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Advanced colorectal carcinoma is currently incurable, and new therapies are urgently needed. We report that phosphotyrosine-dependent Eph receptor signaling sustains colorectal carcinoma cell survival, thereby uncovering a survival pathway active in colorectal carcinoma cells. We find that genetic and biochemical inhibition of Eph tyrosine kinase activity or depletion of the Eph ligand EphrinB2 reproducibly induces colorectal carcinoma cell death by autophagy. Spautin and 3-methyladenine, inhibitors of early steps in the autophagic pathway, significantly reduce autophagy-mediated cell death that follows inhibition of phosphotyrosine-dependent Eph signaling in colorectal cancer cells. A small-molecule inhibitor of the Eph kinase, NVP-BHG712 or its regioisomer NVP-Iso, reduces human colorectal cancer cell growth in vitro and tumor growth in mice. Colorectal cancers express the EphrinB ligand and its Eph receptors at significantly higher levels than numerous other cancer types, supporting Eph signaling inhibition as a potential new strategy for the broad treatment of colorectal carcinoma.
High-resolution cryo-EM structures of respiratory complex I: Mechanism, assembly, and disease
(2019)
Respiratory complex I is a redox-driven proton pump, accounting for a large part of the electrochemical gradient that powers mitochondrial adenosine triphosphate synthesis. Complex I dysfunction is associated with severe human diseases. Assembly of the one-megadalton complex I in the inner mitochondrial membrane requires assembly factors and chaperones. We have determined the structure of complex I from the aerobic yeast Yarrowia lipolytica by electron cryo-microscopy at 3.2-Å resolution. A ubiquinone molecule was identified in the access path to the active site. The electron cryo-microscopy structure indicated an unusual lipid-protein arrangement at the junction of membrane and matrix arms that was confirmed by molecular simulations. The structure of a complex I mutant and an assembly intermediate provide detailed molecular insights into the cause of a hereditary complex I-linked disease and complex I assembly in the inner mitochondrial membrane.
Progranulin deficiency is associated with neurodegeneration in humans and in mice. The mechanisms likely involve progranulin-promoted removal of protein waste via autophagy. We performed a deep proteomic screen of the pre-frontal cortex in aged (13–15 months) female progranulin-deficient mice (GRN−/−) and mice with inducible neuron-specific overexpression of progranulin (SLICK-GRN-OE) versus the respective control mice. Proteins were extracted and analyzed per liquid chromatography/mass spectrometry (LC/MS) on a Thermo Scientific™ Q Exactive Plus equipped with an ultra-high performance liquid chromatography unit and a Nanospray Flex Ion-Source. Full Scan MS-data were acquired using Xcalibur and raw files were analyzed using the proteomics software Max Quant. The mouse reference proteome set from uniprot (June 2015) was used to identify peptides and proteins. The DiB data file is a reduced MaxQuant output and includes peptide and protein identification, accession numbers, protein and gene names, sequence coverage and label free quantification (LFQ) values of each sample. Differences in protein expression in genotypes are presented in "Progranulin overexpression in sensory neurons attenuates neuropathic pain in mice: Role of autophagy" (C. Altmann, S. Hardt, C. Fischer, J. Heidler, H.Y. Lim, A. Haussler, B. Albuquerque, B. Zimmer, C. Moser, C. Behrends, F. Koentgen, I. Wittig, M.H. Schmidt, A.M. Clement, T. Deller, I. Tegeder, 2016) [1].
The highly conserved eukaryotic process of macroautophagy (autophagy) is a non-specific bulk-degradation program critical for maintaining proper cellular homeostasis, and for clearing aged and damaged organelles. This decision is inextricably dependent upon prevailing metabolic demands and energy requirements of the cell. Soluble monomeric decorin functions as a natural tumor repressor that antagonizes a variety of receptor tyrosine kinases. Recently, we discovered that decorin induces endothelial cell autophagy, downstream of VEGFR2. This process was wholly dependent upon Peg3, a decorin-inducible genomically imprinted tumor suppressor gene. However, the signaling cascades responsible have remained elusive. In this report we discovered that Vps34, a class III phosphoinositide kinase, is an upstream kinase required for Peg3 induction. Moreover, decorin triggered differential formation of Vps34/Beclin 1 complexes with concomitant dissolution of inhibitive Bcl-2/Beclin 1 complexes. Further, decorin inhibited anti-autophagic signaling via suppression of Akt/mTOR/p70S6K activity with the concurrent activation of pro-autophagic AMPK-mediated signaling cascades. Mechanistically, AMPK is downstream of VEGFR2 and inhibition of AMPK signaling abrogated decorin-evoked autophagy. Collectively, these findings hint at the complexity of the underlying molecular relays necessary for decorin-evoked endothelial cell autophagy and reveal important therapeutic targets for augmenting autophagy and combatting tumor angiogenesis.
The highly conserved eukaryotic process of macroautophagy (autophagy) is a non-specific bulk-degradation program critical for maintaining proper cellular homeostasis, and for clearing aged and damaged organelles. This decision is inextricably dependent upon prevailing metabolic demands and energy requirements of the cell. Soluble monomeric decorin functions as a natural tumor repressor that antagonizes a variety of receptor tyrosine kinases. Recently, we discovered that decorin induces endothelial cell autophagy, downstream of VEGFR2. This process was wholly dependent upon Peg3, a decorin-inducible genomically imprinted tumor suppressor gene. However, the signaling cascades responsible have remained elusive. In this report we discovered that Vps34, a class III phosphoinositide kinase, is an upstream kinase required for Peg3 induction. Moreover, decorin triggered differential formation of Vps34/Beclin 1 complexes with concomitant dissolution of inhibitive Bcl-2/Beclin 1 complexes. Further, decorin inhibited anti-autophagic signaling via suppression of Akt/mTOR/p70S6K activity with the concurrent activation of pro-autophagic AMPK-mediated signaling cascades. Mechanistically, AMPK is downstream of VEGFR2 and inhibition of AMPK signaling abrogated decorin-evoked autophagy. Collectively, these findings hint at the complexity of the underlying molecular relays necessary for decorin-evoked endothelial cell autophagy and reveal important therapeutic targets for augmenting autophagy and combatting tumor angiogenesis.
The richest compilation to date of essays in the political theory of European integration has just landed with a thud, and is bound to reverberate for some time in the sleek corridors of Brussels and the wood-paneled seminar rooms of Bruges. Edited by Kochenov, de Búrca, and Williams, Europe’s Justice Deficit? is more than an attempt to initiate a discussion about the questions of justice prompted by European integration. With thirty contributions by leading scholars of law, history, political science and philosophy, not much worth noting on this seemingly boundless subject is left unsaid. ...
