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Angeregt durch das Wirken Enea Silvio Piccolominis auf dem Basler Konzil und am Wiener Hof Friedrichs III. bildeten sich seit der Mitte des 15. Jahrhunderts frühe Zentren des Humanismus in Deutschland, vor allem in Heidelberg, Augsburg und Eichstätt. Als einer der wichtigsten Protagonisten dieses süddeutschen Frühhumanismus gilt der fränkische Domherr und Jurist Albrecht von Eyb (1420–1475). ...
Writing the history of archaeology has become increasingly diverse in recent years due to developments in the historiography of the sciences and the humanities. A move away from hagiography and presentations of scientific processes as an inevitable progression has been requested in this context. Historians of archaeology have begun to utilize approved and new historiographical concepts to trace how archaeological knowledge has been acquired as well as to reflect on the historical conditions and contexts in which knowledge has been generated. This volume seeks to contribute to this trend. By linking theories and models with case studies from the nineteenth and twentieth century, the authors illuminate implications of communication on archaeological knowledge and scrutinize routines of early archaeological practices. The usefulness of different approaches such as narratological concepts or the concepts of habitus is thus considered.
The question of Russia’s European identity has traditionally been controversial. Usually, the country is either defined as belonging to Eastern Europe in a narrower sense or, contrarily, totally excluded from the concept of Europe. From the times of Czar Peter the Great (1689–1725), Russia acquired the unquestioned status of a European power; however, despite the "enlightened" reforms of Empress Catherine the Great (1762–1796), its society remained feudal, its economy backward and its government autocratic. Right up until its collapse, the Russian Empire was decidedly less urbanized and less advanced in agriculture in comparison not only with the West but also with East-Central Europe. ...
Der Begleitband zur Ausstellung Fantastische Welten. Albrecht Altdorfer und das Expressive in der Kunst um 1500 gliedert sich, nach einer kurzen Einführung durch Jochen Sander (15–19), in einen knappen Essayteil mit Beiträgen von Guido Messling, Matthias Weniger, Susanne Jaeger und einen Katalogteil der Ausstellungsexponate, die unterteilt in ihre Themengebiete wiederum durch einleitende Texte begleitet werden. ...
Der interdisziplinäre Doktoranden-Workshop "Neue Tendenzen der Italienforschung zu Mittelalter und Renaissance" fand erstmalig vom 13. bis 15. November 2014 am Kunsthistorischen Institut in Florenz, Max-Planck-Institut, statt. Initiatoren und Organisatoren waren seitens der Geschichte INGRID BAUMGÄRTNER (Kassel) und KLAUS HERBERS (Erlangen-Nürnberg) sowie seitens der Kunstgeschichte ALESSANDRO NOVA (Florenz/Frankfurt am Main) und GERHARD WOLF (Florenz/Berlin). Ziel des gut besuchten Workshops war es, aktuelle Ansätze der Italienforschung gemeinsam zu kommentieren und kritisch zu würdigen. Nachwuchswissenschaftler/innen aus verschiedenen Disziplinen, insbesondere Geschichte, Kunstgeschichte und Philosophie, stellten ihre Projekte zur Diskussion. ...
GIUSEPPE CUSA (Frankfurt am Main) referierte über die Laiengeschichtsschreibung in der Mark Verona-Treviso am Übergang von der Kommune zur Signorie. Er fragte nach Unterschieden und Gemeinsamkeiten in den verschiedenen Städten sowie danach, welchen Berufen die geschichtsschreibenden Laien nachgingen und aus welcher Motivation heraus sie Zeitgeschichte dokumentierten. ...
Liberal political philosophy has two alternative options in principle: It can either stick to its original theorems such as the harm principle or the separation of law and morals and from here try to prove large parts of present social and political reality as wrong, illegitimate, dangerous etc. The other option is trying to adjust the original theorems to the apparent needs of modern societies, which is what I would prefer in the long run.
Background & Aims: Hepatitis C virus (HCV) cell entry is mediated by several cell surface receptors, including scavenger receptor class B type I (SR-BI). Oxidized low density lipoprotein (oxLDL) inhibits the interaction between HCV and SR-BI in a noncompetitive manner. We tested whether serum oxLDL levels correlate with sustained virologic response (SVR) rates after interferon-based treatment of chronic hepatitis C.
