch im Verlauf der letzten Jahre angestiegen. Der Schwerpunkt bei den Innovationen lag nach wie vor bei Maßnahmen zur Qualitätssicherung. Es hat sich gezeigt, dass Rheinland-Pfalz zudem im Bereich der Forschung und Entwicklung etwas zurückhaltender ist als der westdeutsche Durchschnitt:
Zum einen findet in Rheinland-Pfalz in anteilig weniger Betrieben FuE statt, zum anderen widmen sich hier durchschnittlich etwas weniger Beschäftigte diesem Aufgabenbereich. Außerdem finden seltener Kooperationen mit Universitäten und/oder anderen Unternehmen in diesem Bereich statt. Bei einer Gegenüberstellung innovativer und nicht-innovativer Betriebe ergaben sich zum Teil Unterschiede zwischen diesen: So ist in innovativen Unternehmen das Qualifikationsniveau höher und sowohl die Beschäftigungs- als auch die Geschäftsentwicklung stellen sich hier positiver dar als in nicht-innovativen Betrieben. Als schwierig erwies sich für Innovatoren jedoch die Besetzung offener Stellen. Hier waren im Vergleich zu Nicht-Innovatoren überdurchschnittlich häufig Schwierigkeiten feststellbar. Gleichzeitig nutzten jedoch beide Gruppen ihr Ausbildungspotenzial nicht voll aus. Hier besteht entsprechend die Möglichkeit, die vorhandenen Stellenbesetzungsprobleme durch verstärkte Ausbildungsaktivitäten zu verringern. Diesbezüglich ist zu betonen, dass sowohl innovative als auch nicht innovative Betriebe ihr Ausbildungspotenzial nicht bzw. nur zum Teil ausschöpfen und hier entsprechend noch Möglichkeiten des Ausbaus bestehen. Das ist vor allem auch deshalb notwendig, da Innovationen vielfach auch daran scheitern, dass Fachkräfte fehlen. Dem könnte mit vermehrter Ausbildung und auch Weiterbildung erfolgreich begegnet werden. Die Weiterbildungsquote der innovativen Betriebe übersteigt das der nicht-innovativen deutlich. Weiterbildung ist somit für innovative Betriebe ein Instrument, ihren Bedarf an qualifizierten Fachkräften zu decken. Aufgrund der Ergebnisse des IAB-Betriebspanels stellt sich nun die Frage, welche Faktoren tatsächlich einen Einfluss auf das Innovationsverhalten der Betriebe haben. Zwar ließen sich im Rahmen dieses Kurzreports Unterschiede zwischen innovativen und nicht-innovativen Betrieben herausarbeiten. Nicht abschließend beantwortet werden kann jedoch die Frage, wodurch diese zustande kommen. So hat sich bspw. gezeigt, dass sich die Ertragslage und die Beschäftigungsentwicklung bei Innovatoren und Nicht Innovatoren unterscheiden, unklar ist jedoch, ob positive Geschäftsentwicklungen Innovationen begünstigen, oder ob es vielmehr umgekehrt ist. Aufgrund einer im Jahr 2004 durchgeführten multivariaten Analyse ist ein signifikanter Zusammenhang zwischen Wirtschaftszweig sowie Betriebsgrößenklasse und Innovationen festgestellt worden. Diese beiden Faktoren haben somit Einfluss auf die Innovationstätigkeit der Unternehmen.
Diesbezüglich ist zu betonen, dass sich Rheinland-Pfalz durch, verglichen mit den alten Bundesländern, überproportional viele Kleinst- und Kleinbetriebe auszeichnet und branchenspezifisch der Schwerpunkt traditionell im Verarbeitenden Gewerbe liegt. Da Klein- und weniger Innovationen durchführen, wirkt dieses Strukturmerkmal sich entsprechend auch auf die vergleichsweise geringere Innovationstätigkeit in Rheinland-Pfalz aus. Ein eindeutiger Einfluss der Ertragslage auf die Durchführung von Neuerungen konnte hingegen nicht bestätigt werden (vgl. Wagner, Schmid (2003)).
Die Internationalisierung der Wirtschaftsbeziehungen sowie der Strukturwandel der Gesellschaft hin zur Informationsgesellschaft erhöhen die Nachfrage nach Fachkräften. Diese Situation erfordert Strategien in den Betrieben, um ihren Bedarf an qualifizierten Beschäftigten zu decken. Die Weiterbildung ist eine zentrale Strategie, um auf geänderte Qualifikationsanforderungen und Fachkräftebedarfe zu reagieren. Insgesamt förderten in Rheinland-Pfalz im ersten Halbjahr 2007 etwa 43 Prozent der Betriebe Weiterbildungsmaßnahmen ihrer Beschäftigten. Seit 2001 hat sich der Anteil um 10 Prozentpunkte deutlich erhöht. Werden die Anteile der Beschäftigten, die weitergebildet werden, an allen Beschäftigten betrachtet, ergibt sich eine Weiterbildungsquote in Rheinland-Pfalz von 23 Prozent. Die Weiterbildungsquote der Frauen liegt mit 24 Prozent leicht darüber.
Nicht nur bei den Betrieben, auch bei den Beschäftigten hat sich der Anteil derjenigen, die an Weiterbildungsmaßnahmen teilnehmen, von 2000 auf 2007 um 8 Prozentpunkte erhöht. Damit sind in Rheinland-Pfalz nicht nur der Anteil der Betriebe, die Fort- und Weiterbildungsmaßnahmen fördern, sondern auch die Anteile der Beschäftigten, die gefördert werden, gestiegen. Somit hat die Bedeutung der Weiterbildung für die Betriebe und die Beschäftigten in Rheinland-Pfalz in den letzten sieben Jahren deutlich zugenommen. Dieses Instrument zur Deckung des Fachkräftebedarfs ist ausgeweitet worden. Erstmalig sind Betriebe des Dienstleistungssektors an der Spitze der weiterbildenden Betriebe. Bezogen auf die Betriebe zeigt sich mit steigender Betriebsgrößenklasse ein steigender Anteil der Betriebe, die weiterbilden. Auch die Weiterbildungsquote der Beschäftigten ist in den Großbetrieben am höchsten. Bezogen auf die Wirtschaftszweige ergibt sich ein anderes Bild als bei den Betrieben: Die meisten Beschäftigten werden anteilig im Verarbeitenden Gewerbe gefördert. Bei der differenzierten Betrachtung der Beschäftigten wird deutlich, dass insbesondere qualifizierte Beschäftigte weitergebildet werden. Die Weiterbildung dieser Qualifikationsgruppe wird damit als Instrument zur Deckung des Fachkräftebedarfs eingesetzt. Mit Hilfe der Daten des IAB-Betriebspanels konnten neben den unterschiedlichen Ausprägungen bezüglich des Wirtschaftszweigs und der Betriebsgröße weitere Zusammenhänge von betrieblichen Merkmalen und der Förderung von Fort- und Weiterbildungsmaßnahmen aufgezeigt werden. Fördernde Betriebe weisen gegenüber nicht fördernden Betrieben eine erhöhte Ausbildungs- und Investitionstätigkeit auf. Weiterhin erwarten fördernde Betriebe eher einen zukünftigen Fachkräftemangel. Für die Planung der Weiterbildung sind Informationen zu ihrer Art notwendig. Der mit Abstand größte Teil an Fort- und Weiterbildungsmaßnahmen besteht in externen Kursen, Seminaren und Lehrgängen. Eine weitere relevante externe Maßnahme ist die Teilnahme an Vorträgen. Darüber hinaus sind die internen Maßnahmen „Weiterbildungen am Arbeitsplatz“ und „interne Kurse“ von Bedeutung. Angaben zur eigentlichen Kostenübernahme, zum Zeitpunkt der Weiterbildung (während oder außerhalb der Arbeitszeiten) und zum Abschluss von Rückzahlungsvereinbarungen müssen als Kosten der Weiterbildung berücksichtigt werden, um das Engagement der Betriebe beurteilen zu können. Die Kosten für die Weiterbildung werden in den meisten Betrieben von ihnen übernommen. Außerdem lassen die meisten Betriebe die Weiterbildung komplett in der Arbeitszeit stattfinden. Auch Rückzahlungsvereinbarungen werden wenig getroffen. Hier ist nur der Anteil in den Großbetrieben hoch. Insgesamt kann von einer relativ großen und deutlich zunehmenden Bedeutung der Weiterbildung in Rheinland-Pfalz gesprochen werden. Überproportional gefördert werden nach wie vor gut qualifizierte Arbeitskräfte, für Geringqualifizierte besteht eine erheblich geringere Chance auf betriebliche Weiterbildung.
