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Lieblingsbild
(2017)
Das Bild zeigt die Kryo-EM-Elektronendichtekarte des bakteriellen Kalium-Aufnahmesystems KtrAB mit ADP gebunden mit einer Auflösung von 6.6 Å. Das Bild ist mein Lieblingsbild, weil man bereits auf den ersten Blick eine dramatische Konformationsänderung im Vergleich zu einer früheren ATPgebundenen Struktur erkennen konnte, nämlich die Ausbildung langgestreckter α-Helices (hier gelb markiert), die die regulatorischen A-Untereinheiten (blau) mit den Kaliumionen-translozierenden B-Untereinheiten (grau) verbinden. ...
"Ästhetisch ist, was hilft"
(2017)
Lieblingsbild
(2017)
Das rechte Bild stellt die Elektronendichte eines menschlichen Proteins dar, gewonnen durch die Röntgenstrahl-Beugung an Kristallen dieses Proteins. Die Struktur hat Sagar Bhogaraju 2016 aufgeklärt. Das linke Bild stellt ein erstes Strukturmodell auf der Basis der gemessenen Elektronendichte dar. ...
Schönheit liegt auch in der Wissenschaft im Auge des Betrachters. So wie Eltern ihre Sprösslinge schön finden, schwärmen auch Forscher wie Mike Heilemann und Ivan Dikic von ihren Bildern fluoreszierender Bakterien. Doch wenn sie es auf das Cover einer Fachzeitschrift schaffen wollen, nehmen sie die Hilfe wissenschaftlicher Illustratorinnen wie Ella Marushchenko in Anspruch.
Lieblingsbild
(2017)
Was ist ein geographisches Bild? Darauf hat sicher jeder eine Antwort: Beim einen poppen im Kopf zunächst die Urlaubsfotos von der finnischen Schären-Küste oder aus Paris auf, die andere denkt an Satellitenaufnahmen des schwindenden Eisrandes der Arktis im GEO-Magazin oder an Claudia Kleinerts Wetterkarte in den Tagesthemen. Auf den ersten Blick scheint klar: alles Bilder, alles irgendwie geographisch.
Das Recht – abstrakt und bilderfeindlich? Ein Fehlurteil. Denn schon immer hat das Recht zu sinnlichen Hilfsmitteln gegriffen, um sich den Menschen verständlich zu machen, teils auf realer, besonders gern aber auf sprachlicher Ebene. Die heutige Bilderflut ist jedoch auch für die Rechtswissenschaft ein neues Phänomen.
Der Aufbau unserer Umwelt folgt bestimmten Regelmäßigkeiten, die für uns so selbstverständlich sind, dass wir ihrer kaum bewusst sind. Doch würden Sie die Milch unter dem Bett suchen oder das Kissen in der Badewanne? Wohl kaum. Die Psychologin Prof. Melissa Lê-Hoa Võ untersucht das erlernte Regelwerk, die Entwicklung von sogenanntem Szenenwissen, mithilfe psychophysischer Verfahren, Blickbewegungsund Hirnpotenzialmessungen.
Der Mensch besteht aus vielen Körperteilen, und doch ist es fast ausschließlich das Gesicht, an dem wir ein Individuum erkennen. Aber erkennen wir es wirklich? In Zeiten des Selfie-Kults und der biometrischen Verfahren ist diese Frage aktueller denn je. Wir leben in einer »fazialen« Gesellschaft: Das Gesicht ist Medium für alle erdenklichen Arten, sich mitzuteilen.
AKTIVA-MCI is a program for patients with mild cognitive impairment (MCI) that aims to enhance participation in cognitively stimulating leisure activities. Participation in cognitively stimulating activities seems to be a potential strategy for people with MCI delaying cognitive decline for a while. In total, 35 MCI patients were enrolled in the pilot study of whom 29 completed the whole program (16 female, 71.1±7.5 years; Mini Mental Status Examination score: 28±2.2). Daily activity protocols were used to measure the frequency of participation in cognitively stimulating activities during the program (12 sessions). Additional standardized psychometric tests and questionnaires were used to assess cognition, mood, and subjective memory decline. Analyses of the daily activity protocols showed that during the intervention participants increased the frequency of several cognitively stimulating leisure activities. Comparison of pre-post data indicates no changes in cognitive status, mood, and subjective memory decline. These findings indicate that the program is suitable for patients with MCI.
Die Arbeit untersucht am Fall der Religionspolitik in den Verfassungsgebungsprozessen der deutschen Bundesländer, ob Verfassungen eher das Ergebnis von Konflikt oder Konsens sind. Die Länderverfassungen zeigen eine hohe religionspolitische Vielfalt, die in dieser Arbeit erstmals vollständig erhoben und systematisiert wird. Die religionspolitischen Normen der Verfassungen werden vier Typen von Religionspolitik zugewiesen (Statusverleihung, Redistribution, Religionsfreiheit und Restriktion). Für die Verbreitung der einzelnen Normen werden die historischen Verläufe von 1919 bis 2015 analysiert und Trends beschrieben. Für die Erklärung der Unterschiede entwickelt die Arbeit ein ökonomisches Modell des Parteienwettbewerbs, in dem religiöse Parteien, insbesondere CDU und CSU, die zentrale Rolle spielen. In dem Modell wird angenommen, dass religiöse Parteien (einschließlich der Union) nur dann die Interessen nicht- und andersreligiöser Wähler berücksichtigen – wenn dies für ihren Wahlerfolg notwendig ist. Die zentrale Idee des Modells ist, dass religionspolitische Policies unterschiedliche Kosten und Nutzen für religiöse und nichtreligiöse Wähler implizieren. Diesen Kosten und Nutzen müssten religiöse Parteien Rechnung tragen, wenn sie Politikergebnis und Wahlergebnis gleichzeitig optimieren – d.h. rational abwägend agieren. Aus der Überprüfung dieses Modells lässt sich ableiten, ob die Religionspolitik in Verfassungen das Ergebnis offener Verhandlungen mit dem Ziel der Herstellung bzw. Abbildung eines gesellschaftlichen Konsenses sind – oder ob sie vielmehr das Ergebnis harter politischer Auseinandersetzungen sind und die gesellschaftlichen Machtverhältnisse reproduzieren. Je weniger Ersteres und je mehr Zweiteres gegeben ist, desto weniger können Verfassungen voraussetzungslos als Rahmen oder Bezugspunkt eines fairen politischen Wettstreits dienen. Die Arbeit belegt dieses Modell empirisch mit einem Mixed-Methods-Ansatz aus multiplen Regressionsanalysen und fuzzy set Qualitative Comparative Analysis (fsQCA).
Historically – if one can say that given the infancy of the field – environmental plastic debris has been the baby of marine research. Driven by the rediscovery of long forgotten, 1970s studies on the occurrence of small plastic fragments (today termed microplastics) in the oceans, oceanographers and marine biologists resurrected the topic in the early 2000s. Since then, the field has rapidly expanded and established that plastics are ubiquitous in the marine system, from the Arctic to Antarctic and from the surface to the deep sea. ...
The focus of this research was to understand the molecular mechanism that lies behind the insertion of tail-anchored membrane proteins into the ER membrane of yeast cells. State-of-art instruments such as LILBID, and Cryo-EM, combined with the introduction of direct electron detectors, were used to analyze the proteins that capture tail-anchored proteins near the ER membrane and help their releases from a chaperone, an ATPase named Get3. Get3 escorts TA proteins to the ER membrane, where both Get3 and the TA proteins interact sequentially to Get3 membrane bound receptors Get1 and Get2. Get1 and Get2 are homologs of mammalian WRB and CAML.
The native host was used to separately produce Get1, Get2, and the Get2/Get1 single chain constructs. The studies showed that when Get1 is expressed alone, Get1 does not seems to be located in the ER membrane but rather in microbodies like shape organelles (or peroxisome). Interestingly, Get1 seems to be located in the ER membrane when it is linked to Get2 as single chain construct.
The localization study of Get2/Get1 fused to GFP shows from the fluorescence intensity that Get2/Get1.GFP has a tube-like morphology or membrane-enclosed sacs (cisterna), implying that Get2/Get1 is actually targeted to the ER membrane and is likely functional. In other words, Get1 and Get2 stabilize each other in the ER membrane.
The expression of Get2/Get1 was found to be already optimum when expressed as single chain construct because the fluorescence counts did not improve when additives such as DMSO or histidine were added. However, when Get1 and Get2 are expressed separately, additives improve their protein production yield. In 1 liter culture, Get1 yield is increased by about 3 mg and Get2 by 1.8 mg. This can be explained by the space that Get1 and Get2 should occupy within the ER membrane as they must coexist with other membrane components to maintain the homeostasis of the cell. Hence, if there were no gain for single chain construct expression, it meant that Get2/Get1 was already well expressed on its own in ER membrane and has reached its optimum expression without the help of additives. The Get2/Get1 overexpression is more stable, tolerated and less toxic for the cells to express it at a high level.
DDM has proved to be the best detergent from the detergents tested to solubilize Get1, Get2, and Get2/Get1.
Thereafter, Get1, Get2 (data not shown), and Get2/Get1 were successfully purified in DDM micelles.
Furthermore, for the first time using LILBID, the actual study has shown that Get1 and Get2 are predominantly a heterotetramer (2xGet1 and 2xGet2) but higher oligomerization may exist as well.
Get3 binds to Get1 in a biphasic way with a specific strong binding of an affinity of 57 nM and the second of 740 nM nonspecific indicative of heterogeneity within the interaction between Get1 and Get3. This heterogeneity is caused by the presence of different conformation of either protein. However, in order to characterize a high-resolution structure model of a specific target one needs highly homogenous and identical molecules of the target protein or complex in solution. The homogeneity increases the chances of growing crystals during crystallography as the good homogeneity will likely generate a perfect packing of unit cells stack (also known as crystal lattice) in the three-dimensional spaces. The same truth goes for the single particles analysis Cryo-EM, especially for smaller complexes where having less or no conformation alterations of specific targets will enable the researcher to classify the particles in 2D and 3D, therefore improving the signal-to-noise-ratio that will ultimately lead to high-resolution structure determination.
Get1, Get2/Get1 and chimeric variants (tGet2/Get1, T4l.Get2/Get1, T4l.Get2.apocyte.Get1) were crystallized but none of the crystals could diffract due to heterogeneity.
This heterogeneity was not only occurring upon the binding of Get3 to its membrane receptors, but seems to be already present within the receptors themselves through possibly different conformation.
In this Ph.D. thesis, the heterogeneity of purified Get2 and Get1 as complex or individually in detergent is then, so far, the limiting factor for obtaining a high-resolution structure model of Get1 and Get2. As mentioned above, the heterogeneity observed was not due to the quality of the sample preparation but rather to the effect of different conformations that could have been native, or just because of the micelle used, as it was proven by the 3-D heterogeneity classification by Cryo-EM.
In general, crosslinking is one way to keep the integrity of protein complexes, however it appeared not to improve the sample quality when it was analyzed in micelles. Often the integrity of some membrane proteins is affected when they are solubilized and purified in detergents.
Finally, in this study, the structural map of Get2 and Get1 complex linked with chimeric protein T4 lysozyme and apocytochrome C b562RIL gene was obtained at 10 Å. However, this single chain construct has a density map corresponding to heterodimer species (one Get1 and Get2). Therefore, based on those data the tertiary structure of Get2/Get1 in micelle is poorly defined. It could be that the membrane extraction in DDM and the purification destabilizes the structure of the complex.
Mimetische Praktiken in der neueren Architektur : Prozesse und Formen der Ähnlichkeitserzeugung
(2017)
Praktiken des Zitierens, Kopierens, der Montage, des Rekonstruierens, der Analogiebildung und der Mimikry sind gängige Verfahren im architektonischen Alltag. Dennoch ist das Paradigma der Originalität bis heute beherrschend und verstellt oft den Blick auf mimetische Phänomene. Der Tagungsband versammelt zwölf im Jahr 2016 auf der Konferenz „Ähnlichkeit: Prozesse und Formen“ in der Bibliothek der Stiftung Werner Oechslin in Einsiedeln gehaltene Vorträge, ergänzt durch zwei Artikel der Herausgeberinnen. Der Fokus der Tagung lag auf aktuellen Forschungen zu Praktiken der Ähnlichkeitserzeugung in der neueren Architektur und wurde von Teilprojekten der DFG-SNF-Forschergruppe „Medien und Mimesis“ organisiert.
Juvenile neuronal ceroid lipofuscinosis (JNCL or Batten disease) caused by mutations in the CLN3 gene is the most prevalent inherited neurodegenerative disease in childhood resulting in widespread central nervous system dysfunction and premature death. The consequences of CLN3 mutation on the progression of the disease, on neuronal transmission, and on central nervous network dysfunction are poorly understood. We used Cln3 knockout (Cln3Δex1-6) mice and found increased anxiety-related behavior and impaired aversive learning as well as markedly affected motor function including disordered coordination. Patch-clamp and loose-patch recordings revealed severely affected inhibitory and excitatory synaptic transmission in the amygdala, hippocampus, and cerebellar networks. Changes in presynaptic release properties may result from dysfunction of CLN3 protein. Furthermore, loss of calbindin, neuropeptide Y, parvalbumin, and GAD65-positive interneurons in central networks collectively support the hypothesis that degeneration of GABAergic interneurons may be the cause of supraspinal GABAergic disinhibition.
Mutations are the ultimate basis of evolution, yet their occurrence rate is known only for few species. We directly estimated the spontaneous mutation rate and the mutational spectrum in the nonbiting midge C. riparius with a new approach. Individuals from ten mutation accumulation lines over five generations were deep genome sequenced to count de novo mutations that were not present in a pool of F1 individuals, representing parental genotypes. We identified 51 new single site mutations of which 25 were insertions or deletions and 26 single nucleotide mutations. This shift in the mutational spectrum compared to other organisms was explained by the high A/T content of the species. We estimated a haploid mutation rate of 2.1 × 10−9 (95% confidence interval: 1.4 × 10−9 – 3.1 × 10-9) that is in the range of recent estimates for other insects and supports the drift barrier hypothesis. We show that accurate mutation rate estimation from a high number of observed mutations is feasible with moderate effort even for nonmodel species.