Der hier zu besprechende Sammelband ist das Begleitbuch zu einer Ausstellung der Abguss-Sammlung des Instituts für Klassische Archäologie der Freien Universität Berlin zum Thema "Realismen in der griechischen Plastik", die von Februar bis Juli 2018 dort zu sehen war. Die Ausstellung war aus Lehrveranstaltungen der beiden Herausgeber hervorgegangen und folgte damit bekannten Vorgängern vergangener Jahrzehnte, deren begleitende Kataloge geradezu Handbuchstatus erlangt haben. ...
Römische Grabbauten sind im Grunde kein Thema, dem es an wissenschaftlicher Aufmerksamkeit mangelt. Allerdings lag der Fokus in den vergangenen Jahrzehnten beinahe durchweg auf den Denkmälern in Rom und Italien, die sowohl aus bautypologischer als auch aus sozial- und kulturhistorischer Perspektive intensiv erforscht wurden und werden. Für die Grabbauten in den Provinzen, insbesondere den Nordwestprovinzen fehlte es dagegen lange an übergreifenden Studien. Diese Lücke wird nun durch die in Teilen auf den Ergebnissen eines EUProjektes zum Thema "Transformation" aufbauende Studie von Markus Scholz (S.) geschlossen, der sich den erhaltenen Denkmälern in detaillierter Weise anhand einer typologischen Methodik annimmt. Der Größe des Untersuchungsgebiets, das von Britannien über die Rhein- und Donauprovinzen bis ans Schwarze Meer reicht, und der damit einhergehend immensen Zahl einbezogener Objekte (ca. 3500 Grabbauten) entspricht auch der Umfang des Werkes, das mit zwei Bänden mit jeweils rund 570 Seiten bereits auf den ersten Blick gewichtig anmutet. ...
Das vorliegende Buch ist als Begleitband zur gleichnamigen Sonderausstellung erschienen, die vom 04.04.-14.09.2008 in der Archäologischen Staatssammlung München gezeigt wurde. Sein Titel weckt hohe Erwartungen, verspricht er doch die Betrachtung einer kurzen, in der oberflächlichen Gesamtwahrnehmung der römischen Militärgrenzen an Rhein und Donau kaum auffälligen Teilstrecke des obergermanischen Limes als Beispiel eines kulturellen Welterbes. Es handelt sich um die rund 50 km lange Strecke der militärisch gesicherten Außengrenze der römischen Provinz Germania Superior, die zwischen dem bei Hanau gelegenen Großkrotzenburg und Miltenberg entlang des westlichen Ufers des Mains verlief. Dieser Limesabschnitt unterscheidet sich einzig dadurch von allen anderen Strecken des obergermanischen Limes, dass die durchgehenden Grenzsperren nicht aus Palisaden bzw. (später) Wall und Graben bestanden, sondern der Fluss selbst die natürliche Grenzsperre zwischen dem römischen Provinzterritorium und den germanischen Stammesgebieten bildete. ...
Der vorliegende Band umfasst vier Themenkomplexe, die in insgesamt elf Aufsätzen behandelt werden. Während sich das erste Kapitel ausschließlich auf eine in der Vulkaneifel (in Duppach-Weiermühle) gelegene Nekropole mit ihren Grabmäler beschränkt, die wie aus dem Vorwort ersichtlich den eigentlichen Anlass und Schwerpunkt des Kolloquiums darstellt, wird der Fokus im zweiten Kapitel auf diverse Grabbauten im Saarland und in Rheinland-Pfalz erweitert. Im dritten Abschnitt werden exemplarisch einige ausgewählte Grabbezirke und Grabbauten aus dem Rheinland, Kärnten und dem Schweizer Jura vorgestellt, bevor im letzten Kapitel unter dem Gesichtspunkt "Struktur und Nutzung" sowohl Grabbauten in Villenkontexten auf der Iberischen Halbinsel gezeigt werden als auch in einem kurzen Aufsatz der Umgang mit römischen Grabbauten in Spätantike und Mittelalter angesprochen wird. ...
Während sich Peter Henrich im ersten Artikel (S. 13-37) auf die Topographie und den Grabungsbefund konzentriert, um gegen Ende noch einen kurzen Ausblick auf die chronologische Entwicklung, die Umnutzung sowie die darauffolgende Zerstörung zu bieten, unternimmt Marianne Tabaczek daraufhin (S. 39-65) den Versuch, die beiden stark zerstörten Grabmäler A und B zu rekonstruieren. ...
So berichten im zweiten Kapitel, welches die Überschrift "Grabbauten der Treverer und Mediomatriker" trägt, Klaus-Peter Henz und Anja Klöckner über Grabmäler bei Tholey im Saarland (S. 69-88), stellt Steven Ditsch Grabbauten des 2. und 3. Jh. n. Chr. aus der Pfalz vor (S. 89-107) und beschäftigt sich Gabrielle Kremer mit kaiserzeitlichen Grabmälern des Mosel- und Rheingebietes, wobei sie ihr Hauptaugenmerk auf den Grabbau von Mersch richtet (S. 109-135). Das Kapitel beschließt Markus Siedow, der mit Kammern versehene Grabbauten aus dem Trierer Raum behandelt (S. 137-164). Die verschiedenen Artikel setzen inhaltlich voneinander abweichende Schwerpunkte. ...
Etwas mehr als zwanzig Jahre nach seiner Entdeckung liegt nun endlich die vollständige Publikation des spätantiken Münzschatzes von Simitthus (das moderne Chimtou in Tunesien) vor. Dies ist sehr erfreulich, stellt er doch einen der umfangreichsten und am vollständigsten dokumentierten Goldschätze der Spätantike da. Umso trauriger ist es, dass der Bearbeiter dieses bedeutenden Fundes die Publikation seines Manuskriptes nicht mehr erleben konnte, starb Dr. Hans Roland Baldus doch in 2011. ...