Das IAB-Betriebspanel ist eine jährliche, repräsentative Betriebsbefragung des Instituts für Arbeitsmarkt und Berufsforschung der Bundesagentur für Arbeit, die seit 1993 in Zusammenarbeit mit der TNS Infratest Sozialforschung GmbH auf Bundesebene erhoben wird. Durch die Beteiligung der Bundesländer konnte die Zahl der befragten Betriebe soweit aufgestockt werden, dass auch gesonderte Auswertungen auf Länderebene möglich sind. Seit der Befragung 2001 ist durch die Unterstützung der Hessischen Landesregierung sowie der Regionaldirektion Hessen der Bundesagentur für Arbeit auch für Hessen eine gesonderte Auswertung möglich. Betraut mit der Auswertung der gewonnenen Paneldaten für das Land Hessen ist das Institut für Wirtschaft, Arbeit und Kultur in Frankfurt am Main.
Ziel des IAB-Betriebspanels ist es, Informationen und Erkenntnisse über die wirtschaftliche Situation, die Entwicklung des Arbeitsmarktes sowie das betriebliche Beschäftigungsverhalten in Hessen zu gewinnen. Die daraus ableitbaren Erkenntnisse bieten regionalen wie auch lokalen Akteuren eine fundierte Basis für problemadäquates Handeln. Zu diesem Zweck werden in regelmäßigen Abständen Kurzreports herausgegeben, welche über zentrale Ergebnisse der Befragung berichten.
Beim vorliegenden Report handelt es sich um den vierten aus der Befragungswelle 2007. Thema des Reports ist das Innovationsverhalten der hessischen Betriebe.
Im vorliegenden Panel basieren die Ausführungen auf der mündlichen Befragung von 1021 Betrieben in Hessen. Sie stehen für etwa 148.000 hessische Betriebe. Grundgesamtheit der Bruttostichprobe ist die Betriebsdatei der Bundesagentur für Arbeit, in der alle Betriebe enthalten sind, welche mindestens einen sozialversicherungspflichtig Beschäftigten bei der Sozialversicherung gemeldet hatten. Soweit dies möglich ist, werden jedes Jahr dieselben Betriebe befragt. Die Ergebnisse wurden auf alle hessischen Betriebe hochgerechnet und sind damit im Hinblick auf die Wirtschaftszweige und Betriebsgrößenklassen repräsentativ.
Im 1. Halbjahr 2005 wurden in Rheinland-Pfalz ca. 59.000 Einstellungen vorgenommen, davon konnte bei ca. 48.000 Stellen differenziert werden, ob es sich um Stellen für Qualifizierte oder um solche für Geringqualifizierte handelte. Etwa 46 Prozent dieser Neueinstellungen betrafen einfache Tätigkeiten, für die keine abgeschlossene Berufsausbildung notwendig ist. Im 1. Halbjahr 2003 waren es noch 57 Prozent. Beschäftigungschancen für Geringqualifizierte gab es in Rheinland-Pfalz fast ausschließlich in den dienstleistungsnahen Branchen, auf diesen Wirtschaftszweig fielen 70 Prozent aller Neueinstellungen von Geringqualifizierten.
Wie wichtig eine sektorale Ausdifferenzierung der Ergebnisse ist, zeigte sich bei der Frage, ob mit diesen Einstellungen auch neue, zusätzliche Arbeitsplätze geschaffen oder ob lediglich bestehende Arbeitsplätze ersetzt wurden. 61 Prozent der Betriebe aus dem Bereich der dienstleistungsnahen Branchen gaben an, dass mit den Einstellungen keine einzige zusätzliche Stelle geschaffen wurde. Beim Produzierenden Gewerbe waren es nur 30 Prozent der Betriebe. Zusätzliche Beschäftigungsmöglichkeiten für Geringqualifizierte bestehen somit nicht nur im Dienstleistungssektor, sondern auch im Produzierenden Gewerbe. Hier gaben 63 Prozent an, dass sie alle Personen für neue zusätzliche Stellen eingestellt haben. Bei den Betriebsgrößenklassen ist die Situation eindeutiger. Kleinst- und Kleinbetriebe stellten über die Hälfte der Geringqualifizierten ein. 38 Prozent aller Betriebe dieser Größen- klasse haben hiermit auch zusätzliche Arbeitsplätze geschaffen. Was den Stellenabbau im Bereich einfacher Tätigkeiten betrifft, konnten in Rheinland-Pfalz keine Anhaltspunkte für eine massive Wegrationalisierung oder Auslagerung solcher Stellen gefunden werden. Im Gegenteil scheint im 1. Halbjahr 2005 in diesem Qualifikationsbereich eher Beschäftigung aufgebaut worden zu sein.
Nur etwa 1 Prozent aller rheinland-pfälzischen Betriebe hatten Stellen für einfache Tätigkeiten abgebaut, immerhin 3 Prozent neue, zusätzliche Arbeitsplätze geschaffen. Betriebe, die Geringqualifizierte einstellten, zeichneten sich zwischen Mitte 2004 und Mitte 2005 durch eine positive Gesamtbeschäftigungsentwicklung aus, auch die sozialversicherungspflichtige Beschäftigung stieg bei diesen Betrieben an. Diese Betriebe entwickelten sich damit entgegen dem allgemeinen Trend in Rheinland-Pfalz, der durch Stagnation der Gesamtbeschäftigung (-0,1 Prozent) und einem leichten Rückgang der sozialversicherungspflichtigen Beschäftigung (-0,7 Prozent) gekennzeichnet war.
Im Zusammenhang mit den demographischen Entwicklungen in Deutschland wird häufig nicht nur ein steigender Fachkräftebedarf sondern ein künftiger Fachkräftemangel erwartet. Dies zeichnet sich laut IAB-Betriebspanel noch nicht für Rheinland-Pfalz ab. Bei der Verteilung des Personals auf Geringqualifizierte und Qualifizierte zeigen sich seit 2000 in Rheinland-Pfalz nur geringe Verschiebungen: Der Anteil der Geringqualifizierten an allen Beschäftigten lag in den letzten fünf Jahren jeweils bei einem Viertel, der der Qualifizierten bei ca. 62 Prozent. Im Vergleich zu Westdeutschland haben qualifizierte Arbeitskräfte in Rheinland-Pfalz weder eine so hohe noch eine im Zeitverlauf zunehmende Bedeutung.
Im ersten Halbjahr 2005 wurden in Rheinland-Pfalz 59.000 Einstellungen vorgenommen und mit 56.000 Personen waren deutlich weniger Personalabgänge zu verzeichnen. Die meisten Personalbewegungen waren im Dienstleistungssektor zu beobachten. Seit 2001 sind in Rheinland-Pfalz sinkende Fluktuationsraten fest zu stellen. Damit nimmt die Dynamik am Arbeitsmarkt in Rheinland-Pfalz ab. Dies kann ein Indikator für eine gewisse Stabilität der Beschäftigungsverhältnisse sein. Von allen Neueinstellungen im 1. Halbjahr 2005 konnte bei knapp 48.000 Stellen differenziert werden, ob es sich um Stellen für Qualifizierte oder um solche für Geringqualifizierte handelte. Etwa 54 Prozent dieser Neueinstellungen betrafen qualifizierte Tätigkeiten, für die eine abgeschlossene Berufsausbildung, vergleichbare Berufserfahrung oder ein Hochschulstudium notwendig ist. Beschäftigungschancen für Fachkräfte gab es in Rheinland-Pfalz insbesondere in dienstleistungsnahen Branchen, auf diesen Wirtschaftsbereich fielen 62 Prozent alle Neueinstellungen von Fachkräften. Wie wichtig eine sektorale Ausdifferenzierung der Ergebnisse ist, zeigte sich bei der Frage, ob mit diesen Einstellungen auch neue, zusätzliche Arbeitsplätze geschaffen wurden oder ob lediglich bestehende Arbeitsplätze ersetzt wurden. 57 Prozent der Betriebe aus den dienstleistungsnahen Branchen gaben an, dass mit den Einstellungen keine einzige zusätzliche Stelle geschaffen wurde. Insbesondere Kleinst- und Kleinbetriebe stellten Fachkräfte ein. In dieser Betriebsgrößenklasse wurden auch die meisten zusätzlichen Arbeitsplätze geschaffen. Stellbesetzungsprobleme bei Fachkräften gab es besonders im Verarbeitenden Gewerbe. Die meisten Betriebe gaben an, diesen Problemen mit eigener betrieblicher Ausbildung zu begegnen.
