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The species, Bactrospora lamprospora (Nyl.) Lendemer is treated as a synonym of B. metabola (Nyl.) Egea & Torrente. The comparission of characters of all accessible materials and type specimens confirmed that B. lamprospora is conspecific with B. metabola. The distinguishing characters of B. metabola from other species in this group are initially a Homalotropa-type ascospores becomes muriform at maturity, with up to 24–30 transverse septa and ascospore size of 48–105 × 7–14 μm.
Endothelial dysfunction plays an important role in different pathological conditions, but whether endothelial cell death contributes to the development and progression of certain pathological conditions is rather unclear. Here we found that endothelial cells undergo cell death during pathologies such as LPS-induced sepsis and in models of hindlimb, renal and cardiac ischemia-reperfusion injury. Analyses of mice lacking endothelial key cell death regulators such as TAK1, RIPK3 and Caspase 8 gave us insight in the role of endothelial cell death in these pathological models. For example, increased endothelial necroptosis along with basal inflammation in lungs of TAK1ECKO mice affects susceptibility to LPS-induced sepsis and mortality, which correlated with elevated IFN-gamma and MIP-2 serum levels. Furthermore, we found that inhibition of RIPK3-mediated endothelial necroptosis could reduce the susceptibility of TAK1ECKO mice to LPS-induced sepsis and mortality. In ischemia or ischemia-reperfusion models, inhibition of RIPK3-mediated endothelial necroptosis did not reduce injury in the heart after ischemia, nor did it have any effect on organ function post-injury in the kidney or the heart. Inhibition of necroptosis also did not alter vascularization processes in hindlimb post-ischemia. Taken together, endothelial necroptosis contributes to increased sepsis severity and progression whereas inhibition of endothelial necroptosis can ameliorate susceptibility to sepsis in the absence of endothelial TAK1. Inhibition of endothelial necroptosis however does not play an important role during ischemia or ischemia-reperfusion induced organ injury.
Cannabinoid drugs are registered for postoperative nausea and emesis, Tourette syndrome and tumor-related anorexia, but are also used for spasticity and pain relief, among other conditions. Clinical studies for spasmolysis have been equivocal and even conclusions from meta-analyses were not consistent. This may be due to uncertainty in diagnostic criteria as well as a lack of direct spasmolytic activity (direct causality). In this review we used the Hill criteria to investigate whether a temporal association is causal or spurious. Methods: A systematic literature search was performed to identify all clinical trials of cannabinoids for spasticity. Studies were evaluated for dose dependency and time association; all studies together were analyzed for reproducibility, coherence, analogy and mechanistic consistency. A Funnel plot was done for all studies to identify selection or publication bias. Results: Twenty-seven studies were included in this meta-analysis. The spasmolytic activity (effect strength) was weak, with a nonsignificant small effect in most studies and a large effect only in a few studies (“enriched” studies, low patient numbers). No dose dependency was seen and plotting effect size vs. daily dose resulted in a slope of 0.004. Most studies titrated the cannabinoid to the optimum dose, e.g., 20 mg/d THC. The effect decreased with longer treatment duration (3–4 months). The spasmolytic effect is consistent for different European countries but not always within a country, nor is the effect specific for an etiology (multiple sclerosis, spinal cord injury, others). For other criteria like plausibility, coherence or analogous effects, no data exist to support or refute them. In most studies, adverse effects were frequently reported indicating a therapeutic effect only at high doses with relevant side effects. Conclusions: Current data do not support a specific spasmolytic effect; a general decrease in CNS activity analogous to benzodiazepines appears more likely. Whether individual patients or specific subgroups benefit from cannabinoids is unclear. Further studies should compare cannabinoids with other, nonspecific spasmolytic drugs like benzodiazepines.
