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Wirtschafts- und Rechnungsbücher bieten mehrdimensionale Zugänge und erfordern multidisziplinäre Annäherungen. Dass sie weit mehr sind als Einnahmen- und Ausgabeverzeichnisse zeigen die hier vorliegenden 17 Beiträge mit Beispielen von Lübeck bis Lyon. Sie vereinen die Ergebnisse eines Workshops, der diese Gattung serieller Quellen von Seiten der Geschichtswissenschaft und der Historischen Sprachforschung, der Editions- und Medienwissenschaft sowie der historischen Wirtschafts- und Betriebswirtschaftswissenschaft in den Blick genommen hat.
Activation of Mitochondrial complex II-dependent respiration is beneficial for α-Synucleinopathies
(2015)
Parkinson’s disease and dementia with Lewy bodies are major challenges in research and clinical medicine world-wide and contribute to the most common neurodegenerative disorders. Previously, specific mitochondrial polymorphisms have been found to enhance clearance of amyloid-β from the brain of APP-transgenic mice leading to beneficial clinical outcome. It has been discussed whether specific mitochondrial alterations contribute to disease progression or even prevent toxic peptide deposition, as seen in many neurodegenerative diseases. Here, we investigated α-synuclein-transgenic C57BL/6J mice with the A30P mutation, and a novel A30P C57BL/6J mouse model with three mitochondrial DNA polymorphisms in the ND3, COX3 and mtRNAArg genes, as found in the inbred NOD/LtJ mouse strain. We were able to detect that the new model has increased mitochondrial complex II-respiration which occurs in parallel to neuronal loss and improved motor performance, although it exhibits higher amounts of high molecular weight species of α-synuclein. High molecular weight aggregates of different peptides are controversially discussed in the light of neurodegeneration. A favourable hypothesis states that high molecular weight species are protective and of minor importance for the pathogenesis of neurodegenerative disorders as compared to the extreme neurotoxic monomers and oligomers. Summarising, our results point to a potentially protective and beneficial effect of specific mitochondrial polymorphisms which cause improved mitochondrial complex II-respiration in α-synucleinopathies, an effect that could be exploited further for pharmaceutical interventions.
European energy policy dates back to the founding days of integration, yet the emergence of supranational governance is a recent development. The article examines the extent to which European policymakers have succeeded in building up governance capacity, and what the facilitating and impeding factors were that have shaped the governance mix. The conceptual framework differentiates between orders of governance in the multilevel context, and between policy modes involving hierarchical and non-hierarchical settings and varying actor constellations. The article finds that governance capacity has emerged where second order governance (institutional and procedural rules) is concerned, while first order governance (the concrete policy process) remains the remit of national and private actors. This becomes even more obvious once the interaction between policy modes is taken into account: governance networks enhance governance capacity in the area of competition policy and agency governance; self-regulation by industry constitutes a fall-back option in case of insufficient governance capacity on cross-border issues; soft governance helps to bridge multiple policy areas and levels of governance. The article concludes that second order governance may prove effective where it combines with hierarchy but that it may fail to overcome both trade-offs between contradicting goals and resistance at lower levels.
The small leucine-rich proteoglycan biglycan (Bgn) is a part of the extracellular matrix providing structure and enhancing fibril stability. In its soluble form, biglycan is able to bind and signal via the innate immune receptors Toll-like receptor (TLR) 2 and 4, thereby activating MAP-kinases and the NF-κB pathway. In macrophages soluble biglycan induces the secretion of several cytokines and chemokines, including TNF-α, CCL2, CXCL5 and CXCL13. A unique feature of biglycan is its ability to stimulate the secretion of mature IL-1β. By orchestrating TLR2 and 4 with the purinergic P2X4 and P2X7 receptor signalling biglycan triggers the activation of the NLRP3/ASC inflammasome, which in turn activates caspase-1 to cleave pro-IL-1β to mature IL-1β. Furthermore, in several inflammatory diseases an upregulated biglycan expression is found. Enhanced levels of biglycan could be measured in plasma and inflamed tissue. In mouse models of sepsis, lupus nephritis and renal ischemic reperfusion injury, biglycan-deficiency improved the disease outcome. Overexpression of soluble biglycan on the other hand increased immune cell infiltration into the kidney by inducing cytokine and chemokine expression in a TLR2/4-dependent manner. These studies emphasise its importance in inflammatory processes, especially in the kidney. Furthermore, the pro-inflammatory effects on macrophages and diseases established biglycan as a danger signalling molecule, yet its role as a soluble molecule in plasma was not further investigated.