Betriebe, die Fachkräfte einstellten, zeichneten sich zwischen Mitte 2004 und Mitte 2005 durch eine positive Gesamtbeschäftigungsentwicklung aus, auch die sozialversicherungspflichtige Beschäftigung stieg bei diesen Betrieben an. Diese Betriebe entwickelten sich damit entgegen der relativen Konstanz der Beschäftigungsentwicklung in Rheinland-Pfalz.
Der vorliegende Report beschäftigt sich mit Determinanten der betrieblichen Ausbildung in rheinland-pfälzischen Betrieben 2005. Dazu wurde in einem ersten Schritt untersucht, welcher Zusammenhang zwischen verschiedenen Merkmalen und dem Ausbildungsverhalten der Betriebe besteht. Analysiert wurde u.a. der Zusammenhang zwischen dem Ausbildungsverhalten der Betriebe und ihren Investitionstätigkeiten, Geschäftsvolumen, Ertragslage, Personalfluktuation, offenen Stellen sowie Personalabgängen und Neueinstellungen.
Laut der Ergebnisse des IAB-Betriebspanels bezüglich der Häufigkeiten können ausbildende Betriebe folgendermaßen charakterisiert werden: Ein höherer Anteil ausbildender Betriebe schätzen die Entwicklung des Geschäftsvolumens und die Ertragslage positiv ein und tätigten Investitionen. Außerdem erfüllten sie verschiedene Merkmale wie die Mitgliedschaft einer Tarifgemeinschaft und das Vorhandensein einer Mitarbeitervertretung im Betrieb. Ein höherer Anteil der ausbildenden Betriebe führen Weiterbildungen durch und haben schriftlich fixierte Pläne für Personalentwicklung und Weiterbildung. Weiterhin sind Betriebe, die ausbilden, dadurch gekennzeichnet, dass ihre Personalfluktuationsrate gering ist. Außerdem wählen zwei Drittel der ausbildenden Betriebe die eigene betriebliche Ausbildung als Personaldeckungsstrategie, um ihren Fachkräftebedarf, soweit vorhanden, zu decken. In der multivariaten Analyse wurde untersucht, welche Kombination von Einflussfaktoren das Ausbildungsverhalten der Betriebe bestimmen.
Insgesamt lässt sich ein signifikanter Einfluss von der Tarifbindung, der Betriebsgröße, der Weiterbildung sowie der Fluktuationsrate auf die Durchführung von Ausbildung feststellen. Große Betriebe, die tarifvertraglich gebunden sind und Weiterbildungen fördern, führen mit einer hohen Wahrscheinlichkeit Ausbildungen durch. Für die Variable „Fluktuationsrate“ ergibt sich dahingehend ein eindeutiger Zusammenhang, als eine durchschnittliche Fluktuationsrate mit der höchsten Wahrscheinlichkeit zur Durchführung von Ausbildungen führt.
Nach den Ergebnissen des IAB-Betriebspanels hat sich die Ausbildungssituation in Rheinland-Pfalz leicht verbessert. Die Ausbildungsquote ist seit 2000 erstmalig wieder leicht gestiegen und liegt wieder über der von Westdeutschland. Auch die Ausbildungszahlen sind im Jahr 2005 erstmalig seit 2001 gestiegen. Allerdings ist die Zahl der neu abgeschlossenen Ausbildungsverträge gegenüber dem Vorjahr, in dem diese erstmals seit Jahren angestiegen ist, konstant geblieben. Obwohl die Ausbildungsbeteiligung leicht gestiegen ist, besteht nach wie vor noch ein hohes ungenutztes Ausbildungspotenzial, wobei vor allem die Betriebe der Baubranche vergleichsweise wenig ausbilden, obwohl sie formal dazu berechtigt sind.
Betriebe, die immer oder fast immer ausbilden, können folgendermaßen charakterisiert werden: Ein hoher Anteil dieser Betriebe schätzt seine Ertragslage als sehr gut/gut ein und bildet seine Mitarbeiterinnen und Mitarbeiter weiter. Der Anteil der ausbildenden Betriebe, der Neueinstellungen tätigt, und derjenige, der Personalabgänge verzeichnet, liegen ebenfalls auf einem hohen Niveau. Dagegen ist die Fluktuations- rate der Betriebe, die (fast) immer ausbilden, auf niedrigem Niveau kaum schwankend. Die Betriebe ohne Ausbildungsberechtigung sind im Gegensatz zu den ausbildenden Betriebe dadurch gekennzeichnet, dass ein niedriger Anteil dieser Betriebe seine Mitarbeiterinnen und Mitarbeiter weiterbildet und seine Ertragslage als sehr gut oder gut einschätzt. Die Personalfluktuationsrate der Betriebe ohne Ausbildungsberechtigung schwankt deutlicher im Zeitablauf als die der ausbildenden Betriebe. Der Anteil der Betriebe ohne Ausbildungsberechtigung, der Neueinstellungen tätigt, und derjenige, der Personalabgänge verzeichnet, liegen gegensätzlich zu dem der Betriebe, die (fast) immer ausbilden, auf einem niedrigen Niveau. Der Anteil der Betriebe, die ausbilden und die Ertragslage positiv einschätzen, sinkt im Untersuchungszeitraum. Die Kurvenverläufe der Betriebe ohne Ausbildungsberechtigung weisen bei der Beobachtung derselben Merkmale auch einen ähnlichen, tendenziell sinkenden Verlauf auf, allerdings auf einem deutlich niedrigerem Niveau als die ausbildenden Betriebe.
Purpose: A clinical implementation of ion-beam radiography (iRad) is envisaged to provide a method for on-couch verification of ion-beam treatment plans. The aim of this work is to introduce and evaluate a method for quantitative water-equivalent thickness (WET) measurements for a specific helium-ion imaging system for WETs that are relevant for imaging thicker body parts in the future.
Methods: Helium-beam radiographs (αRads) are measured at the Heidelberg Ion-beam Therapy Center with an initial beam energy of 239.5 MeV/u. An imaging system based on three pairs of thin silicon pixel detectors is used for ion path reconstruction and measuring the energy deposition (dE) of each particle behind the object to be imaged. The dE behind homogeneous plastic blocks is related to their well-known WETs between 280.6 and 312.6 mm with a calibration curve that is created by a fit to measured data points. The quality of the quantitative WET measurements is determined by the uncertainty of the measured WET of a single ion (single-ion WET precision) and the deviation of a measured WET value to the well-known WET (WET accuracy). Subsequently, the fitted calibration curve is applied to an energy deposition radiograph of a phantom with a complex geometry. The spatial resolution (modulation transfer function at 10 % —MTF10%) and WET accuracy (mean absolute percentage difference—MAPD) of the WET map are determined.
Results: In the optimal imaging WET-range from ∼280 to 300 mm, the fitted calibration curve reached a mean single-ion WET precision of 1.55
0.00%. Applying the calibration to an ion radiograph (iRad) of a more complex WET distribution, the spatial resolution was determined to be MTF10% = 0.49 0.03 lp/mm and the WET accuracy was assessed as MAPD to 0.21 %.
Conclusions: Using a beam energy of 239.5 MeV/u and the proposed calibration procedure, quantitative αRads of WETs between ∼280 and 300 mm can be measured and show high potential for clinical use. The proposed approach with the resulting image qualities encourages further investigation toward the clinical application of helium-beam radiography.