Seventy-four species, forms and varieties of Cubitermes Wasmann, 1906 have been studied, including taxa placed in synonymy with other species. Within this group of taxa, the enteric valve, mainly of the workers and soldiers, provided the best and the only clear-cut criteria for distinguishing some major subsets that are proposed here as species groups.The genus Cubitermes is re-described; the morphologies of the enteric valves are described in detail including the number of spatulae at the downstream end of the primary cushions; the possible presence of crests or bulges near the downstream end of the primary cushions; the overall shape of the primary cushions; the number of lateral supporting bristles; the kind of symmetry of the valve; and the structure of the secondary cushions. These characteristics are used to define nine species groups. For now, these groups have no taxonomic ranking but are helpful as regards species recognition. Identification keys for species groups are provided for soldiers and workers together with a partial key for imagines. Geographical ranges of the groups are also provided. On the basis of enteric valve morphology, some synonymies can no longer be validated: (a) C. planifrons Sjöstedt, 1924 is not a synonym of C. fungifaber (Sjöstedt, 1896); (b) C. kemneri Emerson, 1928 is not a synonym of C. zenkeri (Desneux, 1904); and (c) C. fungifaber var. elongata Sjöstedt, 1924 does not belong to the species C. fungifaber. Cubitermes planifrons and C. kemneri become valid again and C. fungifaber var. elongata is an invalid name.
Relying on the theory of Saward (2010) and Disch (2015), we study political representation through the lens of representative claim-making. We identify a gap between the theoretical concept of claim-making and the empirical (quantitative) assessment of representative claims made in the real world’s representative contexts. Therefore, we develop a new approach to map and quantify representative claims in order to subsequently measure the reception and validation of the claims by the audience. To test our method, we analyse all the debates of the German parliament concerned with the introduction of the gender quota in German supervisory boards from 2013 to 2017 in a two-step process. At first, we assess which constituencies the MPs claim to represent and how they justify their stance. Drawing on multiple correspondence analysis, we identify different claim patterns. Second, making use of natural language processing techniques and logistic regression on social media data, we measure if and how the asserted claims in the parliamentary debates are received and validated by the respective audience. We come to the conclusion that the constituency as ultimate judge of legitimacy has not been comprehensively conceptualized yet.
After the Global Financial Crisis a controversial rush to fiscal austerity followed in many countries. Yet research on the effects of austerity on macroeconomic aggregates was and still is unsettled, mired by the difficulty of identifying multipliers from observational data. This paper reconciles seemingly disparate estimates of multipliers within a unified and state-contingent framework. We achieve identification of causal effects with new propensity-score based methods for time series data. Using this novel approach, we show that austerity is always a drag on growth, and especially so in depressed economies: a one percent of GDP fiscal consolidation translates into 4 percent lower real GDP after five years when implemented in the slump rather than the boom. We illustrate our findings with a counterfactual evaluation of the impact of the U.K. government’s shift to austerity policies in 2010 on subsequent growth.
Die Begriffsgeschichte ist vom Singular besessen. Pluralformen kommen nur unsystematisch und am Rande vor. Darin gleichen die mehrbändigen Lexika, Gumbrechts "Pyramiden des Geistes", den allgemeinen Wörterbüchern, in denen der Plural gemeinhin nur abgekürzt und kodiert zwischen Klammern vorkommt: "(-en, ‑en)". Der Obergrundbegriff ist für Koselleck bezeichnenderweise der "Kollektivsingular", ein Wort, das die Fähigkeit verloren hat, einen Plural zu bilden. Begriffe wie 'Geschichte' und 'Fortschritt' sind im Plural vorgekommen und haben damit verschiedene Prozesse und Zeitverläufe beschreiben können. Aber im Laufe des späten 18. und frühen 19. Jahrhunderts haben eine Verengung und eine Vereinheitlichung stattgefunden, die zur Verdrängung der Pluralbildungen führten. Plötzlich haben sie nicht mehr die Kraft, distributive Pluralformen in die Welt zu bringen, 'Geschichten' und 'Fortschritte', die eine mehrzeitige Welt voraussetzen. Nunmehr treten sie nur im Singular, mit kollektivem Subjekt auf. 'Fortschritt' heißt jetzt immer Fortschritt der Menschheit. Ein für alle Mal grenzt die Begriffsgeschichte Parallelwelten, Multiversen, die Realität der Quantenphysik aus der Semantik der Begriffe aus, im selben Moment, als sie zu "unseren Begriffen", so Koselleck, werden. Um dieser Tendenz entgegenzuwirken, sollte über ein Lexikon des Plurals, der Pluralbildungen nachgedacht werden, ein Lexikon "Geschichtliche Grundbegriffe 'pluralis'", oder "Geschichtliche Grundpluralbildungen".