Although an increase of soluble biglycan in the circulation could be seen in several inflammatory diseases, the source is not fully unravelled. Previously it could be shown that macrophages and dendritic cells secrete soluble biglycan after stimulation with IL-6 and TGF-β1. However, since these cell are resident in organs and do not circulate in the blood stream their contribution to soluble biglycan levels in plasma is likely minor. Therefore, monocytes as precursor of both macrophages and dendritic cells were investigated as a possible source of circulating biglycan. Analysis of blood from septic patients revealed elevated soluble biglycan levels as well as an increased number of monocytes. Isolated monocytes from healthy volunteers incubated with the inflammatory cytokines IL-1β, IL-6 and TGF-β1 displayed increased biglycan mRNA expression and secretion of soluble biglycan into the supernatant, revealing monocytes as a producer of soluble biglycan in blood. Therefore this work was directed to further investigate the influence of soluble biglycan on circulating monocytes, with regard to sepsis.
Monocytes can be classified into three subtypes, while the classical monocytes express CD14 (CD14++CD16low), intermediate monocytes express both CD14 and CD16 (CD14++CD16+) and non-classical monocytes express mainly CD16 (CD14lowCD16++). The intermediate and non-classical monocytes make up about 10 % of all monocytes and are referred to as CD16-positive subtypes. The CD16-positive monocytes express higher levels of TNF-α and IL-1β upon stimulation and display different migration behaviour. In most inflammatory diseases an expansion of CD16-positive monocytes is observed, especially an increased number of intermediate monocytes frequently correlate with disease severity and mortality. Since septic patients had increased circulating biglycan levels and augmented CD16-positive monocytes, a possible correlation between these two parameters was investigated. Using FACS analysis of biglycan-stimulated monocytes from healthy donors revealed a significant shift from classical to intermediate and non-classical monocytes. This shift was mediated by increased expression of CD14 and CD16 on mRNA and protein levels upon biglycan treatment. Furthermore, biglycan induced the mRNA expression of the adhesion molecules ICAM-1, VCAM-1 and ELAM-1 in CD14-positive monocytes. Four hours after biglycan stimulation an increased ICAM-1 protein expression on the cell surface of classical and intermediate monocytes was observed. Additionally, biglycan-treated CD14-positive monocytes rolled and attached to pre-stimulated endothelial cells to a greater extent compared to untreated monocytes. This demonstrates that biglycan not only triggers the expression of CD14 and CD16 but also induces a functional shift of monocytes. ...
Gute Lehre muss sichtbar werden, und über gute Lehre muss gesprochen werden! Ein Ziel unseres Programms "Starker Start ins Studium" ist eine verbesserte Kommunikationsstruktur über und eine verbesserte Kommunikationskultur in der Lehre. Der "Tag der Lehre" der Goethe-Universität, der den Rahmen für die Starker Start-Tagung abgegeben hat, hat mit mehr als 150 Gästen dazu beigetragen. ...
Der viersemestrige Master-Studiengang Biochemie leitet sich aus der langjährigen Tradition in biomolekularer Forschung und Lehre in der Frankfurter Forschungslandschaft her und ist stark forschungsorientiert.
Ziel des Studienganges ist es, fachliche Kenntnisse, Fähigkeiten und Methodenkompetenzen zu vermitteln, mit denen die Absolventen in die Lage versetzt werden, in einem forschungsbezogenem Kontext selbstständig zu arbeiten. ...
Nach langer Vorbereitung war es endlich soweit, die National Model United Nations (NMUN)-Delegation der Goethe-Universität stand im Konferenzhotel und war voller Vorfreude, Aufregung und Tatendrang.
Unter allen Simulationen ist das National Model United Nations in New York dabei die größte und ist in ihrer kulturellen und thematischen Vielfalt kaum zu übertreffen. Innerhalb der Simulation wird die Arbeit der verschiedenen Komitees der Vereinten Nationen mit realen Themen nachgestellt. Die Mitglieder der Delegationen übernehmen dabei die Aufgaben und Positionen der Diplomaten und vertreten die Interessen, Werte und Standpunkte des ihnen zugewiesenen Landes. In diesem Jahr repräsentierten wir die Republik Kuba. ...