Menschen mit Geldbeträgen in Verbindung zu setzen, gilt heute in Deutschland als inakzeptabel, ja sogar sittenwidrig. Zwangsheiraten, bei denen auch Brautgeld fließt, werden als Menschenhandel geahndet. Bei den Brautpreisübergaben der Mossi in Burkina Faso gewinnen Geld und Güter jedoch eine symbolische Dimension. Wer von der Suppe isst, die mit dem Salz des Brautpreises gewürzt ist, erkennt das Bündnis zwischen den Brautleuten an. Die sorgfältig vorbereitete Übergabe des Preises etabliert soziale Bande zwischen den Familien und ist zugleich ein Test für den Bräutigam.
NGO brokers between local needs and global norms: trajectories of development actors in Burkina Faso
(2021)
Local NGO brokers in Africa and beyond negotiate and mediate between (inter)national donors and potential beneficiaries within their communities. They translate local needs into development projects to make them suitable for international donors. This article looks at two main conditions that influence their work: First, windows of opportunity, which open and close according to structures and institutions beyond their sphere of influence; and second, their personality and skills. Based on two case studies from Burkina Faso, this article offers insights into biographies and life stories of such brokers where engagement leads to a distinguished lifestyle that contains aspects of cosmopolitanism and distinctiveness.
NGO brokers between local needs and global norms: trajectories of development actors in Burkina Faso
(2021)
Local NGO brokers in Africa and beyond negotiate and mediate between (inter)national donors and potential beneficiaries within their communities. They translate local needs into development projects to make them suitable for international donors. This article looks at two main conditions that influence their work: First, windows of opportunity, which open and close according to structures and institutions beyond their sphere of influence; and second, their personality and skills. Based on two case studies from Burkina Faso, this article offers insights into biographies and life stories of such brokers where engagement leads to a distinguished lifestyle that contains aspects of cosmopolitanism and distinctiveness.
To truly appreciate the myriad of events which relate synaptic function and vesicle dynamics, simulations should be done in a spatially realistic environment. This holds true in particular in order to explain as well the rather astonishing motor patterns which we observed within in vivo recordings which underlie peristaltic contractionsas well as the shape of the EPSPs at different forms of long-term stimulation, presented both here, at a well characterized synapse, the neuromuscular junction (NMJ) of the Drosophila larva (c.f. Figure 1). To this end, we have employed a reductionist approach and generated three dimensional models of single presynaptic boutons at the Drosophila larval NMJ. Vesicle dynamics are described by diffusion-like partial differential equations which are solved numerically on unstructured grids using the uG platform. In our model we varied parameters such as bouton-size, vesicle output probability (Po), stimulation frequency and number of synapses, to observe how altering these parameters effected bouton function. Hence we demonstrate that the morphologic and physiologic specialization maybe a convergent evolutionary adaptation to regulate the trade off between sustained, low output, and short term, high output, synaptic signals. There seems to be a biologically meaningful explanation for the co-existence of the two different bouton types as previously observed at the NMJ (characterized especially by the relation between size and Po), the assigning of two different tasks with respect to short- and long-time behaviour could allow for an optimized interplay of different synapse types. We can present astonishing similar results of experimental and simulation data which could be gained in particular without any data fitting, however based only on biophysical values which could be taken from different experimental results. As a side product, we demonstrate how advanced methods from numerical mathematics could help in future to resolve also other difficult experimental neurobiological issues.
The morphology of presynaptic specializations can vary greatly ranging from classical single-release-site boutons in the central nervous system to boutons of various sizes harboring multiple vesicle release sites. Multi-release-site boutons can be found in several neural contexts, for example at the neuromuscular junction (NMJ) of body wall muscles of Drosophila larvae. These NMJs are built by two motor neurons forming two types of glutamatergic multi-release-site boutons with two typical diameters. However, it is unknown why these distinct nerve terminal configurations are used on the same postsynaptic muscle fiber. To systematically dissect the biophysical properties of these boutons we developed a full three-dimensional model of such boutons, their release sites and transmitter-harboring vesicles and analyzed the local vesicle dynamics of various configurations during stimulation. Here we show that the rate of transmission of a bouton is primarily limited by diffusion-based vesicle movements and that the probability of vesicle release and the size of a bouton affect bouton-performance in distinct temporal domains allowing for an optimal transmission of the neural signals at different time scales. A comparison of our in silico simulations with in vivo recordings of the natural motor pattern of both neurons revealed that the bouton properties resemble a well-tuned cooperation of the parameters release probability and bouton size, enabling a reliable transmission of the prevailing firing-pattern at diffusion-limited boutons. Our findings indicate that the prevailing firing-pattern of a neuron may determine the physiological and morphological parameters required for its synaptic terminals.
Exploring biophysical properties of virus-encoded components and their requirement for virus replication is an exciting new area of interdisciplinary virological research. To date, spatial resolution has only rarely been analyzed in computational/biophysical descriptions of virus replication dynamics. However, it is widely acknowledged that intracellular spatial dependence is a crucial component of virus life cycles. The hepatitis C virus-encoded NS5A protein is an endoplasmatic reticulum (ER)-anchored viral protein and an essential component of the virus replication machinery. Therefore, we simulate NS5A dynamics on realistic reconstructed, curved ER surfaces by means of surface partial differential equations (sPDE) upon unstructured grids. We match the in silico NS5A diffusion constant such that the NS5A sPDE simulation data reproduce experimental NS5A fluorescence recovery after photobleaching (FRAP) time series data. This parameter estimation yields the NS5A diffusion constant. Such parameters are needed for spatial models of HCV dynamics, which we are developing in parallel but remain qualitative at this stage. Thus, our present study likely provides the first quantitative biophysical description of the movement of a viral component. Our spatio-temporal resolved ansatz paves new ways for understanding intricate spatial-defined processes central to specfic aspects of virus life cycles.
Poster presentation from Twentieth Annual Computational Neuroscience Meeting: CNS*2011 Stockholm, Sweden. 23-28 July 2011. To truly appreciate the myriad of events which relate synaptic function and vesicle dynamics, simulations should be done in a spatially realistic environment. This holds true in particular in order to explain the rather astonishing motor patterns presented here which we observed within in vivo recordings which underlie peristaltic contractions at a well characterized synapse, the neuromuscular junction (NMJ) of the Drosophila larva. To this end, we have employed a reductionist approach and generated three dimensional models of single presynaptic boutons at the Drosophila larval NMJ. Vesicle dynamics are described by diffusion-like partial differential equations which are solved numerically on unstructured grids using the uG platform. In our model we varied parameters such as bouton-size, vesicle output probability (Po), stimulation frequency and number of synapses, to observe how altering these parameters effected bouton function. Hence we demonstrate that the morphologic and physiologic specialization maybe a convergent evolutionary adaptation to regulate the trade off between sustained, low output, and short term, high output, synaptic signals. There seems to be a biologically meaningful explanation for the co-existence of the two different bouton types as previously observed at the NMJ (characterized especially by the relation between size and Po),the assigning of two different tasks with respect to short- and long-time behaviour could allow for an optimized interplay of different synapse types. As a side product, we demonstrate how advanced methods from numerical mathematics could help in future to resolve also other difficult experimental neurobiological issues.
Mathematical models of virus dynamics have not previously acknowledged spatial resolution at the intracellular level despite substantial arguments that favor the consideration of intracellular spatial dependence. The replication of the hepatitis C virus (HCV) viral RNA (vRNA) occurs within special replication complexes formed from membranes derived from endoplasmatic reticulum (ER). These regions, termed membranous webs, are generated primarily through specific interactions between nonstructural virus-encoded proteins (NSPs) and host cellular factors. The NSPs are responsible for the replication of the vRNA and their movement is restricted to the ER surface. Therefore, in this study we developed fully spatio-temporal resolved models of the vRNA replication cycle of HCV. Our simulations are performed upon realistic reconstructed cell structures—namely the ER surface and the membranous webs—based on data derived from immunostained cells replicating HCV vRNA. We visualized 3D simulations that reproduced dynamics resulting from interplay of the different components of our models (vRNA, NSPs, and a host factor), and we present an evaluation of the concentrations for the components within different regions of the cell. Thus far, our model is restricted to an internal portion of a hepatocyte and is qualitative more than quantitative. For a quantitative adaption to complete cells, various additional parameters will have to be determined through further in vitro cell biology experiments, which can be stimulated by the results deccribed in the present study.