The adaptive immune system is able to detect and destroy cells that are malignantly transformed or infected by intracellular pathogens. Specific immune responses against these cells are elicited by antigenic peptides that are presented on major histocompatibility complex class I (MHC I) molecules and recognized by cytotoxic T lymphocytes at the cell surface. Since these MHC I-presented peptides are generated in the cytosol by proteasomal protein degradation, they can be metaphorically described as a window providing immune cells with insights into the state of the cellular proteome. A crucial element of MHC I antigen presentation is the peptide-loading complex (PLC), a multisubunit machinery, which contains as key constituents the transporter associated with antigen processing (TAP) and the MHC I-specific chaperone tapasin (Tsn). While TAP recognizes and shuttles the cytosolic antigenic peptides into the endoplasmic reticulum (ER), Tsn samples peptides in the ER for their ability to form stable complexes with MHC I, a process called peptide proofreading or peptide editing. Through its selection of peptides that improve MHC I stability, Tsn contributes to the hierarchy of immunodominant peptide epitopes. Despite the fact that it concerns a key event in adaptive immunity, insights into the catalytic mechanism of peptide proofreading carried out by Tsn have only lately been gained via biochemical, biophysical, and structural studies. Furthermore, a Tsn homolog called TAP-binding protein-related (TAPBPR) has only recently been demonstrated to function as a second MHC I-specific chaperone and peptide proofreader. Although TAPBPR is PLC-independent and has a distinct allomorph specificity, it is likely to share a common catalytic mechanism with Tsn. This review focuses on the current knowledge of the multivalent protein–protein interactions and the concomitant dynamic molecular processes underlying peptide-proofreading catalysis. We do not only derive a model that highlights the common mechanistic principles shared by the MHC I editors Tsn and TAPBPR, and the MHC II editor HLA-DM, but also illustrate the distinct quality control strategies employed by these chaperones to sample epitopes. Unraveling the mechanistic underpinnings of catalyzed peptide proofreading will be crucial for a thorough understanding of many aspects of immune recognition, from infection control and tumor immunity to autoimmune diseases and transplant rejection.
Viewing of ambiguous stimuli can lead to bistable perception alternating between the possible percepts. During continuous presentation of ambiguous stimuli, percept changes occur as single events, whereas during intermittent presentation of ambiguous stimuli, percept changes occur at more or less regular intervals either as single events or bursts. Response patterns can be highly variable and have been reported to show systematic differences between patients with schizophrenia and healthy controls. Existing models of bistable perception often use detailed assumptions and large parameter sets which make parameter estimation challenging. Here we propose a parsimonious stochastic model that provides a link between empirical data analysis of the observed response patterns and detailed models of underlying neuronal processes. Firstly, we use a Hidden Markov Model (HMM) for the times between percept changes, which assumes one single state in continuous presentation and a stable and an unstable state in intermittent presentation. The HMM captures the observed differences between patients with schizophrenia and healthy controls, but remains descriptive. Therefore, we secondly propose a hierarchical Brownian model (HBM), which produces similar response patterns but also provides a relation to potential underlying mechanisms. The main idea is that neuronal activity is described as an activity difference between two competing neuronal populations reflected in Brownian motions with drift. This differential activity generates switching between the two conflicting percepts and between stable and unstable states with similar mechanisms on different neuronal levels. With only a small number of parameters, the HBM can be fitted closely to a high variety of response patterns and captures group differences between healthy controls and patients with schizophrenia. At the same time, it provides a link to mechanistic models of bistable perception, linking the group differences to potential underlying mechanisms.
The transporter associated with antigen processing (TAP) selectively translocates antigenic peptides into the endoplasmic reticulum. Loading onto major histocompatibility complex class I molecules and proofreading of these bound epitopes are orchestrated within the macromolecular peptide-loading complex, which assembles on TAP. This heterodimeric ABC-binding cassette (ABC) transport complex is therefore a major component in the adaptive immune response against virally or malignantly transformed cells. Its pivotal role predestines TAP as a target for infectious diseases and malignant disorders. The development of therapies or drugs therefore requires a detailed comprehension of structure and function of this ABC transporter, but our knowledge about various aspects is still insufficient. This review highlights recent achievements on the structure and dynamics of antigenic peptides in complex with TAP. Understanding the binding mode of antigenic peptides in the TAP complex will crucially impact rational design of inhibitors, drug development, or vaccination strategies.
Perfectionism nowadays is frequently understood as a multidimensional personality trait with two higher-order dimensions of perfectionistic strivings and perfectionistic concerns. While perfectionistic concerns are robustly found to correlate with negative outcomes and psychological malfunctioning, findings concerning the outcomes of perfectionistic strivings are inconsistent. There is evidence that perfectionistic strivings relate to psychological maladjustment on the one hand but to positive outcomes on the other hand as well. Moreover, perfectionistic strivings and perfectionistic concerns frequently showed substantial overlap. These inconsistencies of differential relations and the substantial overlap of perfectionistic strivings and perfectionistic concerns raise questions concerning the factorial structure of perfectionism and the meaning of its dimensions. In this study, several bifactor models were applied to disentangle the common variance of perfectionistic strivings and perfectionistic concerns at the item level using Hill et al.’s (2004) Perfectionism Inventory (PI). The PI measures a broad range of perfectionism dimensions by four perfectionistic strivings and four perfectionistic concerns subscales. The bifactor-(S – 1) model with one general factor defined by concern over mistakes as the reference facet, four specific perfectionistic strivings factors, and three specific perfectionistic concerns factors showed acceptable fit. The results revealed a clear separation between perfectionistic strivings and perfectionistic concerns, as the general factor represented concern over mistakes, while the perfectionistic strivings factors each explained a substantial amount of reliable variance independent of the general factor. As a result, factor scores of the specific perfectionistic strivings factors and the general factor had differential relationships with achievement motivation, neuroticism, conscientiousness, and self-efficacy that met with theoretical expectations, while results for manifest subscale scores were ambiguous. Our results question the existence of reliable sub-constructs of perfectionistic concerns independent of the general factor when defined by concern over mistakes.
Synaptic release sites are characterized by exocytosis-competent synaptic vesicles tightly anchored to the presynaptic active zone (PAZ) whose proteome orchestrates the fast signaling events involved in synaptic vesicle cycle and plasticity. Allocation of the amyloid precursor protein (APP) to the PAZ proteome implicated a functional impact of APP in neuronal communication. In this study, we combined state-of-the-art proteomics, electrophysiology and bioinformatics to address protein abundance and functional changes at the native hippocampal PAZ in young and old APP-KO mice. We evaluated if APP deletion has an impact on the metabolic activity of presynaptic mitochondria. Furthermore, we quantified differences in the phosphorylation status after long-term-potentiation (LTP) induction at the purified native PAZ. We observed an increase in the phosphorylation of the signaling enzyme calmodulin-dependent kinase II (CaMKII) only in old APP-KO mice. During aging APP deletion is accompanied by a severe decrease in metabolic activity and hyperphosphorylation of CaMKII. This attributes an essential functional role to APP at hippocampal PAZ and putative molecular mechanisms underlying the age-dependent impairments in learning and memory in APP-KO mice.
Although existing research has established that aesthetic pleasure and aesthetic interest are two distinct positive aesthetic responses, empirical research on aesthetic preferences usually considers only aesthetic liking to capture participants’ aesthetic response. This causes some fundamental contradictions in the literature; some studies find a positive relationship between easy-to-process stimulus characteristics and aesthetic liking, while others suggest a negative relationship. The present research addresses these empirical contradictions by investigating the dual character of aesthetic liking as manifested in both the pleasure and interest components. Based on the Pleasure-Interest Model of Aesthetic Liking (PIA Model; Graf and Landwehr, 2015), two studies investigated the formation of pleasure and interest and their relationship with aesthetic liking responses. Using abstract art as the stimuli, Study 1 employed a 3 (stimulus fluency: low, medium, high) × 2 (processing style: automatic, controlled) × 2 (aesthetic response: pleasure, interest) experimental design to examine the processing dynamics responsible for experiencing aesthetic pleasure versus aesthetic interest. We find that the effect of stimulus fluency on pleasure is mediated by a gut-level fluency experience. Stimulus fluency and interest, by contrast, are related through a process of disfluency reduction, such that disfluent stimuli that grow more fluent due to processing efforts become interesting. The second study employed product designs (bikes, chairs, and lamps) as stimuli and a 2 (fluency: low, high) × 2 (processing style: automatic, controlled) × 3 (product type: bike, chair, lamp) experimental design to examine pleasure and interest as mediators of the relationship between stimulus fluency and design attractiveness. With respect to lamps and chairs, the results suggest that the effect of stimulus fluency on attractiveness is fully mediated by aesthetic pleasure, especially in the automatic processing style. Conversely, disfluent product designs can enhance design attractiveness judgments due to interest when a controlled processing style is adopted.
Malignant brain tumors, including gliomas, brain metastases and anaplastic meningiomas, are associated with poor prognosis, and represent an unmet medical need. ASA404 (DMXAA), a vascular disrupting agent, has demonstrated promising results in several preclinical tumor models and early phase clinical trials. However, two phase III trials in non-small cell lung cancer reported insufficient results. The aim of the present study was to determine the effects of ASA404 on brain tumors. The effects of ASA404 were evaluated in vitro and in vivo using subcutaneous, and orthotopical models for malignant glioma (U-87, LN-229, U-251, LN-308 and Tu-2449), brain metastasis (HT-29) and malignant meningioma (IOMM-Lee). The acute effects of ASA404 on tumor tissue were analyzed using conventional and immunohistochemical staining techniques [hematoxylin and eosin, MIB-1 antibody/proliferation maker protein Ki-67, cleaved caspase-8, stimulator of interferon genes (STING), ionized calcium-binding adapter molecule 1]. Furthermore, the sizes of subcutaneous tumors were measured and the symptom-free survival rates of animals with intracranial tumors receiving ASA404 treatment were analyzed. ASA404 demonstrated low toxicity in vitro, but exhibited strong effects on subcutaneous tumors 24 h following a single dose of ASA404 (25 mg/kg). ASA404 induced necrosis, hemorrhages and inhibited the proliferation, and growth of tumors in the subcutaneous glioma models. However, ASA404 failed to demonstrate comparable effects in any of the intracranial tumor models examined and did not result in a prolongation of survival. Expression of STING, the molecular target of ASA404, and infiltration of macrophages, the cells mediating ASA404 activity, did not differ between subcutaneous and intracranial tumors. In conclusion, ASA404 demonstrates clear efficacy in subcutaneous tumor models, but has no relevant activity in orthotopic brain tumor models. The expression of STING and infiltration with macrophages were not determined to be involved in the differential activity observed among tumor models. It is possible that the low penetration of ASA-404 into the brain prevents concentrations sufficient enough reaching the tumor in order to exhibit acute effects in vivo.
Mathematische Basiskompetenzen gelten als wichtiger Prädiktor für die schulische Mathematikleistung. Ebenso offenbaren Studien eine prädiktive Wirkung des selbstregulierten Lernens auf die akademische Leistung. Die Ergebnisse mehrerer Studien zeigen, dass Kinder mit Migrationshintergrund im deutschen Schulsystem schlechter abschneiden. Schon in der Grundschule weisen diese Kinder im Fach Mathematik schlechtere Leistungen auf als ihre Mitschüler[innen] ohne Migrationshintergrund. Vermutlich kann dieser Umstand mit schlechteren Ausgangsbedingungen im mathematischen Vorwissen begründet werden. Darüber hinaus spielen auch mangelnde Sprachfähigkeiten in der Unterrichtssprache eine wichtige Rolle. Daher sollten die fehlenden Kompetenzen im Anfangsunterricht entwicklungsorientiert aufgebaut werden. Zusätzlich sollten auch Methoden zum selbstregulierten Lernen frühzeitig vermittelt werden, da diese Fähigkeit die Übertragung fachlicher Förderungen auf weiterführende Inhalte erleichtert und eine Voraussetzung für die gelingende Umsetzung verschiedener Unterrichtsmethoden darstellt. In der Praxis werden entsprechende Konzepte bislang allerdings nur vereinzelt umgesetzt.
In der vorliegenden Studie sollten daher die Lernvoraussetzungen von Kindern mit Migrationshintergrund in den mathematischen Basiskompetenzen und im selbstregulierten Lernen überprüft werden. Im Anschluss hieran sollte erprobt werden, ob sich die Kombination aus einem Training zur Förderung mathematischer Basiskompetenzen sowie einem Programm zur Förderung selbstregulierten Lernens als Unterrichtskonzept für den Anfangsunterricht mit Kindern mit Migrationshintergrund eignet und hiermit die Disparitäten in den Lernvoraussetzungen der migrierten Kinder ausgeglichen werden können. Hierfür wurde das ursprünglich für den vorschulischen Einsatz konzipierte Trainingsprogramm „Mengen, zählen, Zahlen“ (MZZ, Krajewski, Nieding & Schneider 2007) sowie ein von Otto (2007) ausgearbeitetes Konzept mit selbstregulativen Inhalten (SRL) für den unterrichtsintegrierten Einsatz im Erstunterricht adaptiert. Für die Teilnahme an der Studie konnten 30 Grundschulklassen rekrutiert werden. 517 Schüler[innen] wurden klassenweise einer von drei Versuchsbedingungen zugeordnet: (1) Der ersten Experimentalgruppe, in der die Trainingskombination in der Reihenfolge erst SRL, dann MZZ durchgeführt wurde (EGSRL+MZZ) oder (2) der zweiten Experimentalgruppe, die die Trainingskombination in der umgekehrten Reihenfolge (EGMZZ+SRL) erhielt oder (3) der Kontrollgruppe (KG), in der der reguläre Mathematikunterricht erfolgte. Die Durchführung der Trainingskombination wurde von den jeweiligen Mathematiklehrkräften vorgenommen. Vor der Implementierung der Trainingsprogramme erfolgte eine Erfassung der mathematischen Basiskompetenzen, der Fähigkeiten im selbstregulierten Lernen sowie der Fähigkeiten im Wortverständnis. Zur Überprüfung der Wirksamkeit wurden im Anschluss an die Durchführung der Trainingskombination diese Fähigkeiten erneut erhoben. Zudem wurde die Transferwirkung auf die Fähigkeiten im Basisrechnen untersucht. Ein halbes Jahr später erfolgte eine Follow-up-Untersuchung, bei der abermals die Fähigkeiten im selbstregulierten Lernen sowie der Transfer auf das Basisrechnen und die curriculare Mathematikleitung erfasst wurden.
Die Ergebnisse offenbarten für Kinder mit Migrationshintergrund ein schlechteres Vorwissen in den mathematischen Basiskompetenzen. Hinsichtlich der Fähigkeiten im selbstregulierten Lernen konnten keine Unterschiede gefunden werden. Die Ergebnisse des Posttests konnten einen größeren Kompetenzzuwachs in den mathematischen Basiskompetenzen bei den Kindern mit Migrationshintergrund der ersten Experimentalgruppe (EGSRL+MZZ) im Vergleich zu den Kindern mit Migrationshintergrund der Kontrollgruppe nachweisen. Zudem zeigten sich positive Transfereffekte auf das Basisrechnen. Transfereffekte auf die curriculare Mathematikleistung wurden bei den Kindern mit Migrationshintergrund dagegen nicht ersichtlich. Hinsichtlich der Fähigkeiten im selbstregulierten Lernen ließen sich bei den Kindern mit Migrationshintergrund keine Trainingseffekte aufdecken. In Bezug auf die Kompensation der lückenhaften Lernvoraussetzungen in den mathematischen Basiskompetenzen bei Kindern mit Migrationshintergrund konnte für die erste Experimentalgruppe (EGSRL+MZZ) ein höherer Lernzuwachs bei Kindern nicht deutscher Herkunft festgestellt werden. Bei der zweiten Experimentalgruppe (EGMZZ+SRL) zeigten sich zwar keine Unterschiede zwischen Kindern mit und ohne Migrationshintergrund, doch es offenbarte sich, dass Kinder mit deutscher Muttersprache von der Trainingskombination im Hinblick auf ihre mathematischen Basiskompetenzen mehr profitieren. Die Ergebnisse verweisen auf die Bedeutung der sprachlichen Fähigkeiten bei der entwicklungsorientierten Förderung mathematischer Kompetenzen und werden vor dem Hintergrund einer Ausarbeitung zu einem flächendeckend einsetzbaren Unterrichtskonzept diskutiert.