The genome of S. cerevisae encodes at least twenty hexose transporter-like proteins. Despite extensive research, the functions of Hxt8-Hxt17 have remained poorly defined. Here, we show that Hxt13, Hxt15, Hxt16 and Hxt17 transport two major hexitols in nature, mannitol and sorbitol, with moderate affinities, by a facilitative mechanism. Moreover, Hxt11 and Hxt15 are capable of transporting xylitol, a five-carbon polyol derived from xylose, the most abundant pentose in lignocellulosic biomass. Hxt11, Hxt13, Hxt15, Hxt16 and Hxt17 are phylogenetically and functionally distinct from known polyol transporters. Based on docking of polyols to homology models of transporters, we propose the architecture of their active site. In addition, we determined the kinetic parameters of mannitol and sorbitol dehydrogenases encoded in the yeast genome, showing that they discriminate between mannitol and sorbitol to a much higher degree than the transporters.
Die Propyläen als Toranlage, die zur Akropolis führt, gaben der Kunstzeitschrift Propyläen (1798-1800) den Namen. Goethe gab sie heraus, um durch sie – wie durch ein Tor – die Kunst der Gegenwart zur Orientierung an der Antike zu führen. Das für die Zeitschrift grundlegende Motiv des Tores spielt eine Rolle auch in einem Artikel „Ueber Etrurische Monumente“, den Goethes Freund und Mitarbeiter Johann Heinrich Meyer anonym im ersten Band der Propyläen (S. 66-100) veröffentlichte.
Tagungsbericht zum internationalen Arbeitsgespräch in der Herzog August Bibliothek Wolfenbüttel, 12.-13. September 2000
Die niederländisch-deutschen Kulturbeziehungen sind als ein wichtiges Element im Prozeß der europäischen Kulturgeschichte in den letzten Jahren verstärkt Gegenstand der Forschung geworden. Dabei wurde die Gattung der Lyrik, deren zentrale Rolle im Literatursystem mit je verschiedener Begründung in der Literaturwissenschaft seit einiger Zeit wieder stärker betont wird, noch ungenügend berücksichtigt, auch wenn gelegentlich auf den großen Einfluß niederländischer Dichtung und Poetik (z. B. Heinsius) auf den deutschen Sprachraum im 17. Jahrhundert hingewiesen wurde. Um hier den Erkenntnisstand zu verbessern, fand am 12. und 13. September 2000 im Bibelsaal der Herzog August Bibliothek Wolfenbüttel ein internationales Arbeitsgespräch zum Thema "Die niederländische Lyrik und ihre deutsche Rezeption in der Frühen Neuzeit" statt.
Die Untersuchung versteht sich als Beitrag zur Kartierung von Polylepis-Vorkommen unter extremsten Lebensbedingungen. Dies geschieht allein auf der Basis von Luftbildanalysen mit stützenden Geländeerhebungen, da die topographischen Karten nur irritierende und damit unbrauchbare Angaben enthalten. Durch die Erarbeitung und Diskussion einer Vielzahl von Verbreitungsphänomenen werden Indizien zur Frage der naturbedingten und anthropogen verursachten Vorkommen dieses sonderbaren Extremgehölzes geliefert, um so weitere Mosaiksteine zur Klärung der strittigen Hypothesen (Troll - Ellenberg) beizutragen. Gleichzeitig wird eine Abschätzung der Flächenausdehnung von Polylepis gegeben, da ihr Holz für die sonst baumfreien Regionen ihres Auftretens von einiger wirtschaftlicher Bedeutung ist.
Ziel dieser Arbeit ist es, einen Überblick über die Verhaltensweisen zoolebender Zwergschimpansen (Pan paniscus Schwarz 1929) zu geben. Dabei nimmt die Beschreibung des Sozialverhaltens eine zentrale Stellung ein. Dieser Aspekt ist von besonderem Interesse, weil die Zwergschimpansen oder Bonobos durch eine regelmäßige Überflutung großer Teile ihres Lebensraumes zu einer stärker arborealen Lebensweise gezwungen sind (s. HOFW 1975) als die zweite Schiopansenart, Pan troglodytes. Das läßt neben morphologischen auch ethologische Anpassungen an ein Baumleben erwarten, und zwar sowohl in Bereichen wie Lokomotion etc.. als auch in Bezug auf das Sozialverhalten. Gerade auf diesem Gebiet aber ist unser ohnehin bruchstückhaftes Wissen über die Ethologie des Bonobo besonders gering....