Methods: Baseline oxLDL was determined in 379 participants with chronic HCV genotype 1 infection from the INDIV-2 study using a commercial enzyme-linked immunosorbent assay. The mechanistic in vitro studies used full-length and subgenomic HCV genomes replicating in hepatoma cells.
Results: In the multivariate analysis, oxLDL was found to be an independent predictor of SVR. Oxidized LDL did not correlate with markers of inflammation (alanine transaminase, ferritin), nor was serum oxLDL affected by exogenous interferon administration. Also, oxLDL did not alter the sensitivity of HCV replication to interferon. However, oxLDL was found to be a potent inhibitor of cell-to-cell spread of HCV between adjacent cells in vitro. It could thus reduce the rate at which new cells are infected by HCV through either the cell-free or cell-to-cell route. Finally, serum oxLDL was significantly associated with the estimated infected cell loss rate under treatment.
Conclusions: Oxidized LDL is a novel predictor of SVR after interferon-based therapy and may explain the previously observed association of LDL with SVR. Rather than being a marker of activated antiviral defenses it may improve chances of SVR by limiting spread of infection to naive cells through the cell-to-cell route.
In der neuen Reihe "Geschichte der Antike" des C.H. Beck Verlags, die einem breiteren Publikum eine Einführung in die Großepochen der Alten Geschichte geben will, widmet sich Wolfgang Blösel der römischen Republik, zu der Beck bereits einen kürzeren Überblick von Martin Jehne und einen ausführlicheren von Klaus Bringmann publiziert hat. Martin Jehne, Die römische Republik. Von der Gründung bis Caesar, 3. durchgesehene Aufl., München 2013 (1. Aufl. 2006) und Klaus Bringmann, Geschichte der römischen Republik. Von den Anfängen bis Augustus, 2. durchgesehene Aufl., München 2010 (1. Aufl. 2002). Blösel gelingt es aber, innerhalb einer weithin traditionellen, sehr ereignisgeschichtlich orientierten Erzählung neue Deutungen für den Aufstieg und Fall der Republik zu präsentieren, die auf seinen Spezialstudien beruhen und neueste Literatur mit einbeziehen. ...
Diskus : Nr. 1.15
(2015)
Ubiquitin and the ubiquitin-like protein ATG8 are covalently attached to their respective targets via a coordinated cascade involving E1 activating, E2 conjugating and E3 ligating enzymes. Whereas ubiquitin is conferred to proteins as mono- and/or polymer(s) to alter their stability, localization and/or activity, the ubiquitin-like modifier (UBL) ATG8 is conjugated to the phospholipid phosphatidylethanolamine (PE). The best understood function of ATG8 is during autophagy where ATG8-PE conjugates are incorporated into both layers of incipient autophagosomes and serve as multipurpose docking sites for autophagosomal cargo receptors as well as regulatory factors (termed adaptors) that drive formation and maturation of autophagosomes. Mammalian cells harbor six ATG8 family members that can be subclassified into the LC3- and GABARAP-family and that can all be lipidated. However, it is currently unclear to what extent these proteins are functionally redundant or fulfil unique roles.
Cullin-RING ligase complexes (CRLs) are modular E3 ubiquitin ligases that comprise a RING-finger protein that associates with the ubiquitin-charged E2 enzyme, a substrate recruiting module as well as a cullin scaffold as a linker between RING protein and substrate adaptor. Whereas SCF (SKP1-CUL1-F-box protein) complexes, the most studied CRLs, harbor cullin-1 (CUL1) as scaffold and F-box proteins as substrate binding modules, CUL3-containing CRL complexes employ cullin-3 (CUL3), RING-box protein 1 (RBX1) and BTB proteins as substrate adaptors. Here, the BTB domain serves as binding interface for CUL3 and is usually complemented by an additional protein-protein interaction domain such as MATH or Kelch that mediates binding to the substrate of the E3 ligase complex.
Besides ubiquitylation, guanine nucleotide binding is another common way to regulate protein activity and signaling in cells. Here, small Rho GTPases cycle between active and inactive states by binding of the guanine nucleotides GTP or GDP with the help of regulatory proteins. Whereas GTPase-activating proteins (GAP) render RAC1 inactive by facilitating GTP hydrolysis, guanine exchange factors (GEF) such as T-lymphoma invasion and metastasis-inducing protein 1 (TIAM1) activate RAC1 by stimulating the exchange of GDP to GTP. Local control of RAC1 activity is essential to allow a specific cellular response to stimuli such as growth factors or migratory impulses.