The detailed biophysical mechanisms through which transcranial magnetic stimulation (TMS) activates cortical circuits are still not fully understood. Here we present a multi-scale computational model to describe and explain the activation of different pyramidal cell types in motor cortex due to TMS. Our model determines precise electric fields based on an individual head model derived from magnetic resonance imaging and calculates how these electric fields activate morphologically detailed models of different neuron types. We predict neural activation patterns for different coil orientations consistent with experimental findings. Beyond this, our model allows us to calculate activation thresholds for individual neurons and precise initiation sites of individual action potentials on the neurons’ complex morphologies. Specifically, our model predicts that cortical layer 3 pyramidal neurons are generally easier to stimulate than layer 5 pyramidal neurons, thereby explaining the lower stimulation thresholds observed for I-waves compared to D-waves. It also shows differences in the regions of activated cortical layer 5 and layer 3 pyramidal cells depending on coil orientation. Finally, it predicts that under standard stimulation conditions, action potentials are mostly generated at the axon initial segment of cortical pyramidal cells, with a much less important activation site being the part of a layer 5 pyramidal cell axon where it crosses the boundary between grey matter and white matter. In conclusion, our computational model offers a detailed account of the mechanisms through which TMS activates different cortical pyramidal cell types, paving the way for more targeted application of TMS based on individual brain morphology in clinical and basic research settings.
Die Frankfurter Dissertation von Alexander Krey ist für den Themenkomplex "Rechtsräume" von besonderer Bedeutung. Unter den Leitbegriffen "Gerichtslandschaften" und "Rechtslandschaften" wird anhand der Oberhöfe im Rhein-Main-Gebiet des Spätmittelalters eine vergleichende Untersuchung vorgelegt, die zeigen soll, dass diese juristisch-geographischen Raumbildungen zu einer "Umwälzung in den vielschichtigen Gerichtslandschaften führte, in welche die jeweiligen Oberhöfe eingebettet waren", auch wenn der Terminus "Oberhof" selbst aus der Frühneuzeit stammt. Die bestimmende Frage ist, ob eine "Pluralität lokaler Rechtsordnungen anstelle des einen gemeinen deutschen Rechts" angenommen werden kann. Welchen Stellenwert nehmen Wechselwirkungen zwischen den regional beschränkt wirkenden Oberhöfen ein? Als Untersuchungsgegenstand wählt Krey, wie gesagt, das Rhein-Main-Gebiet, im Einzelnen Frankfurt, Gelnhausen und Ingelheim. ...
Research in cell and developmental biology requires the application of three-dimensional model systems that reproduce the natural environment of cells. Processes in developmental biology are therefore studied in entire systems like insects or plants. In cell biology, three-dimensional cell cultures (e.g. spheroids or organoids) model the physiology and pathology of cells, tissues or organs. In all systems, the cellular neighborhood and interactions, but also physicochemical influences, are realistically presented. The production and handling of these model systems is rather simple and allows for reproducible characterization.
Confocal and light sheet-based fluorescence microscopy (LSFM) enable the observation of these systems while maintaining their three-dimensional integrity. LSFM is applicable to imaging live samples at high spatio-temporal resolution over long periods of time. The quality of the acquired datasets enables the extraction of quantitative features about morphology, functionality and dynamics in the context of the complete system. This approach is referred to as image-based systems biology. Exploiting the potential of the generated datasets requires an image analysis pipeline for data management, visualization and the retrieval of biologically meaningful values.
The goal of this thesis was to identify, develop and optimize modules of the image analysis pipeline. The modules cover data management and reduction, visualization, reconstruction of multiview image datasets, the segmentation and tracking of cell nuclei and the extraction of quantitative features. The modules were developed in an application-driven manner to test and ensure their applicability to real datasets from three-dimensional fluorescence microscopy. The underlying datasets were taken from research projects in developmental biology in insects and plants, as well as from cell biology.
The datasets acquired in fluorescence microscopy are typically complex and require common image processing steps in order to manage, visualize, and analyze the datasets. The first module accomplishes automatic structuring of large image datasets, reduces the data amount by image cropping and compression and computes maximum projection images along different spatial directions. The second module corrects for intensity variations in the generated maximum projection images that occur as a function of time. The program was published as a part of an article in Nature Protocols. Another developed module named BugCube provides a web-based platform to visualize and share the processed image datasets.
In LSFM, samples can be rotated in-between two acquisitions enabling the generation of multiview image datasets. Prior to my work, Frederic Strobl and Alexander Ross acquired the complete embryogenesis of the red flour beetle, Tribolium castaneum, and the field cricket, Gryllus bimaculatus, with LSFM. I evaluated a plugin for the software FIJI as a module for the reconstruction of such datasets. The plugin was optimized for automation and efficiency. We obtained the first high quality three-dimensional reconstructions of Tribolium and Gryllus datasets.
Optical clearing increases the penetration depth into samples, thus providing endpoint images of entire three-dimensional objects with cellular detail. This work contributes a quantitative characterization module that was applied to endpoint images of optically cleared spheroids. A program for the generation of ground truth datasets was developed in order to evaluate the cell nuclei segmentation performance. The program was part of a paper that was published in BMC Bioinformatics. Using the program, I could show that the cell nuclei segmentation is robust and accurate. Approaches from computational topology and graph theory complete the segmentation of cell nuclei. Thus, the developed module provides a comprehensive quantitative characterization of spheroids on the level of the individual cell, the cell neighborhood and the whole cell aggregate. The module was employed in four applications to analyze the influence of different stress conditions on the morphology and cellular arrangement of cells in spheroids. The module was accepted for publication in Scientific Reports along with the results for one application. The cell nuclei segmentation further provided a data source for simulation models that used correlation functions to identify structural zones in spheroids. These results were published in Royal Society Interface.
The final part of this work presents a module for cell tracking and lineage reconstruction. In collaboration with Dr. Alexis Maizel, Dr. Jens Fangerau and Dr. Daniel von Wangenheim, I developed a module to track the positions of all cells involved in lateral root formation in Arabidopsis thaliana and used the extracted positions for extensive data analysis. We reconstructed the cell lineages and established the first atlas of all founder cells that contribute to the formation. The analysis of the retrieved data allowed us to study conserved and individual patterns in lateral root formation. The atlas and parts of the analysis presented in this thesis were published in Current Biology.
In this thesis, I developed modules for an image analysis pipeline in three-dimensional fluorescence microscopy and applied them in interdisciplinary research projects. The modules enabled the organization, processing, visualization and analysis of the datasets. The perspective of the image analysis pipeline is not restricted to image-based systems biology. With ongoing development of the image analysis pipeline, it can also be a valuable tool for medical diagnostics or industrial high-throughput approaches.
The full-length translation-regulating add adenine riboswitch (Asw) from Vibrio vulnificus has a more complex conformational space than its isolated aptamer domain. In addition to the predicted apo (apoA) and holo conformation that feature the conserved three-way junctional purine riboswitch aptamer, it adopts a second apo (apoB) conformation with a fundamentally different secondary structure. Here, we characterized the ligand-dependent conformational dynamics of the full-length add Asw by NMR and by single-molecule FRET (smFRET) spectroscopy. Both methods revealed an adenine-induced secondary structure switch from the apoB-form to the apoA-form that involves no tertiary structural interactions between aptamer and expression platform. This strongly suggests that the add Asw triggers translation by capturing the apoA-form secondary structure in the holo state. Intriguingly, NMR indicated a homogenous, docked aptamer kissing loop fold for apoA and holo, while smFRET showed persistent aptamer kissing loop docking dynamics between comparably stable, undocked and docked substates of the apoA and the holo conformation. Unraveling the folding of large junctional riboswitches thus requires the integration of complementary solution structural techniques such as NMR and smFRET.
SDF-1/CXCR4 expression in head and neck cancer and outcome after postoperative radiochemotherapy
(2017)
Introduction: Outcome after postoperative radiochemotherapy (RT-CT) for patients with advanced head and neck squamous cell carcinomas (HNSCC) remains unsatisfactory, especially among those with HPV negative tumours. Therefore, new biomarkers are needed to further define subgroups for individualised therapeutic approaches. Preclinical and first clinical observations showed that the chemokine receptor CXCR4 and its ligand SDF-1 (CXCL12) play an important role in tumour cell proliferation, survival, cancer progression, metastasis and treatment resistance. However, the data on the prognostic value of SDF-1/CXCR4 expression for HNSCC are conflicting. The aim of our hypothesis-generating study was to retrospectively explore the prognostic potential of SDF-1/CXCR4 in a well-defined cohort of HNSCC patients collected within the multicenter biomarker study of the German Cancer Consortium Radiation Oncology Group (DKTK-ROG).
Material and methods: Patients with stage III and IVA HNSCC of the oral cavity, oropharynx and hypopharynx were treated with resection and adjuvant radiotherapy (RT) with ≥60 Gy and concurrent cisplatin-based chemotherapy (CT). Tissue micro-arrays (TMAs) from a total of 221 patients were generated from surgical specimens, 201 evaluated for the SDF-1 and CXCR4 expression by immunofluorescence and correlated with clinico-pathological and outcome data.
Results: In univariate and multivariate analyses intracellular SDF-1 expression was associated with lower loco-regional control (LRC) in the entire patient group as well as in the HPV16 DNA negative subgroup. CXCR4 expression showed a trend for lower LRC in the univariate analysis which was not confirmed in the multivariate analysis. Neither for SDF-1 nor CXCR4 expression associations with distant metastasis free or overall survival were found.
Conclusions: Our exploratory data support the hypothesis that overexpression of intracellular SDF-1 is an independent negative prognostic biomarker for LRC after postoperative RT-CT in high-risk HNSCC. Prospective validation is warranted and further exploration of SDF-1/CXCR4 as a potential therapeutic target to overcome treatment resistance in HNSCC appears promising.
Motivated by the necessary replacement of the GSI UNILAC poststripper linac, a compact and efficient linac design based on IH-type cavities has been developed. Using KONUS beam dynamics, it was possible to design a linac consisting of only five cavities that can be operated by the existing UNILAC RF amplifier structure. The transversal focusing scheme is based on magnetic quadrupole triplet lenses. The optimized design provides full transmission and low emittance growth for the design current of 15 emA U28+, accelerating the beam from 1.4 MeV/u to 11.4 MeV/u. Extensive error studies were performed to define tolerances and verify the stability of the design with respect to misalignment and injection parameters. The design provides a compact and cost effective alternative to a new Alvarez linac. With a total length of just 22.8 meters it will leave room for future energy upgrades in the UNILAC tunnel.
The Earth's future depends on how we manage the manifold risks of climate change (CC). It is state-of-the-art to assume that risk reduction requires participatory management involving a broad range of stakeholders and scientists. However, there is still little knowledge about the optimal design of participatory climate change risk management processes (PRMPs), in particular with respect to considering the multitude of substantial uncertainties that are relevant for PRMPs. To support the many local to regional PRMPs that are necessary for a successful global-scale reduction of CC risks, we present a roadmap for designing such transdisciplinary knowledge integration processes. The roadmap suggests ways in which uncertainties can be comprehensively addressed within a PRMP. We discuss the concept of CC risks and their management and propose an uncertainty framework that distinguishes epistemic, ontological, and linguistic uncertainty as well as ambiguity. Uncertainties relevant for CC risk management are identified. Communicative and modeling methods that support social learning as well as the development of risk management strategies are proposed for each of six phases of a PRMP. Finally, we recommend how to evaluate PRMPs as such evaluations and their publication are paramount for achieving a reduction of CC risks.
In patients with glioblastoma, antiangiogenic therapy with bevacizumab (BEV) has been shown to improve progression-free survival (PFS), but not overall survival (OS). Especially in patients with an unusual infiltrative phenotype as seen in multifocal glioblastoma, the use of BEV therapy is still more controversial. Therefore, we prepared a retrospective case series with 16 patients suffering from a multifocal glioblastoma treated with BEV. We compared these patients to a matched control cohort of 16 patients suffering from glioblastoma with a single lesion treated with BEV. The objective of this study was to evaluate whether the course of disease differs in glioblastoma patients with a multifocal disease pattern compared to those with a single lesion only. Patients were treated with BEV monotherapy or BEV in combination with irinotecan or lomustine (CCNU). Response rates and PFS were similar in both groups. There was a trend for an unfavorable OS in the patient group with multifocal glioblastoma, which was expected due to the generally worse prognosis of multifocal glioblastoma. We investigated whether BEV therapy affects the invasive growth pattern as measured by the appearance of new lesions on magnetic resonance imaging (MRI). Under BEV therapy, there was a trend for a lower frequency of new lesions both in multifocal and solitary glioblastoma. Based on these results, BEV therapy at relapse appears to be justified to no lesser extent in multifocal glioblastoma than in solitary glioblastoma.
This article describes the motion database for a large sample (n = 2400) of 7-m penalty throws in team handball that includes 1600 disguised throws. Throws were performed by both novice (n = 5) and expert (n = 5) penalty takers. The article reports the methods and materials used to capture the motion data. The database itself is accessible for download via JLU Web Server and provides all raw files in a three-dimensional motion data format (.c3d). Additional information is given on the marker placement of the penalty taker, goalkeeper, and ball together with details on the skill level and/or playing history of the expert group. The database was first used by Helm et al. (2017) to investigate the kinematic patterns of disguised movements. Results of this analysis are reported and discussed in their article "Kinematic patterns underlying disguised movements: Spatial and temporal dissimilarity compared to genuine movement patterns" (doi:10.1016/j.humov.2017.05.010).