In zahlreichen Studien konnte ein tumorwachstumshemmender Effekt der überwiegend in Fischöl vorkommenden Omega-3-Fettsäuren, insbesondere der Eikosapentaensäure (EPA), belegt werden. In den bisher vorliegenden Studien wurde überwiegend der Effekt freier Fettsäuren auf das Wachstum von Tumorzellen untersucht. Ziel dieser Studie war es deshalb, den Effekt einer Fettemulsion mit komplexer Triglyzeridstruktur, die als solche auch am Patienten im Rahmen einer parenteralen Ernährung Anwendung findet, auf das Wachstum der Pankreaskarzinomzelllinie Mia-Paca-2 und der Kolonkarzinomzelllinie Caco-2 zu untersuchen, und die zugrundeliegenden Mechanismen für die erhobenen Effekte zu evaluieren. • Die in der vorliegenden Studie eingesetzte Fischölemulsion hemmte die Proliferation sowohl der Pankreaskarzinomzelllinie Mia-Paca-2 als auch der Kolonkarzinomzelllinie Caco-2 dosis- und zeitabhängig. Dieser Effekt war auf eine Zunahme der Apoptoseinduktion und eine Blockierung der Zellen in der S- und G2/M-Phase des Zellzyklus zurückzuführen. Tumorzellen sind in der Lage, durch Expression von Wachstumsfaktoren ihr Zellwachstum selbständig zu stimulieren. Eine bedeutende Rolle scheint in diesem Zusammenhang der epidermale Wachstumsfaktor (EGF) zu spielen. Bei zahlreichen Tumoren kann eine Überexpression des membranständigen EGF-Rezeptors nachgewiesen werden. Es gibt Hinweise, dass die Modifikation der Lipidkomposition zellulärer Membranen durch ein verändertes Angebot an mehrfach ungesättigten Fettsäuren mit einer Änderung der Aktivität von Membranrezeptoren einhergeht. In weiterführenden Experimenten wurde deshalb der Einfluß von EGF auf das Wachstum der mit der Omega-3-fettsäurereichen Fischölemulsion vorbehandelten Pankreaskarzinomzelllinie Mia-Paca-2 untersucht. • Eine Präinkubation der Mia-Paca-2 Zellen mit der Omega-3-fettsäurereichen Fischölemulsion führte zu einer Umkehrung des wachstumsfördernden Effektes von EGF. Eine entscheidende Determinante in der Entwicklung und dem Wachstum von Tumoren ist deren Sensitivität gegenüber chemotherapeutischer Behandlung. Das Auftreten von chemotherapieresistenten Tumorzellen ist häufig limitierender Faktor für eine erfolgreiche zytostatische Therapie. In einem weiteren Versuchsansatz sollte deshalb der Fragestellung nachgegangen werden, ob eine Verbesserung der Wirksamkeit gängiger Chemotherapeutika in der Antitumortherapie von Pankreas- und Kolonkarzinomen nach kombinierter Behandlung mit der Fischölmulsion zu erwarten ist. • Der Einsatz der Fischölemulsion in Kombination mit Gemcitabin und 5-FU bei Mia-Paca-2 Zellen bzw. Caco-2 Zellen führte zu einem additiven wachstumshemmenden Effekt. Die Ergebnisse der vorliegenden Arbeit belegen, dass Omega-3-fettsäurereiche Lipidemulsionen eine sinnvolle adjuvante therapeutische Maßnahme in der Behandlung des Pankreas- und Kolonkarzinoms darstellen können.