This study reports an unexpected link between the GABARAP subfamily of mammalian ATG8 proteins, the ubiquitin proteasome system and RAC1 through the ubiquitylation of the RAC1 GEF TIAM1. The Kelch repeat and BTB domain-containing proteins 6 (KBTBD6) and 7 (KBTBD7) were established as heterodimeric substrate adaptors for CUL3. Interestingly, a thorough proteomic analysis revealed a number of putative substrates but, out of 11 substrate candidates tested, only the RAC1 GEF TIAM1 appeared to be influenced by depletion of CUL3KBTBD6/KBTBD7. Binding studies showed that KBTBD7 binds TIAM1 via the Kelch repeats and that this binding was markedly enhanced when CUL3 activation was abolished upon treatment with the neddylation inhibitor MLN4924. Also, total TIAM1 abundance was increased upon CUL3KBTBD6/KBTBD7 depletion and accumulation of TIAM1 upon proteasome inhibition suggested that TIAM1 is degraded via the proteasome. In vivo ubiquitylation assays and denaturing immunoprecipitations as well as mass spectrometrical analysis confirmed that CUL3KBTBD6/KBTBD7 ubiquitylates TIAM1 at two distinct lysines (K1404 and K1420) close to its C-terminus.
Previously, KBTBD6 and KBTBD7 were found as interactors of several members of the human ATG8 family of proteins in a proteomic study analyzing the human autophagy network. This association was confirmed in the present work. Furthermore, peptide array technology and mutational analysis revealed that KBTBD6 and KBTBD7 employ a classical ATG8-family interacting motif (AIM; also referred to as LC3-interacting region or LIR) as binding interface. The AIMs of KBTBD6 (W-V-R-V) and KBTBD7 (W-V-Q-V) fulfil the consensus AIM sequence motif (F/W/Y1-X2-X3-I/L/V4) and are preceded by several acidic residues and serines. A series of structural and cell biological experiments revealed a binding preference for the GABARAP subfamily of human ATG8 proteins and most importantly, a requirement of the GABARAP-KBTBD6 and -KBTBD7 interaction for TIAM1 ubiquitylation. The finding that TIAM1 binding to KBTBD6 and KBTBD7 AIM mutants was diminished raised the possibility that GABARAP binding mediates the recruitment of CUL3KBTBD6/KBTBD7 to membranes where TIAM1 is localized. Interestingly, colocalization of KBTBD6, GABARAPL1 and TIAM1 in punctuate structures could be observed. Since only a very small fraction of GABARAPL1 colocalized with LC3B, and colocalization between KBTBD6 and LC3B was not observed, these vesicular structures are most likely distinct from autophagosomes. Furthermore, TIAM1 ubiquitylation was reduced when GABARAP, but not LC3B, was depleted or when lipidation of GABARAP was prevented.
Stabilization of TIAM1 upon KBTBD6 and/or KBTBD7 depletion led to elevated TIAM1-dependent RAC1 activity, altered actin morphology with increased cortical actin and loss of vinculin foci. Re-introduction of wild-type KBTBD6 or KBTBD7 but not AIM mutants reverted all these phenotypes. Moreover, depletion of KBTBD6 or KBTBD7 in human breast cancer cells massively increased their invasiveness, whereas TIAM1 knockdown had the opposite outcome. All physiological effects of KBTBD6 and KBTBD7 depletion were inhibited by additional depletion of TIAM1 or RAC1 confirming that the phenotypes observed are indeed mediated by the CUL3KBTBD6/KBTBD7-TIAM1-RAC1 signaling pathway. Intriguingly, KBTBD6 and KBTBD7 were not subject to autophagosomal degradation, thereby establishing a new function for GABARAP proteins beyond autophagosomal degradation in providing a signaling platform for recruitment of the E3 ligase CUL3KBTBD6/KBTBD7 in close proximity to its substrate TIAM1, enabling localized ubiquitylation.
Local restricted control of RAC1 activity by ubiquitylation has been described for TIAM1-RAC1 signaling previously. Examples are HECT, UBA and WWE domain-containing protein 1 (HUWE1)-mediated TIAM1 ubiquitylation that occurs predominantly at cell-cell-junctions in response to hepatocyte growth factor stimulation in MDCKII cells or inhibition of RAC1 activity by the RAC1 GAP protein BCR (breakpoint cluster region) at the leading edge of astrocytes through binding to the TIAM1-Par (polarity) complex. SCFBTRC mediates ubiquitylation of TIAM1 in response to mitogens or DNA damage, though it has not been explored whether this regulation is spatially restricted. Thus, this study adds a novel layer of complexity to the spatial regulation of RAC1 signaling by implicating membrane-bound human ATG8 proteins in this process.