For the environs of the Late Bronze Age fortification enclosure Iarcuri the hydro-morphological relief characteristics are combined with archaeological evidences. Target of the study is to evaluate the impact of settlement activities in the surroundings of Iarcuri on the development of the channel network. Data analysis is based on topographic map-derived and high resolution DEMs provided by LiDAR scanning; derivatives of the DEMs are used to characterize the different sub-catchments that show varying influences by the fortification ramparts. The tributaries reaching the receiving stream close to the central settlement area source close to the gates in the ramparts in the Late Bronze Age built-up areas. Additionally, also the geometry of these tributaries differs from that of other tributaries. The distinct character of the channel network with repeatedly occurring rectangular bends indicates the capture of channels, which developed as gullies along paths by retrogressive erosion.
Current metabolomics approaches utilize cellular metabolite extracts, are destructive, and require high cell numbers. We introduce here an approach that enables the monitoring of cellular metabolism at lower cell numbers by observing the consumption/production of different metabolites over several kinetic data points of up to 48 hours. Our approach does not influence cellular viability, as we optimized the cellular matrix in comparison to other materials used in a variety of in‐cell NMR spectroscopy experiments. We are able to monitor real‐time metabolism of primary patient cells, which are extremely sensitive to external stress. Measurements are set up in an interleaved manner with short acquisition times (approximately 7 minutes per sample), which allows the monitoring of up to 15 patient samples simultaneously. Further, we implemented our approach for performing tracer‐based assays. Our approach will be important not only in the metabolomics fields, but also in individualized diagnostics.
Current metabolomics approaches utilize cellular metabolite extracts, are destructive, and require high cell numbers. We introduce here an approach that enables the monitoring of cellular metabolism at lower cell numbers by observing the consumption/production of different metabolites over several kinetic data points of up to 48 hours. Our approach does not influence cellular viability, as we optimized the cellular matrix in comparison to other materials used in a variety of in‐cell NMR spectroscopy experiments. We are able to monitor real‐time metabolism of primary patient cells, which are extremely sensitive to external stress. Measurements are set up in an interleaved manner with short acquisition times (approximately 7 minutes per sample), which allows the monitoring of up to 15 patient samples simultaneously. Further, we implemented our approach for performing tracer‐based assays. Our approach will be important not only in the metabolomics fields, but also in individualized diagnostics.
Es war eine heißer, schwüler Sommerabend, als John Rawls im Hörsaal H der Frankfurter Universität einen Vortrag hielt. Er sprach leise, fast schleppend, und er hatte sich vorgenommen, den Text in einer deutschen Übersetzung vorzulesen, was für einen amerikanischen Professor ungewöhnlich war und deshalb Bewunderung verdiente. Doch war die angespannte Konzentration spürbar, die Rawls aufbringen musste, um deutscheWorte mit so wenig amerikanischer Phonetik wiemöglich zu sprechen, und der Vortrag wurde dadurch noch langsamer, die Stimme noch leiser. Außerdem funktionierte das Mikrofon nicht richtig. Deshalb wurde es ihm von seinem Übersetzer, Wilfried Hinsch, mit ausgestrecktem Arm so nahe an denMund gehalten, dass wenigstens ein paar Worte zu verstehen waren. Nach kurzer Zeit verließen die ersten Zuhörer den Hörsaal. Der ausgestreckte Arm des Helfers wurde sichtbar schwerer; Anstrengung und Hitze ließen Schweißbäche rinnen und das Oberhemd nass werden.Der Vortragwar nicht einfach. Rawls machte, wie gewohnt, keinerlei Konzessionen, sondern diktierte einen komplexen Satz nach dem anderen. Wer etwas verstehen wollte, musste von der komischen Situation absehen, alle Kräfte gegen die von der schwülen Hitze geführten Ermüdungsattacken aufbieten und sich irgendwie konzentrieren. Der einzige, der sich davon nicht beirren ließ, sondern hartnäckig Satz für Satz in den schwülen Sommerabend hämmerte, war der kleine, schmächtige, blasse, sein Gesicht hinter einer riesigen Brille verbergende, aber Respekt heischende Professor Rawls. Wenn Geist so unmittelbar präsent ist, wird eben alles andere banal. ...
Zeichen der Herrschaftsausübung, der Gerichtsbarkeit und der Marktfreiheit, öffentlich angebrachte Maße und Gewichte zur Kontrolle des Wirtschaftslebens, mittelalterliche und frühneuzeitliche Gerichtsstätten, Orte und Gegenstände des Strafvollzugs, die der Rechtshistoriker Karl Frölich in den dreißiger bis fünfziger Jahren des 20. Jahrhunderts auf große Glasplatten gebannt hat, berichten anschaulich von der Rechtsausübung vergangener Epochen, indem sie "Sachzeugen des Rechtslebens" abbilden. Die Platten dieser umfangreichen Fotosammlung werden derzeit durch die Bibliothek des Max- Planck-Instituts für europäische Rechtsgeschichte eingescannt, um die Bilder der Forschung zu erhalten und zur Verfügung zu stellen. Ein Teil der "Sammlung Frölich" befindet sich heute in der Obhut von Prof. Dr. Gerhard Dilcher, Frankfurt am Main. Ein weiterer, größerer Teil, ist nach München ins Leopold-Wenger-Institut gelangt (Prof. Dr. Hermann Nehlsen); auch diese Bilder werden nun durch Scannen mit der "Frankfurter Partie" virtuell zusammengeführt. ...
Akte der Realisierung von Recht etwa in Form der "Rechtsprechung" sowie Orte der Rechtsausübung als "Räume des Rechts" sind oft in Bildmedien dargestellt worden, wie zahlreiche Beispiele aus unterschiedlichen Epochen zeigen. Auch in der rechtsikonographischen Forschung haben sie breite Aufmerksamkeit gefunden. Dies gilt hingegen weniger für die bildliche Darstellung der "Gesetzgebung" bzw. des "Gesetzgebers". Im frühneuzeitlichen Staat wurde die Richterfunktion des Herrschers in ihrer Wertigkeit von seiner Rolle als Gesetzgeber abgelöst. ...
Nanopores are key in portable sequencing and research given their ability to transport elongated DNA or small bioactive molecules through narrow transmembrane channels. Transport of folded proteins could lead to similar scientific and technological benefits. Yet this has not been realised due to the shortage of wide and structurally defined natural pores. Here we report that a synthetic nanopore designed via DNA nanotechnology can accommodate folded proteins. Transport of fluorescent proteins through single pores is kinetically analysed using massively parallel optical readout with transparent silicon-on-insulator cavity chips vs. electrical recordings to reveal an at least 20-fold higher speed for the electrically driven movement. Pores nevertheless allow a high diffusive flux of more than 66 molecules per second that can also be directed beyond equillibria. The pores may be exploited to sense diagnostically relevant proteins with portable analysis technology, to create molecular gates for drug delivery, or to build synthetic cells.