Die Mathematik ist gleichermaßen eine Kulturwissenschaft mit langer Tradition als auch treibende Kraft hinter vielen modernen Technologien und damit Schlüsseldisziplin des Informationszeitalters. Zum einen zielt die Mathematik darauf ab, abstrakte Strukturen und ihre Zusammenhänge zu verstehen; zum anderen entwickelt sie kraftvolle Methoden, um Frage- und Problemstellungen in zahlreichen Wissenschaftsdisziplinen zu behandeln. Moderne Anwendungen der Mathematik liegen beispielsweise in den Bereichen der Datensicherheit und -kompression, der Verkehrssteuerung, der Bewertung und Optimierung von Finanzinstrumenten oder der medizinischen Operationsplanung.
In dieser Broschüre stellen wir Ihnen das Profil der Frankfurter Mathematik in Forschung und Lehre sowie speziell die Studiengänge
• Bachelor Mathematik
• Master Mathematik
vor. An der Goethe-Universität ist es auch möglich, Mathematik auf Lehramt (L1, L2, L3, L5) zu studieren. ...
As a surrogate of live cells, proteo-lipobeads are presented, encapsulating functional membrane proteins in a strict orientation into a lipid bilayer. Assays can be performed just as on live cells, for example using fluorescence measurements. As a proof of concept, we have demonstrated proton transport through cytochrome c oxidase.
CD44v6, a member of the CD44 family of transmembrane glycoproteins is a co-receptor for two receptor tyrosine kinases (RTKs), Met and VEGFR-2 (vascular endothelial growth factor receptor 2). CD44v6 is not only required for the activation of these RTKs but also for signalling. In order to understand the role of CD44v6 in Met and VEGFR-2 activation and signalling we tested whether CD44v6 binds to their ligands, HGF (hepatocyte growth factor) and VEGF (vascular endothelial growth factor), respectively. FACS analysis and cellular ELISA showed binding of HGF and VEGF only to cells expressing CD44v6. Direct binding of CD44v6 to HGF and VEGF was demonstrated in pull-down assays and the binding affinities were determined using MicroScale Thermophoresis, fluorescence correlation spectroscopy and fluorescence anisotropy. The binding affinity of CD44v6 to HGF is in the micromolar range in contrast with the high-affinity binding measured in the case of VEGF and CD44v6, which is in the nanomolar range. These data reveal a heparan sulfate-independent direct binding of CD44v6 to the ligands of Met and VEGFR-2 and suggest different roles of CD44v6 for these RTKs.
Thought structures of modelling task solutions and their connection to the level of difficulty
(2015)
Although efforts have been made to integrate the concept of mathematical modelling in school, among others PISA and TIMSS revealed weaknesses of not only German students in the field of mathematical modelling. There may be various reasons starting from educational policy via curricular issues to practical instructional concerns. Studies show that mathematical modelling has not been arrived yet in everyday school class (Blum &BorromeoFerri, 2009, p. 47). Thus, the proportion of mathematical modelling in everyday school classes is low (Jordan et al., 2006). When focusing on the teachers’ point of view there are difficulties which may contribute to avoid modelling tasks in class. The development of reasonable modelling tasks, estimating the task space, valuating the task difficulty and assessing the student solutions are difficulties which occur to an increasing degree compared to ordinary mathematics tasks.The project MokiMaS (transl.: modeling competency in math classes of secondary education) aims at providing inter-year modelling tasks, whose task space and level of difficulty is known, together with an evaluation scheme. In particular a theory based method has been developed to determine the level of difficulty of modelling tasks on the basis of thought structures, representing the cognitive load of solution approaches. The current question is whether this method leads to a realistic rating. To go further into that question an evaluation scheme has been developed which is guided by the daily assessment work of teachers, to investigate the relation of task difficulty and student performance.