Cognitive flexibility, the ability to flexibly switch between tasks, is a core dimension of executive functions (EFs) allowing to control actions and to adapt flexibly to changing environments. It supports the management of multiple tasks, the development of novel, adaptive behavior and is associated with various life outcomes. Cognitive flexibility develops rapidly in preschool and continuously increases well into adolescence, mirroring the growth of neural networks involving the prefrontal cortex. Over the past decade, there has been increasing interest in interventions designed to improve cognitive flexibility in children in order to support the many developmental outcomes associated with cognitive flexibility. This article provides a brief review of the development and plasticity of cognitive flexibility across early and middle childhood (i.e., from preschool to elementary school age). Focusing on interventions designed to improve cognitive flexibility in typically developing children, we report evidence for significant training and transfer effects while acknowledging that current findings on transfer are heterogeneous. Finally, we introduce metacognitive training as a promising new approach to promote cognitive flexibility and to support transfer of training.
Whiteout: animal traces in Werner Herzog’s Grizzly man and encounters at the end of the world
(2017)
Literary animal studies are confronted with a systematic question: How can writing, as a human-made sign system, represent the nonhuman animal as an autonomous agent without falling back into the pitfalls of anthropomorphism? Against the backdrop of this problem, this paper asks how the medium of film allows for a different representation of the animal and analyzes two of Werner Herzog’s later documentary films. Although the depiction of animals and landscapes has always played a significant part in Herzog’s films, critical assessments of his work—including those of Herzog himself—tended to view the role of nature imagery as purely allegorical: it expresses the inner nature, the inner landscapes of the film’s human protagonists. This paper tries to open up a different view. It argues that both Grizzly Man and Encounters at the End of the World develop an aesthetic that depicts nonhuman nature as an autonomous and lively presence. In the close proximity amongst camera, human, and nonhuman agents, a clear distinction between nature and culture is increasingly blurred.
Relativistic jets from active galactic nuclei (AGN) often display a non-uniform structure and are, under certain conditions, susceptible to a number of instabilities. An interesting example is the development of non-axisymmetric, Rayleigh-Taylor type instabilities in the case of differentially rotating two-component jets, with the toroidal component of the magnetic field playing a key role in the development or suppression of these instabilities. We have shown that higher magnetization leads to stability against these non-axisymmetric instabilities. Using ray-casting on data from relativistic MHD simulations of two-component jets, we now investigate the effect of these instabilities on the synchrotron emission pattern from the jets. We recover many well known trends from actual observations, e.g., regarding the polarization fraction and the distribution of the position angle of the electric field, in addition to a different emitting region, depending on the stability of the jet.
CGC aktuell 02/2017
(2017)
Der römische Kaiser Claudius, dritter Prinzeps nach Augustus, regierte von 41 – 54 n. Chr. und wurde vermutlich von Agrippina, seiner letzten Ehefrau, mit einem Pilzgericht vergiftet. Obwohl er wegen seiner angeborenen Körperbehinderung als dynastischer Nachfolger nicht vorgesehen war, folgte er C. Caligula unmittelbar nach dessen Ermordung auf den Kaiserthron.
Die dem Amt inhärenten strukturellen Schwierigkeiten wurden verstärkt durch seine imbecillitas, die nicht nur Seneca, seinen Zeitgenossen, sondern auch Tacitus, Sueton und Cassius Dio, die ihn nachfolgend zum Sujet ihrer Werke machen, erheblich verunsicherte.
Besonders die Vertreter der antiken Historiographie und Biographie stehen vor der Herausforderung, glaubhaft erklären zu müssen, warum ein imbecillus, der Gegenentwurf zu Augustus, an die Macht gelangen und sie 13 Jahre behalten konnte, ohne unterschiedlich motivierten Anschlägen zum Opfer zu fallen. Aus dieser Diskrepanz entstehen – abhängig von der persönlichen Vorstellung des jeweiligen Autors und den gesellschaftlich bedingten Vorurteilen über Behinderung – unterschiedliche Bilder, die nicht nur das Dilemma des behinderten Kaisers, sondern auch das seiner Interpreten illustrieren: Claudius tritt, je nach Situation und Interaktionspartnern, als willenlos Re-agierender oder als taktisch Agierender auf: Als Regierenden hingegen zeigen ihn die Berichte gar nicht oder selten. Unberechenbarkeit, Übertreibung und Wiederholung werden für die antiken Schriftsteller zum Herrschafts- und Persönlichkeitsmerkmal des Prinzeps, die Antithese zum Narrativ.
Das essentielle Kommunikationsproblem des behinderten Claudius scheint, folgt man den Berichten, aus einem bewussten oder charakterbedingten Verzicht auf die patria potestas zu resultieren, mit katastrophalen Auswirkungen auf sein Ansehen als Prinzeps. Die von allen Autoren kritisierte Abhängigkeit von den Mitgliedern seines Hofes, zu deren prominentesten Opfern die junge und unerfahrene Messalina und letztlich Claudius selbst zählen, erregt Spott und Unmut der Plebs und verunsichert die Aristokratie durch eine als willkürlich empfundene Rechtsprechung.
Andererseits verweisen die Darstellungen seiner erstaunlichen Amtserhebung, des siegreichen Britannienfeldzugs, des abrupten Sturzes Messalinas, aber auch Agrippinas plötzlicher Angst, die sie zum Gattenmord veranlasst, auf einen Kaiser, der bei Bedarf offenbar recht gezielt das Klischee des imbecillus als Mittel des Machterhalts zu bedienen vermag.
So entsteht aus Claudius, abhängig vom gesellschaftlichen Status Behinderter, in den antiken und modernen Schriften, die sich mit ihm und seiner Amtsführung befassen, die paradoxe Figur eines schuldigen Opfers bzw. unschuldigen Täters: Sowohl Opfer- als auch Täterrolle sind a priori durch die Behinderung gerechtfertigt und relativiert.
General intelligence is a psychological construct that captures in a single metric the overall level of behavioural and cognitive performance in an individual. While previous research has attempted to localise intelligence in circumscribed brain regions, more recent work focuses on functional interactions between regions. However, even though brain networks are characterised by substantial modularity, it is unclear whether and how the brain’s modular organisation is associated with general intelligence. Modelling subject-specific brain network graphs from functional MRI resting-state data (N = 309), we found that intelligence was not associated with global modularity features (e.g., number or size of modules) or the whole-brain proportions of different node types (e.g., connector hubs or provincial hubs). In contrast, we observed characteristic associations between intelligence and node-specific measures of within- and between-module connectivity, particularly in frontal and parietal brain regions that have previously been linked to intelligence. We propose that the connectivity profile of these regions may shape intelligence-relevant aspects of information processing. Our data demonstrate that not only region-specific differences in brain structure and function, but also the network-topological embedding of fronto-parietal as well as other cortical and subcortical brain regions is related to individual differences in higher cognitive abilities, i.e., intelligence.
In der vorliegenden Arbeit wurde die Dynamik zweier grundlegend verschiedener, deaktivierender Mechanismen von Retinalproteinen untersucht. In einem dritten Projekt wurde die Photodynamik einer Dreifachmutante von visuellem Rhodopsin erforscht, von der eine Mutation zu kongenitaler (angeborener) Nachtblindheit führt und zwei andere Mutationen das Protein über eine Disulfidbrücke stabilisieren. Die Ergebnisse dieser drei Projekte sind im Folgenden zusammengefasst.
Die Aktivität des mikrobiellen Proteorhodopsins als lichtgetriebene Protonenpumpe kann photoinduziert unterbunden werden. Dies erfolgt durch die Absorption von blauem Licht durch das Retinal bei deprotonierter Schiff‘schen Base. Vor dieser Arbeit war allerdings nur wenig über den Mechanismus und die Kinetik dieses Effekts bekannt. Das einzige Retinalprotein, an dem diese Deaktivierungsdynamik auf molekularer Ebene zeitaufgelöst untersucht wurde, ist Bakteriorhodopsin. Doch auch an diesem System wurde die ultraschnelle Primärreaktion in der photoinduzierten Deaktivierungsdynamik - die Photoisomerisierung des 13-cis-Retinals - bisher nicht zeitaufgelöst gemessen.
In dieser Arbeit wurde ein Weg gefunden, diesen Prozess auf einer Sub-Pikosekundenzeitskala zu detektieren. Dazu wurde eine Proteorhodopsinmutante genutzt, in der der primäre Protonendonor E108 durch Glutamin ersetzt ist. Diese Mutante weist eine signifikante Erhöhung der Lebensdauer des M-Intermediats auf. Im photostationären Gleichgewicht führt diese veränderte Kinetik zu einer erheblich erhöhten Akkumulation des Proteins im M-Zustand, die ausreicht, um photoinduzierte Absorptionsänderungen der Deaktivierungsdynamik sowohl im sichtbaren als auch im mittleren Infrarotbereich auf ultrakurzer Zeitskala zu detektieren. Dieses Projekt erfolgte in Kooperation mit dem Arbeitskreis Glaubitz (Goethe-Universität Frankfurt am Main).
Es zeigte sich, dass die Anregung des Retinals von Proteorhodopsin im M-Zustand zur Isomerisierung von 13-cis zu all-trans führt, die nach wenigen Pikosekunden abgeschlossen ist. Der zweite und abschließende Schritt ist die Reprotonierung der Schiff'schen Base. Es stellte sich heraus, dass dieser Prozess auf einer Nanosekundenzeitskala abläuft und über einen Protonentransfer vom primären Protonenakzeptor D97 zur Schiff'schen Base ermöglicht ist.
Die in dieser Arbeit vorgestellte Methodik zur Untersuchung der deaktivierenden Photodynamik von Proteorhodopsin auf ultraschneller Zeitskala, könnte in Zukunft auf weitere mikrobielle Rhodopsine angewandt werden. So ist die Studie der Deaktivierungsdynamik von Channelrhodopsinen von großem Interesse für optogenetische Anwendungen. Eine lichtgesteuerte Kontrolle der Ionenkanalöffnung und -schließung sollte die Präzision in der Regulierung ionischer Permeation erheblich verbessern.
Die Proteorhodopsinmutante E108Q wurde außerdem in ihrer primären Photodynamik sowohl bei grünem als auch blauem Anregungslicht untersucht. Es zeigte sich in beiden Fällen eine Dynamik, die der des Wildtyps sehr ähnlich ist. Eine Beobachtung unterscheidet sich jedoch wesentlich vom Wildtyp. Das K-Intermediat der E108Q-Mutante scheint nach einigen hundert Pikosekunden zumindest partiell zu zerfallen, woraufhin sich eine Signatur im blauen Spektralbereich bildet. Blitzlichtphotolysemessungen lassen vermuten, dass diese blau absorbierende Species im zwei- bis dreistelligen Nanosekundenbereich wieder zerfallen sein muss.
Der zweite Teil dieser Arbeit beschäftigt sich mit dem Photozerfall von visuellem Rhodopsin. Es ist bekannt, dass die Signaltransduktion durch Wechselwirkung zwischen aktiviertem Rhodopsin und Arrestin unterbunden wird. Im ersten Abschnitt wurde der Einfluss der Arrestin-1-Variante p44 auf die Photodynamik visuellen, bovinen Rhodopsins untersucht. In einer Kooperation mit dem Arbeitskreis Schwalbe (Goethe-Universität Frankfurt am Main) konnte gezeigt werden, dass Arrestin erheblichen Einfluss auf die Zerfallsdynamik von Meta II und Meta III hat. Es wurde festgestellt, dass die Wechselwirkung von p44 mit photoaktiviertem Rhodopsin eine erhöhte Population des Intermediats Meta III bewirkt, mit der Folge einer zweifach langsameren Freisetzungskinetik des all-trans-Retinals. Diese Beobachtung weist auf eine physiologische Rolle des Zustands Meta III in der Retinalhomöostase hin.
Gegenstand einer zweiten Studie mit dem Arbeitskreis Schwalbe ist zum einen die Rhodopsinmutation G90D, die mit kongenitaler (angeborener) stationärer Nachtblindheit zusammenhängt, und zum anderen die Doppelmutation N2C und D282C, die zur Ausbildung einer stabilisierenden Disulfidbrücke zwischen den im extrazellulären Bereich eingeführten Cysteinen führt. Im Rahmen dieser Arbeit wurde die Photodynamik des Wildtyps, der Doppelmutante und der stabilisierten G90D-Mutante (Mutationen G90D, N2C und D282C) sowohl auf einer ultrakurzen Zeitskala als auch auf einer Minutenskala untersucht.
Die vorliegende Arbeit untersucht die Möglichkeiten Sozialer Arbeit in segregierten städtischen Gebieten unter den Bedingungen der Festivalisierung von Stadtentwicklungspolitik. Der Hamburger Stadtteil Wilhelmsburg, bisher vorrangig als „benachteiligtes“ oder „gefährliches“ Gebiet charakterisiert, stand bis zum Jahr 2013 im Mittelpunkt des Rahmenprogramms Sprung über die Elbe, dessen zentrale Maßnahmen eine „Internationale Bauausstellung 2013 (IBA)“ und eine „internationale gartenschau 2013 (igs)“ waren. Wenn ein solches Gebiet mit dem Repertoire der unternehmerischen Stadtpolitik entwickelt wird, verändert sich das Verhältnis von Sozialer Arbeit und Stadtentwicklungspolitik.
Eine zentrale Fragestellung der Arbeit beschäftigt sich mit der Veränderung der institutionellen Landschaft in Stadtentwicklungsprozessen: Welche Ausgangslage findet Soziale Arbeit in segregierten Gebieten unter den Bedingungen einer neoliberalisierten Stadtpolitik vor? Ein weiterer Schwerpunkt liegt auf der Untersuchung der Zugänglichkeit von Ressourcen, die die Bewohner_innen des Gebiets für ihre räumliche Reproduktion einsetzen können.
Auffällig am Vorgehen der Hamburger Stadtentwicklungspolitik im Sprung über die Elbe ist, dass sie sich zunächst durch eine veränderte Diskursstrategie definiert, die die Entwick-lungspotentiale des Gebiets hervorhebt. Zentrales Ziel ist die Veränderung der Bevölke-rungszusammensetzung, die mit einer Mischung aus Anreizpolitik für die gewünschten Be-völkerungsgruppen und der Ausrichtung anderer kommunaler Handlungsfelder wie der Kul-turförderung und der Bildungspolitik auf dieses stadtentwicklungspolitische Ziel erreicht wer-den soll. Die dabei transportierte Vorstellung von „Aufwertung“ und der Herstellung einer veränderten Sozialen Mischung geht implizit auf nachfrageorientierte Gentrifizierungstheorien zurück. Institutionen der Sozialen Arbeit sind an diesem Vorgehen nicht beteiligt. Zudem wird deutlich, dass auch die Wissenschaft Sozialer Arbeit dort eine Leerstelle aufweist, wo sie mit der Gentrifizierung städtischer Gebieten konfrontiert ist.
Die Analyse von Interviews mit Bewohner_innen des Untersuchungsgebiets ermöglichte Einblicke in die grundlegender Veränderungen, denen Mietverhältnissen als eine zentrale Form räumlicher Reproduktion unterworfen sind. Dabei ließen sich parallele Entwicklungen zu den Auswirkungen nachweisen, die ein Wandel von Produktionsweisen in Bezug auf Ar-beitsverhältnisse hat.