Der Sammelband enthält die Vorträge einer altertumswissenschaftlichen Tagung, die unter gleichem Titel am Freiburger Antike-Zentrum (dort auch "Antikenzentrum" genannt) stattfand und an der Historiker, Kirchenhistoriker, Philologen und Philosophen teilgenommen haben. ...
Hartmut Leppin dokumentiert exemplarisch das Eindringen christlichen Geistes in das traditionelle Kaiserbild. ...
Für die Erforschung der spätantiken Herrscherideologie hat Andreas Alföldi (1895-1981) Grundlegendes geleistet. Ihm gelang es, bildliche Darstellungen zum Sprechen zu bringen und ihre Bedeutung für die Repräsentation der Kaiser zu verdeutlichen. In dieser Tradition bewegt sich der Tübinger Althistoriker (und zeitweilige Assistent Alföldis) Frank Kolb mit seinem hier anzuzeigenden Buch. Darin führt er die verstreuten, von verschiedenen altertumswissenschaftlichen Disziplinen vorangetriebenen Forschungen zur spätantiken Herrscherideologie zusammen, die er durch eigene Beiträge wesentlich beeinflußt hat. ...
MicroRNAs (miRs) significantly contribute to the regulation of gene expression, by virtue of their ability to interact with a broad, yet specific set of target genes. MiRs are produced and released by almost every cell type and play an important role in horizontal gene regulation in the tumor microenvironment (TME). In the TME, both tumor and stroma cells cross-communicate via diverse factors including miRs, which are taking central stage as a therapeutic target of anti-tumor therapy. One of the immune escape strategies adopted by tumor cells is to release miRs as a Trojan horse to hijack circulating or tumor-localized monocytes/macrophages to tune them for pro-tumoral functions. On the other hand, macrophage-derived miRs exert anti-tumor functions. The transfer of miRs from host to recipient cells depends on the supramolecular structure and composition of miR carriers, which determine the distinct uptake mechanism by recipient cells. In this review, we provide a recent update on the miR-mediated crosstalk between tumor cells and macrophages and their mode of uptake in the TME.
Heute weiß fast jeder, dass ein hoher Blutcholesterinspiegel ein Risikofaktor für Herz-Kreislauf-Erkrankungen ist. Inzwischen gibt es wirksame Therapien, die den Cholesterinstoffwechsel wieder in Gang setzen. Doch die Herzgesundheit hängt von so viel mehr ab als von Cholesterin. Zu den bekannten Mediatoren für Herz-Kreislauf-Erkrankungen sind neue hinzugekommen. Alle können durch Ernährung beeinflusst werden.
IL-27 regulates inflammatory diseases by exerting a pleiotropic impact on immune cells. In cancer, IL-27 restricts tumor growth by acting on tumor cells directly, while its role in the tumor microenvironment is still controversially discussed. To explore IL-27 signaling in the tumor stroma, we used a mammary carcinoma syngraft approach in IL27Rα-deficient mice. Tumor growth in animals lacking IL27Rα was markedly reduced. We noticed a decrease in immune cell infiltrates, enhanced tumor cell death, and fibroblast accumulation. However, most striking changes pertain the tumor vasculature. Tumors in IL27Rα-deficient mice were unable to form functional vessels. Blocking IL-27-STAT1 signaling in endothelial cells in vitro provoked an overshooting migration/sprouting of endothelial cells. Apparently, the lack of the IL-27 receptor caused endothelial cell hyper-activation via STAT1 that limited vessel maturation. Our data reveal a so far unappreciated role of IL-27 in endothelial cells with importance in pathological vessel formation.
Im Gefolge der spanischen Kolonisation bildete sich ein für Hispanoamerika geltendes Normengefüge heraus, das später so genannte Derecho Indiano. Aus Europa stammende Institutionen und Normen wurden in der "Neuen Welt" (re-)produziert, doch gingen in seine Entstehung auch gewohnheitsrechtliche lokale Praktiken ein: spanische ebenso wie indigene aus vorkolonialer Zeit. Um die komplexe Genese dieses multinormativen Rechts verstehen zu können, sind neben den klassischen Quellen auch die jeweilige lokale Rechtsproduktion und der juristische Diskurs zu berücksichtigen. Wichtige diesbezügliche Zeugnisse hinterließen im 16. Jahrhundert zahlreiche in Hispanoamerika wirkende Juristen. Im zentralandinen Raum, dem heutigen Peru und Bolivien, war Polo Ondegardo einer der herausragenden juristischen Autoren und Akteure, dessen Schriften in zwei neuen Auswahlbänden vorliegen. ...
Five hundred years ago, Hernán Cortés launched his invasion of Mexico (1519–1521), which culminated in the fall of Tenochtitlán. A little over a decade later, the Inca realm was destroyed by Francisco Pizarro’s clan in Peru (1532–1533). The decisive factors and myths of the Spanish "conquests" are treated in the pertinent historiography. Recent literature has had less to say on the subsequent phase of early colonial history, when the Castilian Crown and its representatives in the "New World" tried to reinforce their dominance – essentially against the interests of the first generation of conquistadores. This tumultuous period is the subject of Gregorio Salinero’s book, which re-examines disobediences, political trials and governance in Spanish America, as the subtitle reads. It is an augmented version of Salinero’s La trahison de Cortés (Paris 2014), now skillfully translated into Spanish by Manuela Águeda García Garrido. The author, professor of history at the Université Paris 1 Panthéon-Sorbonne, is well known for his research on transatlantic relations between Spain and Spanish America. ...
El testamento representa uno de los géneros de fuente archivística más ricos para el desarrollo de diversos temas de investigación en la época colonial hispanoamericana. Durante mucho tiempo la historia política, legal y social de las Indias solía tener en cuenta testamentos de individuos o grupos particulares, pero por lo general se trataba de españoles. Salvo algunas excepciones, como en el caso de ciertos miembros de la nobleza indígena, no había estudios etnohistóricos sobre los documentos de última voluntad referidos a la población autóctona. Sólo a partir de la década de 1980, comenzaron a ser trabajadas de una manera más sistemática este tipo de fuentes por parte de algunos investigadores mesoamericanistas. Gracias, en particular, al interés lingüístico de la »New Philology« en este tipo de textos, a menudo redactados en náhuatl u otros idiomas prehispánicos (maya, mixteco), se han venido preparando ediciones críticas de un gran número de testamentos procedentes del México central. En los Andes coloniales, por el contrario, los escribanos registraron testamentos en castellano y no en idiomas indígenas (como quechua, aymara o guaraní). Aunque historiadores del virreinato peruano también analizaron y transcribieron testamentos indígenas en algunos de sus estudios, durante el siglo XX no se publicaron ediciones similares. ...