The hepatitis C virus (HCV) RNA replication cycle is a dynamic intracellular process occurring in three-dimensional space (3D), which is difficult both to capture experimentally and to visualize conceptually. HCV-generated replication factories are housed within virus-induced intracellular structures termed membranous webs (MW), which are derived from the Endoplasmatic Reticulum (ER). Recently, we published 3D spatiotemporal resolved diffusion–reaction models of the HCV RNA replication cycle by means of surface partial differential equation (sPDE) descriptions. We distinguished between the basic components of the HCV RNA replication cycle, namely HCV RNA, non-structural viral proteins (NSPs), and a host factor. In particular, we evaluated the sPDE models upon realistic reconstructed intracellular compartments (ER/MW). In this paper, we propose a significant extension of the model based upon two additional parameters: different aggregate states of HCV RNA and NSPs, and population dynamics inspired diffusion and reaction coefficients instead of multilinear ones. The combination of both aspects enables realistic modeling of viral replication at all scales. Specifically, we describe a replication complex state consisting of HCV RNA together with a defined amount of NSPs. As a result of the combination of spatial resolution and different aggregate states, the new model mimics a cis requirement for HCV RNA replication. We used heuristic parameters for our simulations, which were run only on a subsection of the ER. Nevertheless, this was sufficient to allow the fitting of core aspects of virus reproduction, at least qualitatively. Our findings should help stimulate new model approaches and experimental directions for virology.
Establishing local coherence relations is central to text comprehension. Positive-causal coherence relations link a cause and its consequence, whereas negative-causal coherence relations add a contrastive meaning (negation) to the causal link. According to the cumulative cognitive complexity approach, negative-causal coherence relations are cognitively more complex than positive-causal ones. Therefore, they require greater cognitive effort during text comprehension and are acquired later in language development. The present cross-sectional study tested these predictions for German primary school children from Grades 1 to 4 and adults in reading and listening comprehension. Accuracy data in a semantic verification task support the predictions of the cumulative cognitive complexity approach. Negative-causal coherence relations are cognitively more demanding than positive-causal ones. Moreover, our findings indicate that children's comprehension of negative-causal coherence relations continues to develop throughout the course of primary school. Findings are discussed with respect to the generalizability of the cumulative cognitive complexity approach to German.
Objective: To examine risk of malignancy and death in patients with kidney transplant who receive the immunosuppressive drug sirolimus.
Design: Systematic review and meta-analysis of individual patient data.
Data sources: Medline, Embase, and the Cochrane Central Register of Controlled Trials from inception to March 2013.
Eligibility: Randomized controlled trials comparing immunosuppressive regimens with and without sirolimus in recipients of kidney or combined pancreatic and renal transplant for which the author was willing to provide individual patient level data. Two reviewers independently screened titles/abstracts and full text reports of potentially eligible trials to identify studies for inclusion. All eligible trials reported data on malignancy or survival.
Results: The search yielded 2365 unique citations. Patient level data were available from 5876 patients from 21 randomized trials. Sirolimus was associated with a 40% reduction in the risk of malignancy (adjusted hazard ratio 0.60, 95% confidence interval 0.39 to 0.93) and a 56% reduction in the risk of non-melanoma skin cancer (0.44, 0.30 to 0.63) compared with controls. The most pronounced effect was seen in patients who converted to sirolimus from an established immunosuppressive regimen, resulting in a reduction in risk of malignancy (0.34, 0.28 to 0.41), non-melanoma skin cancer (0.32, 0.24 to 0.42), and other cancers (0.52, 0.38 to 0.69). Sirolimus was associated with an increased risk of death (1.43, 1.21 to 1.71) compared with controls.
Conclusions: Sirolimus was associated with a reduction in the risk of malignancy and non-melanoma skin cancer in transplant recipients. The benefit was most pronounced in patients who converted from an established immunosuppressive regimen to sirolimus. Given the risk of mortality, however, the use of this drug does not seem warranted for most patients with kidney transplant. Further research is needed to determine if different populations, such as those at high risk of cancer, might benefit from sirolimus.
In dieser Arbeit geht es um eine theaterwissenschaftliche Analyse ausgewählter Stücke des Theaterregisseurs und Autors René Pollesch. Bei den Stücken handelt es sich um die Heidi Hoh-Trilogie (1999-2001), Insourcing des Zuhause (2001), Der Leopard von Singapur (2003) und Cappuccetto Rosso (2005). Die Sujets und Stilmerkmale des Theaters von Pollesch werden dabei mittels der Theorien des Philosophen Jacques Rancière als Elemente eines politischen Theaters interpretiert, dem es wesentlich darum geht, alle Formen der Regelhaftigkeit, der symbolischen Ordnung oder der etablierten Sichtbarkeit durch Unterbrechung der Regel, Aufhebung der Ordnung, Sichtbarmachung des Unsichtbaren oder Verstimmlichen des Stimmlosen, aber auch durch Formen einer subversiven Wiederholung und Aneignung kritisierter Sicht- und Sprechweisen zu provozieren. Um das Politische bei Pollesch zu erkunden, werden Rancières Theorietexte „angewandt", indem sie während der analytischen Betrachtung der Pollesch-Abende in ästhetische Strategien umgewandelt werden. Dies geschieht auf drei Ebenen: 1: Darstellungsform, 2: Arbeitsweise, 3: Die auf der Bühne sichtbar agierenden Subjekte. Rancière erscheint mit seinem Konzept einer gegebenen gesellschaftlichen Ordnung als „Aufteilung des Sinnlichen" ideal geeignet, um das Politische auf eben diese drei genannten Ebenen aufzuspüren. Sein Modell von Politik, so zeigt diese Arbeit, erlaubt damit die ästhetische Praxis René Polleschs auf verschiedenen Ebenen als politisch zu kennzeichnen, aber es führt auch auf einige Aporien, denen diese Praxis gerade in ihrem politischen Anspruch ausgeliefert ist.
Long-term effects on cirrhosis and portal hypertension of direct antiviral agent (DAA)-based eradication of hepatitis C virus (HCV) are still under debate. We analysed dynamics of liver and spleen elastography to assess potential regression of cirrhosis and portal hypertension 3 years post-treatment. Fifty-four patients with HCV-associated cirrhosis and DAA-induced SVR were included. Liver and spleen stiffness were measured at baseline (BL), end of treatment (EOT), 24 weeks after EOT (FU24) and 1, 2 and 3 (FU144) years post-treatment by transient liver elastography (L-TE) and point shear wave elastography (pSWE) using acoustic radiation force impulse (ARFI) of the liver (L-ARFI) and spleen (S-ARFI). Biochemical, virological and clinical data were also obtained. Liver stiffness assessed by L-TE decreased between BL [median (range), 32.5(9.1–75) kPa] and EOT [21.3(6.7–73.5) kPa; p < .0001] and EOT and FU144 [16(4.1–75) kPa; p = .006]. L-ARFI values improved between EOT [2.5(1.2–4.1) m/s] and FU144 [1.7(0.9–4.1) m/s; p = .001], while spleen stiffness remained unchanged. Overall, L-TE improved in 38 of 54 (70.4%) patients at EOT and 29 of 38 (76.3%) declined further until FU144, whereas L-ARFI values decreased in 30/54 (55.6%) patients at EOT and continued to decrease in 28/30 (93.3%) patients at FU144. Low bilirubin and high albumin levels at BL were associated with improved L-ARFI values (p = .048) at EOT or regression of cirrhosis (<12.5 kPa) by L-TE at FU144 (p = .005), respectively. Liver stiffness, but not spleen stiffness, continued to decline in a considerable proportion of patients with advanced liver disease after HCV eradication.