Die Arbeit beruht auf einem induktiven Vorgehen und besteht aus mehreren empirischen Untersuchungen, die sich auf Teilfragestellungen beziehen. Die Analyse des programmati-schen Vorgehens bedient sich einer diskursanalytischen Dokumentenanalyse und der Aus-wertung von Experteninterviews. Für Veränderungen, die auf die Ressourcenzugänge von Bewohner_innen von segregierten städtischen Gebieten abzielen, kamen leitfadengestützte narrative Interviews zum Einsatz, deren Auswertung sich an dem Dokumentierenden Inter-pretieren orientierte. Die vorliegende Fallanalyse steht in einer Tradition der Untersuchung gesellschaftlicher Veränderungen aus der Perspektive „from below“. Das konkrete und situ-ierte Beforschen eines Stadtentwicklungsprozesses, der zu einem nicht unbeträchtlichen Anteil auf der diskursiven Ebene ausgetragen wird, wird als „Eingreifende Sozialforschung“ entwickelt.
The present PhD thesis comprises structural geology, petrographic and geochronological investiga-tions on crystalline rocks of the Uppermost Unit in the southern Aegean realm. Studies were carried out in three areas: (1) on the island of Anafi, (2) in the area west of Melambes in central Crete and (3) between the villages of Pefkos, Kalami and Sykologos in the municipality of Viannos in eastern Crete.
The Uppermost Unit forms together with the underlying, non-metamorphic Pindos Unit the upper nappe system of the Cretan nappe pile that, unlike the units of the lower nappe system, was not affected by Late Oligocene to Early Miocene subduction-related metamorphism. The upper nappe system must therefore have been at upper levels of the lithosphere in the Late Oligocene. This is of particular im-portance when reconstructing the tectonometamorphic evolution of the Uppermost Unit. The Upper-most Unit is very heterogeneous in composition and is subdivided into several subunits, which differ mainly in their lithological composition and the degree of metamorphic overprint. Usually, it is subdi-vided into several low-grade metamorphic subunits and one high-grade metamorphic subunit. Within the scope of this PhD thesis, three of these subunits were examined; (1) the anchimetamorphic Arvi Unit, (2) the newly described Greenschist Unit and (3) the Asterousia Crystalline Complex (ACC).
The analyses conducted during this PhD thesis include: (1) structural geology investigations in the field, (2) microstructural and petrographic analyses on thin sections, (3) radiometric dating of zircons using isotope dilution thermal ionisation mass spectrometry (ID-TIMS) and laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS), (4) electron microprobe (EMP) analysis, (5) quartz texture analysis using electron-backscattered diffraction (EBSD), (6) semiquantitative analysis of min-eral phases using X-ray powder diffraction (XRD), (7) analysis of the modal composition of intrusive rocks applying point counting on thin sections and (8) X-ray microtomography (micro-CT) on chias-tolite hornfels.
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Freundschaft und Liebe haben eines gemeinsam: die innige und wechselseitige Zuneigung zweier Personen zueinander. Das Mittelalter kennt die diskursive Trennung von Freundschaft und Liebe als Codes der Intimität nicht. Mit dem Terminus "minne" wird in der mittelalterlichen Literatur sowohl die Freundschaft zweier Männer als auch die Liebe zwischen Ritter und Dame beschrieben. Die Gesellschaft des Mittelalters um 1200 ist eine patriarchal organisierte und damit männlich homosozial geprägte Kriegergesellschaft. Vor diesem Hintergrund wird die These formuliert, dass Freundschaft im Mittelalter eher nicht der unwahrscheinliche Code der Intimität ist, sondern die Liebe. Mit dieser These wird die moderne Perspektive auf personale Zweierbeziehungen umgekehrt, die intuitiv die heterosoziale Beziehung und damit Liebe als Code der Intimität präferiert.
Im Zentrum des Interesses stehen männlich homosoziale Freundschaften und heterosoziale Liebesbeziehungen. Diese werden auf Basis linearer und triangulärer Figurenkonstellationen und unter Rückgriff auf Niklas Luhmanns Thesen, die er in „Liebe als Passion“ (1982) entwickelt, untersucht. Luhmann unterscheidet drei historische Stufen des Liebesdiskurses und ordnet diese Epochen zu: die höfische Liebe des Mittelalters, die passionierte Liebe der frühen Neuzeit und die romantische Liebe des 19. Jahrhunderts, die bis heute den Liebesdiskurs prägt. Die strikte Epocheneinteilung, die Luhmann vornimmt, wird für die Analyse der mittelhochdeutschen Texte aufgebrochen um zu zeigen, dass in der Literatur des Mittelalters Beispiele für alle drei Formen der Liebe zu finden sind. Die höfische Epik präsentiert Freundschaft und Liebe als Codes der Intimität, die sich einerseits wechselseitig bedingen, andererseits miteinander konkurrieren. Zwar stehen in den untersuchten Texten die heterosozialen Beziehungen im Fokus, doch mündet die Dominanz der Liebe als Code der Intimität nicht in der Verdrängung der Freundschaft. Im Gegenteil: Freundschaft dient der Liebe als Modell.
Biological ageing is a degenerative and irreversible process, ultimately leading to death of the organism. The process is complex and under the control of genetic, environmental and stochastic traits. Although many theories have been established during the last decades, none of these are able to fully describe the complex mechanisms, which lead to ageing. Generally, biological processes and environmental factors lead to molecular damage and an accumulation of impaired cellular components. In contrast, counteracting surveillance systems are effective, including repair, remodelling and degradation of damaged or impaired components, respectively. Nevertheless, at some point these systems are no longer effective, either because the increasing amount of molecular damages can not longer be removed efficiently or because the repairing and removing mechanisms themselves become affected by impairing effects. The organism finally declines and dies. To investigate and to understand these counteracting mechanisms and the complex interplay of decline and maintenance, holistic and systems biological investigations are required. Hence, the processes which lead to ageing in the fungal model organism Podospora anserina, had been analysed using different advanced bioinformatics methods. In contrast to many other ageing models, P. anserina exhibits a short lifespan, a less biochemical complexity and it provides a good accessibility for genetic manipulations.
To achieve a general overview on the different biochemical processes, which are affected during ageing in P. anserina, an initial comprehensive investigation was applied, which aimed to reveal genes significantly regulated and expressed in an age-dependent manner. This investigation was based on an age-dependent transcriptome analysis. Sophisticated and comprehensive analyses revealed different age-related pathways and indicated that especially autophagy may play a crucial role during ageing. For example, it was found that the expression of autophagy-associated genes increases in the course of ageing.
Subsequently, to investigate and to characterise the autophagy pathway, its associated single components and their interactions, Path2PPI, a new bioinformatics approach, was developed. Path2PPI enables the prediction of protein-protein interaction networks of particular pathways by means of a homology comparison approach and was applied to construct the protein-protein interaction network of autophagy in P. anserina.
The predicted network was extended by experimental data, comprising the transcriptome data as well as newly generated protein-protein interaction data achieved from a yeast two-hybrid analysis. Using different mathematical and statistical methods the topological properties of the constructed network had been compared with those of randomly generated networks to approve its biological significance. In addition, based on this topological and functional analysis, the most important proteins were determined and functional modules were identified, which correspond to the different sub-pathways of autophagy. Due to the integrated transcriptome data the autophagy network could be linked to the ageing process. For example, different proteins had been identified, which genes are continuously up- or down-regulated during ageing and it was shown for the first time that autophagy-associated genes are significantly often co-expressed during ageing.
The presented biological network provides a systems biological view on autophagy and enables further studies, which aim to analyse the relationship of autophagy and ageing. Furthermore, it allows the investigation of potential methods for intervention into the ageing process and to extend the healthy lifespan of P. anserina as well as of other eukaryotic organisms, in particular humans.
A large reef manta ray (Manta alfredi) aggregation has been observed off the north Sudanese Red Sea coast since the 1950s. Sightings have been predominantly within the boundaries of a marine protected area (MPA), which was designated a UNESCO World Heritage Site in July 2016. Contrasting economic development trajectories have been proposed for the area (small-scale ecotourism and large-scale island development). To examine space-use, Wildlife Computers® SPOT 5 tags were secured to three manta rays. A two-state switching Bayesian state space model (BSSM), that allowed movement parameters to switch between resident and travelling, was fit to the recorded locations, and 50% and 95% kernel utilization distributions (KUD) home ranges calculated. A total of 682 BSSM locations were recorded between 30 October 2012 and 6 November 2013. Of these, 98.5% fell within the MPA boundaries; 99.5% for manta 1, 91.5% for manta 2, and 100% for manta 3. The BSSM identified that all three mantas were resident during 99% of transmissions, with 50% and 95% KUD home ranges falling mainly within the MPA boundaries. For all three mantas combined (88.4%), and all individuals (manta 1–92.4%, manta 2–64.9%, manta 3–91.9%), the majority of locations occurred within 15 km of the proposed large-scale island development. Results indicated that the MPA boundaries are spatially appropriate for manta rays in the region, however, a close association to the proposed large-scale development highlights the potential threat of disruption. Conversely, the focused nature of spatial use highlights the potential for reliable ecotourism opportunities.
Background: Identification of families at risk for ovarian cancer offers the opportunity to consider prophylactic surgery thus reducing ovarian cancer mortality. So far, identification of potentially affected families in Germany was solely performed via family history and numbers of affected family members with breast or ovarian cancer. However, neither the prevalence of deleterious variants in BRCA1/2 in ovarian cancer in Germany nor the reliability of family history as trigger for genetic counselling has ever been evaluated.
Methods: Prospective counseling and germline testing of consecutive patients with primary diagnosis or with platinum-sensitive relapse of an invasive epithelial ovarian cancer. Testing included 25 candidate and established risk genes. Among these 25 genes, 16 genes (ATM, BRCA1, BRCA2, CDH1, CHEK2, MLH1, MSH2, MSH6, NBN, PMS2, PTEN, PALB2, RAD51C, RAD51D, STK11, TP53) were defined as established cancer risk genes. A positive family history was defined as at least one relative with breast cancer or ovarian cancer or breast cancer in personal history.
Results: In total, we analyzed 523 patients: 281 patients with primary diagnosis of ovarian cancer and 242 patients with relapsed disease. Median age at primary diagnosis was 58 years (range 16–93) and 406 patients (77.6%) had a high-grade serous ovarian cancer. In total, 27.9% of the patients showed at least one deleterious variant in all 25 investigated genes and 26.4% in the defined 16 risk genes. Deleterious variants were most prevalent in the BRCA1 (15.5%), BRCA2 (5.5%), RAD51C (2.5%) and PALB2 (1.1%) genes. The prevalence of deleterious variants did not differ significantly between patients at primary diagnosis and relapse. The prevalence of deleterious variants in BRCA1/2 (and in all 16 risk genes) in patients <60 years was 30.2% (33.2%) versus 10.6% (18.9%) in patients ≥60 years. Family history was positive in 43% of all patients. Patients with a positive family history had a prevalence of deleterious variants of 31.6% (36.0%) versus 11.4% (17.6%) and histologic subtype of high grade serous ovarian cancer versus other showed a prevalence of deleterious variants of 23.2% (29.1%) and 10.2% (14.8%), respectively. Testing only for BRCA1/2 would miss in our series more than 5% of the patients with a deleterious variant in established risk genes.
Conclusions: 26.4% of all patients harbor at least one deleterious variant in established risk genes. The threshold of 10% mutation rate which is accepted for reimbursement by health care providers in Germany was observed in all subgroups analyzed and neither age at primary diagnosis nor histo-type or family history sufficiently enough could identify a subgroup not eligible for genetic counselling and testing. Genetic testing should therefore be offered to every patient with invasive epithelial ovarian cancer and limiting testing to BRCA1/2 seems to be not sufficient.
Chronic hepatitis C virus (HCV) infection is a leading cause for orthotopic liver transplantation (OLT) in the U.S. We investigated characteristics of HCV-infected patients registered for OLT, and explored factors associated with mortality. Data were obtained from the United Network for Organ Sharing and Organ Procurement and Transplantation network (UNOS/OPTN) registry. Analyses included 41,157 HCV-mono-infected patients ≥18 years of age listed for cadaveric OLT between February 2002 and June 2014. Characteristics associated with pre- and post-transplant survival and time trends over the study period were determined by logistic and Cox proportional hazard regression analyses and Poisson regressions. Most patients were white (69.1%) and male (70.8%). At waitlist registration, mean age was 54.6 years and mean MELD was 16. HCC was recorded in 26.9% of the records. A total of 51.2% of the patients received an OLT, 21.0% died or were too sick; 15.6% were delisted and 10.4% were still waiting. Factors associated with increased waitlist mortality were older age, female gender, blood type 0, diabetes, no HCC and transplant region (p<0.001). OLT recipient characteristics associated with increased risk for post OLT mortality were female gender, age, diabetes, race (p<0,0001), and allocation MELD (p = 0.005). Donor characteristics associated with waitlist mortality included age, ethnicity (p<0.0001) and diabetes (p<0.03). Waitlist registrations and OLTs for HCC significantly increased from 14.4% to 37.3% and 27.8% to 38.5%, respectively (p<0.0001). Pre- and post-transplant survival depended on a variety of patient-, donor-, and allocation- characteristics of which most remain relevant in the DAA-era. Still, intensified HCV screening strategies and timely and effective treatment of HCV are highly relevant to reduce the burden of HCV-related OLTs in the U.S.
The concept of sound iconicity implies that phonemes are intrinsically associated with non-acoustic phenomena, such as emotional expression, object size or shape, or other perceptual features. In this respect, sound iconicity is related to other forms of cross-modal associations in which stimuli from different sensory modalities are associated with each other due to the implicitly perceived correspondence of their primal features. One prominent example is the association between vowels, categorized according to their place of articulation, and size, with back vowels being associated with bigness and front vowels with smallness. However, to date the relative influence of perceptual and conceptual cognitive processing on this association is not clear. To bridge this gap, three experiments were conducted in which associations between nonsense words and pictures of animals or emotional body postures were tested. In these experiments participants had to infer the relation between visual stimuli and the notion of size from the content of the pictures, while directly perceivable features did not support–or even contradicted–the predicted association. Results show that implicit associations between articulatory-acoustic characteristics of phonemes and pictures are mainly influenced by semantic features, i.e., the content of a picture, whereas the influence of perceivable features, i.e., size or shape, is overridden. This suggests that abstract semantic concepts can function as an interface between different sensory modalities, facilitating cross-modal associations.