Also, this study is the first report specifically implicating the GABARAP proteins in cellular signaling events. It will be interesting to explore whether the concept of localized signaling mediated by GABARAPs applies to other substrates of CUL3KBTBD6/KBTBD7 and membranerelated signaling processes in which GABARAP proteins are involved. Controlling RAC1 activity at GABARAP-decorated membranes might also be important for trafficking events or autophagy since it was described that RAC1 has an inhibitory function on autophagy. Therefore, spatial restricted ubiquitylation of TIAM1 resulting in specific deactivation of RAC1 could promote the autophagic process when locally needed. Although the catalytic mTOR inhibitor Torin1 and the lysosomal H+ ATPase inhibitor BafilomycinA1 promoted TIAM1 ubiquitylation by increasing the pool of membrane-conjugated GABARAP, but other signals that stimulate GABARAP-KBTBD6/KBTBD7 association and subsequent TIAM1 ubiquitylation are to be identified. Besides, determining the KBTBD6/KBTBD7 binding site in TIAM1 or uncovering a deubiquitylating enzyme (DUB) that locally counteracts the ubiquitylation of TIAM1 will enable a better comprehension of the complete localized signaling cascade.
Protein–protein interactions are at the core of all cellular functions and dynamic alterations in protein interactions regulate cellular signaling. In the last decade, mass spectrometry (MS)-based proteomics has delivered unprecedented insights into human protein interaction networks. Affinity purification-MS (AP-MS) has been extensively employed for focused and high-throughput studies of steady state protein–protein interactions. Future challenges remain in mapping transient protein interactions after cellular perturbations as well as in resolving the spatial organization of protein interaction networks. AP-MS can be combined with quantitative proteomics approaches to determine the relative abundance of purified proteins in different conditions, thereby enabling the identification of transient protein interactions. In addition to affinity purification, methods based on protein co-fractionation have been combined with quantitative MS to map transient protein interactions during cellular signaling. More recently, approaches based on proximity tagging that preserve the spatial dimension of protein interaction networks have been introduced. Here, we provide an overview of MS-based methods for analyzing protein–protein interactions with a focus on approaches that aim to dissect the temporal and spatial aspects of protein interaction networks.
Sentences with doubly center-embedded relative clauses in which a verb phrase (VP) is missing are sometimes perceived as grammatical, thus giving rise to an illusion of grammaticality. In this paper, we provide a new account of why missing-VP sentences, which are both complex and ungrammatical, lead to an illusion of grammaticality, the so-called missing-VP effect. We propose that the missing-VP effect in particular, and processing difficulties with multiply center-embedded clauses more generally, are best understood as resulting from interference during cue-based retrieval. When processing a sentence with double center-embedding, a retrieval error due to interference can cause the verb of an embedded clause to be erroneously attached into a higher clause. This can lead to an illusion of grammaticality in the case of missing-VP sentences and to processing complexity in the case of complete sentences with double center-embedding. Evidence for an interference account of the missing-VP effect comes from experiments that have investigated the missing-VP effect in German using a speeded grammaticality judgments procedure. We review this evidence and then present two new experiments that show that the missing-VP effect can be found in German also with less restricting procedures. One experiment was a questionnaire study which required grammaticality judgments from participants without imposing any time constraints. The second experiment used a self-paced reading procedure and did not require any judgments. Both experiments confirm the prior findings of missing-VP effects in German and also show that the missing-VP effect is subject to a primacy effect as known from the memory literature. Based on this evidence, we argue that an account of missing-VP effects in terms of interference during cue-based retrieval is superior to accounts in terms of limited memory resources or in terms of experience with embedded structures.
Objective: Cognitive models suggest that the self-concept of persons with psychosis can be fundamentally affected. Self-concepts were found to be related to different symptom domains when measured concurrently. Longitudinal investigations to disentangle the possible causal associations are rare.
Method: We examined a sample of 160 people with a diagnosis of schizophrenia who took part in a psychotherapy study. All participants had the DSM-IV diagnosis of a schizophrenia and pronounced negative symptoms. Neurocognition, symptoms, and self-concepts were assessed at two time points 12 months apart. Structural equation modeling was used to test whether symptoms influence self-concepts (scar-model) or self-concepts affect symptoms (vulnerability model).