NK cells are part of the innate immune system, and are important players in the body’s first defence line against virus-infected and malignantly transformed cells. While T cells recognize neoplastic cells in an MHC-restricted fashion, NK cells do not require prior sensitization and education about the target. In leukemia and lymphoma patients undergoing allogeneic hematopoietic stem cell transplantation not only T cells but also NK cells have been found to mediate potent graft-versus-tumor effects. Hence, autologous or donor-derived NK cells hold great promise for cancer immunotherapy. Since the generation of highly purified NK cell products for clinical applications is labor-intensive and time consuming, established human NK cell lines such as NK-92 are also being considered for clinical protocols. NK-92 cells display phenotypic and functional characteristics similar to activated primary NK cells. While NK-92 cells are highly cytotoxic towards malignant cells of hematologic origin, they do not affect healthy human tissues. NK-92 cells can be expanded under GMP-compliant conditions, and can therefore be provided in sufficient numbers with defined phenotypic characteristics for clinical applications. Safety of NK-92 cells for adoptive immunotherapy was already shown in two phase I/II clinical trials...
TOR1A is the most common inherited form of dystonia with still unclear pathophysiology and reduced penetrance of 30–40%. ∆ETorA rats mimic the TOR1A disease by expression of the human TOR1A mutation without presenting a dystonic phenotype. We aimed to induce dystonia-like symptoms in male ∆ETorA rats by peripheral nerve injury and to identify central mechanism of dystonia development. Dystonia-like movements (DLM) were assessed using the tail suspension test and implementing a pipeline of deep learning applications. Neuron numbers of striatal parvalbumin+, nNOS+, calretinin+, ChAT+ interneurons and Nissl+ cells were estimated by unbiased stereology. Striatal dopaminergic metabolism was analyzed via in vivo microdialysis, qPCR and western blot. Local field potentials (LFP) were recorded from the central motor network. Deep brain stimulation (DBS) of the entopeduncular nucleus (EP) was performed. Nerve-injured ∆ETorA rats developed long-lasting DLM over 12 weeks. No changes in striatal structure were observed. Dystonic-like ∆ETorA rats presented a higher striatal dopaminergic turnover and stimulus-induced elevation of dopamine efflux compared to the control groups. Higher LFP theta power in the EP of dystonic-like ∆ETorA compared to wt rats was recorded. Chronic EP-DBS over 3 weeks led to improvement of DLM. Our data emphasizes the role of environmental factors in TOR1A symptomatogenesis. LFP analyses indicate that the pathologically enhanced theta power is a physiomarker of DLM. This TOR1A model replicates key features of the human TOR1A pathology on multiple biological levels and is therefore suited for further analysis of dystonia pathomechanism.
Aim: Exposure to opioids has been associated with epigenetic effects. Studies in rodents suggested a role of varying degrees of DNA methylation in the differential regulation of μ-opioid receptor expression across the brain.
Methods: In a translational investigation, using tissue acquired postmortem from 21 brain regions of former opiate addicts, representing a human cohort with chronic opioid exposure, μ-opioid receptor expression was analyzed at the level of DNA methylation, mRNA and protein.
Results & conclusion: While high or low μ-opioid receptor expression significantly correlated with local OPRM1 mRNA levels, there was no corresponding association with OPRM1 methylation status. Additional experiments in human cell lines showed that changes in DNA methylation associated with changes in μ-opioid expression were an order of magnitude greater than differences in brain. Hence, different degrees of DNA methylation associated with chronic opioid exposure are unlikely to exert a major role in the region-specificity of μ-opioid receptor expression in the human brain.
Background: The quantification of global DNA methylation has been established in epigenetic screening. As more practicable alternatives to the HPLC-based gold standard, the methylation analysis of CpG islands in repeatable elements (LINE-1) and the luminometric methylation assay (LUMA) of overall 5-methylcytosine content in “CCGG” recognition sites are most widely used. Both methods are applied as virtually equivalent, despite the hints that their results only partly agree. This triggered the present agreement assessments.
Results: Three different human cell types (cultured MCF7 and SHSY5Y cell lines treated with different chemical modulators of DNA methylation and whole blood drawn from pain patients and healthy volunteers) were submitted to the global DNA methylation assays employing LINE-1 or LUMA-based pyrosequencing measurements. The agreement between the two bioassays was assessed using generally accepted approaches to the statistics for laboratory method comparison studies. Although global DNA methylation levels measured by the two methods correlated, five different lines of statistical evidence consistently rejected the assumption of complete agreement. Specifically, a bias was observed between the two methods. In addition, both the magnitude and direction of bias were tissue-dependent. Interassay differences could be grouped based on Bayesian statistics, and these groups allowed in turn to re-identify the originating tissue.
Conclusions: Although providing partly correlated measurements of DNA methylation, interchangeability of the quantitative results obtained with LINE-1 and LUMA was jeopardized by a consistent bias between the results. Moreover, the present analyses strongly indicate a tissue specificity of the differences between the two methods.
Ziel dieser Dissertation war es, die biologische Rolle der Autophagie für die Entwicklung, Alterung und mitochondriale Qualitätskontrolle in dem Ascomyceten Podospora anserina zu untersuchen. Folgende Ergebnisse wurden dabei erzielt:
1. Der Verlust einer funktionalen Autophagie-Maschinerie ist in P. anserina mit einem Defekt der Sporen-Entwicklung bzw. -Keimung charakterisiert.
2. Es konnten drei Methoden zur Untersuchung der Autophagie in P. anserina etabliert werden: 1) Die Verwendung eines Gfp::PaAtg8-Stamms ermöglicht die Fluoreszenzmikroskopische Bestimmung der Autophagosomen-Anzahl; 2) Die phänotypische Charakterisierung des PaAtg1-Deletionsstamms unter verschiedenen Stressbedingungen (z. B. Stickstoffmangel, Rapamycin) liefert Hinweise auf eine mögliche Autophagie-abhängige Stressadaption; 3) Die Verwendung des „GFPcleavage assays“ ermöglicht einen quantitativen Nachweis genereller und selektiver Autophagie (hier: Mitophagie).
3. In zwei voneinander unabhängigen Experimenten wurde ein altersabhängiger Anstieg der Autophagie für P. anserina demonstriert: Das Autophagie-Niveau nimmt in gealterten P. anserina-Kulturen zu. Gleichzeitig resultiert der Verlust der Autophagie in ∆PaAtg1 in eine reduzierte Lebensspanne. Unter Stressbedingungen (hier: Stickstoffmangel) wird dieser positive Einfluss der Autophagie auf die Lebensspanne im Wildtyp sogar noch verstärkt.
4. Der unerwartet „gesunde“ Phänotyp der PaSod3-Deletionsmutante ist abhängig von einer funktionalen Autophagie-Maschinerie. Der Mitophagie wurde eine besondere Rolle als Kompensationsmechanismus für den Verlust von PaSOD3 zugeteilt, da das Mitophagie-Niveau in dieser Mutante erhöht ist. Am Beispiel dieser Mutante, für die ein erhöhter Superoxid-Ausstoß nachgewiesen wurde, konnte eine Dosis-abhängige Wirkung von ROS in P. anserina identifiziert werden. Eine geringe zelluläre ROSMenge verursacht eine mitohormetische Reaktion, die eine Induktion der Mitophagie zur Folge hat und sich positiv auf den Organismus auswirkt. Übersteigt die zelluläre ROS-Dosis einen kritischen Punkt, kommt es zur Induktion des autophagischen Zelltods und damit zum vorzeitigen Tod des Individuums.
5. Der Verlust der PaCLPXP-Protease führt zu Beeinträchtigungen in der Funktion und Zusammensetzung der mitochondrialen Atmungskette. Dieses Defizit im Energiemetabolismus wird über eine Induktion der AOX, vor allem aber über eine ZUSAMMENFASSUNG 127 gesteigerte Autophagie kompensiert. Die deutlich verlängerte Lebensspanne der verschiedenen PaClpXP-Deletionsmutanten (∆PaClpX, ∆PaClpP und ∆PaClpXP) ist abhängig von einer funktionalen Autophagie-Maschinerie. Interessanterweise konnte keine kompensatorische Funktion der Autophagie oder Mitophagie für den Verlust der mitochondrialen i-AAA-Protease PaIAP in P. anserina nachgewiesen werden.
Autophagie/Mitophagie stellt einen übergeordneten Qualitätskontrollmechanismus in P. anserina dar, der den Organismus sehr effektiv vor zellulären Schäden und Dysfunktionen bewahrt und einen positiven Einfluss auf die Alterung, Entwicklung und Energieversorgung einnimmt.