Natural sounds convey perceptually relevant information over multiple timescales, and the necessary extraction of multi-timescale information requires the auditory system to work over distinct ranges. The simplest hypothesis suggests that temporal modulations are encoded in an equivalent manner within a reasonable intermediate range. We show that the human auditory system selectively and preferentially tracks acoustic dynamics concurrently at 2 timescales corresponding to the neurophysiological theta band (4–7 Hz) and gamma band ranges (31–45 Hz) but, contrary to expectation, not at the timescale corresponding to alpha (8–12 Hz), which has also been found to be related to auditory perception. Listeners heard synthetic acoustic stimuli with temporally modulated structures at 3 timescales (approximately 190-, approximately 100-, and approximately 30-ms modulation periods) and identified the stimuli while undergoing magnetoencephalography recording. There was strong intertrial phase coherence in the theta band for stimuli of all modulation rates and in the gamma band for stimuli with corresponding modulation rates. The alpha band did not respond in a similar manner. Classification analyses also revealed that oscillatory phase reliably tracked temporal dynamics but not equivalently across rates. Finally, mutual information analyses quantifying the relation between phase and cochlear-scaled correlations also showed preferential processing in 2 distinct regimes, with the alpha range again yielding different patterns. The results support the hypothesis that the human auditory system employs (at least) a 2-timescale processing mode, in which lower and higher perceptual sampling scales are segregated by an intermediate temporal regime in the alpha band that likely reflects different underlying computations.
Background: Invasive off- or on-pump cardiac surgery (elective and emergency procedures, excluding transplants are routinely performed to treat complications of ischaemic heart disease. Randomised controlled trials (RCT) evaluate the effectiveness of treatments in the setting of cardiac surgery. However, the impact of RCTs is weakened by heterogeneity in outcome measuring and reporting, which hinders comparison across trials. Core outcome sets (COS, a set of outcomes that should be measured and reported, as a minimum, in clinical trials for a specific clinical field) help reduce this problem. In light of the above, we developed a COS for cardiac surgery effectiveness trials.
Methods: Potential core outcomes were identified a priori by analysing data on 371 RCTs of 58,253 patients. We reached consensus on core outcomes in an international three-round eDelphi exercise. Outcomes for which at least 60% of the participants chose the response option "no" and less than 20% chose the response option "yes" were excluded.
Results: Eighty-six participants from 23 different countries involving adult cardiac patients, cardiac surgeons, anaesthesiologists, nursing staff and researchers contributed to this eDelphi. The panel reached consensus on four core outcomes: 1) Measure of mortality, 2) Measure of quality of life, 3) Measure of hospitalisation and 4) Measure of cerebrovascular complication to be included in adult cardiac surgery trials.
Conclusion: This study used robust research methodology to develop a minimum core outcome set for clinical trials evaluating the effectiveness of treatments in the setting of cardiac surgery. As a next step, appropriate outcome measurement instruments have to be selected.
Autophagy is a physiological process for the recycling and degradation of cellular materials. Forming the autophagosome from the phagophore, a cup-shaped double-membrane vesicle, is a critical step in autophagy. The origin of the cup shape of the phagophore is poorly understood. In yeast, fusion of a small number of Atg9-containing vesicles is considered a key step in autophagosome biogenesis, aided by Atg1 complexes (ULK1 in mammals) localized at the preautophagosomal structure (PAS). In particular, the S-shaped Atg17-Atg31-Atg29 subcomplex of Atg1 is critical for phagophore nucleation at the PAS. To study this process, we simulated membrane remodeling processes in the presence and absence of membrane associated Atg17. We show that at least three vesicles need to fuse to induce the phagophore shape, consistent with experimental observations. However, fusion alone is not sufficient. Interactions with 34-nm long, S-shaped Atg17 complexes are required to overcome a substantial kinetic barrier in the transition to the cup-shaped phagophore. Our finding rationalizes the recruitment of Atg17 complexes to the yeast PAS, and their unusual shape. In control simulations without Atg17, with weakly binding Atg17, or with straight instead of S-shaped Atg17, the membrane shape transition did not occur. We confirm the critical role of Atg17-membrane interactions experimentally by showing that mutations of putative membrane interaction sites result in reduction or loss of autophagic activity in yeast. Fusion of a small number of vesicles followed by Atg17-guided membrane shape-remodeling thus emerges as a viable route to phagophore formation.
Objectives: This study identified potential general influencing factors for a mathematical prediction of implant stability quotient (ISQ) values in clinical practice.
Methods: We collected the ISQ values of 557 implants from 2 different brands (SICace and Osstem) placed by 2 surgeons in 336 patients. Surgeon 1 placed 329 SICace implants, and surgeon 2 placed 113 SICace implants and 115 Osstem implants. ISQ measurements were taken at T1 (immediately after implant placement) and T2 (before dental restoration). A multivariate linear regression model was used to analyze the influence of the following 11 candidate factors for stability prediction: sex, age, maxillary/mandibular location, bone type, immediate/delayed implantation, bone grafting, insertion torque, I-stage or II-stage healing pattern, implant diameter, implant length and T1-T2 time interval.
Results: The need for bone grafting as a predictor significantly influenced ISQ values in all three groups at T1 (weight coefficients ranging from -4 to -5). In contrast, implant diameter consistently influenced the ISQ values in all three groups at T2 (weight coefficients ranging from 3.4 to 4.2). Other factors, such as sex, age, I/II-stage implantation and bone type, did not significantly influence ISQ values at T2, and implant length did not significantly influence ISQ values at T1 or T2.
Conclusions: These findings provide a rational basis for mathematical models to quantitatively predict the ISQ values of implants in clinical practice.
We recently demonstrated the effectiveness of blocking CD49d with anti-functional antibodies or small molecule inhibitors as a rational targeted approach to the treatment of acute leukemia in combination with chemotherapy. Antisense oligonucleotide promises to be no less specific than antibodies and inhibitors, but more interesting for pharmacokinetics and pharmacodynamics. We addressed this using the published CD49d antisense drug ATL1102. In vitro, we incubated/nucleofected the ALL cell line Kasumi-2 with ATL1102. In vivo, immunodeficient hosts were engrafted with primary ALL cells and treated with ATL1102. Changes in expression of CD49d mRNA and CD49d protein, and of cooperating gene products, including ß1 integrin and CXCR4, as well as survival in the mouse experiments were quantified. We observed dose-dependent down-regulation of CD49d mRNA and protein levels and its partner integrin ß1 cell surface protein level and, up-regulation of CXCR4 surface expression. The suppression was more pronounced after nucleofection than after incubation, where down-regulation was significant only at the higher doses. In vivo effects of ATL1102 were not sufficient to translate into “clinical” benefit in the leukemia model. In summary, antisense oligonucleotides are successful tools for specifically modulating gene expression but sufficient delivery to down-regulate CD49d in vivo may be difficult to achieve.
Am Ende ging es dann doch recht fix. Hatte der Islamische Staat (IS) noch im März 2017 fast die Hälfte des Territoriums in Syrien unter seiner Kontrolle, ist das Möchtegern-Kalifat mittlerweile so gut wie von der Landkarte getilgt. Das heißt zwar nicht, dass er als Terrororganisation keine Rolle in dem Land mehr spielen wird. Doch als maßgeblicher Bürgerkriegsakteur mit territorialer Basis dürfte der IS weitestgehend aus dem Spiel genommen sein. Das macht diesen verworrenen Bürgerkrieg zunächst einmal ein wenig übersichtlicher. Andererseits wird damit aber auch der Vorhang für das nächste Kapitel geöffnet, das neue Wirrungen verspricht. Denn schließlich waren wegen des Kampfes gegen den IS einige Konfliktlinien erkaltet. Diese könnten nun wieder heiß werden. Allerdings lässt sich aufgrund der vielschichtigen Konstellationen nur schwer einschätzen, welche Dynamiken daraus erwachsen dürften. Der folgende Beitrag soll daher einen Überblick über die vergangenen und neuesten Entwicklungen im Syrischen Bürgerkrieg geben, um zumindest den Ist-Stand ermessen zu können. Die Anfertigung eines solchen Panoramas ist jedoch, zugegeben, eine kleine Herausforderung. Denn aufgrund der zahlreichen Konfliktparteien und multiplen Fronten sind die Entwicklungen derart konfus, dass sie sich nicht so einfach chronologisch zusammenfassen lassen. Der Beitrag stellt daher die jeweiligen Akteursgruppen und Allianzen dar und versucht, deren (ambivalenten) Verhältnisse untereinander zu sortieren und aufzuschlüsseln.
Not unlike the recent report Filling the ranks on the recruitment problems of the British Army shows for the UK, the German armed forces (Bundeswehr) struggle badly to meet their recruitment goals and to fulfill the “Trendwende Personal” (the turnaround in the personnel strength) as proclaimed by the German Defence Minister Ursula von der Leyen. Last year the recruitment department of the Bundeswehr tried a new way of targeting especially young people on YouTube. With a series of 59 episodes called Die Rekruten (The Recruits) YouTube users followed a couple of German Navy recruits through their basic training at the German Navy Technical School.
The series was widely criticised for not showing the serious implications of military service. Two weeks ago, the new series MALI on the deployment of German forces with the United Nations mission MINUSMA in Mali started as a sequel. But does the new series give a realistic impression of the challenges and risks of being a German soldier today and why should this be a requirement for a YouTube series?
In the Global South, private corporations and development aid programs are widely implementing information and communication technology (ICT). Stakeholders export infrastructure (including satellites, drones, and white spaces technology) as well as mobile and internet services (mobile money services, zero-rating), following the proclaimed goal to close the global digital divide. They particularly target under-connected regions in Africa, as Africa shows the lowest levels of internet connectivity (cf. International Telecommunications Union 2017). According to companies and development aid programs, these digitalization efforts in the Global South are key to development and security. However, an ethical perspective points to concerns about the practice of digitalization in the Global South. One central concern is that certain values are inscribed in ICT, and that they may be indirectly implemented through technology in the importing countries. Thus, the export of ICT by Western companies and development aid programs to the Global South may have a "neo-colonial" character. This raises ethical questions about global justice...
Warum werden Frauen Terroristinnen? Wider eine stereotype Betrachtung des weiblichen Terrorismus
(2017)
Punk-Band Frontfrau, Ex-Katholikin, Kosmetikverkäuferin – für die meisten klingt das nicht nach der Biographie einer der aktivsten Anhängerinnen des sogenannten Islamischen Staates (IS). Und doch: Bis Sally Jones jüngst bei einem US-Drohnenangriff ums Leben gekommen ist, war die Britin für mehr als vier Jahre das weibliche Gesicht des IS. Die Geschichte von Jones wirft eine grundlegende Frage auf: Wieso werden Frauen Terroristinnen? Ein Blick auf das breite Spektrum und die Geschichte des weiblichen Terrorismus zeigt, dass Terroristinnen weder neu noch selten, weder vor allem Opfer noch rein persönlich motiviert sind. Wenn an solchen Stereotypen festgehalten wird, steht dies nicht nur einer umfassenden Analyse der Gründe, sondern auch der Prävention von weiblichem Terrorismus im Wege.
Sally Jones Tod im Juni wurde erst vor Kurzem bekannt, und eine letztgültige Bestätigung steht noch aus – genauso wie die Antwort auf die Frage, ob der Drohnenangriff legal war, da angeblich auch ihr 12-jähriger Sohn getötet wurde. So wie Sally Jones möglicherweise posthum als erstes explizit weibliches Ziel eines solchen Angriffs Prominenz erlangen könnte, gibt ihre Person der regelmäßig wiederkehrenden öffentlichen wie wissenschaftlichen Diskussion über die Gründe für weiblichen Terrorismus neue Nahrung. In dieser Debatte sind Antworten auf die Frage, ob Frauen „auch“ Terroristinnen sein können, inzwischen zu einem Dickicht aus Stereotypen und Fantasien mutiert. Wird Religion – vulgo Islam – dieser Mischung hinzugefügt, begibt sich die Diskussion oft vollends auf Abwege. Von den vielen Argumenten, die dabei angeführt werden, halten sich drei mit besonderer Vehemenz: Weiblicher Terrorismus sei erstens ein neues und seltenes Phänomen; Frauen seien zweitens in der Regel Opfer; und drittens hätten Terroristinnen – im Gegensatz zu ihren männlichen Counterparts – in der Regel persönliche Motive. Die beiden ersten Argumente sind schlicht falsch und das dritte greift entschieden zu kurz. Es lohnt also, ein paar Breschen in das Dickicht zu schlagen...
This paper presents new evidence on the expectation formation process of firms from a survey of the German manufacturing sector. It focuses on the expectation about their future business conditions, which enters the widely followed economic sentiment index and which is an important determinant of their employment and investment decisions. We find that firms extrapolate their experience too much and make predictable forecasting errors. Moreover, firms do not seem to anticipate the upcoming reversals of business cycle peaks and troughs which causes suboptimal adjustment of investment and employment and affects their inventories and profits. However, the impact on expectation errors decreases with the size and the age of the firm as firms learn to reduce their extrapolation bias over time.
Facial Width-to-Height Ratio (fWHR) has been linked with dominant and aggressive behavior in human males. We show here that on portrait photographs published online, chief executive officers (CEOs) of companies listed in the Dow Jones stock market index and the Deutscher Aktienindex have a higher-than-normal fWHR, which also correlates positively with their company’s donations to charitable causes and environmental awareness. Furthermore, we show that leaders of the world’s most influential non-governmental organizations and even the leaders of the Roman Catholic Church, the popes, have higher fWHR compared to controls on public portraits, suggesting that the relationship between displayed fWHR and leadership is not limited to profit-seeking organizations. The data speak against the simplistic view that wider-faced men achieve higher social status through antisocial tendencies and overt aggression, or the mere signaling of such dispositions. Instead they suggest that high fWHR is linked with high social rank in a more subtle fashion in both competitive as well as prosocially oriented settings.
The phenomenon of jet quenching provides essential information about the properties of hot and dense matter created in ultra-relativistic heavy-ion collisions. Recent results from experiments at the Large Hadron Collider (LHC) show evidence for an unexpectedly similar suppression of both light and heavy flavor jets. Furthermore, the role of radiative energy loss of heavy quarks is still under active discussion within the theoretical community. By employing the parton cascade Boltzmann Approach to Multi-Parton Scatterings (BAMPS), which numerically solves the 3+1 D Boltzmann equation both for light and heavy flavor partons, we calculate the nuclear modification factor of inclusive and b-tagged reconstructed jets in 0–10% central sLHC=2.76ATeV Pb + Pb collisions. Based on perturbative QCD cross sections we find a suppression of both light and heavy flavor jets. While the inclusive jets are slightly too strong suppressed within Bamps in comparison with data, both elastic + radiative and only elastic interactions lead to a realistic b-tagged jet suppression. To further investigate light and heavy flavor energy loss we predict the R dependence of inclusive and b-tagged jet suppression. Furthermore, we propose the medium modification of b-tagged jet shapes as an observable for discriminating between different heavy quark energy loss scenarios.
Background. Arterial ex situ back-table perfusion (BP) reportedly reduces ischemic-type biliary lesion after liver transplantation. We aimed to verify these findings in a prospective investigation.