Während des atlantischen Zeitalters der Revolutionen fanden in weiten Teilen des spanischen Amerika antikoloniale Rebellionen statt, die gemeinhin weniger bekannt sind als die Amerikanische oder die Französische Revolution. In der andinen Geschichte gilt das 18. Jahrhundert als "Zeitalter der Aufstände". Mehr als hundert Revolten seit den 1730er Jahren kulminierten in den Rebellionen von 1780–1783. Auf dem Gebiet der heutigen Staaten Peru und Bolivien (Hochperu) bedrohten diese die spanische Kolonialherrschaft massiv und sollten in vier Jahren etwa 100.000 Todesopfer fordern. Tupac Amaru führte 1780–1781 die größte und berühmteste Rebellion im kolonialen Hispanoamerika an. Ihr widmet Charles Walker, Historiker an der University of California, Davis, seine jüngste Monographie. Nach einem Werk zum Erdbeben von Lima 1746 knüpft das hier besprochene Buch an Gedanken an, die er 1999 im zweiten Kapitel von Smoldering Ashes formuliert hatte. Dort bildete die Rebellion Tupac Amarus den Beginn der Untersuchung, nun steht sie im Mittelpunkt. ...
In cells the interorganelle communication comprises vesicular and non-vesicular mechanisms. Non-vesicular material transfer predominantly takes place at regions of close organelle apposition termed membrane contact sites and is facilitated by a growing number of specialized proteins. Contacts of the endoplasmic reticulum (ER) and mitochondria are now recognized to be essential for diverse biological processes such as calcium homeostasis, phospholipid biosynthesis, apoptosis, and autophagy. In addition to these universal roles, ER-mitochondria communication serves also cell type-specific functions. In this review, we summarize the current knowledge on ER-mitochondria contacts in cells of the innate immune system, especially in macrophages. We discuss ER- mitochondria communication in the context of macrophage fatty acid metabolism linked to inflammatory and ER stress responses, its roles in apoptotic cell engulfment, activation of the inflammasome, and antiviral defense.
Cancer-associated fibroblasts (CAFs) in the tumor microenvironment contribute to all stages of tumorigenesis and are usually considered to be tumor-promoting cells. CAFs show a remarkable degree of heterogeneity, which is attributed to developmental origin or to local environmental niches, resulting in distinct CAF subsets within individual tumors. While CAF heterogeneity is frequently investigated in late-stage tumors, data on longitudinal CAF development in tumors are lacking. To this end, we used the transgenic polyoma middle T oncogene-induced mouse mammary carcinoma model and performed whole transcriptome analysis in FACS-sorted fibroblasts from early- and late-stage tumors. We observed a shift in fibroblast populations over time towards a subset previously shown to negatively correlate with patient survival, which was confirmed by multispectral immunofluorescence analysis. Moreover, we identified a transcriptomic signature distinguishing CAFs from early- and late-stage tumors. Importantly, the signature of early-stage CAFs correlated well with tumor stage and survival in human mammary carcinoma patients. A random forest analysis suggested predictive value of the complete set of differentially expressed genes between early- and late-stage CAFs on bulk tumor patient samples, supporting the clinical relevance of our findings. In conclusion, our data show transcriptome alterations in CAFs during tumorigenesis in the mammary gland, which suggest that CAFs are educated by the tumor over time to promote tumor development. Moreover, we show that murine CAF gene signatures can harbor predictive value for human cancer.
Cystathionine γ lyase (CSE) is the major source of hydrogen sulfide-derived species (H2Sn) in endothelial cells and plays an important role in protecting against atherosclerosis. Here we investigated the molecular mechanisms underlying the regulation of CSE expression in endothelial cells by fluid shear stress/flow. Fluid shear stress decreased CSE expression in human and murine endothelial cells and was negatively correlated with the transcription factor Krüppel-like factor (KLF) 2. CSE was identified as a direct target of the KLF2-regulated microRNA, miR-27b and high expression of CSE in native human plaque-derived endothelial cells, was also inversely correlated with KLF2 and miR-27b levels. One consequence of decreased CSE expression was the loss of Prx6 sulfhydration (on Cys47), which resulted in Prx6 hyperoxidation, decamerization and inhibition, as well as a concomitant increase in endothelial cell reactive oxygen species and lipid membrane peroxidation. H2Sn supplementation in vitro was able to reverse the redox state of Prx6. Statin therapy, which is known to activate KLF2, also decreased CSE expression but increased CSE activity by preventing its phosphorylation on Ser377. As a result, the sulfhydration of Prx6 was partially restored in samples from plaque containing arteries from statin-treated donors. Taken together, the regulation of CSE expression by shear stress/disturbed flow is dependent on KLF2 and miR-27b. Moreover, in murine and human arteries CSE acts to maintain endothelial redox balance at least partly by targeting Prx6 to prevent its decamerization and inhibition of its peroxidase activity.
Enhanced labeling density and whole-cell 3D dSTORM imaging by repetitive labeling of target proteins
(2018)
With continuing advances in the resolving power of super-resolution microscopy, the inefficient labeling of proteins with suitable fluorophores becomes a limiting factor. For example, the low labeling density achieved with antibodies or small molecule tags limits attempts to reveal local protein nano-architecture of cellular compartments. On the other hand, high laser intensities cause photobleaching within and nearby an imaged region, thereby further reducing labeling density and impairing multi-plane whole-cell 3D super-resolution imaging. Here, we show that both labeling density and photobleaching can be addressed by repetitive application of trisNTA-fluorophore conjugates reversibly binding to a histidine-tagged protein by a novel approach called single-epitope repetitive imaging (SERI). For single-plane super-resolution microscopy, we demonstrate that, after multiple rounds of labeling and imaging, the signal density is increased. Using the same approach of repetitive imaging, washing and re-labeling, we demonstrate whole-cell 3D super-resolution imaging compensated for photobleaching above or below the imaging plane. This proof-of-principle study demonstrates that repetitive labeling of histidine-tagged proteins provides a versatile solution to break the "labeling barrier" and to bypass photobleaching in multi-plane, whole-cell 3D experiments.