The degradation of nonfunctional mitochondrial proteins is of fundamental relevance for maintenance of cellular homeostasis. The heteromeric CLPXP protein complex in the mitochondrial matrix is part of this process. In the fungal aging model Podospora anserina, ablation of CLPXP leads to an increase in healthy lifespan. Here, we report that this counterintuitive increase depends on a functional autophagy machinery. In PaClpXP mutants, autophagy is involved in energy conservation and the compensation of impairments in respiration. Strikingly, despite the impact on mitochondrial function, it is not mitophagy but general autophagy that is constitutively induced and required for longevity. In contrast, in another long-lived mutant ablated for the mitochondrial PaIAP protease, autophagy is neither induced nor required for lifespan extension. Our data provide novel mechanistic insights into the capacity of different forms of autophagy to compensate impairments of specific components of the complex mitochondrial quality control network and about the biological role of mitochondrial CLPXP in the control of cellular energy metabolism.
Inducing cell death in tumor cells is a major goal of anti-cancer therapy. However, the preferable mode of cell death to induce is under debate. Apoptosis is known to be an anti-inflammatory and pro-resolving type of programmed cell death, whereas necroptosis results in the release of danger-associated molecular patterns (DAMPs) and is pro-inflammatory. Efferocytosis of apoptotic cells by macrophages results in a pro-resolving switch of macrophages polarization and is required to induce resolution of inflammation. This impact of apoptotic cells on macrophages is a non-desired consequence of cell death in tumors, which are often characterized by an overshooting wound healing response. Moreover, apoptosis resistance is frequently observed in cancer cells. To overcome apoptosis resistance in cancer cells, necroptosis can be induced as an alternative mechanism for cancer treatment. Interferons (IFNs) play an important role in tumor immune responses and act by inducing the expression of IFN-stiumlated genes (ISGs). Furthermore, IFNs were shown to be able to induce necroptosis together with Smac-mimetics when caspases are inhibited in different cancer cell lines. Necroptosis is induced by phosphorylation and activation of receptor-interacting serine/threonine-protein kinase 1 (RIPK1), RIPK3 and pseudokinase mixed lineage kinase domain-like (MLKL).
In my thesis, we first identified MLKL as an ISG in various cancer cell lines. MLKL upregulation was found to be a general feature of IFN signaling since both type I and type II IFNs increase the expression of MLKL. IFNy was able to upregulate MLKL at messenger ribonucleic acid (mRNA) and protein level indicating that MLKL is elevated transcriptionally. Indeed, Actinomycin D chase experiments showed that inhibition of transcription abolished MLKL upregulation upon IFN treatment. Both, knockdown of the IFNy-activated transcription factors interferon regulatory factor 1 (IRF1) and signal transducer and activator of transcription 1 (STAT1) as well as knockout of IRF1 significantly dampened MLKL mRNA upregulation, demonstrating that STAT1 and especially IRF1 are necessary to induce MLKL expression. This first part of the study highlights the upregulation of MLKL by IFNy as valuable tool to sensitize cells towards necroptosis and by that overcome apoptosis resistance in cancers.
When compared to apoptosis, the immune response to necroptotic cells and the polarization of macrophages phagocytosing necroptotic cells is not well studied. In most studies, cell death was induced by biological or chemical compounds, which may lead to artifacts by affecting the macrophages and triggering of unrelated signaling pathways. Therefore, in the second part of my thesis we used a pure cell death system of NIH 3T3 cells expressing either dimerizable caspase 8 or oligomerizable RIPK3 to induce cell death. Addition of B/B-Homodimerizer (dimerizer) to the cells resulted in apoptosis or necroptosis, which was confirmed by caspase 3/7 activation, phosphorylation of MLKL and inhibitor experiments, respectively. We analyzed the effect of dying cells on peritoneal macrophages by establishing a co-culture in a transwell system. The genetic profile of macrophages co-cultured with dying cells was evaluated by whole transcriptome RNA sequencing. In macrophages co-cultured with necroptotic cells genes corresponding to chemotaxis and hypoxia pathways were upregulated. A significant proportion of hypoxia-related pathways are mediated by hypoxia-inducible factor 1-alpha (HIF-1α), which also induces metabolic changes in polarized macrophages. We could show that macrophages co-cultured with necroptotic cells showed a decreased mitochondrial respiration, indicating an inflammatory (M1) polarization. Protein levels of chemokine C-X-C motif ligand 1 (CXCL1), which was increased in the RNA sequencing data, were also upregulated in supernatant of co-cultured macrophages and of necroptotic cells, demonstrating that necroptotic cells both secrete CXCL1 and induce gene expression of CXCL1 in peritoneal macrophages. This may influence the recruitment of neutrophils as inhibition of necroptosis during Zymosan-A-induced peritonits in mice decreased the levels of neutrophils at day 1 of this model of self-resolving inflammation.
Furthermore, RNA sequencing revealed an unexpected impact of apoptotic cells on macrophage biology as cell cycle and cell division pathways were increased. Enhanced proliferation of macrophages was confirmed by two functional assay with peritoneal macrophages isolated from mice and IC-21 macrophages. Inhibition of apoptosis during Zymosan-A-induced peritonits in mice demonstrated decreased mRNA levels of cell cycle mediators in peritoneal macrophages. Simultaneously with cell cycle activation, gene sets of prostaglandin E2 (PGE2) signaling were upregulated during RNA sequencing. In the second part of my thesis we could demonstrate, that apoptotic cells induce transcription of cell cycle genes and proliferation of macrophages and necroptotic cells are able to influence the chemokine profile of macrophages and thereby the recruitment of neutrophils.
The interaction of macrophages with apoptotic cells is required for efficient resolution of inflammation. While apoptotic cell removal prevents inflammation due to secondary necrosis, it also alters the macrophage phenotype to hinder further inflammatory reactions. The interaction between apoptotic cells and macrophages is often studied by chemical or biological induction of apoptosis, which may introduce artifacts by affecting the macrophages as well and/or triggering unrelated signaling pathways. Here, we set up a pure cell death system in which NIH 3T3 cells expressing dimerizable Caspase-8 were co-cultured with peritoneal macrophages in a transwell system. Phenotype changes in macrophages induced by apoptotic cells were evaluated by RNA sequencing, which revealed an unexpectedly dominant impact on macrophage proliferation. This was confirmed in functional assays with primary peritoneal macrophages and IC-21 macrophages. Moreover, inhibition of apoptosis during Zymosan-induced peritonitis in mice decreased mRNA levels of cell cycle mediators in peritoneal macrophages. Proliferation of macrophages in response to apoptotic cells may be important to increase macrophage numbers in order to allow efficient clearance and resolution of inflammation.
Interferons (IFNs) are key players in the tumor immune response and act by inducing the expression of IFN-stimulated genes (ISGs). Here, we identify the mixed-lineage kinase domain-like pseudokinase (MLKL) as an ISG in various cancer cell lines. Both type I and type II IFNs increase the expression of MLKL indicating that MLKL up-regulation is a general feature of IFN signaling. IFNγ up-regulates mRNA as well as protein levels of MLKL demonstrating that IFNγ transcriptionally regulates MLKL. This notion is further supported by Actinomycin D chase experiments showing that IFNγ-stimulated up-regulation of MLKL is prevented in the presence of the transcriptional inhibitor Actinomycin D. Also, knockdown of the transcription factor IFN-regulatory factor 1 (IRF1) and signal transducer and activator of transcription (STAT) 1 as well as knockout of IRF1 significantly attenuate IFNγ-mediated induction of MLKL mRNA levels. Up-regulation of MLKL by IFNγ provides a valuable tool to sensitize cells towards necroptotic cell death and to overcome apoptosis resistance of cancer cells.
The current Review article provides a narrative review about the neurobiological underpinnings and treatment of treatment resistant late-life depression (TRLLD). The manuscript focuses on therapeutic targets of late-life depression, which include pharmacological, psychological, biophysical and exercise treatment approaches. Therefore, we summarize available evidences on that kind of therapies for patients suffering from late-life depression. The search for evidences of therapeutic options of late-life depression were done using searching websites as “pubmed”, and using the searching terms “depression”, “late-life depression”, “treatment”, “biophysical therapy”, “exercise therapy”, “pharmacological therapy” and “psychological therapy”. To the end, we summarize and discuss current data, providing some directions for further research.