Cyclic GMP (cGMP) signalling regulates multiple biological functions through activation of protein kinase G and cyclic nucleotide-gated (CNG) channels. In sensory neurons, cGMP permits signal modulation, amplification and encoding, before depolarization. Here we implement a guanylyl cyclase rhodopsin from Blastocladiella emersonii as a new optogenetic tool (BeCyclOp), enabling rapid light-triggered cGMP increase in heterologous cells (Xenopus oocytes, HEK293T cells) and in Caenorhabditis elegans. Among five different fungal CyclOps, exhibiting unusual eight transmembrane topologies and cytosolic N-termini, BeCyclOp is the superior optogenetic tool (light/dark activity ratio: 5,000; no cAMP production; turnover (20 °C) ∼17 cGMP s−1). Via co-expressed CNG channels (OLF in oocytes, TAX-2/4 in C. elegans muscle), BeCyclOp photoactivation induces a rapid conductance increase and depolarization at very low light intensities. In O2/CO2 sensory neurons of C. elegans, BeCyclOp activation evokes behavioural responses consistent with their normal sensory function. BeCyclOp therefore enables precise and rapid optogenetic manipulation of cGMP levels in cells and animals.
Mitochondrial respiratory supercomplexes (mtRSCs) are stoichiometric assemblies of electron transport chain (ETC) complexes in the inner mitochondrial membrane. They are hypothesized to regulate electron flow, the generation of reactive oxygen species (ROS) and to stabilize ETC complexes. Using the fungal ageing model Podospora anserina, we investigated the impact of homologues of the Saccharomyces cerevisiae respiratory supercomplex factors 1 and 2 (termed PaRCF1 and PaRCF2) on mtRSC formation, fitness and lifespan. Whereas PaRCF2’s role seems negligible, ablation of PaRCF1 alters size of monomeric complex IV, reduces the abundance of complex IV-containing supercomplexes, negatively affects vital functions and shortens lifespan. PaRcf1 overexpression slightly prolongs lifespan, though without appreciably influencing ETC organization. Overall, our results identify PaRCF1 as necessary yet not sufficient for mtRSC formation and demonstrate that PaRCF1-dependent stability of complex IV and associated supercomplexes is highly relevant for maintenance of the healthy lifespan in a eukaryotic model organism.
Filamentous, heterocyst-forming cyanobacteria exchange nutrients and regulators between cells for diazotrophic growth. Two alternative modes of exchange have been discussed involving transport either through the periplasm or through septal junctions linking adjacent cells. Septal junctions and channels in the septal peptidoglycan are likely filled with septal junction complexes. While possible proteinaceous factors involved in septal junction formation, SepJ (FraG), FraC, and FraD, have been identified, little is known about peptidoglycan channel formation and septal junction complex anchoring to the peptidoglycan. We describe a factor, SjcF1, involved in regulation of septal junction channel formation in the heterocyst-forming cyanobacterium Anabaena sp. strain PCC 7120. SjcF1 interacts with the peptidoglycan layer through two peptidoglycan-binding domains and is localized throughout the cell periphery but at higher levels in the intercellular septa. A strain with an insertion in sjcF1 was not affected in peptidoglycan synthesis but showed an altered morphology of the septal peptidoglycan channels, which were significantly wider in the mutant than in the wild type. The mutant was impaired in intercellular exchange of a fluorescent probe to a similar extent as a sepJ deletion mutant. SjcF1 additionally bears an SH3 domain for protein-protein interactions. SH3 binding domains were identified in SepJ and FraC, and evidence for interaction of SjcF1 with both SepJ and FraC was obtained. SjcF1 represents a novel protein involved in structuring the peptidoglycan layer, which links peptidoglycan channel formation to septal junction complex function in multicellular cyanobacteria. Nonetheless, based on its subcellular distribution, this might not be the only function of SjcF1.
Previous research on working memory (WM) in children with poor mathematical skills has yielded heterogeneous results, possibly due to inconsistent consideration of the IQ-achievement discrepancy and additional reading and spelling difficulties. To examine the impact of both, the WM of 68 average-achieving and 68 low-achieving third-graders in mathematics was assessed. Preliminary analyses showed that poor mathematical skills were associated with poor WM. Afterwards, children with isolated mathematical difficulties were separated from those with additional reading and spelling difficulties. Half of each group fulfilled the IQ-achievement discrepancy, resulting in a 2 (additional reading and spelling difficulties: yes/no) by 2 (IQ-achievement discrepancy: yes/no) factorial design. Analyses revealed that not fulfilling the IQ achievement discrepancy was associated with poor visual WM, whereas additional reading and spelling difficulties were associated with poor central executive functioning in children fulfilling the IQ-achievement discrepancy. Therefore, WM in children with poor mathematical skills differs according to the IQ-achievement discrepancy and additional reading and spelling difficulties.