Results: Negative symptoms correlated concurrently with self-concepts. Neurocognitive deficits are associated with more negative self-concepts 12 months later. Interpersonal self-concepts were found to be relevant for paranoia.
Conclusion: The findings implicate that if deficits in neurocognition are present, fostering a positive self-concept should be an issue in therapy. Negative interpersonal self-concept indicates an increased risk for paranoid delusions in the course of 1 year. New aspects for cognitive models in schizophrenia and clinical implications are discussed.
"Nothing is more soothing to the nerves than a detailed discussion of homage and lordship …" If William de Briwerr, fictional English knight and narrator in Alfred Duggan’s historical novel Lord Geoffrey’s Fancy, is right, then a conference held in April 2011 will have set the participants at ease. Following the call of the Konstanzer Arbeitskreis für mittelalterliche Geschichte and the conference organiser, Karl-Heinz Spieß, they had gathered to discuss the "Formation and dissemination of feudalism in the Empire and in Italy during the 12th and 13th century". The conference proceedings have now been published, and I suppose William de Briwerr would have approved of the intensity of discussion contained therein. ...
Ziel der vorliegenden Arbeit ist der Aufbau von koaxialen Plasmabeschleunigern und deren Verwendung für die Untersuchung der Eigenschaften von kollidierenden Plasmen. Zukünftig sollen diese kollidierenden Plasmen als intensive Strahlungsquelle im Bereich der ultravioletten (UV-) und vakuumultravioletten (VUV-)Strahlung sowie in der Grundlagenforschung als Target zur Ionenstrahl-Plasma-Wechselwirkung Verwendung finden. Für diese Anwendungen steht dabei eine Betrachtung der physikalischen Grundlagen im Vordergrund. So sind neben der Kenntnis der Plasmadynamik auch Aussagen bezüglich der Elektronendichte, der Elektronentemperatur und der Strahlungsintensität von Bedeutung. Im Einzelnen konnte gezeigt werden, dass es möglich ist, durch eine Plasmakollision die Elektronendichte des Plasmas im Vergleich zu der eines einzelnen Plasmas deutlich zu erhöhen - im Maximalfall um den Faktor vier. Gleichzeitig stieg durch die Plasmakollision die Lichtintensität im Wellenlängenbereich der UV- und VUV-Strahlung um den Faktor drei an...
A Borges, como es bien sabido, le interesaban más aquellos universos tejidos por las palabras que ese otro espacio teñido de desconfianza que algunos persistían en llamar realidad. Dicha pulsión creadora de mundos propios transfirió a sus lectores la risa profunda, el don de la ironía pero también, como algunos lo reconocen, un cierto malestar. Algo similar, pero con una pretensión centrada no ya en lo ficcional sino en las políticas del lenguaje y en los modos de reencontrar claves antropológicas de diversas codificaciones de lo inteligible, acaece con la reciente publicación colectiva «Tour du monde des concepts», dirigida por Pierre Legendre. ...
Peter Oestmann unterscheidet in seiner Intervention drei Arten der Rechtsgeschichtsschreibung, die er Normen-, Wissenschafts- und Praxisgeschichte nennt. Als bekennender Vertreter der letzten Kategorie setzt er sich für deren Emanzipation von der rechtsdogmatischen "Normenkontrolle" ein. Er bezeichnet es als "unfair, wenn Vertreter der Normengeschichte erwarten, diejenigen, die sich mit der Rechtspraxis beschäftigen, müssten im gleichen Maße die Rechtsliteratur und normative Quellen in ihre Untersuchungen einbeziehen wie andere Rechtshistoriker auch" (8). Zugleich bricht er eine Lanze für die "erheblich unjuristischere" Rechtsgeschichte der Praxis (ebd.). Wir pflichten diesem Anliegen vorbehaltlos bei. Zugleich beobachten wir, dass Oestmanns Kritik an Grundlagen des rechtshistorischen Selbstverständnisses rührt, die zur Diskussion zu stellen im deutschsprachigen Raum erfahrungsgemäß schwer fällt. Auch bleibt Oestmann zu oft in den Kategorien des von ihm Kritisierten befangen. Unsere Replik setzt sich mit den historischen Ursachen dieses strukturellen Unbehagens in der Rechtsgeschichte auseinander.