Treatment recommendations for elderly depressive patients favour a multimodal approach, containing psychological, pharmacological and secondary biophysical therapeutic options. Particularly, a combination of psychotherapy and antidepressant medication reflects the best therapeutic option. However, mostly accepted and used is the pharmacological treatment although evidence suggests that the drug therapy is not as effective as it is in younger depressive patients. Further studies employing larger samples and longer follow-up periods are necessary and may focus on comparability of study designs and involve novel approaches to establish the validity and reliability of multimodal treatment programs.
We investigated the effects of sexual arousal induced by olfactory stimuli on the expression of neuromodulators, neurotransmitters and sexual steroid receptors in the suprachiasmatic nucleus (SCN, the circadian pacemaker of mammals) and other cerebral entities of Syrian hamsters (Mesocricetus auratus) compared to manual sleep deprivation and immobilization stress. The hamsters kept under a 12:12 hours (h) light:dark cycle were deprived of sleep by sexual stimulation, gentle manual handling or immobilization stress for 1 h at the beginning of the light phase and subsequently sacrificed at zeitgeber time 01:00, respectively; for comparison, hamsters were manually sleep deprived for 6 or 20 h or sacrificed after completing a full sleep phase. As demonstrated by immunohistochemistry, apart from various alterations after manual sleep deprivation, sexual stimulation caused down-regulation of arginine-vasopressin (AVP), vasointestinal peptide (VIP), serotonin (5-HT), substance P (SP), and met-enkephalin (ME) in the SCN. Somatostatin (SOM) was diminished in the medial periventricular nucleus (MPVN). In contrast, an increase in AVP was observed in the PVN, that of oxytocin (OXY) in the supraoptic nucleus (SON), of tyrosine-hydroxylase (TH) in the infundibular nucleus (IN), and dopamine beta-hydroxylase (DBH) in the A7 neuron population of the brain stem (A7), respectively. Testosterone in plasma was increased. The results indicate that sexual arousal extensively influences the neuropeptide systems of the SCN, suggesting an involvement of the SCN in reproductive behavior.
A potential clinical and etiological overlap between schizophrenia (SZ) and bipolar disorder (BD) has long been a subject of discussion. Imaging studies imply functional and structural alterations of the hippocampus in both diseases. Thus, imaging this core memory region could provide insight into the pathophysiology of these disorders and the associated cognitive deficits. To examine possible shared alterations in the hippocampus, we conducted a multi-modal assessment, including functional and structural imaging as well as neurobehavioral measures of memory performance in BD and SZ patients compared with healthy controls. We assessed episodic memory performance, using tests of verbal and visual learning (HVLT, BVMT) in three groups of participants: BD patients (n = 21), SZ patients (n = 21) and matched (age, gender, education) healthy control subjects (n = 21). In addition, we examined hippocampal resting state functional connectivity, hippocampal volume using voxel-based morphometry (VBM) and fibre integrity of hippocampal connections using diffusion tensor imaging (DTI). We found memory deficits, changes in functional connectivity within the hippocampal network as well as volumetric reductions and altered white matter fibre integrity across patient groups in comparison with controls. However, SZ patients when directly compared with BD patients were more severely affected in several of the assessed parameters (verbal learning, left hippocampal volumes, mean diffusivity of bilateral cingulum and right uncinated fasciculus). The results of our study suggest a graded expression of verbal learning deficits accompanied by structural alterations within the hippocampus in BD patients and SZ patients, with SZ patients being more strongly affected. Our findings imply that these two disorders may share some common pathophysiological mechanisms. The results could thus help to further advance and integrate current pathophysiological models of SZ and BD.
An increasing body of evidences from preclinical as well as epidemiological and clinical studies suggest a potential beneficial role of dietary intake of omega-3 fatty acids for cognitive functioning. In this narrative review, we will summarize and discuss recent findings from epidemiological, interventional and experimental studies linking dietary consumption of omega-3 fatty acids to cognitive function in healthy adults. Furthermore, affective disorders and schizophrenia (SZ) are characterized by cognitive dysfunction encompassing several domains. Cognitive dysfunction is closely related to impaired functioning and quality of life across these conditions. Therefore, the current review focues on the potential influence of omega-3 fatty acids on cognition in SZ and affective disorders. In sum, current data predominantly from mechanistic models and animal studies suggest that adjunctive omega-3 fatty acid supplementation could lead to improved cognitive functioning in SZ and affective disorders. However, besides its translational promise, evidence for clinical benefits in humans has been mixed. Notwithstanding evidences indicate that adjunctive omega-3 fatty acids may have benefit for affective symptoms in both unipolar and bipolar depression, to date no randomized controlled trial had evaluated omega-3 as cognitive enhancer for mood disorders, while a single published controlled trial suggested no therapeutic benefit for cognitive improvement in SZ. Considering the pleiotropic mechanisms of action of omega-3 fatty acids, the design of well-designed controlled trials of omega-3 supplementation as a novel, domain-specific, target for cognitive impairment in SZ and affective disorders is warranted.
We study continuous dually epi-translation invariant valuations on certain cones of convex functions containing the space of finite-valued convex functions. Using the homogeneous decomposition of this space, we associate a certain distribution to any homogeneous valuation similar to the Goodey-Weil embedding for translation invariant valuations on convex bodies. The support of these distributions induces a corresponding notion of support for the underlying valuations, which imposes certain restrictions on these functionals, and we study the relation between the support of a valuation and its domain. This gives a partial answer to the question which dually epi-translation invariant valuations on finite-valued convex functions can be extended to larger cones of convex functions.
We also study topological properties of spaces of valuations with support contained in a fixed compact set. As an application of these results, we introduce the class of smooth valuations on convex functions and show that the subspace of smooth dually epi-translation invariant valuations is dense in the space of continuous dually epi-translation invariant valuation on finite-valued convex functions. These smooth valuations are given by integrating certain smooth differential forms over the graph of the differential of a convex function. We use this construction to give a characterization of a dense subspace of all continuous valuations on finite-valued convex functions that are rotation invariant as well as dually epi-translation invariant.
Using results from Alesker's theory of smooth valuations on convex bodies, we also show that any smooth valuation can be written as a convergent sum of mixed Hessian valuations. In particular, mixed Hessian valuations span a dense subspace, which is a version of McMullen’s conjecture for valuations on convex functions.
Phosphodiesterase type 2A (PDE2A) hydrolyzes cyclic nucleotides cAMP and cGMP, thus efficiently controlling cNMP-dependent signaling pathways. PDE2A is composed of an amino-terminal region, two regulatory GAF domains, and a catalytic domain. Cyclic nucleotide hydrolysis is known to be activated by cGMP binding to GAF-B; however, other mechanisms may operate to fine-tune local cyclic nucleotide levels. In a yeast two-hybrid screening we identified XAP2, a crucial component of the aryl hydrocarbon receptor (AhR) complex, as a major PDE2A-interacting protein. We mapped the XAP2 binding site to the GAF-B domain of PDE2A. PDE assays with purified proteins showed that XAP2 binding does not change the enzymatic activity of PDE2A. To analyze whether PDE2A could affect the function of XAP2, we studied nuclear translocation of AhR, i.e. the master transcription factor controlling the expression of multiple detoxification genes. Notably, regulation of AhR target gene expression is initiated by tetrachlorodibenzodioxin (TCDD) binding to AhR and by a poorly understood cAMP-dependent pathway followed by the translocation of AhR from the cytosol into the nucleus. Binding of PDE2A to XAP2 inhibited TCDD- and cAMP-induced nuclear translocation of AhR in Hepa1c1c7 hepatocytes. Furthermore, PDE2A attenuated TCDD-induced transcription in reporter gene assays. We conclude that XAP2 targets PDE2A to the AhR complex, thereby restricting AhR mobility, possibly by a local reduction of cAMP levels. Our results provide first insights into the elusive cAMP-dependent regulation of AhR.