Inflammatory activation of astroglia adds to the pathology of various neurological diseases. Astrocytes respond to microglia-derived cytokines such as interleukin-1α (IL-1α) with enhanced inflammatory signaling. This provokes pro-inflammatory gene expression of, among others, the eicosanoid-generating enzyme prostaglandin endoperoxide synthase 2 (Ptgs2). Whereas metabolic regulation of innate immune cell inflammatory responses is intensely studied, pathways related to how metabolism modulates inflammatory signaling in astrocytes are underexplored. Here, we examined how mitochondrial oxidative phosphorylation affects inflammatory responses towards IL-1α and tumor necrosis factor α in neonatal rat astrocytes. Blocking respiratory complex I and III or adenosine triphosphate (ATP) synthase did not affect activation of inflammatory signaling by IL-1α, but did elicit differential effects on inflammatory gene mRNA expression. Remarkably, mRNA and protein expression of Ptgs2 by IL-1α was consistently up-regulated when oxidative phosphorylation was inhibited. The increase of Ptgs2 resulted from mRNA stabilization. Mitochondrial inhibitors also increased IL-1α-triggered secretion of eicosanoids, such as prostaglandin E2, prostaglandin F2α, and 6-keto-prostaglandin F1α, as assessed by liquid chromatography/mass spectrometry. Mechanistically, attenuating oxidative phosphorylation elevated adenosine monophosphate (AMP) and activated AMP-activated protein kinase (AMPK). AMPK silencing prevented Ptgs2 up-regulation by mitochondrial inhibitors, while AMPK activators recapitulated Ptgs2 mRNA stability regulation. Our data indicate modulation of astrocyte inflammatory responses by oxidative metabolism, with relevance towards eicosanoid production.
Lipoxygenases (LOXs) catalyze the stereo-specific peroxidation of polyunsaturated fatty acids (PUFAs) to their corresponding hydroperoxy derivatives. Human macrophages express two arachidonic acid (AA) 15-lipoxygenating enzymes classified as ALOX15 and ALOX15B. ALOX15, which was first described in 1975, has been extensively characterized and its biological functions have been investigated in a number of cellular systems and animal models. In macrophages, ALOX15 functions to generate specific phospholipid (PL) oxidation products crucial for orchestrating the nonimmunogenic removal of apoptotic cells (ACs) as well as synthesizing precursor lipids required for production of specialized pro-resolving mediators (SPMs) that facilitate inflammation resolution. The discovery of ALOX15B in 1997 was followed by comprehensive analyses of its structural properties and reaction specificities with PUFA substrates. Although its enzymatic properties are well described, the biological functions of ALOX15B are not fully understood. In contrast to ALOX15 whose expression in human monocyte-derived macrophages is strictly dependent on Th2 cytokines IL-4 and IL-13, ALOX15B is constitutively expressed. This review aims to summarize the current knowledge on the regulation and functions of ALOX15 and ALOX15B in human macrophages.
Myeloid-specific deletion of the AMPK2 subunit alters monocyte protein expression and atherogenesis
(2019)
The AMP-activated protein kinase (AMPK) is an energy sensing kinase that is activated by a drop in cellular ATP levels. Although several studies have addressed the role of the AMPKα1 subunit in monocytes and macrophages, little is known about the α2 subunit. The aim of this study was to assess the consequences of AMPKα2 deletion on protein expression in monocytes/macrophages, as well as on atherogenesis. A proteomics approach was applied to bone marrow derived monocytes from wild-type mice versus mice specifically lacking AMPKα2 in myeloid cells (AMPKα2∆MC mice). This revealed differentially expressed proteins, including methyltransferases. Indeed, AMPKα2 deletion in macrophages increased the ratio of S-adenosyl methionine to S-adenosyl homocysteine and increased global DNA cytosine methylation. Also, methylation of the vascular endothelial growth factor and matrix metalloproteinase-9 (MMP9) genes was increased in macrophages from AMPKα2∆MC mice, and correlated with their decreased expression. To link these findings with an in vivo phenotype, AMPKα2∆MC mice were crossed onto the ApoE-/- background and fed a western diet. ApoExAMPKα2∆MC mice developed smaller atherosclerotic plaques than their ApoExα2fl/fl littermates, that contained fewer macrophages and less MMP9 than plaques from ApoExα2fl/fl littermates. These results indicate that the AMPKα2 subunit in myeloid cells influences DNA methylation and thus protein expression and contributes to the development of atherosclerotic plaques.
Debatten über den relativen Beitrag von Konfessionalisierung und Säkularisierung zum Werden der modernen Welt bleiben von der Frage bestimmt, in welchem Verhältnis die theologischen Debatten der Reformation und die Gestalt der entstehenden Konfessionskirchen zu unseren Vorstellungen der Moderne stehen. Dabei muss berücksichtigt werden, dass Reformation und Konfessionalisierung den Glaubensgegnern, und dann auch protestantischen Juristen in Konflikten mit ihren eigenen Konfessionskirchen, Argumente zur Verteidigung ihrer Positionen aufzwangen, die sich nach wie vor auf Grundpositionen und zentrale Autoritäten der eigenen Glaubensüberzeugung beriefen, aber der Sache nach tiefgreifende Transformationen im Verhältnis von Glauben, Gesellschaft und Bürger begründeten. Solche Argumente wurzelten in Reformation und Konfessionalisierung nicht allein deswegen, weil sie ohne diese nie entwickelt worden wären, sondern legten durch ihre Berufung beispielsweise auf Luther auch die Entwicklungspotentiale der Reformation frei, so wenig Ziele und Wünsche der Reformatoren umstandslos mit denen der sich auf sie berufenden Späteren gleichgesetzt werden können. Die frühe Neuzeit darf denn auch nicht in eine mehr dem Mittelalter angehörende frühere Epoche – etwa bis zum Westfälischen Frieden – und eine schließlich in die Aufklärung und den modernen Staat mündende Epoche des späteren 17. und des 18. Jahrhunderts zweigeteilt werden. ...
In den großen Linien ist die Geschichte, die Christopher Brooks erzählt, bekannt. Es sind die Details, das Hinabtauchen in unzählige bislang unberücksichtigte Manuskripte und damit vor allem die Berücksichtigung zahlreicher Akteure in den Grafschaften, Städten und selbst Dörfern, die Reiz, Wert und besonderes Schwergewicht seiner Darstellung ausmachen – und ihm eine erstaunliche Pointe der Argumentation ermöglichen. ...