Proton-pumping complex I of the mitochondrial respiratory chain is among the largest and most complex membrane protein complexes. The enzyme contributes substantially to oxidative energy-conversion in eukaryotic cells. Its malfunctions are implicated in many hereditary and degenerative disorders. Here, we report the X-ray structure of mitochondrial complex I at 3.6- 3.9 Å resolution describing in detail the central subunits that execute the bioenergetic function. A continuous axis of basic and acidic residues running centrally through the membrane arm connects the ubiquinone reduction site in the hydrophilic arm to four putative proton-pumping units. The binding position for a substrate analogous inhibitor and blockage of the predicted ubiquinone binding site provide a model for the ‘deactive’ form of the enzyme. The proposed transition into the active form is based on a concerted structural rearrangement at the ubiquinone reduction site rendering support for a two-state stabilization-change mechanism of protonpumping.
Models propose an auditory-motor mapping via a left-hemispheric dorsal speech-processing stream, yet its detailed contributions to speech perception and production are unclear. Using fMRI-navigated repetitive transcranial magnetic stimulation (rTMS), we virtually lesioned left dorsal stream components in healthy human subjects and probed the consequences on speech-related facilitation of articulatory motor cortex (M1) excitability, as indexed by increases in motor-evoked potential (MEP) amplitude of a lip muscle, and on speech processing performance in phonological tests. Speech-related MEP facilitation was disrupted by rTMS of the posterior superior temporal sulcus (pSTS), the sylvian parieto-temporal region (SPT), and by double-knock-out but not individual lesioning of pars opercularis of the inferior frontal gyrus (pIFG) and the dorsal premotor cortex (dPMC), and not by rTMS of the ventral speech-processing stream or an occipital control site. RTMS of the dorsal stream but not of the ventral stream or the occipital control site caused deficits specifically in the processing of fast transients of the acoustic speech signal. Performance of syllable and pseudoword repetition correlated with speech-related MEP facilitation, and this relation was abolished with rTMS of pSTS, SPT, and pIFG. Findings provide direct evidence that auditory-motor mapping in the left dorsal stream causes reliable and specific speech-related MEP facilitation in left articulatory M1. The left dorsal stream targets the articulatory M1 through pSTS and SPT constituting essential posterior input regions and parallel via frontal pathways through pIFG and dPMC. Finally, engagement of the left dorsal stream is necessary for processing of fast transients in the auditory signal.
The dopamine β-hydroxylase (DβH) enzyme transforms dopamine into noradrenaline. We hypothesized that individuals with low activity DBH genotypes (rs1611115 CT/TT) are more sensitive to the influence of cannabis and cocaine on cognitive impulse control and functional connectivity in the limbic ‘reward’ circuit because they experience a drug induced hyperdopaminergic state compared to individuals with high activity DBH genotypes (rs1611115 CC). Regular drug users (N = 122) received acute doses of cannabis (450 μg/kg THC), cocaine HCl 300 mg and placebo. Cognitive impulse control was assessed by means of the Matching Familiar Figures Test (MFFT). Resting state fMRI was measured in a subset of participants to determine functional connectivity between the nucleus accumbens (NAc) and (sub)cortical areas. The influence of cannabis and cocaine on impulsivity and functional connectivity significantly interacted with DBH genotype. Both drugs increased cognitive impulsivity in participants with CT/TT genotypes but not in CC participants. Both drugs also reduced functional connectivity between the NAc and the limbic lobe, prefrontal cortex, striatum and thalamus and primarily in individuals with CT/TT genotypes. Correlational analysis indicated a significant negative association between cognitive impulsivity and functional connectivity in subcortical areas of the brain. It is concluded that interference of cannabis and cocaine with cognitive impulse control and functional corticostriatal connectivity depends on DBH genotype. The present data provide a neural substrate and behavioral mechanism by which drug users can progress to drug seeking and may also offer a rationale for targeted pharmacotherapy in chronic drug users with high risk DBH genotypes.