Single-particle electron cryo-microscopy (cryoEM) has undergone a “resolution revolution” that makes it possible to characterize megadalton (MDa) complexes at atomic resolution without crystals. To fully exploit the new opportunities in molecular microscopy, new procedures for the cloning, expression and purification of macromolecular complexes need to be explored. Macromolecular assemblies are often unstable, and invasive construct design or inadequate purification conditions or sample preparation methods can result in disassembly or denaturation. The structure of the 2.6 MDa yeast fatty acid synthase (FAS) has been studied by electron microscopy since the 1960s. We report a new, streamlined protocol for the rapid production of purified yeast FAS for structure determination by high-resolution cryoEM. Together with a companion protocol for preparing cryoEM specimens on a hydrophilized graphene layer, our new protocol has yielded a 3.1 Å map of yeast FAS from 15,000 automatically picked particles within a day. The high map quality enabled us to build a complete atomic model of an intact fungal FAS.
Single-particle electron cryo-microscopy (cryoEM) has undergone a `resolution revolution' that makes it possible to characterize megadalton (MDa) complexes at atomic resolution without crystals. To fully exploit the new opportunities in molecular microscopy, new procedures for the cloning, expression and purification of macromolecular complexes need to be explored. Macromolecular assemblies are often unstable, and invasive construct design or inadequate purification conditions and sample-preparation methods can result in disassembly or denaturation. The structure of the 2.6 MDa yeast fatty acid synthase (FAS) has been studied by electron microscopy since the 1960s. Here, a new, streamlined protocol for the rapid production of purified yeast FAS for structure determination by high-resolution cryoEM is reported. Together with a companion protocol for preparing cryoEM specimens on a hydrophilized graphene layer, the new protocol yielded a 3.1 Å resolution map of yeast FAS from 15 000 automatically picked particles within a day. The high map quality enabled a complete atomic model of an intact fungal FAS to be built.
In this thesis, we characterized megasynthases such as fatty acid synthases (FASs) and polyketide synthases. The obtained insights into structure and function were used to engineer such systems to produce new-to-nature compounds.
The in vitro characterization of megasynthases requires reproducible access to these enzymes in high quality. Therefore, we established purification strategies for the yeast FAS and the methylsalicylic acid synthase (MSAS) from Saccharopolyspora erythraea (SerMSAS) and applied the latter one on MSAS from Penicillium patulum (PenPaMSAS) and on 6-deoxyerythronolide B synthase (DEBS) module 6. With the purified samples, we were able to obtain initial structural data for SerMSAS and solve the complete structure of the yeast FAS (PDB: 6TA1). On the example of the yeast FAS, we could show that the sample can suffer from adsorption to the water-air interface during the grid preparation for electron microscopy and presented how the use of graphene-based grids can overcome this problem. The combined structural and functional analysis of the yeast FAS showed that the structural domains trimerization module and dimerization module 2 are not essential for the assembly of the whole system. Therefore, they can potentially be used for domain exchange approaches. The in-depth functional analysis of SerMSAS revealed that not SerMSAS itself releases the product, but a 3-oxoacyl-(acyl-carrier protein) synthase like enzyme within the gene cluster transfers 6-methyl salicylic acid from SerMSAS to another carrier protein for subsequent modifications. In contrast, we showed that PenPaMSAS can release its product by hydrolysis and that non-native substrates can be incorporated although at significantly slower turnover rates compared to the native starter substrate. Our further investigation demonstrated that the substrate specificity of the acyltransferase (AT) is a critical factor for the incorporation of non-native substrates.
With the insight from the functional and structural characterization, we engineered megasynthases for the biosynthesis of natural product derivatives. We targeted the AT of PenPaMSAS for active site mutagenesis and discovered a mutant which can transfer non-native substrates significantly faster (~200-300%). Additionally, the malonyl/acetyl transferase (MAT) of the mammalian FAS was used as a promising target for protein engineering because of its previously reported properties including polyspecificity, fast transfer kinetics, robustness, and plasticity. We showed that the MAT can transfer fluorinated substrates and accept the acyl carrier protein of DEBS module 6. By exchanging the substrate specific AT of DEBS with the polyspecific MAT of the mammalian FAS, we demonstrated an efficient DEBS/FAS hybrid and an optimal truncation site for the applied ATs. In contrast to the wild type system, the DEBS/FAS enzyme was able to synthesize demethylated and fluorinated derivatives. The production and purification of a fluoro-methyl-disubstituted polyketide was of particular interest, as it has a high potential for the generation of new drugs and shows the potential of protein engineering. Furthermore, the incorporation of the disubstituted substrate had important implication in the mechanistic details of the ketosynthase-mediated C-C bond formation.