Martin Heckels monumentale Kompilation kennt – soweit ich sehe – kein vergleichbares Werk, weder zum Thema noch dem Genre nach. Auf nicht ganz tausend Seiten – rund 170 davon eine inhaltlich strukturierte Literaturübersicht – verhandelt der Autor in großer Quellennähe, beeindruckender analytischer Durchdringung und präziser Diktion die drei großen Sachbereiche, welche der Untertitel nennt: die "Entwicklung der Theologie Luthers", die "Auswirkung auf das Recht", die Rahmenbedingungen Reichsreform und Territorialstaatsbildung, und die Auseinandersetzung mit "Rom und den Schwärmern". ...
It was seventeen years ago when the first same-sex marriage was celebrated in a civil ceremony in Amsterdam, right after the Dutch Parliament passed legislation that legalized same-sex marriages. Since then, same-sex marriage has become legal in over two dozen countries worldwide. Last year, the German Bundestag added Germany to the growing list of countries where same-sex couples can obtain a legal marriage license. The past decades have indeed witnessed social mobilizations around the globe for LGBTI+ rights. Whether through legislation, court rulings, or popular referenda, 25 countries grant full juridical marital recognitions only recently enjoyed by opposite-sex partners to all citizens, regardless of their gender and sexual preferences. However, this legal evolution has been uneven. Currently, in many countries, LGBTI+ relations not only contravene moral codes but are still punishable crimes with varying amounts of prison time, fines, and in a few cases, with the death penalty. ...
Los últimos años han sido testigos de un creciente interés por el derecho indiano desde el mundo académico anglosajón. Varios autores han tocado distintos aspectos de la construcción de un imperio legal en la América española (véase por ejemplo los trabajos de Woodrow Borah, Charles Cutter, Tamar Herzog, Susan Kellog, Brian P. Owensby y Yanna Yanakakis), buscando comprender las complejidades detrás de la formación de un régimen normativo colonial cimentado sobre la traslación de sistemas jurídicos europeos, un aparato de prácticas locales y la efervescencia de normatividades contingentes al proceso colonial. En esta dirección se han estudiado las instituciones jurídicas de la América española, los agentes jurídicos coloniales, y más recientemente, los actores indígenas, estos últimos no solo como usuarios del sistema legal, sino también como contribuyentes netos a la vertebración del nuevo orden normativo en la América española. Estos estudios aducen que en estos territorios el derecho castellano se adaptó a los nuevos escenarios coloniales en parte por la coexistencia de diferentes niveles normativos basados en los usos y costumbres, las compilaciones legales y el ius commune, además de códigos normativos que emanaban de las autoridades religiosas. Este último aspecto, sobre todo lo relacionado con el derecho canónico y la teología moral, sólo recientemente ha sido objeto de estudio como parte intrínseca de las multinormatividades que enmarcaban las vidas diarias de las personas en el periodo moderno. Por todo esto el nuevo libro del profesor Osvaldo F. Pardo, Honor and Personhood in Early Modern Mexico, un gran conocedor de los procesos culturales ocurridos en el México del siglo XVI, resulta muy bienvenido. ...
uORF-tools—workflow for the determination of translation-regulatory upstream open reading frames
(2019)
Ribosome profiling (ribo-seq) provides a means to analyze active translation by determining ribosome occupancy in a transcriptome-wide manner. The vast majority of ribosome protected fragments (RPFs) resides within the protein-coding sequence of mRNAs. However, commonly reads are also found within the transcript leader sequence (TLS) (aka 5’ untranslated region) preceding the main open reading frame (ORF), indicating the translation of regulatory upstream ORFs (uORFs). Here, we present a workflow for the identification of translation-regulatory uORFs. Specifically, uORF-Tools uses Ribo-TISH to identify uORFs within a given dataset and generates a uORF annotation file. In addition, a comprehensive human uORF annotation file, based on 35 ribo-seq files, is provided, which can serve as an alternative input file for the workflow. To assess the translation-regulatory activity of the uORFs, stimulus-induced changes in the ratio of the RPFs residing in the main ORFs relative to those found in the associated uORFs are determined. The resulting output file allows for the easy identification of candidate uORFs, which have translation-inhibitory effects on their associated main ORFs. uORF-Tools is available as a free and open Snakemake workflow at https://github.com/Biochemistry1-FFM/uORF-Tools. It is easily installed and all necessary tools are provided in a version-controlled manner, which also ensures lasting usability. uORF-Tools is designed for intuitive use and requires only limited computing times and resources.
Macrophage S1PR1 signaling alters angiogenesis and lymphangiogenesis during skin inflammation
(2019)
The bioactive lipid sphingosine-1-phosphate (S1P), along with its receptors, modulates lymphocyte trafficking and immune responses to regulate skin inflammation. Macrophages are important in the pathogenesis of psoriasiform skin inflammation and express various S1P receptors. How they respond to S1P in skin inflammation remains unknown. We show that myeloid specific S1P receptor 1 (S1PR1) deletion enhances early inflammation in a mouse model of imiquimod-induced psoriasis, without altering the immune cell infiltrate. Mechanistically, myeloid S1PR1 deletion altered the formation of IL-1β, VEGF-A, and VEGF-C, and their receptors’ expression in psoriatic skin, which subsequently lead to reciprocal regulation of neoangiogenesis and neolymphangiogenesis. Experimental findings were corroborated in human clinical datasets and in knockout macrophages in vitro. Increased blood vessel but reduced lymph vessel density may explain the exacerbated inflammatory phenotype in conditional knockout mice. These findings assign a novel role to macrophage S1PR1 and provide a rationale for therapeutically targeting local S1P during skin inflammation.
Für die Rechtsgeschichte in Lateinamerika scheint heutzutage eine neue Phase anzubrechen; jüngere Forscher erweitern ihr Betätigungsfeld hinsichtlich der Themen, Chronologie und Methodologie, und ihre Forschungsarbeiten führen zu einer neuen Auseinandersetzung mit der aktuellen Aufgabe des Rechtshistorikers. Es handelt sich um sehr unterschiedliche Arbeiten, was Charakteristika, Ansätze, Ausrichtung, Voraussetzungen und Kontext anbelangt; sie illustrieren Rechtserfahrungen, die – obwohl relativ homogen – nur zum Teil auf ein kontinentales unicum zurückgeführt werden können. ...