Methods. Our prospective, randomized, controlled, multicenter study involved livers retrieved from patients in 2 German regions, and compared the outcomes of standard aortic perfusion to those of aortic perfusion combined with arterial ex situ BP. The primary endpoint was the incidence of ischemic-type biliary lesions over a follow-up of 2 years after liver transplantation, whereas secondary endpoints included 2-year graft survival, initial graft damage as reflected by transaminase levels, and functional biliary parameters at 6 months after transplantation.
Results. A total of 75 livers preserved via standard aortic perfusion and 75 preserved via standard aortic perfusion plus arterial BP were treated using a standardized protocol. The incidence of clinically apparent biliary lesions after liver transplantation (n = 9 for both groups; P = 0.947), the 2-year graft survival rate (standard aortic perfusion, 74%; standard aortic perfusion plus arterial BP, 68%; P = 0.34), and incidence of initial graft injury did not differ between the 2 perfusion modes. Although 33 of the 77 patients with cholangiography workups exhibited injured bile ducts, only 10 had clinical symptoms.
Conclusions. Contrary to previous findings, the present study indicated that additional ex situ BP did not prevent ischemic-type biliary lesions or ischemia-reperfusion injury after liver transplantation. Moreover, there was considerable discrepancy between cholangiography findings regarding bile duct changes and clinically apparent cholangiopathy after transplantation, which should be considered when assessing ischemic-type biliary lesions.
Background: Ischemia-reperfusion injury (IRI) is a major challenge in liver transplantation. The mitochondrial pathway plays a pivotal role in hepatic IRI. Levosimendan, a calcium channel sensitizer, was shown to attenuate apoptosis after IRI in animal livers. The aim of this study was to investigate the effect of levosimendan on apoptosis in human hepatocytes.
Methods: Primary human hepatocytes were either exposed to hypoxia or cultured under normoxic conditions. After the hypoxic phase, reoxygenation was implemented and cells were treated with different concentrations of levosimendan (10ng/ml, 100ng/ml, 1000ng/ml). The overall metabolic activity of the cells was measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), and aspartate aminotransferase (AST) levels were determined in order to quantify hepatic injury. Fluorescence-activated cell sorting (FACS) analysis was applied to measure necrosis and apoptosis. Finally, Western blotting was performed to analyze apoptotic pathway proteins.
Results: Administration of levosimendan during reperfusion increases the metabolic activity of human hepatocytes and decreases AST levels. Moreover, apoptosis after IRI is reduced in treated vs. untreated hepatocytes, and levosimendan prevents down-regulation of the anti-apoptotic protein Bcl-2 as well as up-regulation of the pro-apoptotic protein BAX.
Conclusion: The present study suggests a protective effect of levosimendan on human hepatocytes. Our findings suggest that treatment with levosimendan during reperfusion attenuates apoptosis of human hepatocytes by influencing BAX and Bcl-2 levels.
Systemic sclerosis (SSc) is a rare multi-organ autoimmune disease characterized by progressive skin fibrosis. Inflammation, type 2 immunity, and fibrogenic processes are involved in disease development and may be affected by sphingolipids. However, details about early-stage pathophysiological mechanisms and implicated mediators remain elusive. The sphingolipid sphingosine-1-phosphate (S1P) is elevated in the sera of SSc patients, and its receptor S1P5 is expressed in skin tissue. Nevertheless, almost nothing is known about the dermatological contribution of S1P5 to inflammatory and pro-fibrotic processes leading to the pathological changes seen in SSc. In this study, we observed a novel effect of S1P5 on the inflammatory processes during low-dose bleomycin (BLM)-induced fibrogenesis in murine skin. By comparing 2-week-treated skin areas of wild-type (WT) and S1P5-deficient mice, we found that S1P5 is important for the transcriptional upregulation of the Th2 characteristic transcription factor GATA-3 under treatment-induced inflammatory conditions, while T-bet (Th1) and FoxP3 (Treg) mRNA expression was regulated independently of S1P5. Additionally, treatment caused a regulation of S1P receptor 1 and S1P receptor 3 mRNA as well as a regulation of long-chain ceramide profiles, which both differ significantly between the genotypes. Despite S1P5-dependent differences regarding inflammatory processes, similar macroscopic evidence of fibrosis was detected in the skin histology of WT and S1P5-deficient mice after 4 weeks of subcutaneous BLM treatment. However, at the earlier 2-week point in time, the mRNA data of pro-collagen type 1 and SMAD7 indicate a pro-fibrotic S1P5 contribution in the applied SSc mouse model. In conclusion, we propose that S1P5 plays a role as a novel modulator during the early phase of BLM-caused fibrogenesis in murine skin. An immediate relationship between dermal S1P5 expression and fibrotic processes leading to skin alterations, such as formative for SSc pathogenesis, is indicated but should be studied more profound in further investigations. Therefore, this study is an initial step in understanding the role of S1P5-mediated effects during early stages of fibrogenesis, which may encourage the ongoing search for new therapeutic options for SSc patients.
This dissertation explores the linguistic identity changes of Chinese international students in Germany, and the relationship between their identity reconstruction and their multilingual competence. With the social turn (Block, 2003) of applied linguistics, research on study abroad has shown that student sojourners abroad encounter challenges not only to their language abilities, but also to their identities, which explains the vast individual differences in the measurable outcomes of student sojourns abroad. However, the realm of learners’ linguistic identity development in the English as a lingua franca (ELF) and multilingual contexts remains to be further explored, since most existing studies examined learners in the target language community. Guided by poststructuralist views and sociocultural theories, this study is designed with a view towards investigating the lived experience of Chinese international students at German universities.
Employing a qualitative approach, my research tracked seventeen Chinese students’ experiences of language learning and use in both their social lives and academic settings over one year. The empirical work combined semi-structured, in-depth interviews and emails. Three rounds of one-to-one interviews were conducted every 6 months and each round focused on students’ respective past, present and future. The grounded theory approach (Corbin & Strauss, 2015) was used in this study to analyse the data, aiming at generating theoretical explanations for phenomena through constant comparison.
The results of the category-based analysis offer a new lens on the intricate linguistic identity development of Chinese students in the study abroad context. The construction of their new identity facets is related to various contextual elements in experiences of their language learning and use. More importantly, learners’ identity changes related to the use of ELF is conceived as within a framework of multilingualism (Jenkins, 2015). In any given social interaction, learners’ linguistic identities are influenced by a combination of factors: perceived linguistic proficiency gap, power distribution,preferred communication styles, sensitivity to second/third language self-images and openness to new cultures. It is these factors, instead of the lingua franca context or
target language context per se, that come into play in the reformation of learners’
linguistic identities. Learners’ linguistic identity changes, together with their priority setting in studying abroad, are in turn interconnected with their multilingual competence development.
The findings of my study suggest theories for understanding learners’ linguistic identity development and the outcomes of their language learning in the study abroad context in the face of the complexity of individual experiences. My study also demonstrates the importance to foster learners’ “self-presentational competence” (Pellegrino Aveni, 2005: 145-146) so that they could successfully negotiate new subject positions when crossing the borders.
Die Interpretation der Moses-Ḫiḍr-Erzählung in Ibn ʿArabīs Werken „al-Futūḥāt al-Makkīya“und „Fuṣūṣ al-ḥikam“
Die Moses-Ḫiḍr-Erzählung in den Versen 60-82 der Sura Kahf, der in der sufischen Tradition eine enorme Bedeutung zugemessen wird, wurde im Laufe der Geschichte zum Gegenstand unterschiedlicher Interpretationen. Es besteht somit kein Zweifel, dass eine der bemerkenswertesten dieser Interpretationen, die einen besonderen Platz in der Geschichte des Sufismus hat, von Ibn ʿArabī stammt. Er bewertete die Ereignisse zwischen Moses und der koranischen Figur, die er entsprechend der Tradition „Ḫiḍr” benannt hat, anders. Neben der literarischen Bedeutung der Personen und Ereignisse, die in der Erzählung vorkommen, etabliert Ibn Arabi dazu neue Zusammenhänge, indem er zu deren verborgenen Bedeutungen übergeht. Nach ihm ist nichts so, wie es scheint
Background: Research has implicated that changes in zinc (Zn) metabolism may be associated with the biological underpinnings of eating disorders, in particular anorexia nervosa. However, to date research on the role of Zn in patients with bulimia nervosa (BN) is scarce.
Objective: We aimed to explore serum Zn concentrations in young patients with BN, with a focus on the stage of the disorder, comparing acutely ill and recovered patients with BN with healthy controls.
Methods: Serum Zn concentrations were obtained from healthy controls and from acutely ill and remitted young patients with BN. Mean duration of remission was 4.0±3.5 years.
Results: Remitted patients showed elevated serum Zn concentrations when compared to controls (Cohen’s d=2.022), but concentrations were still in the normal range. Acutely ill patients also had higher serum Zn levels when compared to controls (all values still being within the reference range, Cohen’s d=0.882). There was no difference between acutely ill and remitted patients with BN in serum Zn concentrations. Of note, remitted patients had a significantly higher body weight when compared to the other two groups. Overall, there were no significant differences in dietary preferences with regard to Zn containing foods between the groups.
Conclusion: The present study provides preliminary evidence that the underlying factors for changes in Zn serum concentrations in young patients with BN do not vary with regard to the stage of illness (acute versus remitted BN). Further prospective research is needed in order to disentangle the possible interplay between serum Zn status and bulimic eating behaviors.
Phylogenetic reconstruction from transposable elements (TEs) offers an additional perspective to study evolutionary processes. However, detecting phylogenetically informative TE insertions requires tedious experimental work, limiting the power of phylogenetic inference. Here, we analyzed the genomes of seven bear species using high-throughput sequencing data to detect thousands of TE insertions. The newly developed pipeline for TE detection called TeddyPi (TE detection and discovery for Phylogenetic Inference) identified 150,513 high-quality TE insertions in the genomes of ursine and tremarctine bears. By integrating different TE insertion callers and using a stringent filtering approach, the TeddyPi pipeline produced highly reliable TE insertion calls, which were confirmed by extensive in vitro validation experiments. Analysis of single nucleotide substitutions in the flanking regions of the TEs shows that these substitutions correlate with the phylogenetic signal from the TE insertions. Our phylogenomic analyses show that TEs are a major driver of genomic variation in bears and enabled phylogenetic reconstruction of a well-resolved species tree, despite strong signals for incomplete lineage sorting and introgression. The analyses show that the Asiatic black, sun, and sloth bear form a monophyletic clade, in which phylogenetic incongruence originates from incomplete lineage sorting. TeddyPi is open source and can be adapted to various TE and structural variation callers. The pipeline makes it possible to confidently extract thousands of TE insertions even from low-coverage genomes (∼10×) of nonmodel organisms. This opens new possibilities for biologists to study phylogenies and evolutionary processes as well as rates and patterns of (retro-)transposition and structural variation.
Introduction: Microsurgery courses, taught external to surgical training programs, are essential for acquiring the high level of technical skill required for clinical proficiency.
Methods: The Frankfurt microsurgery course is a 5-day, intensive course that teaches arterial and venous anastomosis using end-to-end, end-to-side, one-way-up, continuous-suture, and vessel graft techniques. During the course, the instructor records the level of skill (in-course data) achieved by each trainee by assessing anastomosis completion and patency. Demographic information is also collected. Post-course trainees are invited to complete an online survey (post-course data) to get their opinions of the courses’ effectiveness.
Results: The in-course “skill achievement” and post-course “course effectiveness” data are presented below. In-course data: 94.8 and 59.9% of participants completed patent end-to-end arterial and venous anastomoses, respectively, while 85.4% performed a patent end-to-side anastomosis. 96.1 and 57.1% of participants who attempted arterial and venous anastomoses using the one-way-up technique were successful, as were 90.9% of those attempting continuous-suture technique. Patent venous grafts were performed by 54.7% of participants.
Post-course data: All respondents indicated significant improvement of their microsurgical skills after taking the course. 66.7% of respondents considered the full-time presence of the instructor to be the most valuable aspect of the course. All respondents would highly recommend the course to colleagues.
Conclusion: The microcourse significantly increased trainees’ clinical microsurgery skills, confidence, and the number of clinical cases they perform. Of all the anastomosis techniques taught, venous anastomosis and grafting were the most difficult to learn. The presence of a full-time experienced instructor was most important.
Structural biology often employs a combination of experimental and computational approaches to unravel the structure-function paradigm of biological macromolecules. This thesis aims to approach this combination by the application of Pulsed Electron-Electron Double Resonance (PELDOR/DEER) spectroscopy and structural modelling. In this respect, PELDOR spectroscopy in combination with site-directed spin labelling (SDSL) of proteins is frequently used to gain distance restraints in the range from 1.8 to 8 nm. The inter-spin distance and the flexibility of the spin labelled protein domains are encoded in the oscillation and the dampening of the PELDOR signal. The intrinsic flexibility of the commonly used MTSSL (1-Oxyl-2,2,5,5-tetramethylpyrroline-3-methyl) spin label itself can be an obstacle for structural modelling if the flexibility of the label is large compared to the flexibility of the protein domains. In this thesis the investigation of two multi-domain proteins by the 4-pulse PELDOR sequence is presented. At first, the N-terminal polypeptide transport-associated (POTRA) domains of anaOmp85, a rigid three domain protein, giving well-defined PELDOR distance restraints, is investigated. The experimental restraints are used for structure refinement of the X-ray structure and reveal a strong impact of the intrinsic flexibility of MTSSL on the accuracy of structural refinement. The second example, K48-linked diubiquitin, is a highly flexible multi-domain protein on which the flexibility of MTSSL is of minor impact on structural modelling. In this case, the distance restraints are utilized to determine conformational ensembles. Due to the high intrinsic flexibility already characterizing diubiquitin the recently developed 7-pulse Carr-Purcell (CP) PELDOR sequence was applied to investigate longer ubiquitin chains. This sequence enables to measure dipolar oscillations with an extended time window, allowing a good separation between inter- and intramolecular contributions even for long distance and broad conformational distributions, thereby providing an increased accuracy of the obtained distance distributions.
The asymmetric unit of the title co-crystalline adduct, 1,3,6,8-tetraazatricyclo[4.4.1.13,8]dodecane (TATD)–4-iodophenol (1/2), C8H16N4·2C6H5IO, comprises a half molecule of the aminal cage polyamine plus a 4-iodophenol molecule. A twofold rotation axis generates the other half of the adduct. The components are linked by two intermolecular O—H⋯N hydrogen bonds. The adducts are further linked into a three-dimensional framework structure by a combination of N⋯I halogen bonds and weak non-conventional C—H⋯O and C—H⋯I hydrogen bonds.
Can variances of latent variables be scaled in such a way that they correspond to eigenvalues?