The assumed space : pre-reflective spatiality and doctrinal configurations in juridical experience
(2015)
The purpose of this contribution is to analyse, by means of the legal-historical perspective, the relationship between the pre-reflections of space and the configurations of legal concepts and categories. Three examples of the interplay between doctrinal configurations and the spatial dimension within the context of three different historical periods will be illustrated: given space in the Middle Ages, possible space in the Modern Age and decided space in the Contemporary Age. From this basis, the essay considers the heuristic importance of such an analytical approach – mindful of the profiles of presupposition, such as the space assumption, underlying the conceptualisation of ideas – for a history attentive to the constraints of the theoretical sustainability of legal concepts.
Invincible ignorance is defined as the state in which one cannot overcome his ignorance, despite one’s utmost diligence, and hence cannot be blamed for the acts resulting from that circumstance. It is particularly relevant with regard to law and principles that one is bound to know. The main problem with the admission that such a state may occur results from the difficulty of assessing the subjective element present in such a state: How can we know that one applied his diligence to the utmost extent?
This notion emerged in the 12th century. But while medieval theologians elaborated such a notion, they nonetheless stressed that in reality no one could be guiltlessly ignorant of natural and divine law. The arrival of the Spaniards to the Americas triggered the awareness that entire nations could, in fact, be invincibly ignorant of Christianity. The Spanish theologians then started to use this notion, admitting the existence of invincible ignorance of some principles of divine and natural law. Their argumentative strategy rested on emphasising the subjective element of invincible ignorance.
In this article, I examine Vitoria’s Relectio de Indis against the medieval doctrinal background. I also analyse Vitoria’s, Domingo de Soto’s and Juan Gil de Nava’s unedited lectures on Aquinas’s Summa theologiae as well as the works by Matías de Paz, Juan López de Palacios Rubios, Juan de Celaya and Bartolomé de Las Casas.
The sphingolipid sphingosine-1-phosphate (S1P) is produced by sphingosine kinases to either signal through intracellular targets or to activate a family of specific G-protein-coupled receptors (S1PR). S1P levels are usually low in peripheral tissues compared to the vasculature, forming a gradient that mediates lymphocyte trafficking. However, S1P levels rise during inflammation in peripheral tissues, thereby affecting resident or recruited immune cells, including macrophages. As macrophages orchestrate initiation and resolution of inflammation, the sphingosine kinase/S1P/S1P-receptor axis emerges as an important determinant of macrophage function in the pathogenesis of inflammatory diseases such as cancer, atherosclerosis, and infection. In this review, we therefore summarize the current knowledge how S1P affects macrophage biology.
Over the last years, many microRNAs (miRNAs) have been identified that regulate the formation of bioactive lipid mediators such as prostanoids and leukotrienes. Many of these miRNAs are involved in complex regulatory circuits necessary for the fine-tuning of biological functions including inflammatory processes or cell growth. A better understanding of these networks will contribute to the development of novel therapeutic strategies for the treatment of inflammatory diseases and cancer. In this review, we provide an overview of the current knowledge of miRNA regulation in eicosanoid pathways with special focus on novel miRNA functions and regulatory circuits of leukotriene and prostaglandin biosynthesis.
The lysosomal polypeptide transporter TAPL belongs to the superfamily of ATP-binding cassette transporters. TAPL forms a homodimeric transport complex, which translocates oligo- and polypeptides into the lumen of lysosomes driven by ATP hydrolysis. Although the structure and the function of ABC transporters were intensively studied in the past, details about the single steps of the transport cycle are still elusive. Therefore, we analyzed the coupling of peptide binding, transport and ATP hydrolysis for different substrate sizes. Although longer and shorter peptides bind with the same affinity and are transported with identical Km values, they differ significantly in their transport rates. This difference can be attributed to a higher activation energy for the longer peptide. TAPL shows a basal ATPase activity, which is inhibited in the presence of longer peptides. Uncoupling between ATP hydrolysis and peptide transport increases with peptide length. Remarkably, also the type of nucleotide determines the uncoupling. While GTP is hydrolyzed as good as ATP, peptide transport is significantly reduced. In conclusion, TAPL does not differentiate between transport substrates in the binding process but during the following steps in the transport cycle, whereas, on the other hand, not only the coupling efficiency but also the activation energy varies depending on the size of peptide substrate.
Live-cell labelling techniques to visualize proteins with minimal disturbance are important; however, the currently available methods are limited in their labelling efficiency, specificity and cell permeability. We describe high-throughput protein labelling facilitated by minimalistic probes delivered to mammalian cells by microfluidic cell squeezing. High-affinity and target-specific tracing of proteins in various subcellular compartments is demonstrated, culminating in photoinduced labelling within live cells. Both the fine-tuned delivery of subnanomolar concentrations and the minimal size of the probe allow for live-cell super-resolution imaging with very low background and nanometre precision. This method is fast in probe delivery (∼1,000,000 cells per second), versatile across cell types and can be readily transferred to a multitude of proteins. Moreover, the technique succeeds in combination with well-established methods to gain multiplexed labelling and has demonstrated potential to precisely trace target proteins, in live mammalian cells, by super-resolution microscopy.
A current challenge in life sciences is to image cell membrane receptors while characterizing their specific interactions with various ligands. Addressing this issue has been hampered by the lack of suitable nanoscopic methods. Here we address this challenge and introduce multifunctional high-resolution atomic force microscopy (AFM) to image human protease-activated receptors (PAR1) in the functionally important lipid membrane and to simultaneously localize and quantify their binding to two different ligands. Therefore, we introduce the surface chemistry to bifunctionalize AFM tips with the native receptor-activating peptide and a tris-N-nitrilotriacetic acid (tris-NTA) group binding to a His10-tag engineered to PAR1. We further introduce ways to discern between the binding of both ligands to different receptor sites while imaging native PAR1s. Surface chemistry and nanoscopic method are applicable to a range of biological systems in vitro and in vivo and to concurrently detect and localize multiple ligand-binding sites at single receptor resolution.
Das griechische Recht ist, so stellt der Verfasser dieser Passauer juristischen Dissertation zu Recht fest, nicht hinreichend erforscht worden. Althistoriker behandeln es nebenher mit, typischerweise ohne juristische Expertise; Spezialisten für antike Rechtsgeschichte wenden sich zumeist anderen Rechtskulturen zu. Zeitler will in diese Lücke vorstoßen, mit einem Schwerpunkt auf dem Prozess des Sokrates – nun gerade einer der meistdiskutierten Fälle griechischen Rechts. Doch sind diesem gerade knapp 30 Seiten von etwas mehr als 200 gewidmet. ...