(2017)
The paper reports an investigation of whether sums of squared factor loadings obtained in confirmatory factor analysis correspond to eigenvalues of exploratory factor analysis. The sum of squared factor loadings reflects the variance of the corresponding latent variable if the variance parameter of the confirmatory factor model is set equal to one. Hence, the computation of the sum implies a specific type of scaling of the variance. While the investigation of the theoretical foundations suggested the expected correspondence between sums of squared factor loadings and eigenvalues, the necessity of procedural specifications in the application, as for example the estimation method, revealed external influences on the outcome. A simulation study was conducted that demonstrated the possibility of exact correspondence if the same estimation method was applied. However, in the majority of realized specifications the estimates showed similar sizes but no correspondence.
In the title compound, C26H24N2O2, the oxazine moiety is fused to a naphthalene ring system. The asymmetric unit consists of one half of the molecule, which lies about an inversion centre. The C atoms of the ethylene spacer group adopt an antiperiplanar arrangement. The oxazine ring adopts a half-chair conformation. In the crystal, supramolecular chains running along the b axis are formed via short C—H⋯π contacts. The crystal studied was a non-merohedral twin with a fractional contribution of 0.168 (2) of the minor twin component.
In their post-traumatic course, trauma patients suffering from multiple injuries have a high risk for immune dysregulation, which may contribute to post-injury complications and late mortality. Monocytes as specific effector cells of the innate immunity play a crucial role in inflammation. Using their Pattern Recognition Receptors (PRRs), notably Toll-Like Receptors (TLR), the monocytes recognize pathogens and/or pathogen-associated molecular patterns (PAMPs) and organize their clearance. TLR2 is the major receptor for particles of gram-positive bacteria, and initiates their phagocytosis. Here, we investigated the phagocytizing capability of monocytes in a long-term porcine severe trauma model (polytrauma, PT) with regard to their TLR2 expression. Polytrauma consisted of femur fracture, unilateral lung contusion, liver laceration, hemorrhagic shock with subsequent resuscitation and surgical fracture fixation. After induction of PT, peripheral blood was withdrawn before (-1 h) and directly after trauma (0 h), as well as 3.5 h, 5.5 h, 24 h and 72 h later. CD14+ monocytes were identified and the expression levels of H(S)LA-DR and TLR2 were investigated by flow cytometry. Additionally, the phagocytizing activity of monocytes by applying S. aureus particles labelled with pHrodo fluorescent reagent was also assessed by flow cytometry. Furthermore, blood samples from 10 healthy pigs were exposed to a TLR2-neutralizing antibody and subsequently to S. aureus particles. Using flow cytometry, phagocytizing activity was determined. P below 0.05 was considered significant. The number of CD14+ monocytes of all circulating leukocytes remained constant during the observational time period, while the percentage of CD14+H(S)LA-DR+ monocytes significantly decreased directly, 3.5 h and 5.5 h after trauma. The percentage of TLR2+ expressing cells out of all monocytes significantly decreased directly, 3.5 h and 5.5 h after trauma. The percentage of phagocytizing monocytes decreased immediately and remained lower during the first 3.5 h after trauma, but increased after 24 h. Antagonizing TLR2 significantly decreased the phagocytizing activity of monocytes. Both, decreased percentage of activated as well as TLR2 expressing monocytes persisted as long as the reduced phagocytosis was observed. Moreover, neutralizing TLR2 led to a reduced capability of phagocytosis as well. Therefore, we assume that reduced TLR2 expression may be responsible for the decreased phagocytizing capacity of circulating monocytes in the early post-traumatic phase.
The purpose of the data presented in this article is to use it in ex post estimations of interest rate decisions by the European Central Bank (ECB), as it is done by Bletzinger and Wieland (2017) [1]. The data is of quarterly frequency from 1999 Q1 until 2013 Q2 and consists of the ECB's policy rate, inflation rate, real output growth and potential output growth in the euro area. To account for forward-looking decision making in the interest rate rule, the data consists of expectations about future inflation and output dynamics. While potential output is constructed based on data from the European Commission's annual macro-economic database, inflation and real output growth are taken from two different sources both provided by the ECB: the Survey of Professional Forecasters and projections made by ECB staff. Careful attention was given to the publication date of the collected data to ensure a real-time dataset only consisting of information which was available to the decision makers at the time of the decision.
The turnover of endoplasmic reticulum (ER) ensures the correct biological activity of its distinct domains. In mammalian cells, the ER is degraded via a selective autophagy pathway (ER-phagy), mediated by two specific receptors: FAM134B, responsible for the turnover of ER sheets and SEC62 that regulates ER recovery following stress. Here, we identified reticulon 3 (RTN3) as a specific receptor for the degradation of ER tubules. Oligomerization of the long isoform of RTN3 is sufficient to trigger fragmentation of ER tubules. The long N-terminal region of RTN3 contains several newly identified LC3-interacting regions (LIR). Binding to LC3s/GABARAPs is essential for the fragmentation of ER tubules and their delivery to lysosomes. RTN3-mediated ER-phagy requires conventional autophagy components, but is independent of FAM134B. None of the other reticulon family members have the ability to induce fragmentation of ER tubules during starvation. Therefore, we assign a unique function to RTN3 during autophagy.
Loss of neuronal stimulation enhances protein breakdown and reduces protein synthesis, causing rapid loss of muscle mass. To elucidate the pathophysiological adaptations that occur in atrophying muscles, we used stable isotope labelling and mass spectrometry to quantify protein expression changes accurately during denervation-induced atrophy after sciatic nerve section in the mouse gastrocnemius muscle. Additionally, mice were fed a stable isotope labelling of amino acids in cell culture (SILAC) diet containing 13C6-lysine for 4, 7 or 11 days to calculate relative levels of protein synthesis in denervated and control muscles. Ubiquitin remnant peptides (K-ε-GG) were profiled by immunoaffinity enrichment to identify potential substrates of the ubiquitin-proteasomal pathway. Of the 4279 skeletal muscle proteins quantified, 850 were differentially expressed significantly within 2 weeks after denervation compared with control muscles. Moreover, pulse labelling identified Lys6 incorporation in 4786 proteins, of which 43 had differential Lys6 incorporation between control and denervated muscle. Enrichment of diglycine remnants identified 2100 endogenous ubiquitination sites and revealed a metabolic and myofibrillar protein diglycine signature, including myosin heavy chains, myomesins and titin, during denervation. Comparative analysis of these proteomic data sets with known atrogenes using a random forest approach identified 92 proteins subject to atrogene-like regulation that have not previously been associated directly with denervation-induced atrophy. Comparison of protein synthesis and proteomic data indicated that upregulation of specific proteins in response to denervation is mainly achieved by protein stabilization. This study provides the first integrated analysis of protein expression, synthesis and ubiquitin signatures during muscular atrophy in a living animal.
Current theories of schizophrenia (ScZ) posit that the symptoms and cognitive dysfunctions arise from a dysconnection syndrome. However, studies that have examined this hypothesis with physiological data at realistic time scales are so far scarce. The current study employed a state-of-the-art approach using Magnetoencephalography (MEG) to test alterations in large-scale phase synchronization in a sample of n = 16 chronic ScZ patients, 10 males and n = 19 healthy participants, 10 males, during a perceptual closure task. We identified large-scale networks from source reconstructed MEG data using data-driven analyses of neuronal synchronization. Oscillation amplitudes and interareal phase-synchronization in the 3–120 Hz frequency range were estimated for 400 cortical parcels and correlated with clinical symptoms and neuropsychological scores. ScZ patients were characterized by a reduction in γ-band (30–120 Hz) oscillation amplitudes that was accompanied by a pronounced deficit in large-scale synchronization at γ-band frequencies. Synchronization was reduced within visual regions as well as between visual and frontal cortex and the reduction of synchronization correlated with elevated clinical disorganization. Accordingly, these data highlight that ScZ is associated with a profound disruption of transient synchronization, providing critical support for the notion that core aspect of the pathophysiology arises from an impairment in coordination of distributed neural activity.
Background/Aims: Alcohol (ethanol, EtOH) as significant contributor to traumatic injury is linked to suppressed inflammatory response, thereby influencing clinical outcomes. Alcohol-induced immune-suppression during acute inflammation (trauma) was linked to nuclear factor-kappaB (NF-ĸB). Here, we analyzed alcohol`s effects and mechanisms underlying its influence on NF-ĸB-signaling during acute inflammation in human lung epithelial cells. Methods: A549-cells were stimulated with interleukin (IL)-1β, or sera from trauma patients (TP) or healthy volunteers, with positive/negative blood alcohol concentrations (BAC), and subsequently exposed to EtOH (170 Mm, 1h). IL-6-release and neutrophil adhesion to A549 were analyzed. Specific siRNA-NIK mediated downregulation of non-canonical, and IKK-NBD-inhibition of canonical NF-ĸB signaling were performed. Nuclear levels of activated p50 and p52 NF-ĸB-subunits were detected using TransAm ELISA. Results: Both stimuli significantly induced IL-6-release (39.79±4.70 vs. 0.58±0.8 pg/ml) and neutrophil adhesion (132.30±8.80 vs. 100% control, p<0.05) to A549-cells. EtOH significantly decreased IL-6-release (22.90±5.40, p<0.05) and neutrophil adherence vs. controls (105.40±14.5%, p<0.05). IL-1β-induced significant activation of canonical/p50 and non-canonical/p52 pathways. EtOH significantly reduced p50 (34.90±23.70 vs. 197.70±36.43, p<0.05) not p52 activation. Inhibition of canonical pathway was further increased by EtOH (less p50-activation), while p52 remained unaltered. Inhibition of non-canonical pathway was unchanged by EtOH. Conclusion: Here, alcohol`s anti-inflammatory effects are mediated via decreasing nuclear levels of activated p50-subunit and canonical NF-ĸB signaling pathway.
We propose a long-run risk model with stochastic volatility, a time-varying mean reversion level of volatility, and jumps in the state variables. The special feature of our model is that the jump intensity is not affine in the conditional variance but driven by a separate process. We show that this separation of jump risk from volatility risk is needed to match the empirically weak link between the level and the slope of the implied volatility smile for S&P 500 options.
This thesis is concerned with quantum dynamical propagation methods suitable for high-dimensional systems, and their application to excitation energy transfer (EET), electron transfer (ET), and intra-molecular vibrational redistribution (IVR) in molecular aggregates. The theoretical description of these processes, which are often ultrafast – with time scales in the range of femtoseconds to picoseconds – is challenging, both with regard to quantum dynamical simulations and electronic structure calculations.
The present thesis comprises two parts. The first part concerns the implementation of a novel quantum dynamical method based on Gaussian Wavepackets (GWPs): the 2-Layer Gaussian-MCTDH (2L-GMCTDH) method. This method, which has recently been proposed in [S. Römer, M. Ruckenbauer, I. Burghardt, The Journal of Chemical Physics, 2013, 138, 064106] was implemented in a Fortran90 code and applied to various high-dimensional test systems. The second part of the thesis addresses the combined electronic structure and dynamical study of a novel type of donor-acceptor systems that have been investigated in a joint project with experimental collaboration partners at Strasbourg University. In both parts, numerical applications focus on high-dimensional model Hamiltonians for EET and ET processes.
Regarding the first part, the interest of using GWP-based methods is two-fold: First, GWPs represent spatially localized basis sets that are useful for on-the-fly dynamics in conjunction with electronic structure calculations. Second, they are naturally suited for the explicit representation of quantum mechanical system-bath type problems where a large number of vibrational bath modes are weakly perturbed from equilibrium. In this context, various methods exist that are based upon classically evolving GWP bases. A major improvement results from variational methods which involve optimized, non-classical GWP trajectories. In particular, the variational Gaussian-based Multi-Configuration Time-Dependent Hartree (GMCTDH) and its variational Multi-Configurational Gaussians (vMCG) variant were originally derived as semiclassical variants of the Multi-Configuration Time-Dependent Hartree (MCTDH) method. However, the G-MCTDH and vMCG methods mostly use Frozen Gaussian (FG) basis sets that are far less flexible than the single-particle (SPF) representation of standard MCTDH. As a consequence, a significantly larger number of GWPs are generally required to reach convergence. To remedy the lack of flexibility of the FG basis sets, the abovementioned two-layer (2L-G-MCTDH) approach has been introduced: Here, the first layer is composed of flexible SPFs, while the second layer is composed of low-dimensional FGs. The numerical scaling properties are significantly improved as compared with the conventional G-MCTDH and vMCG schemes. The first implementation of the method in an in-house Fortran90 code is presented, along with applications to (i) a model of site-to-site vibrational energy flow in the presence of intra-site vibrational energy redistribution (IVR) and (ii) a multidimensional donor-acceptor electron transfer system described within a linear vibronic coupling model. The second system relates to a model for ET at an oligothiophene-fullerene interface relevant to organic photovoltaics. Besides the description of the implementation, a detailed assessment of the convergence properties and comparison with multi-layer MCTDH (ML-MCTDH) benchmark calculations is presented. Finally, a perspective is given on the future combination with the existing ML-MCTDH scheme; indeed, such a combination is straightforward since the first layer of the 2L-G-MCTDH approach can be chosen to be orthogonal.
Regarding the second part of the thesis, two generations of a novel donor-acceptor (DA) system for organic photovoltaics applications, involving self-assembled block co-oligomers DA dyads and triads with perylene-diimide (PDI) accepter units, are addressed within a collaborative project with S. Haacke and S. Mery (University of Strasbourg). Based upon detailed excited-state electronic structure investigations along with quantum dynamical and kinetic studies, the relevant ET formation and recombination steps are characterized quantitatively, in view of optimizing the chemical design and reducing recombination losses.
In a first-generation variant of the abovementioned DA systems, which involves liquid-crystalline triads, we were able to show that a highly efficient inter-chain ET process prevails over intra-molecular ET, leading to fast recombination. Due to the latter, this system turns out to be inefficient for photovoltaic applications. To fully understand the elementary steps, high-dimensional quantum dynamics simulations were carried out using the ML-MCTDH method, in collaboration with Matthias Polkehn from our group. In the second-generation variant, which is in the focus of the present thesis, both the nanomorphology and the chemical design were modified. The present work, focuses upon the aspect of chemical design, by characterizing a series of modified DA’s, with donor units of varying length while the PDI accepter units remain unchanged. The intra-molecular ET is observed in these systems, but the processes are comparatively slow, of the order of tens to hundreds of picoseconds. Hence, a kinetic analysis using the Marcus-Levich-Jortner rate theory is employed. Among the main results of the study is that addition of an electron donating amine unit strongly increases the lifetime of the charge-separated state, and therefore reduced recombination losses.
Overall, the present thesis shows how a combination of high-dimensional quantum dynamics, electronic structure calculations, and vibronic coupling model Hamiltonians can be employed to obtain an accurate picture of EET, ET, and IVR in high-dimensional molecular assemblies. Furthermore, the 2L-GMCTDH method paves the way for accurate and efficient on-the-fly calculations; a suitable set-up for such calculations is currently in progress.
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